vx-770 and Cystic-Fibrosis

Cystic fibrosis is a life-limiting, autosomal recessive genetic disorder resulting in multi-organ disease due to CF transmembrane conductance regulator (. In this review, we will describe the clinical trials leading to approval of the highly effective CFTR modulator, elexacaftor-tezacaftor-ivacaftor (ETI), with a focus on the safety and efficacy of this treatment in children aged 6-11 years.. The use of ETI in variant-eligible children aged 6-11 is associated with marked clinical improvements with a favorable safety profile. We anticipate that introduction of ETI in early childhood may result in the prevention of pulmonary, gastrointestinal, and endocrine complications from CF, consequently leading to previously unimaginable gains in the quality and quantity of life. However, there is an urgent need to develop effective treatments for the remaining 10% of people with CF who are not eligible or unable to tolerate ETI treatment, and to increase access of ETI to more pwCF across the world.

Topics: Aminophenols; Benzodioxoles; Child; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation

Cystic fibrosis (CF) is characterized by mucus accumulation impairing the lungs, gastrointestinal tract, and other organs. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators (ivacaftor, tezacaftor, elexacaftor, and lumacaftor) significantly improve lung function and nutritional status; however, they are substrates, inhibitors, and/or inducers of certain CYP enzymes and transporters, raising the risk of drug-drug interactions (DDI) with common CF medications.. A literature search was conducted for DDIs involving CFTR modulators by reviewing new drug applications, drug package inserts, clinical studies, and validated databases of substrates, inhibitors, and inducers. Clinically, CYP3A inducers and inhibitors significantly decrease and increase systemic concentrations of elexacaftor/tezacaftor/ivacaftor, respectively. Additionally, lumacaftor and ivacaftor alter concentrations of CYP3A and P-gp substrates. Potential DDIs without current clinical evidence include ivacaftor and elexacaftor's effect on CYP2C9 and OATP1B1/3 substrates, respectively, and OATP1B1/3 and P-gp inhibitors' effect on tezacaftor. A literature review was conducted using PubMed.. Dosing recommendations for CFTR modulators with DDIs are relatively comprehensive; however, recommendations on timing of dosing transition of CFTR modulators when CYP3A inhibitors are initiated or discontinued is incomplete. Certain drug interactions may be managed by choosing an alternative treatment to avoid/minimize DDIs. Next generation CFTR modulator therapies under development are expected to provide increased activity with reduced DDI risk.

Topics: Aminopyridines; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Drug Interactions; Humans; Mutation

Cystic fibrosis, a genetic disorder defined by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects more than 30 000 individuals in the US and approximately 89 000 worldwide. Absent or decreased function of the CFTR protein is associated with multiorgan dysfunction and shortened life expectancy.. CFTR is an anion channel in the apical membrane of epithelial cells. Loss of function leads to obstructed exocrine glands. Of people with cystic fibrosis in the US, approximately 85.5% have the gene variant F508del. Manifestations of cystic fibrosis in patients with the F508del gene variant begin in infancy with steatorrhea, poor weight gain, and respiratory symptoms (coughing, wheezing). As people with cystic fibrosis age, chronic respiratory bacterial infections cause loss of lung function and bronchiectasis. With the availability of universal newborn screening in multiple countries including the US, many people with cystic fibrosis are asymptomatic at diagnosis. With multidisciplinary care teams that included dietitians, respiratory therapists, and social workers, treatment of cystic fibrosis can slow disease progression. Median survival has improved from 36.3 years (95% CI, 35.1-37.9) in 2006 to 53.1 years (95% CI, 51.6-54.7) in 2021. Pulmonary therapies for patients with cystic fibrosis consist of mucolytics (eg, dornase alfa), anti-inflammatories (eg, azithromycin), and antibiotics (such as tobramycin delivered by a nebulizer). Four small molecular therapies, termed CFTR modulators, that facilitate CFTR production and/or function have received regulatory approval. Examples are ivacaftor and elexacaftor-tezacaftor-ivacaftor. For example, in patients with 1 F508del variant, the combination of ivacaftor, tezacaftor, and elexacaftor improved lung function from -0.2% in the placebo group to 13.6% (difference, 13.8%; 95% CI, 12.1%-15.4%) and decreased the annualized estimated rate of pulmonary exacerbations from 0.98 to 0.37 (rate ratio, 0.37; 95% CI, 0.25-0.55). Improved respiratory function and symptoms have lasted up to 144 weeks in postapproval observational studies. An additional 177 variants are eligible for treatment with the elexacaftor-tezacaftor-ivacaftor combination.. Cystic fibrosis affects approximately 89 000 people worldwide and is associated with a spectrum of disease related to exocrine dysfunction, including chronic respiratory bacterial infections and reduced life expectancy. First-line pulmonary therapies consist of mucolytics, anti-inflammatories, and antibiotics, and approximately 90% of people with cystic fibrosis who are 2 years or older may benefit from a combination of ivacaftor, tezacaftor, and elexacaftor.

Topics: Aminophenols; Anti-Bacterial Agents; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Expectorants; Humans; Infant, Newborn; Mutation

Safety and efficacy data regarding cystic fibrosis transmembrane conductance regulator (CFTR) modulator use in the setting of pregnancy or breastfeeding remains lacking due to exclusion from key trials and lack of multicenter prospective and retrospective studies in the post-CFTR modulator era. A scoping review of English articles from the period of January 1, 2012, to July 31, 2023, was conducted utilizing PubMed and EmBase databases with the following terms: "special population (pregnancy, lactation, breastfeeding)" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use." Search results were reviewed by title and abstract for duplications and relevance. Relative to pregnancy or breastfeeding, a total of 18 publications were included for review. Majority of case reports and surveys concluded maternal and infant health were preserved throughout gestation. Likewise, breastfeeding infant case reports show possible changes in liver function and lens opacities, though risk may be increased with both in-utero and breastfeeding exposure. Ivacaftor (IVA) and lumacaftor (LUM) concentrations in fetal cord blood and maternal blood were found to be equivalent. Yet, low concentrations of IVA and LUM were detectable in breastmilk and infant plasma. Current safety data surrounding CFTR modulator use in the setting of pregnancy and lactation is relatively reassuring; however, long-term safety remains unclear, necessitating ongoing observation, and reporting by care teams. As such, treatment decisions should be individualized and coproduced.

Topics: Aminophenols; Benzodioxoles; Breast Feeding; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Lactation; Mutation; Off-Label Use; Pregnancy; Prospective Studies; Retrospective Studies

Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del is the commonest CF-causing variant (found in up to 90% of people with CF (pwCF)). The F508del variant lacks meaningful CFTR function - faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. Corrective therapy could benefit many pwCF. This review evaluates single correctors (monotherapy) and any combination of correctors (most commonly lumacaftor, tezacaftor, elexacaftor, VX-659, VX-440 or VX-152) and a potentiator (e.g. ivacaftor) (dual and triple therapies).. To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del).. We searched the Cochrane CF Trials Register (28 November 2022), reference lists of relevant articles and online trials registries (3 December 2022).. Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations.. Two authors independently extracted data, assessed risk of bias and judged evidence certainty (GRADE); we contacted investigators for additional data.

Topics: Adult; Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dyspnea; Humans; Mutation

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of this disease. We present an ethical dilemma involving an 11-year-old child with CF and end-stage lung disease. Shortly after starting treatment with elexacaftor-tezacaftor-ivacaftor, the family received notification that a matched donor lung had been allocated. Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other are limited. A survey of CF center team members was conducted for the purpose of this article. Ethical principles that may guide us in these situations are discussed. Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared with other team members, are more likely to provide a specific recommendation vs presenting the information to the family and letting them decide (OR, 4.0; 95% CI, 1.2-12.8; P = .021). A shared decision-making model, stressing our moral obligation as physicians to respect autonomy by appreciating family values, while offering to participate in the decision-making process and ensuring nonmaleficence, is presented. In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. The current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision-making. Shared decision-making, which is focused on respecting autonomy, is our preferred approach in these situations.

Topics: Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Lung; Lung Transplantation; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have revolutionised the treatment of cystic fibrosis (CF). Chest computed tomography (CT) is key in the diagnosis and follow-up of anatomical damage to the lungs. Our study aimed to evaluate changes on lung CT scans of patients with CF after receiving elexacaftor-tezacaftor-ivacaftor (ETI) therapy for one year.. We conducted a retrospective, observational, single-centre study between 2018 and 2021 on adult patients with CF administered ETI. We reviewed chest CT scans before and at least one year after starting ETI. The Brody-II score (BSII) was measured by two experienced radiologists who were blinded to the treatment. Paranasal sinus CT scans and clinical and functional data were also compared. Wilcoxon tests were used to compare differences, and Spearman's correlation coefficient was used to evaluate changes in forced expiratory volume in one second (FEV. In the period, 63 patients were given ETI, and 12 met the criteria for analysis. The inter-observer reproducibility of BSII was satisfactory (intraclass correlation coefficient = 0.83, 95% confidence interval 0.57-0.91). The BSII decreased after one year of treatment (-18 ± 16, p = 0.002) due to lower mucous plugging (-7 ± 4, p < 0.001) and peribronchial thickening (-9 ± 10, p = 0.002) scores. Bronchial, parenchymal, and hyperinflation scores were unchanged. Clinical and functional parameters were significantly improved, except for total lung capacity. The correlation between ΔFEV. ETI decreased pulmonary and sinus morphological abnormalities after one year of treatment.

Topics: Adult; Aminophenols; Benzodioxoles; Cystic Fibrosis; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Reproducibility of Results; Retrospective Studies; Tomography, X-Ray Computed

FROM GENETICS TO TREATMENT PERSONALIZED. Cystic fibrosis is a severe monogenic disease that affects around 7 300 patients in France. Mutations (> 2 000) in CFTR, the gene encoding for an epithelial ion channel that normally transports chloride and bicarbonate ions, lead to mucus dehydration and impaired bronchial clearance and pancreatic functions. Systematic neonatal screening in France has allowed early diagnosis since 2002. Although highly restrictive, supportive treatments including daily chest physiotherapy, inhaled aerosol therapy, frequent antibiotic courses, nutritional and pancreatic extracts have improved the prognosis. Median age at death is now beyond 30 years of age. Ivacaftor was the first CFTR potentiator found to both reduce sweat chloride concentrations and improve pulmonary function. Then, combinations of a potentiator and various correctors such as lumacaftor + ivacaftor or tezacaftor + ivacaftor have been tested. Finally, the triple association ivacaftor + tezacaftor + elexacaftor was recently shown to normalize sweat chloride concentration, significantly improve pulmonary function testing, reduce the need for antibiotic treatments, and ultimately improve the quality of life in patients with at least oneF508del mutation (83% of patients in France).. AVANCÉES THÉRAPEUTIQUES DANS LA MUCOVISCIDOSE : DE LA GÉNÉTIQUE AU TRAITEMENT PERSONNALISÉ. La mucoviscidose est une maladie monogénique affectant environ 7 300 patients en France. Plus de 2 000 mutations dans le gène CFTR codant pour la protéine CFTR, canal épithélial qui transporte les ions chlorure et bicarbonate, conduisent à la production d’un mucus déshydraté et visqueux qui altère les fonctions respiratoire et pancréatique. Le dépistage néonatal est systématique en France depuis 2002. Bien que très contraignants, les traitements symptomatiques ont permis de porter l’âge médian au décès au-delà de 30 ans. L’ivacaftor, un potentiateur de la fonction CFTR, a été le premier médicament à faire la preuve de son efficacité, avec une diminution nette des symptômes. Puis ont été testées les combinaisons d’un potentiateur et de correcteurs de la protéine CFTR : lumacaftor-ivacaftor ou tezacaftor-ivacaftor. Enfin, la triple association ivacaftor-tezacaftor- elexacaftor a permis de normaliser la teneur en chlorure sudoral (biomarqueur de la fonction protéique CFTR au niveau des glandes sudorales), d’améliorer durablement la fonction respiratoire (VEMS), de diminuer les exacerbations pulmonaires et la consommation d’antibiotiques chez les patients homozygotes ou hétérozygotes composites pour la mutation F508del (83 % des patients en France).

Topics: Aminophenols; Anti-Bacterial Agents; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Quality of Life; Sweat

Cystic fibrosis (CF) is one of the most common monogenic diseases. Genetic testing is becoming increasingly reasoned to establish or confirm the diagnosis by detecting abnormal mutations.. In order to develop a diagnostic strategy for cystic fibrosis and to facilitate mutation-specific treatments, the genetic revision of the Hungarian Cystic Fibrosis Registry was performed.. 582 patients' data and samples were used for the revision (528 originally included in the register and 54 received during the revision). First we reviewed the patients' existing genetic findings. Wherever necessary, a comprehensive three-level genetic analysis of the CFTR gene was done.. According to our study, of the 528 patients present in the Registry, 395 (74.8%) had 2 pathogenic CFTR mutations. We completed and corrected 94 patients' previously incomplete genetic status. 73 different pathogenic variants were described, in which 1 aberration was not previously reported (c.3130G>A). The 5 most common mutations were: F508del (68.4%); CFTRdele2,3 (3.7%); G542X (3.2%); 2184insA (2.7%); W1282X (2.3%). Based on genotype and age, in Hungary 211 patients are eligible for the available lumacaftor-ivacaftor combination therapy, and 361 patients for the ivacaftor-tezacaftor-elexacaftor therapy.. Due to the revision, we could identify the patients who can benefit from mutation-specific drugs instead of symptomatic therapy. In addition, the data obtained have been used to map the Hungarian distribution of mutations in the CFTR gene, which will help to develop a diagnostic strategy. Orv Hetil. 2022; 163(51): 2052-2059.. Bevezetés: A cystás fibrosis (CF) az egyik leggyakoribb monogénes betegség. A genetikai vizsgálat a kóros mutációk kiderítésével a diagnózis felállításához, illetve megerősítéséhez egyre inkább elengedhetetlenné válik. A magyar CF-betegek genetikai revízióját a kornak megfelelő diagnosztikai stratégia kialakítása tette szükségessé. Ezt a törekvést később kiegészítette a CF-ben alkalmazható mutációspecifikus kezelés elvárása, mely genetikai alapokon nyugszik. Célkitűzés: A munkacsoport célként tűzte ki a magyar Cystás Fibrosis Regiszterben nyilvántartott betegek genetikai adatainak revideálását, illetve átfogó genotípus-elemzését. Módszer: A revízió során összesen 582 (528, regiszterben szereplő és 54, a revízió ideje alatt érkezett) beteg adataival, illetve mintáival dolgoztunk. A meglévő leletek áttekintése után, amennyiben azok nem igazolták a CF diagnózisát, a CFTR-gén háromszintű genetikai analízisét végeztük el. Eredmények: A regiszterben szereplő 528 vizsgált beteg közül 395 (74,8%) esetében sikerült igazolni mindkét kóroki variánst. Vizsgálataink felderítették, illetve javították 94, korábban 1 mutációval rendelkező vagy kimutatott mutációval nem rendelkező beteg genetikai statusát is. Összesen 73 különböző mutációt detektáltunk, melyek között egy korábban még nem közölt, patogén eltérést is leírtunk (c.3130G>A). Az első öt leggyakoribb mutáció a hazai populációban: F508del (68,4%); CFTRdele2,3 (3,7%); G542X (3,2%); 2184insA (2,7%); W1282X (2,3%). Genotípus és életkor alapján 211 beteget találtunk alkalmasnak a lumakaftor–ivakaftor kombinált készítményre és 361-et az ivakaftor–tezakaftor–elexakaftor terápiára, melyek már hazánkban is elérhetők. Következtetés: A revízió eredményeképpen felismerésre kerültek azok a betegek, akik tüneti terápia helyett a mutációspecifikus gyógyszereknek köszönhetően oki terápiában részesülhetnek. Emellett a meglévő eredmények alapján sikerült feltérképezni a CFTR-gén mutációinak hazai megoszlását, ami segít a diagnosztikus stratégia kialakításában. Orv Hetil. 2022; 163(51): 2052–2059.

Topics: Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Hungary; Mutation; Registries

Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer-term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual-agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA-based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizat

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child; Chloride Channel Agonists; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Development; Humans; Indoles; Quinolones

Cystic fibrosis is the most common life-limiting genetic disease in the Caucasian population, with median predicted survival progressively improving up to 50 years, thanks to highly standardized multidisciplinary approach. Patients with p.Phe508del homozygosity usually have poorer lung function and higher mortality rates per year than other groups. By reason of that, this population has been among the most eligible target of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new class of drugs that can partially restore CFTR function by the correction of CFTR misfolding and trafficking to the cell surface. This narrative review summarizes the current preclinical and clinical evidence of the triple combination of elexacaftor-tezacaftor-ivacaftor, the new benchmark among highly effective CFTR modulators. It provides details on the efficacy and safety that led to drug regulation and approval and discusses future developments in clinical and translational research.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Cystic fibrosis (CF) is the most common life-limiting inherited condition in Caucasians. It is a multisystem autosomal recessive disorder caused by variants in the gene for cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cell-surface localised chloride channel that regulates absorption and secretion of salt and water across epithelia. Until recently, the treatment for CF was predicated on ameliorating and preventing the downstream symptoms of CFTR dysfunction, primarily recurrent respiratory infections and pancreatic exocrine failure. But a new class of therapy-the CFTR modulators, which treat the basic defect and decrease the complications of CF, leads to significantly improved pulmonary function, decreased respiratory infections and improved nutrition. The newest agent, a combination of elexacaftor, tezacaftor and ivacaftor, will be suitable for approximately 90% of all people with CF and is likely to decrease the morbidity and significantly increase the life expectancy for most people with CF. The major barrier to their widespread introduction has been their cost, with many countries unwilling or unable to fund them. Nevertheless, such is their therapeutic efficacy and their likely potent effect on life expectancy that their advent has wider societal implications for the care of children and adults with CF.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Genetic Variation; Humans; Indoles; Outcome Assessment, Health Care; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) which instigates a myriad of respiratory complications including increased vulnerability to lung infections and lung inflammation. The extensive influx of pro-inflammatory cells and production of mediators into the CF lung leading to lung tissue damage and increased susceptibility to microbial infections, creates a highly inflammatory environment. The CF inflammation is particularly driven by neutrophil infiltration, through the IL-23/17 pathway, and function, through NE, NETosis, and NLRP3-inflammasome formation. Better understanding of these pathways may uncover untapped therapeutic targets, potentially reducing disease burden experienced by CF patients. This review outlines the dysregulated lung inflammatory response in CF, explores the current understanding of CFTR modulators on lung inflammation, and provides context for their potential use as therapeutics for CF. Finally, we discuss the determinants that need to be taken into consideration to understand the exaggerated inflammatory response in the CF lung.

Topics: Aminophenols; Aminopyridines; Anti-Inflammatory Agents; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Inflammation; Ion Transport; Lung; Macrophages; Pneumonia; Quinolones; Signal Transduction

The effects of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators on lung function, pulmonary exacerbations, and quality of life have been well documented. However, CF is a multiorgan disease, and therefore an evidence base is emerging on the systemic effects of CFTR modulators beyond the pulmonary system. This is of great clinical importance, as many of these studies provide proof of concept that CFTR modulators might be used one day to prevent or treat extrapulmonary manifestations stemming from CFTR dysfunction. In this concise review of the literature, we summarize the results of key publications that have evaluated the effects of CFTR modulators on weight and growth, pancreatic function, the gastrointestinal and hepatobiliary systems, sinus disease, bone disease, exercise tolerance, fertility, mental health, and immunity. Although many of these studies have reported beneficial extrapulmonary effects related to the use of ivacaftor (IVA) in patients with CF with at least one gating mutation, most of the evidence is low or very low quality, given the limited number of patients evaluated and the lack of control groups. Based on an even smaller number of studies evaluating the extrapulmonary effects of lumacaftor-IVA, the benefits are less clear. Although limited, these studies may provide the basis for future clinical trials to evaluate CFTR modulators on the extrapulmonary manifestations of CF.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Quinolones; Signal Transduction

Cystic fibrosis (CF) remains the most common life-shortening hereditary disease in white populations, with high morbidity and mortality related to chronic airway mucus obstruction, inflammation, infection, and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Sodium Channel Blockers; Humans; Indoles; Molecular Targeted Therapy; Mucociliary Clearance; Mutation; Precision Medicine; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Cystic fibrosis (CF) is a genetic disease that may result in multiple systemic disorders and potentially fatal severe respiratory compromise. However, the advent of CF transmembrane conductance regulator (CFTR) modulators has changed the management of CF for patients with select mutations. Although clinical trials have highlighted increased pulmonary function and decreased exacerbations as a result of these novel therapies, their effect on the sinuses has not been well-described.. Our objective is to review the CFTR modulators to provide otolaryngologists, physicians who frequently care for patients with CF, a basic understanding of these drugs and their effects on chronic rhinosinusitis (CRS) in patients with CF.. The clinically approved and available CFTR modulators and specific indications for their use are reviewed. Additionally, a systematic review of these therapies and effects on CRS in CF was performed.. Four Food and Drug Administration approved CFTR modulators are available for patients with CF. Current drugs are approved for gating, residual function, or F508del mutations. Multiple reports describe CFTR modulators' increase in transepithelial ion transport in nasal epithelial cultures; however, clinical studies regarding effects of these modulators on sinonasal health are limited to 5 studies that present new data of the effects of CFTR modulators in CRS.. CFTR modulators have changed management of CF. Initial studies of these medications demonstrate promising results in CF; however, there is a paucity of literature describing the effect of CFTR modulators on CF-associated CRS, although initial results are encouraging.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chronic Disease; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Humans; Indoles; Mutation; Nasal Mucosa; Otolaryngologists; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Cystic Fibrosis (CF) is the most common life-shortening genetic disease among Caucasians, resulting from mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). While work to understand this protein has resulted in new treatment strategies, it is important to emphasize that CFTR exists within a complex lipid bilayer - a concept largely overlooked when performing structural and functional studies. In this review we discuss cellular lipid imbalances in CF, mechanisms by which lipids affect membrane protein activity, and the specific impact of detergents and lipids on CFTR function.

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Epithelial Cells; Humans; Lung; Membrane Lipids; Membrane Microdomains; Mutation; Protein Conformation; Protein Stability; Protein Transport; Quinolones; Structure-Activity Relationship

Cystic fibrosis transmembrane conductance receptor (CFTR) modulators are a new class of drugs that treat the underlying cause of cystic fibrosis. To date, there are four approved medications, which are mutation-specific. Although the number of mutations that respond to these agents is expanding, effective CFTR modulators are not available to all cystic fibrosis patients. The purpose of this article is to review the approved CFTR modulators and discuss the mutations that can be treated with these agents, as well as, review the long-term benefits of modulator therapy.. More people with cystic fibrosis can be effectively treated with CFTR modulators. The new, highly effective triple therapy, elexacaftor/tezacaftor/ivacaftor is indicated for more than 90% of patients with cystic fibrosis and ivacaftor is now approved for children as young as 6 months of age with 1 of 30 CFTR mutations. Long-term use of modulator therapy is associated with fewer pulmonary exacerbations, maintenance of lung function, improved weight gain, and quality of life.. CFTR modulators are the first therapies developed to treat the underlying defect in cystic fibrosis. Their use is associated with preserved lung function and improved health in patients with cystic fibrosis.

Topics: Aminophenols; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quality of Life; Quinolones; Treatment Outcome

Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1-5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.

Topics: Adolescent; Age Factors; Aminophenols; Carrier Proteins; Chloride Channel Agonists; Cystic Fibrosis; Duration of Therapy; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Feces; Female; Humans; Pancreatic Elastase; Quinolones; Recovery of Function

Cystic fibrosis (CF) is a genetic disease with mutational changes leading to profound dysbiosis, both pulmonary and intestinal, from a very young age. This dysbiosis plays an important role in clinical manifestations, particularly in the lungs, affected by chronic infection. The range of microbiological tools has recently been enriched by metagenomics based on next-generation sequencing (NGS). Currently applied essentially in a gene-targeted manner, metagenomics has enabled very exhaustive description of bacterial communities in the CF lung niche and, to a lesser extent, the fungi. Aided by progress in bioinformatics, this now makes it possible to envisage shotgun sequencing and opens the door to other areas of the microbial world, the virome, and the archaeome, for which almost everything remains to be described in cystic fibrosis. Paradoxically, applying NGS in microbiology has seen a rebirth of bacterial culture, but in an extended manner (culturomics), which has proved to be a perfectly complementary approach to NGS. Animal models have also proved indispensable for validating microbiome pathophysiological hypotheses. Description of pathological microbiomes and correlation with clinical status and therapeutics (antibiotic therapy, cystic fibrosis transmembrane conductance regulator (CFTR) modulators) revealed the richness of microbiome data, enabling description of predictive and follow-up biomarkers. Although monogenic, CF is a multifactorial disease, and both genotype and microbiome profiles are crucial interconnected factors in disease progression. Microbiome-genome interactions are thus important to decipher.

Topics: Aminophenols; Animals; Archaea; Bacteria; Biomarkers; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Disease Progression; Dysbiosis; Fungi; Gastrointestinal Microbiome; Genotype; High-Throughput Nucleotide Sequencing; Humans; Lung; Mammals; Metagenomics; Microbiota; Organ Specificity; Prognosis; Quinolones; Viruses

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder. The clinical manifestations of the disease are caused by ∼2,000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is unlikely that any one approach will be efficient in correcting all defects. The recent approvals of ivacaftor, lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor represent the genesis of a new era of precision combination medicine for the CF patient population. In this review, we discuss targeted translational readthrough approaches as mono and combination therapies for CFTR nonsense mutations. We examine the current status of efficacy of translational readthrough/nonsense suppression therapies and their limitations, including non-native amino acid incorporation at PTCs and nonsense-mediated mRNA decay (NMD), along with approaches to tackle these limitations. We further elaborate on combining various therapies such as readthrough agents, NMD inhibitors, and corrector/potentiators to improve the efficacy and safety of suppression therapy. These mutation specific strategies that are directed towards the basic CF defects should positively impact CF patients bearing nonsense mutations.

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Codon, Nonsense; Cystic Fibrosis; Dose-Response Relationship, Drug; Humans; Indoles; Molecular Structure; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Structure-Activity Relationship

This paper reviews the most important clinical papers in cystic fibrosis published in 2018, having searched all the literature on Pubmed. Focus is on CFTR modulator therapy, randomised controlled trials, and infection/microbiology issues.

Topics: Administration, Inhalation; Aminophenols; Aminopyridines; Anti-Bacterial Agents; Azithromycin; Benzodioxoles; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Chloride Channel Agonists; Cough; Cross Infection; Cystic Fibrosis; Disease Progression; Drug Combinations; Drug Therapy, Combination; Humans; Indoles; Lung Transplantation; Microbiological Techniques; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Nebulizers and Vaporizers; Proton Pump Inhibitors; Pseudomonas aeruginosa; Pseudomonas Infections; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Randomized Controlled Trials as Topic; Saline Solution, Hypertonic; Specimen Handling; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

Detailed knowledge of how mutations in the cystic fibrosis transmembrane conductance regulator (

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Humans; Indoles; Mutation; Quinolones; Randomized Controlled Trials as Topic

Small molecules that address fundamental defects underlying cystic fibrosis (CF), including modulators such as the approved drugs ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have advanced dramatically over the past few years and are transforming care and prognosis among individuals with this disease. The new treatment strategies are predicated on established scientific insight concerning pathogenesis, and applying "personalized" or "precision" interventions for specific abnormalities of the cystic fibrosis transmembrane conductance regulator (CFTR). Even with the advent of highly effective triple drug combinations-which hold great promise for the majority of patients with CF worldwide-barriers to precision therapy remain. These include refractory CFTR variants (premature truncation codons, splice defects, large indels, severe missense mutations, and others) not addressed by available modulators, and access to leading-edge therapeutic compounds for patients with ultrarare forms of CF. In addition to describing the remarkable progress that has occurred regarding CF precision medicine, this review outlines some of the remaining challenges. The CF experience is emblematic of many conditions for which personalized interventions are actively being sought.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Precision Medicine; Quinolones

A fixed-dose combination tablet of the cystic fibrosis transmembrane conductance regulator (CFTR) corrector tezacaftor and the CFTR potentiator ivacaftor with the next-generation CFTR corrector elexacaftor (hereafter referred to as elexacaftor/ivacaftor/tezacaftor) [Trikafta™] has been developed by Vertex Pharmaceuticals Inc. to treat patients with the most common cystic fibrosis mutation (F508del). Its use has been associated with statistically significant and/or clinically meaningful improvements in lung function and respiratory-related quality of life compared with comparator regimens (placebo or ivacaftor/tezacaftor) in multinational phase II and III studies, and in October 2019 elexacaftor/ivacaftor/tezacaftor was approved by the US FDA for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene. A regulatory assessment for elexacaftor/ivacaftor/tezacaftor as a treatment for cystic fibrosis is underway in the EU. This article summarizes the milestones in the development of elexacaftor/ivacaftor/tezacaftor leading to this first approval for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; United States; United States Food and Drug Administration

Cystic fibrosis (CF) is the commonest inherited life-shortening illness in white populations, caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation mainly affects the airways where excess salt absorption dehydrates the airway lining leading to impaired mucociliary clearance. Consequently, thick, sticky mucus accumulates making the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Other complications include malnutrition, diabetes and subfertility.Increased understanding of the condition has allowed pharmaceutical companies to design mutation-specific therapies targeting the underlying molecular defect. CFTR potentiators target mutation classes III and IV and aim to normalise airway surface liquid and mucociliary clearance, which in turn impacts on the chronic infection and inflammation. This is an update of a previously published review.. To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with CF.. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles, reviews and online clinical trial registries. Last search: 21 November 2018.. Randomised controlled trials (RCTs) of parallel design comparing CFTR potentiators to placebo in people with CF. A separate review examines trials combining CFTR potentiators with other mutation-specific therapies.. The authors independently extracted data, assessed the risk of bias in included trials and used GRADE to assess evidence quality. Trial authors were contacted for additional data.. We included five RCTs (447 participants with different mutations) lasting from 28 days to 48 weeks, all assessing the CFTR potentiator ivacaftor. The quality of the evidence was moderate to low, mainly due to risk of bias (incomplete outcome data and selective reporting) and imprecision of results, particularly where few individuals experienced adverse events. Trial design was generally well-documented. All trials were industry-sponsored and supported by other non-pharmaceutical funding bodies.F508del (class II) (140 participants)One 16-week trial reported no deaths, or changes in quality of life (QoL) or lung function (either relative or absolute change in forced expiratory volume in one second (FEV1) (moderate-quality evidence). Pulmonary exacerbations and cough were the most reported adverse events in ivacaftor and placebo groups, but there was no difference between groups (low-quality evidence); there was also no difference between groups in participants interrupting or discontinuing treatment (low-quality evidence). Number of days until the first exacerbation was not reported, but there was no difference between groups in how many participants developed pulmonary exacerbations. There was also no difference in weight. Sweat chloride concentration decreased, mean difference (MD) -2.90 mmol/L (95% confidence interval (CI) -5.60 to -0.20).G551D (class III) (238 participants)The 28-day phase 2 trial (19 participants) and two 48-week phase 3 trials (adult trial (167 adults), paediatric trial (52 children)) reported no deaths. QoL scores (respiratory domain) were higher with ivacaftor in the adult trial at 24 weeks, MD 8.10 (95% CI 4.77 to 11.43) and 48 weeks, MD 8.60 (95% CI 5.27 to 11.93 (moderate-quality evidence). The adult trial reported a higher relative change in FEV1 with ivacaftor at 24 weeks, MD 16.90% (95% CI 13.60 to 20.20) and 48 weeks, MD 16.80% (95% CI 13.50 to 20.10); the paediatric trial reported this at 24 weeks, MD 17.4% (P < 0.0001)) (moderate-quality evidence). These trials demonstrated absolute improvements in FEV1 (% predicted) at 24 weeks, MD 10.80% (95% CI 8.91 to 12.69) and 48 weeks, MD 10.44% (95% CI 8.56 to 12.32). The phase 3 trials reported increased cough, odds ratio (OR) 0.57 (95% CI 0.33 to 1.00) and episodes of decreased pulmonary function, OR 0.29 (95% CI 0.10 to 0.82) in the placebo group; ivacaftor led to increased dizziness in adults, OR 10.55 (95% CI 1.32 to 84.47). There was no difference between groups in participant. There is no evidence supporting the use of ivacaftor in people with the F508del mutation. Both G551D phase 3 trials demonstrated a clinically relevant impact of ivacaftor on outcomes at 24 and 48 weeks in adults and children (over six years of age) with CF. The R117H trial demonstrated an improvement in the respiratory QoL score, but no improvement in respiratory function.As new mutation-specific therapies emerge, it is important that trials examine outcomes relevant to people with CF and their families and that adverse events are reported robustly and consistently. Post-market surveillance is essential and ongoing health economic evaluations are required.

Topics: Adult; Age Factors; Aminophenols; Child; Chloride Channel Agonists; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forced Expiratory Volume; Humans; Molecular Targeted Therapy; Mucociliary Clearance; Mutation; Quality of Life; Quinolones; Randomized Controlled Trials as Topic

Prenatal and postnatal treatment with a CFTR modifier attenuates pathological changes in a ferret model of cystic fibrosis (Sun

Topics: Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Ferrets; Pregnancy; Quinolones

Newborn screening for cystic fibrosis (CF) has become a widely accepted and endorsed public health strategy in economically developed countries, although there is little consensus on optimal screening methods and gene panels. Increasing understanding of CFTR genetics and consequent unpredictability of phenotypic and clinical outcomes lead to diagnostic uncertainty, and emergence of Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CF-SPID). Many of these children are clinically well or have a mild phenotype yet may still experience the psychosocial impact of a CF diagnosis. This questions the role of newborn screening and how best to manage those it identifies with CF-SPID.

Topics: Aminophenols; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; False Positive Reactions; Health Policy; Humans; Infant, Newborn; Mutation; Neonatal Screening; Penetrance; Phenotype; Quinolones; Risk Assessment; Sweat

Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forced Expiratory Volume; Gene Deletion; Humans; Indoles; Polymorphism, Single Nucleotide; Quinolones; Treatment Outcome

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Indoles; Quinolones; Treatment Outcome

Cystic fibrosis (CF) is a life-shortening genetic disease caused by mutations of CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator. Despite considerable progress in CF therapies, targeting specific CFTR genotypes based on small molecules has been hindered because of the substantial genetic heterogeneity of CFTR mutations in patients with CF, which is difficult to assess by animal models in vivo. There are broadly four classes (e.g., II, III, and IV) of CF genotypes that differentially respond to current CF drugs (e.g., VX-770 and VX-809). In this review, we shed light on the pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Biological Assay; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Humans; Molecular Targeted Therapy; Mutation; Organoids; Pharmacogenomic Variants; Quinolones; Stem Cells

Cystic fibrosis (CF) is a life-limiting disease caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) activity. The recent advent of the FDA-approved CFTR modulator drug ivacaftor, alone or in combination with lumacaftor or tezacaftor, has enabled treatment of the majority of patients suffering from CF. Even before the identification of the CFTR gene, gene therapy was put forward as a viable treatment option for this genetic condition. However, initial enthusiasm has been hampered as CFTR gene delivery to the lungs has proven to be more challenging than expected. This review covers the contemporary clinical and scientific knowledge base for small molecule CFTR modulator drug therapy, gene delivery vectors and CRISPR/Cas9 gene editing and highlights the prospect of these technologies for future treatment options.

Topics: Aminophenols; Animals; CRISPR-Cas Systems; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Quinolones

The aim of this study was to describe the newest development in cystic fibrosis (CF) care, CF transmembrane conductance regulator (CFTR) modulator therapies.. Phase II results showing CFTR modulator triple therapies are more effective than current CFTR modulators.. CFTR modulator therapy targets the protein defective in CF and boosts its function, but the drug must match mutation pathobiology. Ivacaftor, a CFTR potentiator, was the first modulator approved in 2012, with impressive improvement in lung function and other measures of disease in patients with gating and other residual function mutations (∼10% of CF patients). In 2015, the combination of lumacaftor, a CFTR corrector, and ivacaftor was approved for patients homozygous for the F508del mutation (∼40-50% of the CF population) with positive but less impressive clinical response and 10-20% incidence of intolerance. A next-generation CFTR corrector, tezacaftor, with ivacaftor equally effective and better tolerated than lumacaftor, has also received US Food and Drug Administration approval. Novel CFTR correctors, entering Phase 3 trials in triple modulator combination with tezacaftor-ivacaftor, appear substantially more effective for patients who are homozygous for the F508del mutation and can provide benefit for patients with a single F508del mutation. This offers promise of effective CFTR modulator therapy for nearly 90% of CF patients.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Biomarkers; Clinical Trials, Phase II as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Indoles; Precision Medicine; Quinolones; Respiratory System Agents

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains one of the most common life-shortening genetic diseases affecting the lung and other organs. CFTR functions as a cyclic adenosine monophosphate-dependent anion channel that transports chloride and bicarbonate across epithelial surfaces, and disruption of these ion transport processes plays a central role in the pathogenesis of CF. These findings provided the rationale for pharmacologic modulation of ion transport, either by targeting mutant CFTR or alternative ion channels that can compensate for CFTR dysfunction, as a promising therapeutic approach. High-throughput screening has supported the development of CFTR modulator compounds. CFTR correctors are designed to improve defective protein processing, trafficking, and cell surface expression, whereas potentiators increase the activity of mutant CFTR at the cell surface. The approval of the first potentiator ivacaftor for the treatment of patients with specific CFTR mutations and, more recently, the corrector lumacaftor in combination with ivacaftor for patients homozygous for the common F508del mutation, were major breakthroughs on the path to causal therapies for all patients with CF. The present review focuses on recent developments and remaining challenges of CFTR-directed therapies, as well as modulators of other ion channels such as alternative chloride channels and the epithelial sodium channel as additional targets in CF lung disease. We further discuss how patient-derived precision medicine models may aid the translation of emerging next-generation ion channel modulators from the laboratory to the clinic and tailor their use for optimal therapeutic benefits in individual patients with CF.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Genotype; Humans; Indoles; Ion Channels; Precision Medicine; Quinolones

Cystic fibrosis is a genetic disease that affects approximately 75,000 individuals around the world. Long regarded as a lethal and life-limiting disease, with the most severe manifestations expressed in the progressive decline of lung function, treatment advances focusing on airway clearance and management of chronic lung infection have resulted in improved outcomes for individuals with cystic fibrosis. These advances have been realized in conjunction with an improved understanding of the genetic basis of this disease, dating back to the discovery of the cystic fibrosis gene in 1989. The identification of the cystic fibrosis gene and the advancement of our understanding of the resultant cystic fibrosis transmembrane conductance regulator protein have led to the development of a new class of cystic fibrosis therapies designed to directly impact the function of this protein. These therapeutic developments have progressed, targeting the various mutations that can cause cystic fibrosis. These new medications, known as cystic fibrosis transmembrane conductance regulator modulators, have changed the landscape of cystic fibrosis care and cystic fibrosis research. Their demonstrated effect in patients with specific cystic fibrosis mutations has ignited the hope that such therapies will soon be available to more individuals with this disease, moving the cystic fibrosis community significantly closer to the ultimate goal of curing this disease.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Drug Development; Humans; Indoles; Molecular Targeted Therapy; Mutation; Quinolones

Despite hope that a cure was imminent when the causative gene was cloned nearly 30 years ago, cystic fibrosis (CF [MIM: 219700]) remains a life-shortening disease affecting more than 70 000 individuals worldwide. However, within the last 6 years the Food and Drug Administration's approval of Ivacaftor, the first drug that corrects the defective cystic fibrosis transmembrane conductance regulator protein [CFTR (MIM: 602421)] in patients with the G551D mutation, marks a watershed in the development of novel therapeutics for this devastating disease. Here we review recent progress in diverse research areas, which all focus on curing CF at the genetic, biochemical or physiological level. In the near future it seems probable that development of mutation-specific therapies will be the focus, since it is unlikely that any one approach will be efficient in correcting the more than 2000 disease-associated variants. We discuss the new drugs and combinations of drugs that either enhance delivery of misfolded CFTR protein to the cell membrane, where it functions as an ion channel, or that activate channel opening. Next we consider approaches to correct the causative genetic lesion at the DNA or RNA level, through repressing stop mutations and nonsense-mediated decay, modulating splice mutations, fixing errors by gene editing or using novel routes to gene replacement. Finally, we explore how modifier genes, loci elsewhere in the genome that modify CF disease severity, may be used to restore a normal phenotype. Progress in all of these areas has been dramatic, generating enthusiasm that CF may soon become a broadly treatable disease.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Genotype; Humans; Mutation; Phenotype; Quinolones

Cystic fibrosis (CF) is a common life-shortening condition caused by mutation in the gene that codes for that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a salt transporter. F508del, the most common CFTR mutation that causes CF, is found in up to 80% to 90% of people with CF. In people with this mutation, a full length of protein is transcribed, but recognised as misfolded by the cell and degraded before reaching the cell membrane, where it needs to be positioned to effect transepithelial salt transport. This severe mutation is associated with no meaningful CFTR function. A corrective therapy for this mutation could positively impact on an important proportion of the CF population.. To evaluate the effects of CFTR correctors on clinically important outcomes, both benefits and harms, in children and adults with CF and class II CFTR mutations (most commonly F508del).. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register. We also searched reference lists of relevant articles and online trials registries. Most recent search: 24 February 2018.. Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to placebo in people with CF with class II mutations. We also included RCTs comparing CFTR correctors combined with CFTR potentiators to placebo.. Two authors independently extracted data, assessed risk of bias and quality of the evidence using the GRADE criteria. Study authors were contacted for additional data.. We included 13 RCTs (2215 participants), lasting between 1 day and 24 weeks. Additional safety data from an extension study of two lumacaftor-ivacaftor studies were available at 96 weeks (1029 participants). We assessed monotherapy in seven RCTs (317 participants) (4PBA (also known as Buphenyl), CPX, lumacaftor or cavosonstat) and combination therapy in six RCTs (1898 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) compared to placebo. Twelve RCTs recruited individuals homozygous for F508del, one RCT recruited participants with one F508del mutation and a second mutation with residual function.Risk of bias varied in its impact on the confidence we have in our results across different comparisons. Some findings were based on single RCTs that were too small to show important effects. For five RCTs, results may not be applicable to all individuals with CF due to age limits of recruited populations (i.e. adults only, children only) or non-standard design of converting from monotherapy to combination therapy.Monotherapy versus placeboNo deaths were reported and there were no clinically relevant improvements in quality of life in any RCT. There was insufficient evidence available from individual studies to determine the effect of any of the correctors examined on lung function outcomes.No placebo-controlled study of monotherapy demonstrated a difference in mild, moderate or severe adverse effects; however, it is difficult to assess the clinical relevance of these events with the variety of events and the small number of participants.Combination therapy versus placeboNo deaths were reported during any RCT (moderate- to high-quality evidence). The quality of life scores (respiratory domain) favoured combination therapy (both lumacaftor-ivacaftor and tezacaftor-ivacaftor) compared to placebo at all time points. At six months lumacaftor (600 mg once daily or 400 mg once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores by a small amount compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect size was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg) although the quality of evidence was low (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evi. There is insufficient evidence that monotherapy with correctors has clinically important effects in people with CF who have two copies of the F508del mutation.Combination therapies (lumacaftor-ivacaftor and tezacaftor-ivacaftor) each result in similarly small improvements in clinical outcomes in people with CF; specifically improvements quality of life (moderate-quality evidence), in respiratory function (high-quality evidence) and lower pulmonary exacerbation rates (moderate-quality evidence). Lumacaftor-ivacaftor is associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (high-quality evidence). These adverse effects were not observed for tezacaftor-ivacaftor. Tezacaftor-ivacaftor has a better safety profile, although data are not available for children younger than 12 years. In this age group, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns, but this should be balanced against the increase in blood pressure and shortness of breath seen in longer-term data in adults when considering this combination for use in young people with CF.

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Genetic Therapy; Humans; Indoles; Mutation; Phenylbutyrates; Quinolones; Randomized Controlled Trials as Topic

Cystic fibrosis (CF) is the most common, life-limiting autosomal recessive disease in Caucasians, and is caused by defects in production of the CFTR ion channel. Until recently, there were no available treatments targeting the disease-causing defects in CFTR but newly developed CFTR modulators are changing the course of disease in CF. The newest modulator, tezacaftor, is a CFTR corrector that was recently approved by the FDA to be used in combination with the first approved CFTR potentiator, ivacaftor. Areas covered: A detailed review of the clinical trials and published literature, focusing on safety and efficacy, leading to the approval of tezacaftor in CF. Expert commentary: Recent trials have demonstrated that the combination of tezacaftor-ivacaftor is a slightly superior combination to its predecessor, lumacaftor-ivacaftor, with respect to an increase in FEV1, adverse event profile, and drug-drug interactions. It is also approved for a large number of non-F508del, residual function mutations that are predicted to respond based on in vitro testing. The horizon for continued improvements in CFTR-targeted treatments is promising, with three-drug combinations currently in Phase 3 clinical trials, and other drugs with novel mechanisms of action being studied. Within the next 5 years, the vast majority of patients with CF are expected to have a modulator approved for their genotype.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Genotype; Humans; Indoles; Mutation; Quinolones

The treatment of cystic fibrosis (CF) with CF transmembrane conductance regulator (CFTR) modulators continues to develop at a fast pace. These compounds are potentially disease modifying but are only available to certain patient subsets based on genotype. This review discusses the role of theratyping in CF and the potential to assess all patients' response to current and emerging therapies.. There are limitations to treatment determined by mutation, as variable clinical response to CFTR modulators has been observed within the same genotype. Patients with rare mutations not currently licensed for CFTR modulator therapy have demonstrated response to these medications. Patient-specific cellular models called organoids can be used to demonstrate response to different CFTR modulators in vitro prior to their clinical application and represent a method of theratyping.. Theratyping charts patients' clinical response to different treatments on an individual basis. This overcomes the limitations of genotype being used to predict response to individual therapies and includes all patients regardless of mutation. The use of organoids in high throughput screening allows numerous compounds to be tested on patient-specific tissue preclinically. This could lead to the extension of theratyping beyond CFTR modulators.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Gene Editing; Genetic Therapy; Genotype; Humans; Indoles; Mutation; Organoids; Oxadiazoles; Precision Medicine; Quinolones

CFTR modulators are a class of drugs which directly target the defective CFTR protein in cystic fibrosis (CF), improving its function with resultant clinical improvements. Currently these drugs are confined to people with a limited selection of genetic mutations. New modulators are in development which will lead to the majority of patients with CF becoming eligible for treatment. CFTR modulators are currently considered contraindicated in patients with a solid organ transplant. This excludes many patients who may benefit from the multisystem effects of CFTR modulator treatment. In this review, we discuss issues regarding drug interactions, organ transplantation and CFTR modulation.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Male; Molecular Targeted Therapy; Organ Transplantation; Quinolones; Young Adult

We reviewed the impact of ivacaftor on Scottish paediatric patients with cystic fibrosis ≥6 years of age after 12 months of treatment. Statistically significant improvements in FEV

Topics: Aminophenols; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones; Scotland; Treatment Outcome

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder affecting around 75,000 individuals worldwide. It is a multi-system disease but the main morbidity and mortality is caused by chronic lung disease. Due to newborn screening, a multidisciplinary approach to care and intensive symptomatic treatment, the prognosis has dramatically improved over the last decades and there are currently more adults than children in many countries. However, CF is still a very severe disease with a current median age of life expectancy in the fourth decade of life. The disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes the CFTR protein, a protein kinase A-activated ATP-gated anion channel that regulates the transport of electrolytes such as chloride and bicarbonate. More than 2000 mutations have been reported, although not all of these have functional consequences. An enormous research effort and progress has been made in understanding the consequences of these mutations on the CFTR protein structure and function, and this has led to the approval of two new drug therapies that are able to bind to defective CFTR proteins and partially restore their function. They are mutation-specific therapies and available at present for specific mutations only. They are the first personalized medicine for CF with a possible disease-modifying effect. A pipeline of other compounds is under development with different mechanisms of action. It is foreseeable that new combinations of compounds will further improve the correction of CFTR function. Other strategies including premature stop codon read-through drugs, antisense oligonucleotides that correct the basic defect at the mRNA level or gene editing to restore the defective gene as well as gene therapy approaches are all in the pipeline. All these strategies are needed to develop disease-modifying therapies for all patients with CF.

Topics: Adolescent; Adult; Aminophenols; Child; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Mutational Analysis; Exocrine Pancreatic Insufficiency; Genetic Therapy; Humans; Infant; Infant, Newborn; Interdisciplinary Communication; Intersectoral Collaboration; Life Expectancy; Phenotype; Prognosis; Quinolones; Young Adult

Evolving cystic fibrosis 'standards of care' have influenced recent cystic fibrosis clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection.. Three cystic fibrosis therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced cystic fibrosis transmembrane conductance regulator [CFTR] protein function) differ with respect to the duration for which recognized 'standards of care' have been available. However, developers of new therapies in all the three areas are affected by similar challenges: standards of care have become so strongly entrenched that traditional placebo-controlled studies in cystic fibrosis populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active-comparator trial designs, that have substantial challenges of their own. Foremost among these are the selection of 'valid' active comparator(s), estimation of a comparator's current clinical efficacy (required for testing noninferiority hypotheses), and effective blinding of commercially available comparators.. Recent and future cystic fibrosis clinical trial designs will have to creatively address this collateral result of successful past development of effective cystic fibrosis therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies.

Topics: Aminophenols; Aminopyridines; Anti-Bacterial Agents; Benzodioxoles; Chloride Channel Agonists; Clinical Trials as Topic; Comparative Effectiveness Research; Cystic Fibrosis; Disease Progression; Drug Combinations; Humans; Pseudomonas Infections; Quinolones; Standard of Care; Treatment Outcome

As technology yields new treatments, pediatric pulmonologists need determine how best to use them and how to decide which ones are best for any specific group or individual patient. Physicians have always customized therapies based upon patient response, but the new concept of "Personalized (or precision) medicine" focuses attention to a greater degree on the individual needs of patients based on their genetic, biomarker, phenotypic, or psychosocial characteristics. The newly developed biologics for treatment of asthma and CFTR modulators for treatment of cystic fibrosis (CF) highlight this newer approach. As we have more treatments available, new approaches to testing efficacy and effectiveness of these new therapies is necessary in order to efficiently bring them to market and compare their benefits in real world practice. While comparative effectiveness can be tested in pragmatic clinic trials, the most common approaches make use of observational data such as administrative databases and patient registries but their use for this is fraught with pitfalls that may or may not be methodologically surmountable. Once new therapies have been shown to be efficacious and effective, it is important to be cognizant of methods for ensuring that all patients actually receive the treatments that will be best for them. Comparisons of the effectiveness of clinical practice in the form of benchmarking is helpful for this, and consideration of costs and cost-effectiveness is essential to judging the best treatment for patients in a real-world setting.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aminophenols; Anti-Bacterial Agents; Asthma; Chloride Channel Agonists; Comparative Effectiveness Research; Cost-Benefit Analysis; Cystic Fibrosis; Equivalence Trials as Topic; Humans; Leukotriene Antagonists; Precision Medicine; Quality-Adjusted Life Years; Quinolones; Treatment Outcome

Several new therapeutic modalities have recently become available to be used in patients with cystic fibrosis such as potentiators, modulators, and probiotics. Although the effects on pulmonary function have been well documented, gastrointestinal outcomes have been addressed only rarely.. Both the potentiator (ivacaftor) and the potentiator/modulator combination (ivacaftor/lumacaftor) that are currently on the market have a positive effect on BMI. Young patients (2-5 years of age) with a gating mutation may show improvement of exocrine pancreatic function on ivacaftor. In this specific patient population this agent also seems to improve intestinal pH and reflux. The effect of these medications on other gastrointestinal outcomes, such as intestinal inflammation and cystic fibrosis liver disease, has not been described so far. Furthermore, the results of several trials suggest that probiotics might reduce intestinal inflammation. Finally, organoids might be used to predict in vitro the clinical effect of potentiators and modulators.. The effect of new interventions on the gastrointestinal outcomes studied so far is favourable. Future studies should address the effect on other gastrointestinal parameters.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Body Mass Index; Chloride Channel Agonists; Cystic Fibrosis; Digestive System; Drug Combinations; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Intestinal Diseases; Liver Diseases; Probiotics; Quinolones; Treatment Outcome; Weight Gain

To provide an insight and overview of the challenges in the diagnosis, follow-up and treatment of cystic fibrosis-related liver disease (CFLD).. The variable pathophysiology of CFLD complicates its diagnosis and treatment. A 'gold standard' for CFLD diagnosis is lacking. Over the past years, new techniques to diagnose features of CFLD, such as transient elastography, have been investigated. Although most of these tests confirm cystic fibrosis-related liver involvement (CFLI), they are, however, not suitable to distinguish various phenotypical presentations or predict progression to clinically relevant cirrhosis or portal hypertension. A combined initiative from the European and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has been started, aimed to obtain consensus on CFLD criteria and definitions. Currently, only ursodeoxycholic acid is used in CFLD treatment, although it has not been convincingly demonstrated to change the natural course of the disease. Drugs that directly target cystic fibrosis transmembrane conductance regulator protein dysfunction show promising results; however, more long-term follow-up and validation studies are needed.. CFLD is an umbrella term referring to a wide variety of liver manifestations with variable clinical needs and consequences. CFLD with portal hypertension is the most severe form of CFLD due to its significant implications on morbidity and mortality. The clinical relevance of other CFLI is uncertain. Consensus on CFLD definitions is essential to validate new diagnostic tools and therapeutic outcome measures.

Topics: Aftercare; Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cholagogues and Choleretics; Cystic Fibrosis; Drug Combinations; Elasticity Imaging Techniques; Humans; Liver Diseases; Liver Transplantation; Quinolones; Ursodeoxycholic Acid

With over 1900 variants reported in the cystic fibrosis transmembrane conductance regulator (CFTR), enhanced understanding of cystic fibrosis (CF) genotype-phenotype correlation represents an important and expanding area of research. The potentiator Ivacaftor has proven an effective treatment for a subset of individuals carrying missense variants, particularly those that impact CFTR gating. Therapeutic efforts have recently focused on correcting the basic defect resulting from the common F508del variant, as well as many less frequent missense alleles. Modest enhancement of F508del-CFTR function has been achieved by combining Ivacaftor with Lumacaftor, a compound that aids maturational processing of misfolded CFTR. Continued development of in silico and in vitro models will facilitate CFTR variant characterization and drug testing, thereby elucidating heterogeneity in the molecular pathogenesis, phenotype, and modulator responsiveness of CF.

Topics: Alleles; Aminophenols; Animals; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Variation; Humans; Mutation, Missense; Quinolones

One major breakthrough in cystic fibrosis research in the past decade is the development of drugs that target the root cause of the disease-dysfunctional CFTR protein. One of the compounds, Ivacaftor or Kalydeco, which has been approved for clinical use since 2012, acts by promoting the gating function of CFTR. Our recent studies have led to a gating model that features energetic coupling between nucleotide-binding domain (NBD) dimerization and gate opening/closing in CFTR's transmembrane domains (TMDs). Based on this model, we showed that ATP analogs can enhance CFTR gating by facilitating NBD dimerization, whereas Ivacaftor works by stabilizing the open channel conformation of the TMDs. This latter idea also explains the near omnipotence of Ivacaftor. Furthermore, this model identifies multiple approaches to synergistically boost the open probability of CFTR by influencing distinct molecular events that control gating conformational changes.

Topics: Adenosine Triphosphate; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Precision Medicine; Quinolones

These are exciting times in the development of therapeutics for cystic fibrosis (CF). New correctors and potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) are being developed in academic laboratories and pharmaceutical companies, and the field is just beginning to understand their mechanisms of action. Studies of CFTR modulators are also yielding insight into the general principles and strategies that can be used when developing pharmacological chaperones, a new class of drugs. Combining two or even three correctors with a potentiator is an especially promising approach which should lead to further improvements in efficacy and clinical benefit for patients.

Topics: Aminophenols; Binding Sites; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Mutation; Quinolones

Cystic fibrosis (CF) is a life-shortening condition with no cure. Available therapies relieving the symptoms of CF are complex and time-consuming. A comprehensive review assessing adherence to different CF therapies, association of adherence with outcomes, and factors influencing adherence could inform optimal patient management strategies. Areas covered: A targeted literature review of studies published from 2010-2016 assessed adherence to CF therapies. Nineteen studies qualified for inclusion. Adherence to CF therapies was sub-optimal, and varied by treatment, mode of treatment administration, age, season, time and method of adherence measurement. Adherence to ivacaftor and inhaled antibiotics were reported higher than dornase alfa or hypertonic saline, oral pancreatic enzyme and vitamin supplements, and airway clearance therapy. Several patient, healthcare provider and treatment related factors influenced adherence. Sub-optimal adherence was shown to impact clinical and economic burden of the disease. Expert commentary: Higher adherence to CF therapies can lower disease burden, and improve patient outcomes. Healthcare providers and policy makers should devise patient-centered and caregiver-enabled interventions to improve adherence. Research on long-term adherence and outcomes associated with promising oral treatments such as CFTR modulators is needed. Identifying ways to overcome key barriers to adherence can positively affect outcomes associated with CF.

Topics: Administration, Inhalation; Administration, Oral; Aminophenols; Anti-Bacterial Agents; Cystic Fibrosis; Deoxyribonuclease I; Humans; Medication Adherence; Quinolones; Recombinant Proteins; Saline Solution, Hypertonic

The treatment of cystic fibrosis has been symptom-based for a number of years. New therapies that aim to improve CFTR protein function are now emerging.. The results of gene therapy has been modest but a recent clinical trial shows a positive effect on FEV1. Recent research has focused primarily on CFTR protein function. Significant respiratory improvement (an average 10% FEV1 increase and a decrease in the frequency of exacerbations) has been achieved with ivacaftor, a CFTR potentiator, in patients with gating mutations, resulting in its marketing authorization (in 2012 for the G551D mutation and in 2015 for rarer mutations). In phe508del homozygous patients, the combination of ivacaftor with a CFTR corrector (lumacaftor) has also led to respiratory improvement, albeit less impressive. The effectiveness of ataluren in patients with nonsense mutations is being evaluated.. New CFTR correctors and potentiators are being developed. CFTR protein therapy could change the course of the disease but cost/effectiveness issues should not be overlooked.. Ivacaftor can be prescribed in CF patients with a class 3 mutation from the age of 6 years. The Orkambi

Topics: Age Factors; Aminophenols; Aminopyridines; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Genetic Therapy; Humans; Molecular Targeted Therapy; Quinolones

Personalized medicine promises that medical decisions, practices and products are tailored to the individual patient. Cystic fibrosis, an inherited disorder of chloride and bicarbonate transport in exocrine glands, is the first successful example of customized drug development for mutation-specific therapy. There are two classes of CFTR modulators: potentiators that increase the activity of CFTR at the cell surface, and correctors that either promote the read-through of nonsense mutations or facilitate the translation, folding, maturation and trafficking of mutant CFTR to the cell surface. The potentiator ivacaftor and the corrector lumacaftor are approved in Germany for the treatment of people with cystic fibrosis who carry a gating mutation such as p.Gly551Asp or who are homozygous for the most common mutation p.Phe508del, respectively. This report provides an overview of the basic defect in cystic fibrosis, the population genetics of CFTR mutations in Germany and the bioassays to assess CFTR function in humans together with the major achievements of preclinical research and clinical trials to bring CFTR modulators to the clinic. Some practical information on the use of ivacaftor and lumacaftor in daily practice and an update on pitfalls, challenges and novel strategies of bench-to-bedside development of CFTR modulators are also provided.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Biomarkers, Tumor; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Drug Combinations; Evidence-Based Medicine; Genetic Markers; Genetic Predisposition to Disease; Humans; Precision Medicine; Quinolones; Treatment Outcome

Ivacaftor is indicated for treatment of cystic fibrosis (CF) mediated by 10 mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that causes gating or partial function abnormalities. In placebo-controlled and open-label studies, ivacaftor-treated subjects showed improved pulmonary function, nutrition and quality of life measures. This article reviews ivacaftor safety.. Safety findings in ivacaftor clinical trials, and reported subsequently, were accessed by a PubMed search using key words "VX-770" or "ivacaftor". Additional information was accessed via Google Search. Transaminitis was noted in ivacaftor and combination lumacaftor-ivacaftor trials. Ivacaftor was associated with cataracts in juvenile rat pups in pre-clinical studies; non-congenital cataracts have been found in children taking ivacaftor. Ivacaftor is a CYP3A substrate; CYP3A inhibitors and inducers should be avoided during its administration. Ivacaftor and its M1 metabolite may inhibit CYP3A and P-gp; therefore, ivacaftor may increase systemic exposure to drugs which are substrates of CYP3A and/or P-gp, increasing the potential for adverse events.. Ivacaftor therapy may be associated with ocular and hepatic side effects; specific recommendations for monitoring are available. Potential drug interactions should be evaluated in patients taking ivacaftor. High clinical efficacy suggests that the risk benefit ratio of ivacaftor favors therapy.

Topics: Aminophenols; Animals; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Interactions; Humans; Mutation; Quality of Life; Quinolones; Rats

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder that affects about 70,000 people worldwide. The clinical manifestations of the disease are caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The discovery of the CFTR gene in 1989 has led to a sophisticated understanding of how thousands of mutations in the CFTR gene affect the structure and function of the CFTR protein. Much progress has been made over the past decade with the development of orally bioavailable small molecule drugs that target defective CFTR proteins caused by specific mutations. Furthermore, there is considerable optimism about the prospect of gene replacement or editing therapies to correct all mutations in cystic fibrosis. The recent approvals of ivacaftor and lumacaftor represent the genesis of a new era of precision medicine in the treatment of this condition. These drugs are having a positive impact on the lives of people with cystic fibrosis and are potentially disease modifying. This review provides an update on advances in our understanding of the structure and function of the CFTR, with a focus on state of the art targeted drugs that are in development.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Discovery; Drug Therapy, Combination; Forced Expiratory Volume; Forecasting; Genetic Therapy; Homozygote; Humans; Molecular Targeted Therapy; Mutation; Oxadiazoles; Phosphodiesterase 5 Inhibitors; Practice Guidelines as Topic; Precision Medicine; Quinolones

Development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, small molecule therapies that target the basic defect in cystic fibrosis (CF), represents a new era in CF treatment. This review highlights recent progress in CF therapeutics as an example of precision medicine and personalized approaches to test CFTR modulators using preclinical model systems.. CFTR modulators are now clinically available for approximately 50% of the United States CF population. The CFTR potentiator, ivacaftor, is approved for people with CF ages 2 years and older with at least one gating mutation (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) or the R117H conductance mutation. The recent Food and Drug Administration approval of the corrector/potentiator combination, lumacaftor/ivacaftor, expands modulator therapy to people with CF homozygous for the F508del mutation, ages 12 years and older. Ivacaftor and lumacaftor, however, do not fully restore CFTR activity. Thus, next-generation correctors and potentiators are in development. Read-through agents targeting nonsense mutations and genotype agnostic treatments (gene-editing and gene therapy) are also in various phases of clinical development.. CFTR modulators promise to transform the therapeutic landscape in CF in a precision based fashion. Areas of ongoing research include developing drugs for all mutation classes so that all persons with CF can benefit from these therapies, and refining preclinical assays that allow the selection of the most effective treatments on an individual basis.

Topics: Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Genotype; Humans; Mutation; Precision Medicine; Quinolones; United States

The cystic fibrosis drug, Kalydeco, has attracted attention both for its effectiveness in particular CF patients and its substantial price tag. An analysis of newspaper portrayals of Kalydeco provides an opportunity to examine how policy issues associated with rare diseases and orphan drugs are being represented in the popular press.. We conducted a content analysis of 203 newspaper articles in Canada and the U.S. that mention Kalydeco. Articles were analyzed for their main frame, discussion of Kalydeco, including issues of drug development, patient access, and reimbursement, and overall tone.. In Canadian newspaper coverage, 77.4% of articles were framed as human interest stories featuring individual patients seeking public funding for Kalydeco, yet only 7.5% mentioned any budgetary limitations in doing so. In contrast, U.S. newspaper coverage was framed as a financial/economic story in 43.1% of articles and a medical/scientific story in 27.8%.. Newspaper coverage varied significantly between Canada, where Kalydeco is predominantly a story about increasing patient access through full government funding, and the U.S., where Kalydeco is largely a financial story about the economic impact of Kalydeco. The difference in coverage may be due to differences in public funding between the healthcare systems of these two countries.

Topics: Aminophenols; Canada; Cross-Cultural Comparison; Cystic Fibrosis; Drug Costs; Health Services Accessibility; Humans; Newspapers as Topic; Orphan Drug Production; Quinolones; Reimbursement Mechanisms; United States

Cystic fibrosis (CF) is a life-shortening inherited disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel activity resulting from mutations in the CFTR gene. Phe508del is the most prevalent mutation, with approximately 90% of all CF patients carrying it on at least one allele. Over the past two or three decades, significant progress has been made in understanding the pathogenesis of CF, and in the development of effective CF therapies. The approval of Orkambi® (lumacaftor/ivacaftor) marks another milestone in CF therapeutics development, which, with the advent of personalized medicine, could potentially revolutionize CF care and management. This article reviews the rationale, progress and future direction in the development of lumacaftor/ivacaftor combination to treat CF patients homozygous for the Phe508del-CFTR mutation.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Mutation; Precision Medicine; Quinolones

Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function.. Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies. Eligible patients from 187 participating centres in North America, Australia, and the European Union (both trials) were aged 12 years or older with a confirmed diagnosis of cystic fibrosis, homozygous for the Phe508del CFTR mutation, and with a percent predicted FEV1 (ppFEV1) of 40-90 at the time of screening. Patients were randomly assigned with an interactive web response system (1:1:1) to receive placebo, lumacaftor (600 mg once daily) plus ivacaftor (250 mg every 12 h), or lumacaftor (400 mg every 12 h) plus ivacaftor (250 mg every 12 h) for 24 weeks. Prespecified subgroup analyses of pooled efficacy and safety data by lung function, as measured by ppFEV1, were done for patients with baseline ppFEV1 (<40 and ≥40) and screening ppFEV1 (<70 and ≥70). The primary endpoint was the absolute change from baseline in ppFEV1 at week 24 analysed in all randomised patients who received at least one dose of study drug. Both trials are registered with ClinicalTrials.gov (TRAFFIC: NCT01807923; TRANSPORT: NCT01807949).. Both trials were done between April, 2013, and April, 2014. Of the 1108 patients included in the efficacy analysis, 81 patients had a ppFEV1 that decreased to lower than 40 between screening and baseline and 1016 had a ppFEV1 of 40 or higher at baseline. At screening, 730 had a ppFEV1 of less than 70, and 342 had a ppFEV1 of 70 or higher. Improvements in the absolute change from baseline at week 24 in ppFEV1 were observed with both lumacaftor/ivacaftor doses in the subgroup with baseline ppFEV1 levels lower than 40 (least-squares mean difference vs placebo was 3·7 percentage points [95% CI 0·5-6·9; p=0·024] in the lumacaftor [600 mg/day]-ivacaftor group and 3·3 percentage points [0·2-6·4; p=0·036] in the lumacaftor [400 mg/12 h]-ivacaftor group). Improvements in ppFEV1 compared with placebo were also reported in the subgroup with baseline ppFEV1 levels of 40 or higher (3·3 percentage points [2·3-4·4; p<0·0001] in the lumacaftor [600 mg per day]-ivacaftor group and 2·8 percentage points [1·7-3·8; p<0·0001] in the lumacaftor [400 mg/12 h]-ivacaftor group). Similar absolute improvements in ppFEV1 compared with placebo were observed in subgroups with screening ppFEV1 levels lower than 70 and ppFEV1 levels of 70 or higher. Increases in body-mass index and reduction in number of pulmonary exacerbation events were observed in both lumacaftor/ivacaftor dose groups compared with placebo across all lung function subgroups. Treatment was generally well tolerated, although the incidence of some respiratory adverse events was higher with lumacaftor/ivacaftor than with placebo in all subgroups. In patients with baseline ppFEV1 levels lower than 40, these adverse events included cough, dyspnoea, and abnormal respiration.. These analyses confirm that lumacaftor/ivacaftor combination therapy benefits patients with cystic fibrosis homozygous for Phe508del CFTR who have varying degrees of lung function impairment.. Vertex Pharmaceuticals.

Topics: Adolescent; Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Chloride Channel Agonists; Clinical Trials, Phase III as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Homozygote; Humans; Lung; Male; Middle Aged; Quinolones; Randomized Controlled Trials as Topic; Respiratory Function Tests; Treatment Outcome; Young Adult

Lumacaftor/ivacaftor (Orkambi™) is a fixed-dose tablet containing a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel's open probability and transport of chloride. In two 24-week trials in the approved patient population (TRAFFIC and TRANSPORT), lumacaftor 400 mg plus ivacaftor 250 mg, administered every 12 h in combination with standard therapy, was associated with an ≈3 % statistically significant improvement in lung function relative to placebo (as measured by the percent predicted forced expiratory volume in 1 s). Lumacaftor plus ivacaftor did not significantly improve respiratory symptoms, although reduced pulmonary exacerbations to a clinically meaningful extent and, in one trial (TRANSPORT), significantly improved body mass index (BMI). In an ongoing extension of these studies (PROGRESS), lumacaftor plus ivacaftor provided clinical benefit over a further 72 weeks of treatment. Lumacaftor plus ivacaftor had an acceptable tolerability profile, with the most common adverse events being respiratory or gastrointestinal in nature. Thus, lumacaftor/ivacaftor expands the treatment options available for patients with cystic fibrosis homozygous for the F508del-CFTR mutation, although its precise place in clinical practice remains to be determined.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Mutation; Quinolones

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are clinically available personalized medicines approved for some individuals with cystic fibrosis (CF) to target the underlying defect of disease. This review summarizes strategies used to develop CFTR modulators as therapies that improve function and availability of CFTR protein. Lessons learned from dissemination of ivacaftor across the CF population responsive to this therapy and future approaches to predict and monitor treatment response of CFTR modulators are discussed. The goal remains to expand patient-centered and personalized therapy to all patients with CF, ultimately improving life expectancy and quality of life for this disease.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Molecular Targeted Therapy; Mutation; Quinolones

Cystic fibrosis (CF) is the most common genetic life-shortening condition in Caucasians. Despite being a multi-organ disease, CF is classically diagnosed by symptoms of acute/chronic respiratory disease, with persistent pulmonary infections and mucus plugging of the airways and failure to thrive. These multiple symptoms originate from dysfunction of the CF transmembrane conductance regulator (CFTR) protein, a channel that mediates anion transport across epithelia. Indeed, establishment of a definite CF diagnosis requires proof of CFTR dysfunction, commonly through the so-called sweat Cl(-) test. Many drug therapies, including mucolytics and antibiotics, aim to alleviate the symptoms of CF lung disease. However, new therapies to modulate defective CFTR, the basic defect underlying CF, have started to reach the clinic, and several others are in development or in clinical trials. The novelty of these therapies is that, besides targeting the basic defect underlying CF, they are mutation specific. Indeed, even this monogenic disease is influenced by a large number of different genes and biological pathways as well as by environmental factors that are difficult to assess. Accordingly, every person with CF is unique and so functional assessment of patients' tissues ex vivo is key for diagnosing and predicting the severity of this disease. Of note, such assessment will also be crucial to assess drug responses, in order to effectively treat all CF patients. It is not because it is a monogenic disorder that personalized treatment for CF is much easier than for complex disorders.

Topics: Aminoglycosides; Aminophenols; Anti-Bacterial Agents; Anti-Inflammatory Agents; Biomarkers; Codon, Nonsense; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Evidence-Based Medicine; Frameshift Mutation; Genistein; Humans; Oxadiazoles; Phenotype; Precision Medicine; Purinergic Antagonists; Quinolones; Rare Diseases; Severity of Illness Index; Sweat Glands

Cystic fibrosis is the most common inherited life-shortening illness in Caucasians and caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation most notably affects the airways of people with cystic fibrosis. Excess salt absorption by defective CFTR dehydrates the airway lining and leads to defective mucociliary clearance. Consequent accumulation of thick, sticky mucus makes the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Additionally, abnormalities with CFTR lead to systemic complications like malnutrition, diabetes and subfertility.Since the discovery of the causative gene, our understanding of the structure and function of CFTR and the impact of different mutations has increased and allowed pharmaceutical companies to design new mutation-specific therapies targeting the underlying molecular defect. Therapies targeting mutation classes III and IV (CFTR potentiators) aim to normalise airway surface liquid and help re-establish mucociliary clearance, which then has a beneficial impact on the chronic infection and inflammation that characterizes lung disease in people with cystic fibrosis. These therapies may also affect other mutations.. To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis.. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 05 March 2015.We searched the EU Clinical Trials Register, clinicaltrials.gov (US Clinical Trials Register) and the International Clinical Trials Registry Platform (ICTRP). Last search of clinical trial registries: 06 February 2014.. Randomised controlled trials of parallel design comparing CFTR potentiators to placebo in people with cystic fibrosis. In a post hoc change we excluded trials combining CFTR potentiators with other mutation-specific therapies. These will be considered in a separate review.. The authors independently extracted data and assessed the risk of bias in included trials; they contacted trial authors for additional data. Meta-analyses were undertaken on outcomes at a number of time points.. We included four randomised controlled trials (n = 378), lasting from 28 days to 48 weeks, comparing the potentiator ivacaftor to placebo. Trials differed in terms of design and participant eligibility criteria, which limited the meta-analyses. The phase 2 trial (n = 19) and two phase 3 trials (adult trial (n = 167), paediatric trial (n = 52)), recruited participants with the G551D mutation (class III). The fourth trial (n = 140) enrolled participants homozygous for the ΔF508 mutation (class II).Risks of bias in the trials were moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented. Participant blinding was less clear throughout all trials; in three trials, some participant data were excluded from the analysis. Selective outcome reporting was apparent in three trials. All trials were sponsored by industry and supported by other non-pharmaceutical funding bodies.No trial reported any deaths. Significantly higher quality of life scores in the respiratory domain were reported by the adult phase 3 G551D trial at 24 weeks, mean difference 8.10 (95% confidence interval (CI) 4.77 to 11.43) and 48 weeks, mean difference 8.60 (95% CI 5.27 to 11.93); but not by the paediatric phase 3 G551D trial. The adult phase 3 G551D trial reported improvements in relative change from baseline in forced expiratory volume at one second at 24 weeks, mean difference 16.90% (95% CI 13.60 to 20.20) and 48 weeks, mean difference 16.80% (95% CI 13.50 to 20.10); as did the paediatric G551D trial at 24 weeks, mean difference 17.4% (P < 0.0001)). No improvements in quality of life or lung function were reported in the ΔF508 participants.Combined data from both phase 3 G551D trials demonstrated increased reporting of cough, odds ratio 0.57 (95% CI 0.33 to 1.00) and increased episodes of decreased pulmonary function, odds ratio 0.29 (95% CI 0.10 to 0.82) in the placebo group. The adult phase 3 G551D trial demonstrated increased reporting of dizziness amongst the ivacaftor group, OR 10.55 (95% CI 1.32 to 84.47). No trial showed a difference between treatment arms in the number of participants interrupting or discontinuing the trial drug.In the phase 3 G551D trials, fewer participants assigned to ivacaftor developed serious pulmonary exacerbations. When considering all data for exacerbations, participants taking ivacaftor in the adult phase 3 G551D study developed fewer exacerbations, odds ratio 0.54 (95% CI 0.29 to 1.01). In the othe. Both G551D phase 3 trials (n = 219) demonstrated a clinically relevant impact of the potentiator ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of this treatment in adults and children (over six years of age) with cystic fibrosis and the G551D mutation (class III). There is no evidence to support the use of ivacaftor in people with the ΔF508 mutation (class II) (n = 140). Trials on ivacaftor in people with different mutations are ongoing.

Topics: Adult; Age Factors; Aminophenols; Child; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forced Expiratory Volume; Humans; Molecular Targeted Therapy; Mucociliary Clearance; Mutation; Quality of Life; Quinolones; Randomized Controlled Trials as Topic

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by malfunction of CF transmembrane regulator (CFTR). The deletion of a phenylalanine at residue 508 (F508del) is the most common mutation that causes cellular processing, chloride channel gating and protein stability defects in CFTR. Pharmacological modulators of F508del-CFTR, aimed at correcting the cellular processing defect (correctors) and the gating defect (potentiators) in CFTR protein, are regarded as promising therapeutic agents for CF disease. Endeavors in searching F508del-CFTR modulators have shown encouraging results, with several small-molecule compounds having entered clinical trials or even represented clinical options.. This review covers the discovery of F508del-CFTR correctors described in both patents (2005 - present) and scientific literatures.. Cyclopropane carboxamide derivatives of CFTR correctors continue to dominate in this area, among which lumacaftor (a NBD1-MSD1/2 interface stabilizer) is the most promising compound and is now under the priority review by US FDA. However, the abrogation effect of ivacaftor (potentiator) on lumacaftor suggests the requirement of discovering new correctors and potentiators that can cooperate well. Integration screening for simultaneously identifying combinations of correctors (particularly NBD1 stabilizer) and potentiators should provide an alternative strategy. A recently reported natural product fraction library may be useful for the integration screening.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Design; Humans; Mutation; Patents as Topic; Quinolones

Topics: Adult; Aminophenols; Child; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones; Respiratory Function Tests

Recently, a significant number of additional key medications have become licensed in Europe for the treatment of patients with cystic fibrosis (CF), including a number of inhaled antibiotics, such as nebulised aztreonam and dry powder versions of colistin and tobramycin for inhalation; dry powder inhaled mannitol, an agent to improve airway hydration and aid airway clearance; and ivacaftor, an oral therapy that directly acts on dysfunctional CFTR to correct the basic defect encountered in CF patients with the G551D CF gene mutation. The marked success of ivacaftor both in clinical trials and in post-licensing evaluation studies in treating patients with G551D and other gating mutations has greatly encouraged the ongoing development of similar therapies that can directly target the underlying cause of CF. Other therapies, including a number of anti-infectives, anti-inflammatories and replacement pancreatic enzymes, are currently undergoing clinical studies. This article reviews those treatments that have been recently licensed for CF and highlights some of the exciting emerging therapies presently under evaluation in clinical trials. In addition, it discusses some of the potential challenges being encountered by research and clinical teams in developing and delivering treatments for this condition.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Design; Humans; Mutation; Quinolones

Cystic Fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene resulting in abnormal protein function. Recent advances of targeted molecular therapies and high throughput screening have resulted in multiple drug therapies that target many important mutations in the CFTR protein. In this review, we provide the latest results and current progress of CFTR modulators for the treatment of cystic fibrosis, focusing on potentiators of CFTR channel gating and Phe508del processing correctors for the Phe508del CFTR mutation. Special emphasis is placed on the molecular basis underlying these new therapies and emerging results from the latest clinical trials. The future directions for augmenting the rescue of Phe508del with CFTR modulators are also emphasized.

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Design; Homozygote; Humans; Mice; Molecular Targeted Therapy; Mutation; Protein Folding; Quinolones

Therapy for cystic fibrosis (CF) has progressed during the past several decades. Much of this progress is because of advances in genetic testing to precisely identify the underlying cause of CF transmembrane regulator (CFTR) dysfunction. However, with more than 1900 mutations that can produce a faulty CFTR, the management of CF can remain a challenge. Several innovative drugs recently approved by the Food and Drug Administration, termed genetic modulators, target the underlying disease by modulating the CFTR defect. This review provides physicians with an established simple classification scheme to guide their use of these drugs. The treatment challenge of 1900 CFTR mutations has been simplified into 6 physiologic classes, each paired with an available therapy to offer patients the most functional improvement. Drug therapy monitoring, adverse effects, and indications for discontinuation must also be considered.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; DNA Mutational Analysis; Humans; Mutation; Oxadiazoles; Quinolones

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Markers; Humans; Mucociliary Clearance; Quinolones; Treatment Outcome

Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status. In 2012, a new era of precision medicine in cystic fibrosis therapeutics began with the licensing of a small molecule, ivacaftor, which successfully targets the underlying defect and improves CFTR function in a subgroup of patients in a genotype-specific manner. Here, we review the three main targeted approaches that have been adopted to improve CFTR function: potentiators, which recover the function of CFTR at the apical surface of epithelial cells that is disrupted in class III and IV genetic mutations; correctors, which improve intracellular processing of CFTR, increasing surface expression, in class II mutations; and production correctors or read-through agents, which promote transcription of CFTR in class I mutations. The further development of such approaches offers great promise for future therapeutic strategies in cystic fibrosis.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Molecular Targeted Therapy; Quinolones

Cystic fibrosis (CF) is a genetic disorder that causes multiorgan morbidity and premature death, most commonly from pulmonary dysfunction. Mutations in the CF transmembrane conductance regulator (CFTR) gene, of which almost 2000 have been described, result in a dysfunctional CFTR protein. This protein is an adenosine triphosphate binding anion channel, present primarily at the surface of epithelial cells. Loss of function mutations in this anion channel result in decreased or absent chloride/bicarbonate transport. The subsequent abnormal salt and water transport at epithelial cell surfaces leads to thickened secretions, and infection or inflammation in affected organs. In the last 20 years, therapeutics have been developed to treat the signs and symptoms of CF. However, in 2012, the small molecule drug, ivacaftor, became the first approved therapy that addresses the basic defect in CF. Ivacaftor is a potentiator of CFTR channels defective in their chloride/bicarbonate gating/conductance, but present at the epithelial cell surface. It is only approved for 10 mutations carried by approximately 7% of the population of patients with CF. F508del is the most common CFTR mutation, present in homozygosity in approximately 50% of patients with CF. The F508del mutation results in multiple CFTR channel defects that require both correction (stabilization of misfolded CFTR and trafficking to the epithelial cell membrane) and potentiation. This article reviews the in vitro and clinical trial data for the potential use of the potentiator, ivacaftor, and the corrector, lumacaftor, in patients with CF.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Mutational Analysis; Drug Combinations; Genetic Predisposition to Disease; Humans; Lung; Mutation; Patient Selection; Phenotype; Precision Medicine; Quinolones; Respiratory System Agents; Treatment Outcome

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Carrier Screening; Humans; Molecular Targeted Therapy; Mutation; Quinolones

Cystic fibrosis is a single gene, autosomal recessive disorder, in which more than 1,900 mutations grouped into 6 classes have been described. It is an example a disease that could be well placed to benefit from personalised medicine. There are currently 2 very different approaches that aim to correct the basic defect: gene therapy, aimed at correcting the genetic alteration, and therapy aimed at correcting the defect in the CFTR protein. The latter is beginning to show promising results, with several molecules under development. Ataluren (PTC124) is a molecule designed to make the ribosomes become less sensitive to the premature stop codons responsible for class i mutations. Lumacaftor (VX-809) is a CFTR corrector directed at class ii mutations, among which Phe508del is the most frequent, with encouraging results. Ivacaftor (VX-770) is a potentiator, the only one marketed to date, which has shown good efficacy for the class iii mutation Gly551Asp in children over the age of 6 and adults. These drugs, or a combination of them, are currently undergoing various clinical trials for other less common genetic mutations. In the last 5 years, CFTR has been designated as a therapeutic target. Ivacaftor is the first drug to treat the basic defect in cystic fibrosis, but only provides a response in a small number of patients. New drugs capable of restoring the CFTR protein damaged by the most common mutations are required.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Molecular Targeted Therapy; Mutation; Quinolones

We present the recent therapeutic advances in the cystic fibrosis care. It concerns improvements in symptomatic treatment with the development of dry powder inhaled antibiotics that improved quality of life, and innovative treatments namely the modulators of the cystic fibrosis transmembrane protein conductance regulator (CFTR), molecules which act specifically at the level of the defective mechanisms implied in the disease. The life expectancy of cystic fibrosis patients born after 2000, is estimated now to be about 50 years. This improvement of survival was obtained with the organization of the care within the specialized centers for cystic fibrosis (Centre de ressource et de compétences de la mucoviscidose) and remains still based on heavy symptomatic treatments. Dry powder inhaled antibiotics constitute a significant time saving for patients to whom all the care can achieve two hours daily. Since 2012, the modulators of CFTR, molecules allowing a pharmacological approach targeted according to the type of the mutations, allows a more specific approach of the disease. Ivacaftor (Kalydeco(®)) which potentialises the function of the CFTR protein expressed on the cellular surface is now available for patients with the G551D mutation. Lumacaftor is going to be tested in association with ivacaftor in patients with the F508del mutation, that is present in at least 75% of the patients. The ataluren which allows the production of a functional protein CFTR in patients with a no sense mutation is the third representing of this new therapeutic class. We presently have numerous symptomatic treatments for the cystic fibrosis care. The development of CFTR modulators, today available to a restricted number of patients treated with ivacaftor represents a very promising therapeutic avenue. It will represent probably the first step to a personalized treatment according to CFTR genotype.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Oxadiazoles; Quinolones

Ivacaftor (Kalydeco(®), Vertex Pharmaceuticals) is the first of a new class of drugs that target the underlying protein defect in cystic fibrosis (CF). It is aimed at patients with the G551D (glycine to aspartate change in nucleotide 1784 in exon 11) mutation; 5.7% of patients with CF in the UK have this mutation.. To review the clinical effectiveness and cost-effectiveness of ivacaftor for the treatment of CF in patients aged ≥ 6 years who have the G551D mutation.. Ten databases, including MEDLINE and EMBASE, were searched from inception to July 2012. Studies that evaluated ivacaftor for the treatment of adults and children (≥ 6 years) with at least one G551D mutation were eligible. There were insufficient data to conduct a formal meta-analysis. The manufacturer of ivacaftor, Vertex Pharmaceuticals, submitted a deterministic patient-level simulation model for the assessment of the lifetime cost-effectiveness of ivacaftor. We modified the model where values were not UK-specific or not recent, or where better estimates could be found. The only change to the model structure was the addition of lung transplantations. We changed utility values, annual decline in percentage predicted forced expiratory volume in 1 second (FEV1), and the baseline exacerbation rate, and used data from the CF Registry to estimate the relation between costs, age and percentage predicted FEV1. Estimates of treatment effect of ivacaftor came from the clinical effectiveness review. We modelled three scenarios for the longer-term effects of ivacaftor. We also modelled an 'optimistic' scenario for patients aged < 12 years with little lung damage. We conducted a budget impact analysis to estimate the total cost to the NHS of introducing ivacaftor in England.. Three studies were included: a randomised controlled trial (RCT) in adults (n = 167) (≥ 12 years), a RCT in children (n = 26) (6-11 years), and an open-label extension study of the two RCTs. Both RCTs reported significantly greater changes from baseline in all measures of lung function in patients receiving ivacaftor than in those receiving placebo. The mean difference in change in percentage predicted FEV1 was 10.5 [95% confidence interval (CI) 8.5 to 12.5] percentage points in the adults' study and 10.0 (95% CI 4.5 to 15.5) percentage points in the children's study at 48 weeks. Improvements in lung function were seen across all subgroups investigated (age, sex, study region and lung function). There were significantly greater improvements in the ivacaftor group than in the placebo group for all outcomes assessed (exacerbations, quality of life, sweat chloride and weight) with the exception of quality of life in children. Improvements were maintained in the open-label trial. Adverse events were mainly minor and comparable across treatment groups. Both RCTs reported more withdrawals in the placebo group than in the ivacaftor group. The incremental cost-effectiveness ratio varied between £335,000 and £1,274,000 per quality-adjusted life-year gained. The total additional lifetime costs for all eligible CF patients in England ranged from £438M to £479M; the lifetime cost for standard care only was £72M.. The available evidence suggests that ivacaftor is a clinically effective treatment for patients with CF and the G551D mutation; the high cost of ivacaftor may prove an obstacle in the uptake of this treatment. The main priority for further research is the long-term effectiveness of ivacaftor.. This study is registered as PROSPERO CRD42012002516.. The National Institute for Health Research Health Technology Assessment programme.

Topics: Adolescent; Adult; Age Factors; Aminophenols; Child; Cost-Benefit Analysis; Cystic Fibrosis; England; Female; Humans; Lung Transplantation; Male; Models, Economic; Mutation; Quality-Adjusted Life Years; Quinolones; Randomized Controlled Trials as Topic; Respiratory Function Tests; Sex Factors; State Medicine

Topics: Aminophenols; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bronchodilator Agents; Cystic Fibrosis; Enzyme Replacement Therapy; Expectorants; Humans; Quinolones; Vitamins

Among the new molecular entities approved by the EMEA and the FDA in 2012, four have caught our attention for their significant contribution to the health of patient. First of all, among the notable 2012 approvals, is ivacaftor or Kalydeco®. This is the first treatment that targets one of the gene defects that is underlying cause of cystic fibrosis. This is also an example of the promise of personalized medicine. The benefits with bedaquiline or Sirturo® are its ability to likely provide clinically relevant activity as part of multi-drug regimens against tuberculosis (TB) based on clinical data in multi-drug resistant tuberculosis (MDR TB) patients, who were defined as being at least resistant against the two major tuberculostatic medicines (isaoniazide and rifampicine). On December 2012 and then, on December 2013, the FDA and European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended granting a conditional marketing authorization for Sirturo® (bedaquiline), respectively, for use as part of a combination therapy for pulmonary multidrug resistant tuberculosis in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. Amyvid®, which is a solution for injection that contains the active substance florbetapir (18F), is a radiopharmaceutical that emits low amounts of radiation and works by targeting and attaching to β-amyloid plaques in the brain. This enables doctors to know whether or not significant amount of plaques are present in order to know if the patient is unlikely or not, to have Alzheimer's disease. Finally, the last topics addresses the propranolol, which is a beta-blocker, used alone or together with other medicines to treat high blood pressure. Propranolol is gaining a new lease of life for treating infantile hemangioma.

Topics: Adrenergic beta-Antagonists; Adult; Alzheimer Disease; Aminophenols; Aniline Compounds; Antitubercular Agents; Cystic Fibrosis; Diarylquinolines; Drug Resistance, Bacterial; Ethylene Glycols; Hemangioma; Humans; Infant; Propranolol; Quinolones; Radionuclide Imaging; Radiopharmaceuticals; Tuberculosis; Tuberculosis, Multidrug-Resistant

Ivacaftor is an oral bioavailable potentiator of the cystic fibrosis transmembrane conductance regulator protein. It is the first therapeutic agent that has been registered for clinical use which targets the basic defect in people with cystic fibrosis who carry a G551D mutation or other rarer specific gating mutations. Clinical trials have shown consistent and impressive clinical benefit that appears to be sustained over time in people with cystic fibrosis who carry a G551D mutation and similar benefits have been seen in those who carry rarer gating mutations. Ivacaftor is orally administered twice daily with a dose that does not vary between children aged 6 years through to adult life in patients with G551D. It appears to be well tolerated although there are potential interactions with drugs that are metabolised through CYPP450 CYP3A. Ivacaftor is also currently being trialled in combination with correctors for patients with the most common mutation of cystic fibrosis transmembrane conductance regulator the F508del mutation.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones

Significant improvements in the treatment of cystic fibrosis over the last few decades have altered this lethal disease in children to a multisystem disorder with survival into adult life now common. In most developed countries the numbers of adult cystic fibrosis patients outnumber children. This is mainly due to improvements in care during early life. The principal cause of morbidity and mortality is pulmonary disease, and so the focus of new treatments has targeted the lungs. Identification of the underlying gene defect in the cystic fibrosis transmembrane conductance regulator has ushered in a new era in cystic fibrosis research, with prospects of a cure. In this article, we review the most exciting recent advances that correct defects in cellular processing, chloride channel function and gene therapy.

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Humans; Quinolones

Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

Topics: Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Discovery; Genetic Predisposition to Disease; Genetic Therapy; High-Throughput Screening Assays; Humans; Molecular Targeted Therapy; Mutation; Phenotype; Precision Medicine; Prognosis; Protein Conformation; Quinolones; Respiratory System Agents; Structure-Activity Relationship

Cystic fibrosis (CF) is an autosomal recessive lethal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for CFTR, an epithelial cell-surface expressed protein responsible for the transport of chloride (Cl(-)). Gating mutations associated with defective conductance can be modulated by CFTR potentiators. Ivacaftor is a CFTR potentiator approved for the treatment of CF patients >6 yrs of age with at least one copy of the G551D-CFTR mutation. Herein, the clinical trial development programme for ivacaftor will be reviewed, including two pivotal studies in adolescents/adults and in children. These studies report sustained improvements in lung function and sweat chloride concentrations, and a reduction in pulmonary exacerbations over a 48-week treatment period. In the era of personalised medicine, ivacaftor offers an effective and well-tolerated treatment for the clinical management of CF patients with the G551D mutation. A long-term, open-label study will report the effects of ivacaftor over a further 48 weeks.

Topics: Adolescent; Adult; Aminophenols; Child; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Predisposition to Disease; Humans; Lung; Molecular Targeted Therapy; Mutation; Patient Selection; Phenotype; Precision Medicine; Quinolones; Respiratory System Agents; Sweat; Time Factors; Treatment Outcome; Young Adult

The field of cystic fibrosis (CF) is changing dramatically as the scientific knowledge accumulated since the cloning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is being translated into effective therapies to correct the basic defect and provide better disease models and in-depth understanding of the basic mechanisms of disease.. This review focuses on three main aspects of the recent advances in the field: understanding the lung disease pathophysiology (in particular, the early events that condition its onset), better definition of the complex microbiology of the CF airway, and therapeutic developments. Although the most recently developed therapies, whether approved or under study, do not constitute a definitive cure, the benefit to patients is already becoming clearly apparent.. As the field continues to change rapidly and new therapies are being identified, CF has become a paradigm for the application of concepts such as translational medicine, genomic medicine, and personalized care, with measurable clinical benefit for the patients affected by this disease.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genomics; Humans; Molecular Targeted Therapy; Mutation; Quinolones; Respiratory Tract Infections

Cystic fibrosis is an autosomal recessive genetic disease due to mutations in the (cystic fibrosis transmembrane conductance regulator) CFTR gene. The CFTR protein is a chloride channel expressed at the surface of several epithelial cells. Defective function of the CFTR protein leads to a severe disease in which lung disease is the leading cause of death. Current treatments are symptomatic. Nevertheless, with specialist and holistic care in dedicated cystic fibrosis centres, the median survival has improved. But the average age of death remains 29 years. Innovative molecules aiming to correct the CFTR protein itself are under development. These will be personalised treatments depending on the genotype or the type of CFTR dysfunction. The first molecule, ivacaftor, has just been approved in Europe and the USA. Adults and children treated with ivacaftor in clinical trials had a 10% improvement in FEV1 that was maintained for more than a year. Although at present ivacaftor is approved for only a small percentage of patients, the therapeutic strategy of correcting CFTR protein has been proved a valid approach. Other molecules targeting other defects in the CFTR protein are under evaluation.

Topics: Adult; Aminophenols; Animals; Combined Modality Therapy; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Humans; Molecular Targeted Therapy; Quinolones; Therapies, Investigational

Cystic fibrosis (CF), a severe genetic disease, is caused by mutations that alter the structure and function of CFTR, a plasma membrane channel permeable to chloride and bicarbonate. Defective anion transport in CF irreversibly damages the lungs, pancreas, liver, and other organs. CF mutations cause loss of CFTR function in multiple ways. In particular, class 3 mutations such as p.Gly551Asp strongly decrease the time spent by CFTR in the open state (gating defect). Instead, class 2 mutations impair the maturation of CFTR protein and its transport from the endoplasmic reticulum to the plasma membrane (trafficking defect). The deletion of phenylalanine 508 (p.Phe508del), the most frequent mutation among CF patients (70-90 %), destabilizes the CFTR protein, thus causing both a trafficking and a gating defect. These two defects can be overcome with drug-like molecules generically called correctors and potentiators, respectively. The potentiator Kalydeco™ (also known as Ivacaftor or VX-770), developed by Vertex Pharmaceuticals, has been recently approved by the US FDA and the European Medicines Agency (EMA) for the treatment of CF patients carrying at least one CFTR allele with the p.Gly551Asp mutation (2-5 % of all patients). In contrast, the corrector VX-809, which significantly improves p.Phe508del-CFTR trafficking in vitro, is still under study in clinical trials. Because of multiple defects caused by the p.Phe508del mutation, it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action. This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Molecular Targeted Therapy; Mutation; Quinolones

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia. Nearly 2000 mutations in the CFTR gene have been identified that cause disease by impairing its translation, cellular processing, and/or chloride channel gating. The fundamental premise of CFTR corrector and potentiator therapy for CF is that addressing the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will result in clinical benefit by addressing the basic defect underlying CF. Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP-dependent chloride channel activity to mutant CFTRs at the cell surface. This article reviews the discovery of CFTR potentiators and correctors, what is known regarding their mechanistic basis, and encouraging results achieved in clinical testing.

Topics: Aminophenols; Aminopyridines; Bayes Theorem; Benzodioxoles; Chloride Channels; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Discovery; Humans; Mutation; Quinolones; Randomized Controlled Trials as Topic; Technology, Pharmaceutical

Pharmacogenomics offers an entrance in the field of personalized medicine. This form of adapted therapy is going to be the future concerning the reduction of side effects and efficacy of the treatment of severe diseases. Vemurafenib and Ivacaftor are the first FDA approved drugs specially addressing mutated proteins. Both substances showed promising results in all clinical trials combined with relatively mild side effects by vemurafenib and placebo-like side effects by ivacaftor. The efficacy in addressing the specific mutation of each compound was confirmed in preclinical and clinical development.

Topics: Aminophenols; Animals; Chemistry, Pharmaceutical; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cystic Fibrosis; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Indoles; Mitogen-Activated Protein Kinases; Precision Medicine; Quinolones; Sulfonamides; Vemurafenib

Cystic fibrosis (CF) is a recessive disorder caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. CFTR protein is a chloride and bicarbonate channel that is critical for normal epithelial ion transport and hydration of epithelial surfaces. Current CF care is supportive, but recent breakthroughs have occurred with the advent of novel therapeutic strategies that assist the function of mutant CFTR proteins. The development and key clinical trial results of ivacaftor, a small molecule that targets gating defects in disease-causing CFTR mutations including G551D CFTR, are summarized in this review. The G551D mutation is reasonably common in the CF patient population and produces a CFTR protein that localizes normally to the plasma membrane, but fails to open in response to cellular cues. Ivacaftor treatment produces dramatic improvements in lung function, weight, lung disease stability, patient-reported outcomes, and CFTR biomarkers in patients with CF harboring the G551D CFTR mutation compared with placebo controls and patients with two copies of the common F508del CFTR mutation. The unprecedented success of ivacaftor treatment for the G551D CF patient population has generated excitement in the CF care community regarding the expansion of its use to other CF patient populations with primary or secondary gating defects.

Topics: Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Predisposition to Disease; Humans; Lung; Molecular Targeted Therapy; Mutation; Phenotype; Quinolones; Respiratory System Agents; Treatment Outcome

Ivacaftor (Kalydeco™) is a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first drug that treats an underlying cause of cystic fibrosis to be licensed for use. Ivacaftor increases the open probability (i.e. gating) of CFTR channels with the G551D mutation, thus enhancing chloride transport, and is indicated in a number of countries for the treatment of cystic fibrosis in patients aged ≥6 years who carry this mutation. This review focuses on pharmacological, clinical efficacy and tolerability data relevant to the use of ivacaftor in this indication. In two 48-week, double-blind, phase III trials in patients aged ≥12 (STRIVE) or 6-11 (ENVISION) years with cystic fibrosis and the G551D mutation, oral ivacaftor 150 mg every 12 h significantly improved lung function relative to placebo, when used in combination with standard care. Significant improvements in pulmonary exacerbation risk (in STRIVE) as well as bodyweight and some aspects of health-related quality of life (both studies) were also seen with the drug versus placebo. Moreover, the beneficial effects of ivacaftor on parameters such as lung function and bodyweight were maintained over up to 96 weeks of treatment in an ongoing open-label extension of these studies. Ivacaftor was generally well tolerated, with headache, oropharyngeal pain, upper respiratory tract infection and nasal congestion being among the most common adverse events. Thus, ivacaftor expands the current treatment options for patients with cystic fibrosis who have the G551D mutation. Its potential for use in patients with other CFTR mutations is also of interest.

Topics: Aminophenols; Clinical Trials, Phase III as Topic; Cystic Fibrosis; Double-Blind Method; Humans; Quinolones

Cystic fibrosis (CF) is a life-limiting, multisystem disease characterized by thick viscous secretions leading to recurrent lung infections, bronchiectasis, and progressive deterioration in lung function. CF is caused by loss or dysfunction of the CF transmembrane conductance regulator (CFTR) protein which is responsible for transepithelial chloride and water transport. Improved understanding of CFTR protein dysfunction has allowed the development of mutation-specific small-molecule compounds which directly target the underlying CFTR defect. Ivacaftor is the first licensed small-molecule compound for CF patients which targets the CFTR gating mutation Gly551Asp (previously termed G551D) and has the potential to be truly disease-modifying. Ivacaftor is an oral medication given twice daily and has shown benefit in terms of an increase in lung function, decreased sweat chloride, weight gain, improvement in patient-reported quality of life, and reduction in number of respiratory exacerbations in clinical trials. Although ivacaftor is currently only licensed for use in approximately 5% of the CF population (those who have at least one Gly551Asp mutation), the developmental pathway established by ivacaftor paves the way for other CFTR modulators that may benefit many more patients. In particular, a CFTR modulator for those with the Phe508del deletion (previously ∆F508) would allow 90% of the CF population to benefit from disease-modifying treatment.

Topics: Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Design; Humans; Molecular Targeted Therapy; Mutation; Quality of Life; Quinolones

Recent therapies directed at proximal targets within cystic fibrosis (CF) pathophysiology hold potential to modulate disease. This review highlights recent clinical trials and future therapies focused on these early steps of disease.. Recent approval of a CF transmembrane conductance regulator (CFTR) protein modulator, ivacaftor (Kalydeco), has ignited a wave of investigations for other modulators directed at CFTR mutation classes. Gene replacement therapy continues to be pursued at a slower pace in early phase clinical trials. Airway surface liquid strategies such as dry-powder mannitol and alternate ion channel regulation are discussed as genotype-independent methods of early modulation.. The breadth of therapies for early targets of CF holds considerable hope to modify the natural history of this disease. Ongoing focus to develop novel markers of early disease state is paramount. The progress of drug development requires concurrent attention on a spectrum of targets to achieve maximal impact.

Topics: Aminophenols; Biomarkers; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genetic Markers; Genetic Therapy; Humans; Male; Mannitol; Mutation; Phenotype; Quinolones; Respiratory System Agents; Saline Solution, Hypertonic

Cystic fibrosis is caused by dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial chloride channel that has a key role in maintaining homoeostasis of the airway surface liquid layer in the lungs. More than 1900 CFTR mutations that might result in a disease phenotype have been identified; these can be grouped into classes on the basis of their effect on CFTR protein production, trafficking, function, and stability. In the past 2 years, landmark clinical trials have shown that correction of CFTR function leads to substantial clinical benefit for individuals with cystic fibrosis. These findings are ushering in a new era of cystic fibrosis treatments designed to correct the underlying CFTR defect caused by different mutation classes. With analysis of continuing trials and available patient registries, here we assess mutation types and the number and geographical distribution of patients who are likely to benefit from CFTR-correcting treatment.

Topics: Aminophenols; Biological Transport; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forecasting; Humans; Mutation; Oxadiazoles; Precision Medicine; Protein Biosynthesis; Quinolones; Respiratory System Agents; Treatment Outcome

A great deal of excitement and hope has followed the successful trials and US Food and Drug Administration approval of the drug ivacaftor (Kalydeco), the first therapy available that targets the underlying defect that causes cystic fibrosis (CF). Although this drug has currently demonstrated a clinical benefit for a small minority of the CF population, the developmental pathway established by ivacaftor paves the way for other CF transmembrane conductance regulator (CFTR) modulators that may benefit many more patients. In addition to investigating CFTR modulators, researchers are actively developing numerous other innovative CF therapies. In this review, we use the catalog of treatments currently under evaluation with the support of the Cystic Fibrosis Foundation, known as the Cystic Fibrosis Foundation Therapeutics Pipeline, as a platform to discuss the variety of candidate treatments for CF lung disease that promise to improve CF care. Many of these approaches target the individual components of the relentless cycle of airway obstruction, inflammation, and infection characteristic of lung disease in CF, whereas others are aimed directly at the gene defect, or the resulting dysfunctional protein, that instigates this cycle. We discuss how new findings from the laboratory have informed not only the development of novel therapeutics, but also the rationales for their use and the outcomes used to measure their effects. By reviewing the breadth of candidate treatments currently in development, as well as the recent progress in CF therapies reflected by the evolution of the therapeutics pipeline over the past few years, we hope to build upon the optimism and anticipation generated by the recent success of Kalydeco.

Topics: Aminophenols; Anti-Bacterial Agents; Anti-Inflammatory Agents; Cystic Fibrosis; Drug Therapy; Humans; Quinolones

Topics: Aminophenols; Clinical Trials, Phase II as Topic; Codon, Terminator; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drugs, Investigational; Female; Forecasting; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Ion Transport; Male; Molecular Targeted Therapy; Mutation; Needs Assessment; Quinolones; Randomized Controlled Trials as Topic; Sodium Channels

Although affecting only 4-5% of those with cystic fibrosis (CF), the G551D-CFTR mutation is the target of the recently approved 'orphan drug', ivacaftor. The promise of such genomically guided therapies heralds a new era in the management of CF. A phase 3 trial demonstrated significant improvements in forced expiratory volume in 1 s (FEV(1)) from baseline, average weight gain, concentration in sweat chloride and reductions in pulmonary exacerbations [Ramsey, B.W., et al. A CFTR potentiator in patients with CF and the G551D mutation. N. Engl. J. Med., 2011. 365: 1663-1672.)]. Ivacaftor is among a group of recently approved, novel, mutation guided 'orphan drug' therapies that have established clinical benefits within their respective disease categories. They do not, however, offer a cure. Pharmaceutical and biotech companies have leveraged the incentivized benefits of the Orphan Drug Act to develop more of these drugs for orphan disorders affecting populations of <200 000 patients. With marked clinical efficacy via DNA sequence guidance, these drugs have also set a precedent in terms of the substantial annual costs and if this trend continues, such expenditures may become unsustainable. This paper explores the genomic pathophysiology of CF and how therapies such as ivacaftor provide benefit to those with the disease but at a considerably elevated price point.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Mutation; Orphan Drug Production; Quinolones

Understanding the molecular and cellular processes responsible for the development of lung disease in cystic fibrosis (CF) has led to evaluation of a broad range of new therapies within multiple therapeutic classes. For these reasons, clinical research in CF is accelerating, as new agents progress through the early stages of drug development, move into clinical trials and are offered to study patients. This review focuses on the most notable clinical trials of pulmonary therapies reported in the last year.. Progress in gene therapy remains slow, but is offset by significant gains in development of cystic fibrosis transmembrane conductance regulator modulators and drugs that restore airway surface liquid. Although addressing downstream consequences of CF lung pathophysiology, the substantial burden of chronic infection makes both antibiotic and anti-inflammatory therapies a critical component of treatment, such that additional agents to manage sustained inflammation and resistant microorganisms along with improved delivery systems are needed.. The pace of drug development in CF will require an expanding pool of patients willing to participate in clinical research to test new agents. Although these potential therapies will likely improve quality of life for people with CF and contribute to improved survival, it will be important to avoid adding excessively to the already high burden of treatment. If the demands on patients' time continue to grow, a decrease in adherence to effective therapies may paradoxically lead to worse outcomes and negate the benefits new treatments bring.

Topics: Aminophenols; Aminopyridines; Anti-Infective Agents; Anti-Inflammatory Agents; Benzodioxoles; Biomarkers; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Markers; Genetic Therapy; Humans; Mutation; Oxadiazoles; Quinolones; Respiratory System Agents; Saline Solution, Hypertonic

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F) in two pivotal Phase 3 trials, significantly improving percentage predicted forced expiratory volume in 1 second, Cystic Fibrosis Questionnaire-Revised, Respiratory Domain (CFQ-R RD) scores, and sweat chloride concentration. Here, we analyzed the 11 non-respiratory domains (non-RDs) of the CFQ-R, which assess general health-related quality of life (i.e., Physical Functioning, Role Functioning, Vitality, Health Perceptions, Emotional Functioning, and Social Functioning) and quality of life impacted by CF (i.e., Body Image, Eating Problems, Treatment Burden, Weight, and Digestive Symptoms), for participants in these two Phase 3 trials. ELX/TEZ/IVA treatment led to higher scores in all CFQ-R non-RDs, with improvements in most domains compared with control treatments. These findings demonstrate that ELX/TEZ/IVA improves a range of CF-specific symptoms and general functioning and well-being.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quality of Life

Study 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks.. Part B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV. 464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A.. TEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation

Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation.. We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV. The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population.. Vertex Pharmaceuticals.

Topics: Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quality of Life; Quinolones

Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study.. This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index. One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQ‑R respiratory domain score, and BMI observed from parent study baseline to Week 96.. Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.

Topics: Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Homozygote; Humans; Indoles; Mutation; Quinolones

Elexacaftor/tezacaftor/ivacaftor is highly effective in treating people with cystic fibrosis (pwCF) who have ≥ 1 responsive mutation. Liver disease occurs in approximately 10%-20% of pwCF. The objective of this study was to assess the safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor in people with moderate hepatic impairment, which is necessary to inform on its use and guide dosing recommendations.. The safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor were evaluated in subjects without CF with moderate hepatic impairment versus matched healthy controls. Twenty-two subjects (11 with moderate hepatic impairment and 11 healthy subjects) received half the standard adult daily dose of elexacaftor/tezacaftor/ivacaftor (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 150 mg) orally for 10 days.. Elexacaftor/tezacaftor/ivacaftor was safe and well tolerated in subjects with moderate hepatic impairment and healthy controls. On day 10, the mean values of the area under the curve during the dosing interval (AUC. A dose reduction of elexacaftor/tezacaftor/ivacaftor is warranted in people with moderate hepatic impairment. (Trial registry number 2018-002570-40; registered 2 July 2018.).. Elexacaftor/tezacaftor/ivacaftor is a combination product (made up of the three drugs elexacaftor, tezacaftor, and ivacaftor) that can effectively treat cystic fibrosis (CF). About 10%–20% of people with CF have liver disease, and the liver plays an important role in breaking down these drugs. Thus, it is important to understand how liver disease or reduced liver function affects the amounts of these drugs in the body over time. This can help determine how much of the drug (i.e., what dose) people should take.We gave people with reduced liver function and healthy people (with normal liver function) elexacaftor/tezacaftor/ivacaftor for 10 days. We looked at the safety of the combination and measured the amounts of elexacaftor, tezacaftor, and ivacaftor in the body over time.We found that when people with moderately reduced liver function take elexacaftor/tezacaftor/ivacaftor, they have higher amounts of the drugs elexacaftor, tezacaftor, and ivacaftor in their bodies compared with healthy people with normal liver function. These findings mean that people with moderately reduced liver function should take a lower dose of elexacaftor/tezacaftor/ivacaftor.

Topics: Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Liver Diseases

The CFTR modulator tezacaftor/ivacaftor was efficacious and generally safe and well tolerated in Phase 3 studies in participants ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous with a residual function-CFTR mutation (F/F or F/RF respectively). We evaluated tezacaftor/ivacaftor's efficacy and safety over 8 weeks in participants 6 through 11 years of age with these mutations.. Participants were randomized 4:1 to tezacaftor/ivacaftor or a blinding group (placebo for F/F, ivacaftor for F/RF). The primary endpoint was within-group change from baseline in the lung clearance index 2·5 (LCI. Tezacaftor/ivacaftor improved lung function (assessed using LCI) and CFTR function (measured by SwCl concentration) in participants 6 through 11 years of age with F/F or F/RF genotypes. Tezacaftor/ivacaftor was safe and well tolerated; no new safety concerns were identified.

Topics: Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Female; Heterozygote; Homozygote; Humans; Indoles; Male; Mutation; Quinolones; Treatment Outcome

Topics: Aminophenols; Bayes Theorem; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forced Expiratory Volume; Humans; Mutation; Quinolones

In previous work, participants with a G970R mutation in cystic fibrosis transmembrane conductance regulator (CFTR) (c.2908G>C) had numerically lower sweat chloride responses during ivacaftor treatment than participants with other CFTR gating mutations. The objective of this substudy was to characterize the molecular defect of the G970R mutation in vitro and assess the benefit of ivacaftor in participants with this mutation. This substudy assessed sweat chloride, spirometry findings, and nasal potential difference on and off ivacaftor treatment in three participants with a G970R/F508del genotype. Intestinal organoids derived from rectal biopsy specimens were used to assess ivacaftor response ex vivo and conduct messenger RNA splice and protein analyses. No consistent or meaningful trends were observed between on-treatment and off-treatment clinical assessments. Organoids did not respond to ivacaftor in forskolin-induced swelling assays; no mature CFTR protein was detected in Western blots. Organoid RNA analysis demonstrated that 3 novel splice variants were created by G970R-CFTR: exon 17 truncation, exons 13-15 and 17 skipping, and intron 17 retention. Functional and molecular analyses indicated that the c.2908G>C mutation caused a cryptic splicing defect. Organoids lacked an ex vivo response with ivacaftor and supported identification of the mechanism underlying the CFTR defect caused by c.2908G>C. Analysis of CFTR mutations indicated that cryptic splicing was a rare cause of mutation misclassification in engineered cell lines. This substudy used organoids as an alternative in vitro model for mutations, such as cryptic splice mutations that cannot be fully assessed using cDNA expressed in recombinant cell systems.

Topics: Adolescent; Adult; Aminophenols; Biopsy; Cell Line; Cells, Cultured; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Exons; Female; Humans; Intestinal Mucosa; Male; Mutation; Organoids; Precision Medicine; Primary Cell Culture; Quinolones; Rectum; RNA Splicing; Treatment Outcome; Young Adult

The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied.. We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO. Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.

Topics: Adolescent; Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Humans; Male; Oxygen Consumption; Quinolones

In patients with cystic fibrosis (CF) who carry the G551D mutation, treatment with ivacaftor improves lung function and weight; however, short- and long-term impacts on body composition have not been well studied.. Twenty adults with CF carrying the G551D mutation (mean ± standard deviation body mass index [BMI] 23.3 ± 4.3 kg/m. After 28 d of treatment with ivacaftor, weight increased by 1.1 ± 1.3 kg, BMI by 0.4 ± 0.5 kg/m. Small gains were seen in FFM in the first month of ivacaftor treatment. Weight, BMI, and fat-mass gains in the first 6 mo on ivacaftor plateaued by 2.5 y. The metabolic and clinical consequences of weight and fat-mass gains remain to be determined.

Topics: Adult; Aminophenols; Body Composition; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

Topics: Adolescent; Adult; Aminophenols; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Inflammation Mediators; Longitudinal Studies; Male; Middle Aged; Mutation; Nasal Lavage; Nasal Lavage Fluid; Quinolones; Young Adult

Ivacaftor shows benefit in patients with cystic fibrosis (CF) and CFTR mutations associated with residual CF transmembrane conductance regulator (CFTR) function. Here we further assess the effect of ivacaftor in such patients using an N-of-1 study design.. Patients aged ≥12 years with CF with clinical or molecular evidence of residual CFTR function were randomized to 1 of 4 treatment sequences for two 4-week, double-blind crossover cycles (each divided into 2 weeks of ivacaftor treatment and placebo) followed by 8 weeks of open-label ivacaftor treatment. The primary endpoint was absolute change from cycle baseline of percent predicted forced expiratory volume in 1 s (ppFEV. Absolute change (SD) from study baseline in ppFEV. Ivacaftor improved lung function during the double-blind and open-label treatment periods in patients with CF and CFTR mutations associated with residual CFTR function (ClinicalTrials.gov, NCT01685801).

Topics: Adolescent; Aminophenols; Chloride Channel Agonists; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Female; Forced Expiratory Volume; Functional Residual Capacity; Humans; Male; Mutation; Quinolones; Respiratory Function Tests; Treatment Outcome; Young Adult

Lumacaftor/ivacaftor (LUM/IVA) modestly improves lung function following 1 month of treatment but it is unknown if this translates into improvements in exercise endurance and exertional symptoms.. Adult CF participants completed a symptom-limited constant load cycling test with simultaneous assessments of dyspnea and leg discomfort ratings pre- and 1 month post-initiation of LUM/IVA.. Endurance time, exertional dyspnea and leg discomfort ratings at submaximal exercise did not change significantly. There was a significant inverse correlation between changes in leg discomfort and endurance time (r = - 0.88; p = 0.009) following 1-month of LUM/IVA.. Overall, 1-month of LUM/IVA did not increase endurance time or modify exertional dyspnea or leg discomfort ratings. However, individuals who experienced a reduction in leg discomfort following LUM/IVA had an improvement in endurance time. Future studies with a larger sample size are needed to verify these findings and to assess the long-term effects of LUM/IVA on exercise outcomes.. ClinicalTrials.gov Identifier: NCT02821130. Registered July 1, 2016.

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Drug Combinations; Exercise Test; Female; Forced Expiratory Volume; Humans; Male; Physical Exertion; Pulmonary Ventilation; Quinolones; Treatment Outcome; Young Adult

The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations.. In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids.. A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma.. We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed.

Topics: Adolescent; Adult; Aminophenols; Child; Chloride Channel Agonists; Curcumin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genistein; Humans; Male; Organoids; Quinolones

Tezacaftor/ivacaftor is a CFTR modulator approved to treat people with cystic fibrosis (pwCF) who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function mutation (F/RF). This randomized, double-blind, placebo-controlled Phase 3 study evaluated the efficacy, safety, tolerability, and pharmacokinetics (PK) of tezacaftor/ivacaftor in participants ≥12 years of age heterozygous for the F508del-CFTR mutation and a minimal function mutation (F/MF), which produces no CFTR protein or a protein unresponsive to tezacaftor/ivacaftor in vitro.. Tezacaftor/ivacaftor did not show a clinically meaningful benefit in participants with F/MF genotypes but was generally safe and well tolerated, consistent with the safety profile reported in other Phase 3 studies (NCT02516410).

Topics: Adult; Alleles; Aminophenols; Benzodioxoles; Body Mass Index; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Combinations; Female; Genotype; Humans; Indoles; Male; Quinolones; Respiratory Function Tests

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.. This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV. Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.. Vertex Pharmaceuticals.

Topics: Adolescent; Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indoles; Male; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Sweat

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del. We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV. A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV. Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Genotype; Humans; Indoles; Male; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Sweat; Young Adult

The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years.. In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight <14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132.. The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24.. Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of disease.. Vertex Pharmaceuticals Incorporated.

Topics: Age Factors; Aminophenols; Aminopyridines; Benzodioxoles; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Female; Homozygote; Humans; Male; Quinolones

KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI.. Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function.. All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters.. Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

Topics: Aminophenols; Body Mass Index; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Ion Channel Gating; Liver Function Tests; Male; Pancreas; Quinolones; Sodium Chloride; Sweat; Transaminases; Treatment Outcome; Weight Gain

Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation.. Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms.. Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects.. GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators.. Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523.

Topics: Administration, Oral; Adult; Aminophenols; Benzoates; Benzopyrans; Biological Availability; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Male; Mutation; Quinolones; Respiratory Function Tests; Sweat; Treatment Outcome

Investigation of novel cystic fibrosis transmembrane conductance regulator (CFTR) potentiators, such as GLPG1837, for CF patients with gating mutations is challenging as trials require patients to withhold ivacaftor, the current standard of care. This study explored the feasibility of such a study and the impact of one-week ivacaftor withdrawal.. This open-label, single-arm study aimed to enrol 32 adults ≥18 years of age with CF and at least one p.Gly551Asp (G551D) mutation. Patients received three increasing GLPG1837 dosages twice-daily for two 7-day and one 14-day period following a one-week ivacaftor washout. The primary outcome was safety; secondary outcomes were changes in sweat chloride concentration, spirometry outcomes, and pharmacokinetics.. Twenty-six patients enrolled; 24 completed the study. Adverse events were reported by 53.8-76.9% of patients (dosage-dependent), with respiratory adverse events most common. Mean sweat chloride concentrations decreased from 97.7 mmol/L (baseline) to 68.7 mmol/L (end of GLPG1837 treatment). In ivacaftor-pre-treated patients, mean sweat chloride concentrations rose from 42.5 mmol/L at screening to 98.5 mmol/L after ivacaftor washout. Levels were decreased following GLPG1837 treatment (to 68.8 mmol/L at treatment end). Percent predicted forced expiratory volume in 1 s declined from 73.3% at screening to 68.5% after ivacaftor washout but returned to screening level at treatment end (73.1%).. Patient willingness to participate in the study suggests that the need for a short period of ivacaftor withdrawal may not be a barrier to development of novel potentiators, such as GLPG1837. A one-week ivacaftor washout was generally well tolerated, but resulted in a decline in lung function, which was reversed with GLPG1837 treatment to pre-washout levels. Combined with the concentration-dependent decrease in sweat chloride concentration, results show that GLPG1837 increases CFTR activity in G551D-CF patients. FUND: This work was supported by Galapagos NV.. NCT02707562; EudraCT 2015-003291-77.

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Drug Monitoring; Drug Substitution; Female; Humans; Male; Pyrans; Pyrazoles; Quinolones; Respiratory Function Tests; Sweat; Treatment Outcome; Withholding Treatment

Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations.. Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV. After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV. Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.

Topics: Aminophenols; Benzodioxoles; Biological Availability; Child; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Indoles; Male; Mutation; Quinolones; Respiratory Function Tests; Sweat; Treatment Outcome

G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised.. Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4month double-blind, placebo-controlled, crossover study of ivacaftor with 28days of active treatment. Sputum microbiota composition was assessed by 16S rRNA gene amplicon sequencing and quantitative PCR at five key time points, along with regular clinical review, respiratory function assessment, and peripheral blood testing.. No significant difference in microbiota composition was observed in subjects following ivacaftor treatment or placebo (PERMANOVA P=0.95, square root ECV=-4.94, 9479 permutations). Microbiota composition variance was significantly greater between subjects, than within subjects over time (P<0.0001, Mann Whitney U test), and an additional within-patient paired assessment of microbiota similarity was therefore performed. Again, change in microbiota composition was not significantly greater during treatment with ivacaftor compared to placebo (Wilcoxon test, P=0.51). A significant change in microbiota composition was however associated with any change in antibiotic exposure, regardless of whether ivacaftor or placebo was administered (P=0.006). In a small, subgroup analysis of subjects whose antibiotic exposure did not change within the study period, a significant reduction in total bacterial load was observed during treatment with ivacaftor (P=0.004, two-tailed paired Student's t-test).. The short-term impact of ivacaftor therapy on sputum microbiota composition in patients with G551D mutations are modest compared to those resulting from antibiotic exposure, and may be masked by changes in antibiotic treatment regimen.

Topics: Adult; Aminophenols; Analysis of Variance; Anti-Bacterial Agents; Chloride Channel Agonists; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Microbiota; Mutation; Outcome Assessment, Health Care; Quinolones; Respiratory System; Sputum

Ivacaftor is generally safe and effective in patients aged 2 years and older who have cystic fibrosis and specific CFTR mutations. We assessed its use in children aged 12 to <24 months.. The ARRIVAL study is a phase 3, single-arm, two-part, multicentre study. Eligible children were aged 12 to <24 months at enrolment and had a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele and could participate in one or both parts of the study. Children received 50 mg (bodyweight 7 to <14 kg) or 75 mg (bodyweight ≥14 to <25 kg) ivacaftor orally every 12 h. In study part A, children received ivacaftor for 3 days plus one morning. In study part B, children received 24 weeks of treatment. Children were enrolled into part A at seven sites in Australia (one site), the UK (one), and the USA (five) and into part B at 13 sites in Australia (two sites), Canada (one), the UK (three), and the USA (seven). Primary endpoints were pharmacokinetics (part A) and safety (parts A and B) in children who received at least one dose of ivacaftor. Secondary endpoints in part B were pharmacokinetics in children who received at least one dose of ivacaftor and absolute change from baseline in sweat chloride concentration. We also explored changes in growth parameters and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02725567.. Children aged 12 to <24 months were enrolled between Aug 25, 2016, and Nov 1, 2017. Seven children were enrolled in part A, of whom five received 50 mg and two received 75 mg ivacaftor. All completed treatment. Of 19 children enrolled in part B, including one from part A, all received 50 mg ivacaftor and 18 completed treatment (one withdrew because of difficulty with blood draws). All children received at least one dose of ivacaftor. Pharmacokinetics indicated exposure was similar to that in children aged 2 to <6 years and adults. No children discontinued because of adverse events or safety findings. In part A, three (43%) of seven children had treatment-emergent adverse events, all of which were mild and deemed not to be or unlikely to be related to ivacaftor. By 24 weeks in part B, treatment-emergent adverse events had been reported in 18 (95%) of 19 children, of which most were mild or moderate and the most frequent was cough (14 [74%] children). Two children in part B had four serious adverse events: one had constipation (possibly related to ivacaftor), distal intestinal obstruction syndrome, and eczema herpeticum, and one had persistent cough, all needing hospital admission. In five (28%) of 18 children aspartate or alanine aminotransferase concentrations rose to more than three times the upper limit of normal (to more than eight times in two children with concurrent infections). At week 24, the mean absolute change from baseline in sweat chloride concentration was -73·5 (SD 17·5) mmol/L. Growth parameters for age were normal at baseline and at week 24. At week 24, concentrations of faecal elastase-1 had increased and concentrations of immunoreactive trypsinogen had decreased from baseline. Mean serum lipase and amylase were raised at baseline and rapidly decreased after treatment was started.. Ivacaftor was generally safe and well tolerated in children aged 12 to <24 months for up to 24 weeks and was associated with rapid and sustained reductions in sweat chloride concentrations. Improvements in biomarkers of pancreatic function suggest that ivacaftor preserves exocrine pancreatic function if started early. The study is continuing in infants younger than 12 months.. Vertex Pharmaceuticals Incorporated.

Topics: Aminophenols; Australia; Canada; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Infant; Male; Mutation; Quinolones; Treatment Outcome; United Kingdom; United States

VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445-tezacaftor-ivacaftor).. We evaluated the effects of VX-445-tezacaftor-ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV. In vitro, VX-445-tezacaftor-ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV. The use of VX-445-tezacaftor-ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471 ; and EudraCT number, 2017-000797-11 .).

Topics: Adolescent; Adult; Alleles; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Genotype; Humans; Indoles; Male; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Sweat; Young Adult

The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis.. We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV. VX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV. Robust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).

Topics: Adolescent; Adult; Alleles; Aminophenols; Benzodioxoles; Cells, Cultured; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Genotype; Humans; Indoles; Male; Mutation; Pyrazoles; Pyrrolidines; Quinolones; Sweat; Young Adult

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Next to progressive airway disease, CF is also associated with intestinal inflammation and dysbiosis. Ivacaftor, a CFTR potentiator, has improved pulmonary and nutritional status but its effects on the intestinal microbiota and inflammation are unclear. Hence, we assessed the changes on the intestinal microbial communities (16S rRNA variable 3 gene region) and inflammatory markers (calprotectin and M2-pyruvate kinase [M2-PK]) in 16 CF individuals (8 children and 8 adults) before and after (median 6.1 months) ivacaftor. Stool calprotectin significantly decreased following ivacaftor (median [IQR]: 154.4 [102.1-284.2] vs. 87.5 [19.5-190.2] mg/kg, P = 0.03). There was a significant increase in Akkermansia with ivacaftor. Increased abundance of Akkermansia was associated with normal stool M2-PK concentrations, and decreased abundances of Enterobacteriaceae correlated with decreased stool calprotectin concentrations. In summary, changes in the gut microbiome and decrease in intestinal inflammation was associated with Ivacaftor treatment among individuals with CF carrying at least one gating CFTR mutation. Thus, CFTR-modifying therapy may adequately improve the aberrant pathophysiology and milieu of the CF gut to favor a more healthy microbiota, which in turn reduces intestinal inflammation.

Topics: Adolescent; Adult; Aminophenols; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dysbiosis; Enterobacteriaceae; Female; Gastrointestinal Microbiome; Humans; Inflammation; Intestinal Diseases; Male; Middle Aged; Mutation; Quinolones

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator ivacaftor (Kalydeco®) improves clinical outcome in G551D cystic fibrosis (CF) patients. Here, we have investigated whether ivacaftor has a clinical impact on non-G551D gating mutations and function of circulating leukocytes as well.. Seven patients were treated with ivacaftor and evaluated at baseline, and at 1-3 and 6 months. Besides clinical and systemic inflammatory parameters, circulating mononuclear cells (MNC) were evaluated for CFTR-dependent chloride efflux by spectrofluorimetry, neutrophils for oxidative burst by cytofluorimetry and HVCN1 mRNA expression by real time PCR.. Ivacaftor determined a significant decrease in sweat chloride concentrations at all time points during treatment. Body mass index (BMI), FEV. In patients with non-G551D mutations, ivacaftor improved both chloride transport in sweat ducts and chloride efflux in MNC, that is, functions directly imputed to CFTR.

Topics: Adolescent; Adult; Aminophenols; C-Reactive Protein; Child; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Leukocytes, Mononuclear; Male; Mutation; Neutrophils; Quinolones; Respiratory Function Tests; Sweat; Young Adult

The aim of this study was to determine the pharmacokinetic interaction between ivacaftor and ritonavir.. A liquid chromatography mass spectrometry (LC-MS) method was developed for the measurement of ivacaftor in plasma. An open-label, sequential, cross-over study was conducted with 12 healthy volunteers. Three pharmacokinetic profiles were assessed for each volunteer: ivacaftor 150 mg alone (study A), ivacaftor 150 mg plus ritonavir 50 mg daily (study B), and ivacaftor 150 mg plus ritonavir 50 mg daily after two weeks of ritonavir 50 mg daily (study C).. Addition of ritonavir 50 mg daily to ivacaftor 150 mg resulted in significant inhibition of the metabolism of ivacaftor. Area under the plasma concentration-time curve from time 0 to infinity (AUC. Ritonavir resulted in significant inhibition of the metabolism of ivacaftor. These data suggest that ritonavir may be used to inhibit the metabolism of ivacaftor in patients with cystic fibrosis (CF). Such an approach may increase the effectiveness of ivacaftor in 'poor responders' by maintaining higher plasma concentrations. It also has the potential to significantly reduce the cost of ivacaftor therapy.

Topics: Adult; Aminophenols; Area Under Curve; Chloride Channel Agonists; Chromatography, Liquid; Cross-Over Studies; Cystic Fibrosis; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Administration Schedule; Drug Interactions; Female; Half-Life; Healthy Volunteers; Humans; Male; Quinolones; Ritonavir; Tandem Mass Spectrometry; Young Adult

G551D, a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, results in impaired chloride channel function in cystic fibrosis (CF) with multiple end-organ manifestations. The effect of ivacaftor, a CFTR-potentiator, on exercise capacity in CF is unknown. Twenty G551D-CF patients were recruited to a single-centre, double-blind, placebo-controlled, 28-day crossover study of ivacaftor. Variables measured included percentage change from baseline (%Δ) of. ClinicalTrials.gov-NCT01937325.

Topics: Adolescent; Adult; Aged; Aminophenols; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Exercise Test; Female; Humans; Lung; Male; Middle Aged; Mutation, Missense; Oxygen; Quality of Life; Quinolones; Young Adult

Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR.. We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor-ivacaftor, ivacaftor monotherapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV. The number of analyzed intervention periods was 162 for tezacaftor-ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV. CFTR modulator therapy with tezacaftor-ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation. (Funded by Vertex Pharmaceuticals and others; EXPAND ClinicalTrials.gov number, NCT02392234 .).

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Child; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Heterozygote; Humans; Indoles; Male; Mutation; Quality of Life; Quinolones; Young Adult

Combination treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators tezacaftor (VX-661) and ivacaftor (VX-770) was designed to target the underlying cause of disease in patients with cystic fibrosis.. In this phase 3, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial, we evaluated combination therapy with tezacaftor and ivacaftor in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. Patients were randomly assigned in a 1:1 ratio to receive either 100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily or matched placebo for 24 weeks. The primary end point was the absolute change in the percentage of the predicted forced expiratory volume in 1 second (FEV. Of the 510 patients who underwent randomization, 509 received tezacaftor-ivacaftor or placebo, and 475 completed 24 weeks of the trial regimen. The mean FEV. The combination of tezacaftor and ivacaftor was efficacious and safe in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. (Funded by Vertex Pharmaceuticals; EVOLVE ClinicalTrials.gov number, NCT02347657 .).

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Body Mass Index; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Homozygote; Humans; Indoles; Male; Mutation; Quality of Life; Quinolones; Young Adult

Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial.. In subjects with G551D at least 12years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48weeks. We explored 1062 pilocarpine sweat test values obtained in 78 placebo patients of the VX08-770-102 trial.. Mean overall sweat chloride value (all patients, all tests, n=1062) was 100.8mmol/L (SD 12.7mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9mmol/L (95% CI 7.4-10.6) and within-subject SD was 8.1mmol/L (95% CI 7.5-8.7). Limits of repeatability for repeat measurements were -19.7 to +21.6mmol/L using values from one arm, and -13.3 to 11.8mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial.. Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter.

Topics: Adolescent; Adult; Aminophenols; Biological Variation, Population; Biomarkers; Child; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Middle Aged; Mutation; Quinolones; Retrospective Studies; Sweat

Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, decreases sweat chloride concentration, and improves pulmonary function in 6% of cystic fibrosis (CF) patients with specific CFTR mutations. Ivacaftor increases chloride transport in many other CFTR mutations in non-human cells, if CFTR is in the epithelium. Some CF patients have CFTR in the epithelium with residual CFTR function. The effect of ivacaftor in these patients is unknown.. This was a series of randomized, crossover N-of-1 trials of ivacaftor and placebo in CF patients ≥8 years old with potential residual CFTR function (intermediate sweat chloride concentration, pancreatic sufficient, or mild bronchiectasis on chest CT). Human nasal epithelium (HNE) was obtained via nasal brushing and cultured. Sweat chloride concentration change was the in vivo outcome. Chloride current change in HNE cultures with ivacaftor was the in vitro outcome.. Three subjects had decreased sweat chloride concentration (-14.8 to -40.8 mmol/L, P < 0.01). Two subjects had unchanged sweat chloride concentration. Two subjects had increased sweat chloride concentration (+23.8 and +27.3 mmol/L, P < 0.001); both were heterozygous for A455E and pancreatic sufficient. Only subjects with decreased sweat chloride concentration had increased chloride current in HNE cultures.. Some CF patients with residual CFTR function have decreased sweat chloride concentration with ivacaftor. Increased chloride current in HNE cultures among subjects with decreased sweat chloride concentrations may predict clinical response to ivacaftor. Ivacaftor can increase sweat chloride concentration in certain mutations with unclear clinical effect. Pediatr Pulmonol. 2017;52:472-479. © 2017 Wiley Periodicals, Inc.

Topics: Administration, Oral; Adolescent; Adult; Aminophenols; Chloride Channel Agonists; Chlorides; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Middle Aged; Quinolones; Sweat; Treatment Outcome; Young Adult

This pilot study evaluated the effect of short- and long-term ivacaftor treatment on hyperpolarized. Part A (single-blind) comprised 4weeks of ivacaftor treatment; Part B (open-label) comprised 48weeks of treatment. The primary outcome was change from baseline in total ventilation defect (TVD; total defect volume:total lung volume ratio).. Mean change in TVD ranged from -8.2% (p=0.0547) to -12.8% (p=0.0078) in Part A (n=8) and -6.3% (p=0.1953) to -9.0% (p=0.0547) in Part B (n=8) as assessed by human reader and computer algorithm, respectively.. TVD responded to ivacaftor therapy.

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Administration Schedule; Drug Monitoring; Female; Forced Expiratory Volume; Helium; Humans; Isotopes; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Outcome Assessment, Health Care; Pilot Projects; Pulmonary Ventilation; Quinolones; Single-Blind Method

Cystic fibrosis (CF) is known for its impact on the lung and pancreas of individuals; however, impaired growth is also a common complication. We hypothesized that targeting the biological defect in the CF transmembrane conductance regulator (CFTR) protein may affect growth outcomes.. In this post hoc analysis, we assessed linear growth and weight in 83 children (aged 6-11 years) enrolled in 2 clinical trials, the longitudinal-observation GOAL study and the placebo-controlled ENVISION study, to evaluate the effects of ivacaftor, a CFTR potentiator. We calculated height and weight z scores and height and weight growth velocities (GVs).. In ivacaftor-treated children in GOAL, height and weight z scores increased significantly from baseline to 6 months (increases of 0.1 [P < .05] and 0.26 [P < .0001], respectively); height GV increased significantly from 3 to 6 months (2.10-cm/year increase; P < .01). In ivacaftor-treated children in ENVISION, height and weight z scores increased significantly from baseline to 48 weeks (increases of 0.17 [P < .001] and 0.35 [P < .001], respectively). Height and weight GVs from baseline to 48 weeks were also significantly higher with ivacaftor than with placebo (differences of 1.08 cm/year [P < .05] and 3.11 kg/year [P < .001], respectively).. Ivacaftor treatment in prepubescent children may help to address short stature and altered GV in children with CF; results from these analyses support the existence of an intrinsic defect in the growth of children with CF that may be ameliorated by CFTR modulation.

Topics: Aminophenols; Body Height; Body Weight; Child; Cystic Fibrosis; Double-Blind Method; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Quinolones; Treatment Outcome

Ivacaftor is the first therapeutic agent approved for the treatment of cystic fibrosis (CF) that targets the underlying molecular defect. Patients with severe lung disease were excluded from the randomized Phase 3 trials. This open-label study was designed to provide ivacaftor to patients in critical medical need prior to commercial product availability.. CF patients aged ≥6 years with a G551D-CFTR mutation and FEV1 ≤ 40% predicted or listed for lung transplant received ivacaftor 150 mg every 12 h. The primary endpoint was safety as determined by adverse events. Secondary endpoints included assessment of lung function and weight.. The rate of serious adverse events was consistent with disease severity. At 24 weeks of treatment with ivacaftor, there was a mean absolute increase in percent predicted FEV1 of 5.5 percentage points and a 3.3 kg mean absolute increase in weight from baseline.. In patients with severe lung disease, ivacaftor was well tolerated and was associated with improved lung function and weight gain.

Topics: Adolescent; Adult; Aminophenols; Animals; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Mutation; Quinolones; Respiratory Function Tests; Treatment Outcome

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gating mutation G551D prevents sufficient ion transport due to reduced channel-open probability. Ivacaftor, an oral CFTR potentiator, increases the channel-open probability.. To further analyze improvements in weight and body mass index (BMI) in two studies of ivacaftor in patients aged ≥6 years with CF and the G551D mutation.. Patients were randomized 1:1 to ivacaftor 150 mg or placebo every 12 h for 48 weeks. Primary end point (lung function) was reported previously. Other outcomes included weight and height measurements and CF Questionnaire-Revised (CFQ-R).. Studies included 213 patients (aged ≤ 20 years, n = 105; aged > 20 years, n = 108). In patients ≤20 years, adjusted mean change from baseline to week 48 in body weight was 4.9 versus 2.2 kg (ivacaftor vs. placebo, p = 0.0008). At week 48, change from baseline in mean weight-for-age z-score was 0.29 versus -0.06 (p < 0.0001); change in mean BMI-for-age z-score was 0.26 versus -0.13 (p < 0.0001). In patients >20 years, adjusted mean change from baseline to week 48 in body weight was 2.7 versus -0.2 kg (p = 0.0003). Mean BMI change at week 48 was 0.9 versus -0.1 kg/m(2) (p = 0.0003). There was no linear correlation evident between changes in body weight and improvements in lung function or sweat chloride. Significant CFQ-R improvements were seen in perception of eating, body image, and sense of ability to gain weight.. Nutritional status improved following treatment with ivacaftor for 48 weeks.

Topics: Administration, Oral; Adolescent; Adult; Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Administration Schedule; Female; Genetic Predisposition to Disease; Humans; Male; Membrane Transport Modulators; Mutation; Nutritional Status; Phenotype; Quinolones; Surveys and Questionnaires; Time Factors; Treatment Outcome; Weight Gain; Young Adult

Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years.. In the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight <14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145.. Between Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of -46·9 mmol/L (SD 26·2, p<0·0001), weight Z score by 0·2 (0·3; p<0·0001), BMI Z score by 0·4 (0·4, p<0·0001), and height Z score by -0·01 (0·3; p=0·84).. Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted.. Vertex Pharmaceuticals Incorporated.

Topics: Aminophenols; Child, Preschool; Chloride Channel Agonists; Chlorides; Cough; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Genotype; Humans; Male; Mutation; Quinolones; Sweat

Clinical studies in patients with cystic fibrosis and G551D-CFTR showed that the group treated with ivacaftor had improved clinical outcomes. To better understand the effect of ivacaftor therapy across the distribution of individual FEV(1) responses, data from Phase 3 studies (STRIVE/ENVISION) were re-examined. In this post-hoc analysis of patients (n = 209) who received 48 weeks of ivacaftor or placebo, patients were assigned to tertiles according to FEV(1) response. These groups were then used to evaluate response (FEV(1), sweat chloride, weight, CFQ-R, and pulmonary exacerbation). The number needed to treat (NNT) was calculated for specific thresholds for each outcome. Across all tertiles, numerical improvements in FEV(1), sweat chloride, CFQ-R and the frequency of pulmonary exacerbations were observed in ivacaftor-treated patients: the treatment difference versus placebo was statistically significant for all outcomes in the upper tertile and for some outcomes in the lower and middle tertiles. The NNT for a ≥ 5% improvement in %predicted FEV(1) was 1.90, for a ≥ 5% body weight increase was 5.74, and to prevent a pulmonary exacerbation was 3.85. This analysis suggests that the majority of patients with clinical characteristics similar to STRIVE/ENVISION patients have the potential to benefit from ivacaftor therapy.

Topics: Adolescent; Adult; Aminophenols; Child; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Female; Forced Expiratory Volume; Humans; Male; Mutation; Numbers Needed To Treat; Quinolones; Respiratory Function Tests; Surveys and Questionnaires; Sweat; Weight Gain; Young Adult

Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation.. We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.. A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo.. These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.).

Topics: Adolescent; Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Homozygote; Hospitalization; Humans; Male; Middle Aged; Mutation; Quinolones; Young Adult

Ivacaftor has been previously assessed in patients with cystic fibrosis with Gly551Asp-CFTR or other gating mutations. We assessed ivacaftor in patients with Arg117His-CFTR, a residual function mutation.. We did a 24-week, placebo-controlled, double-blind, randomised clinical trial, which enrolled 69 patients with cystic fibrosis aged 6 years and older with Arg117His-CFTR and percentage of predicted forced expiratory volume in 1 s (% predicted FEV1) of at least 40. We randomly assigned eligible patients (1:1) to receive placebo or ivacaftor 150 mg every 12 h for 24 weeks. Randomisation was stratified by age (6-11, 12-17, and ≥18 years) and % predicted FEV1 (<70, ≥70 to ≤90, and >90). The primary outcome was the absolute change from baseline in % predicted FEV1 through week 24. Secondary outcomes included safety and changes in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores. An open-label extension enrolled 65 of the patients after washout; after 12 weeks, we did an interim analysis.. After 24 weeks, the treatment difference in mean absolute change in % predicted FEV1 between ivacaftor (n=34) and placebo (n=35) was 2·1 percentage points (95% CI -1·13 to 5·35; p=0·20). Ivacaftor treatment resulted in significant treatment differences in sweat chloride (-24·0 mmol/L, 95% CI -28·01 to -19·93; p<0·0001) and CFQ-R respiratory domain (8·4, 2·17 to 14·61; p=0·009). In prespecified subgroup analyses, % predicted FEV1 significantly improved with ivacaftor in patients aged 18 years or older (treatment difference vs placebo: 5·0 percentage points, 95% CI 1·15 to 8·78; p=0·01), but not in patients aged 6-11 years (-6·3 percentage points, -11·96 to -0·71; p=0·03). In the extension study, both placebo-to-ivacaftor and ivacaftor-to-ivacaftor groups showed % predicted FEV1 improvement (absolute change from post-washout baseline at week 12: placebo-to-ivacaftor, 5·0 percentage points [p=0·0005]; ivacaftor-to-ivacaftor, 6·0 percentage points [p=0·006]). We did not identify any new safety concerns. The studies are registered with ClinicalTrials.gov (the randomised, placebo-controlled study, number NCT01614457; the open-label extension study, number NCT01707290).. Although this study did not show a significant improvement in % predicted FEV1, ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with Arg117His-CFTR, indicating that ivacaftor might benefit patients with Arg117His-CFTR who have established disease.. Vertex Pharmaceuticals Incorporated.

Topics: Adolescent; Adult; Aged; Aminophenols; Child; Chloride Channels; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Mutation; Quinolones; Respiratory System Agents; Treatment Outcome; Young Adult

Cystic fibrosis (CF) is an inherited, rare autosomal recessive disease that results in chronically debilitating morbidities and high premature mortality. We evaluated how ivacaftor treatment affected CF symptoms, functioning, and well-being, as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a widely-used patient-reported outcome (PRO) measure.. STRIVE, a double-blind, placebo-controlled randomized trial, evaluated ivacaftor (150 mg) in CF patients aged 12+ with the G551D-CFTR mutation for 48 weeks. Treatment effect analysis used a mixed-effects repeated measures model. Treatment benefit analyses applied the cumulative distribution function and a categorical analysis of change scores ("improvement," "no change," or "decline"). Content-based interpretation examined treatment effect on specific item responses.. Data from 152 patients with a baseline CFQ-R assessment were analyzed. The treatment effect analysis favored treatment with ivacaftor over placebo on the Body Image, Eating, Health Perceptions, Physical Functioning, Respiratory, Social Functioning, Treatment Burden, and Vitality scales. Findings were supported by the analysis of categorical change. On all CFQ-R scales, the percentage of patients who improved was greater for ivacaftor. In the content-based analysis, the treatment benefit was characterized by better scores across a broad range of domains.. Results illustrate broad benefits of ivacaftor treatment across many domains: respiratory symptoms, physical and social functioning, health perceptions, and vitality, as measured by the CFQ-R. The breadth of improvements reflects the systemic mechanism of action of ivacaftor compared to other therapies. Findings support the patient-reported value of ivacaftor treatment in this patient population.. ClinicalTrials.gov NCT00909532.

Topics: Adolescent; Adult; Aged; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Female; Humans; Male; Middle Aged; Molecular Targeted Therapy; Mutation; Patient Outcome Assessment; Quality of Life; Quinolones; Young Adult

We examined data from a Phase 2 trial {NCT00457821} of ivacaftor, a CFTR potentiator, in cystic fibrosis (CF) patients with aG551D mutation to evaluate standardized approaches to sweat chloride measurement and to explore the use of sweat chloride and nasal potential difference (NPD) to estimate CFTR activity.. Sweat chloride and NPD were secondary endpoints in this placebo-controlled, multicenter trial. Standardization of sweat collection, processing,and analysis was employed for the first time. Sweat chloride and chloride ion transport (NPD) were integrated into a model of CFTR activity.. Within-patient sweat chloride determinations showed sufficient precision to detect differences between dose-groups and assess ivacaftor treatment effects. Analysis of changes in sweat chloride and NPD demonstrated that patients treated with ivacaftor achieved CFTR activity equivalent to approximately 35%–40% of normal.. Sweat chloride is useful in multicenter trials as a biomarker of CFTR activity and to test the effect of CFTR potentiators.

Topics: Adult; Aminophenols; Biomarkers; Child; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Mutation; Nasal Mucosa; Quinolones; Reproducibility of Results; Respiratory System Agents; Specimen Handling; Sweat; Treatment Outcome

The phe508del CFTR mutation causes cystic fibrosis by limiting the amount of CFTR protein that reaches the epithelial cell surface. We tested combination treatment with lumacaftor, an investigational CFTR corrector that increases trafficking of phe508del CFTR to the cell surface, and ivacaftor, a CFTR potentiator that enhances chloride transport of CFTR on the cell surface.. In this phase 2 clinical trial, we assessed three successive cohorts, with the results of each cohort informing dose selection for the subsequent cohort. We recruited patients from 24 cystic fibrosis centres in Australia, Belgium, Germany, New Zealand, and the USA. Eligibility criteria were: confirmed diagnosis of cystic fibrosis, age at least 18 years, and a forced expiratory volume in 1 s (FEV1) of 40% or more than predicted. Cohort 1 included phe508del CFTR homozygous patients randomly assigned to either lumacaftor 200 mg once per day for 14 days followed by addition of ivacaftor 150 mg or 250 mg every 12 h for 7 days, or 21 days of placebo. Together, cohorts 2 and 3 included phe508del CFTR homozygous and heterozygous patients, randomly assigned to either 56 days of lumacaftor (cohort 2: 200 mg, 400 mg, or 600 mg once per day, cohort 3: 400 mg every 12 h) with ivacaftor 250 mg every 12 h added after 28 days, or 56 days of placebo. The primary outcomes for all cohorts were change in sweat chloride concentration during the combination treatment period in the intention-to-treat population and safety (laboratory measurements and adverse events). The study is registered with ClinicalTrials.gov, number NCT01225211, and EudraCT, number 2010-020413-90.. Cohort 1 included 64 participants. Cohort 2 and 3 combined contained 96 phe508del CFTR homozygous patients and 28 compound heterozygotes. Treatment with lumacaftor 200 mg once daily and ivacaftor 250 mg every 12 h decreased mean sweat chloride concentration by 9.1 mmol/L (p<0.001) during the combination treatment period in cohort 1. In cohorts 2 and 3, mean sweat chloride concentration did not decrease significantly during combination treatment in any group. Frequency and nature of adverse events were much the same in the treatment and placebo groups during the combination treatment period; the most commonly reported events were respiratory. 12 of 97 participants had chest tightness or dyspnoea during treatment with lumacaftor alone. In pre-planned secondary analyses, a significant decrease in sweat chloride concentration occurred in the treatment groups between day 1 and day 56 (lumacaftor 400 mg once per day group -9.1 mmol/L, p<0.001; lumacaftor 600 mg once per day group -8.9 mmol/L, p<0.001; lumacaftor 400 mg every 12 h group -10.3 mmol/L, p=0.002). These changes were significantly greater than the change in the placebo group. In cohort 2, the lumacaftor 600 mg once per day significantly improved FEV1 from day 1 to 56 (difference compared with placebo group: +5.6 percentage points, p=0.013), primarily during the combination period. In cohort 3, FEV1 did not change significantly across the entire study period compared with placebo (difference +4.2 percentage points, p=0.132), but did during the combination period (difference +7.7 percentage points, p=0·003). Phe508del CFTR heterozygous patients did not have a significant improvement in FEV1.. We provide evidence that combination lumacaftor and ivacaftor improves FEV1 for patients with cystic fibrosis who are homozygous for phe508del CFTR, with a modest effect on sweat chloride concentration. These results support the further exploration of combination lumacaftor and ivacaftor as a treatment in this setting.. Vertex Pharmaceuticals, Cystic Fibrosis Foundation Therapeutics Development Network.

Topics: Adolescent; Adult; Aminophenols; Aminopyridines; Base Sequence; Benzodioxoles; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Heterozygote; Homozygote; Humans; Male; Quinolones; Sequence Deletion; Sweat; Young Adult

Ivacaftor is used to treat patients with CF and a G551D gating mutation; the KONNECTION study assessed the efficacy and safety of ivacaftor in patients with CF and a non-G551D gating mutation.. Patients with CF ≥6-years- old with non-G551D gating mutations received ivacaftor 150mg q12h or placebo for 8weeks in this 2-part, double-blind crossover study (Part 1) with a 16-week open-label extension (Part 2). The primary efficacy outcome was absolute change in FEV1 through 8 and 24weeks of ivacaftor treatment; secondary outcomes were changes in BMI, sweat chloride, and CFQ-R and safety through 8 and 24weeks of treatment.. Eight weeks of ivacaftor resulted in significant improvements in percent predicted FEV1, BMI, sweat chloride, and CFQ-R scores that were maintained through 24weeks. Ivacaftor was generally well tolerated.. Ivacaftor was efficacious in a group of patients with CF who had selected non-G551D gating mutations.

Topics: Adolescent; Adult; Aminophenols; Body Mass Index; Child; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Ion Channel Gating; Male; Middle Aged; Mutation; Outcome Assessment, Health Care; Quinolones; Young Adult

Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. We assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION).. In this phase 3, open-label extension study, patients received ivacaftor 150 mg every 12 h in addition to their prescribed cystic fibrosis therapies. Patients who received placebo in their previous study initiated ivacaftor in this extension study. Patients were eligible if they had a Gly551Asp-CFTR mutation on at least one allele. The primary objective was to assess the long-term safety profile of ivacaftor as assessed by adverse events, clinical laboratory assessments, electrocardiograms, vital signs, and physical examination; secondary measures included change in forced expiratory volume in one second (FEV1), weight, and pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT01117012 and EudraCT, number 2009-012997-11.. Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (≥12 years) from STRIVE and 48 children (6-11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (<1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9·4 and 10·3 % points and absolute increase in weight was 4·1 kg and 14·8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study.. At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study.. Vertex Pharmaceuticals Inc.

Topics: Adolescent; Adult; Aminophenols; Child; Cough; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Female; Forced Expiratory Volume; Humans; Male; Mutation; Quinolones; Respiratory Tract Infections; Time Factors; Weight Gain; Young Adult

Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation.. This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6-11 years with a G551D-CFTR mutation on at least one allele.. Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies.. Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was -53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups.. In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo. Clinical trial registered with www.clinicaltrials.gov (NCT00909727).

Topics: Administration, Oral; Alleles; Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Dose-Response Relationship, Drug; Double-Blind Method; Forced Expiratory Volume; Humans; Lung; Mutation; Quinolones; Respiratory Function Tests; Treatment Outcome

Nasal potential difference (NPD) is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. We evaluated methods to detect changes in chloride and sodium transport by NPD based on a secondary analysis of a Phase II CFTR-modulator study. Thirty-nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (Kalydeco™; also known as VX-770) in four doses or placebo twice daily for at least 14 days. All data were analyzed by a single investigator who was blinded to treatment assignment. We compared three analysis methods to determine the best approach to quantify changes in chloride and sodium transport: (1) the average of both nostrils; (2) the most-polarized nostril at each visit; and (3) the most-polarized nostril at screening carried forward. Parameters of ion transport included the PD change with zero chloride plus isoproterenol (CFTR activity), the basal PD, Ringer's PD, and change in PD with amiloride (measurements of ENaC activity), and the delta NPD (measuring CFTR and ENaC activity). The average and most-polarized nostril at each visit were most sensitive to changes in chloride and sodium transport, whereas the most-polarized nostril at screening carried forward was less discriminatory. Based on our findings, NPD studies should assess both nostrils rather than a single nostril. We also found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects (± 2.8 mV). Therefore, we have confirmed an assay of reasonable reproducibility for detecting chloride-transport improvements in response to CFTR modulation.

Topics: Adult; Amino Acid Substitution; Aminophenols; Biological Transport; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Demography; Epithelial Sodium Channels; Female; Humans; Male; Membrane Potentials; Middle Aged; Mutation; Nose; Placebos; Quinolones; Sample Size; Sodium; Solutions; Young Adult

To determine whether the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector-ivacaftor.. This open-label pilot study was conducted in CF patients with the G551D mutation given new prescriptions for ivacaftor. At baseline and 4 wk after daily ivacaftor therapy, intravenous glucose tolerance tests (IVGTT) and oral glucose tolerance tests (OGTT) were performed.. Five patients aged 6-52 were studied. After 1 month on ivacaftor, the insulin response to oral glucose improved by 66-178% in all subjects except one with long-standing diabetes. OGTT glucose levels were not lower in the two individuals with diabetes or the two with normal glucose tolerance (NGT), but the glucose tolerance category in the subject with impaired glucose tolerance (IGT) improved to NGT after treatment. In response to intravenous glucose, the only patient whose acute insulin secretion did not improve had newly diagnosed, untreated CFRD. The others improved by 51-346%. Acute insulin secretion was partially restored in two subjects with no measurable acute insulin response at baseline, including the one with IGT and the one with long-standing diabetes.. This small pilot study suggests there is a direct role of CFTR in human insulin secretion. Larger, long-term longitudinal studies are necessary to determine whether early initiation of CFTR correction, particularly in young children with CF who have not yet lost considerable β-cell mass, will delay or prevent development of diabetes in this high-risk population.

Topics: Adolescent; Adult; Amino Acid Substitution; Aminophenols; Child; Cross-Sectional Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Mutation; Pilot Projects; Prediabetic State; Quinolones

Ivacaftor has shown a clinical benefit in patients with cystic fibrosis who have the G551D-CFTR mutation and reduced lung function. Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV1) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry. The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV1 >90% predicted.. This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV1 >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg. Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days' treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI. The study is registered at ClinicalTrials.gov, NCT01262352.. Between February and November, 2011, 21 patients were enrolled, of which 11 were assigned to the sequence 1 group, and 10 to the sequence 2 group. 20 of these patients received treatment and 17 completed the trial (eight in sequence 1 group and 9 in sequence 2 group). Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001). Adverse events experienced by study participants were similar between treatment groups; at least one adverse event was reported by 15 (79%) of 19 patients who received placebo and 13 (72%) of 18 patients who received ivacaftor. No deaths occurred during study period.. In patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in LCI. LCI might be a more sensitive alternative to FEV1 in detecting response to intervention in these patients with mild lung disease.. Vertex Pharmaceuticals Incorporated.

Topics: Adolescent; Adult; Aminophenols; Child; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Mucociliary Clearance; Mutation; Quinolones; Respiratory System Agents; Spirometry; Young Adult

Ivacaftor (VX-770) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that was approved in the United States for the treatment of cystic fibrosis (CF) in patients ≥ 6 years of age who have a G551D mutation; however, the most prevalent disease-causing CFTR mutation, F508del, causes a different functional defect. The objectives of this study were to evaluate the safety of ivacaftor in a larger population and for a longer time period than tested previously and to assess the efficacy of ivacaftor in subjects with CF who are homozygous for F508del-CFTR.. This was a phase 2 study with a 16-week randomized (4:1), double-blind, placebo-controlled period (part A) and an open-label extension (part B) for subjects who met prespecified criteria.. Part A: The safety profile of ivacaftor was comparable to that of the placebo. The overall adverse event frequency was similar in the ivacaftor (87.5%) and placebo (89.3%) groups through 16 weeks. The difference in the change of FEV₁ % predicted from baseline through week 16 (primary end point) between the ivacaftor and placebo groups was 1.7% (P = .15). Sweat chloride, a biomarker of CFTR activity, showed a small reduction in the ivacaftor vs placebo groups of -2.9 mmol/L (P = .04) from baseline through week 16. Part B: No new safety signals were identified. The changes in FEV₁ or sweat chloride in part A were not sustained with ivacaftor treatment from week 16 to week 40.. These results expand the safety information for ivacaftor and support its continued evaluation. Lack of a clinical effect suggests that a CFTR potentiator alone is not an effective therapeutic approach for patients who have CF and are homozygous for F508del-CFTR.. ClinicalTrials.gov; No.: NCT00953706; URL: www.clinicaltrials.gov.

Topics: Adolescent; Adult; Alleles; Aminophenols; Biomarkers; Child; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Female; Homozygote; Humans; Male; Middle Aged; Mutation; Pharmacogenetics; Quinolones; Sweat; Treatment Outcome; Young Adult

Several types of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene lead to abnormal CFTR protein and alterations of chloride and sodium transmembrane transportation in cystic fibrosis (CF). Some investigational compounds such as VX-770 can improve CFTR protein function.. This paper discusses the results of a Phase II study investigating the safety and efficacy of VX-770 in patients with CF.. VX-770 is able to improve chloride and sodium transportation and has a good safety profile. Although such compounds have limited therapeutic targeting potential, preliminary results show great promise in the context of CF therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminophenols; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Humans; Ion Transport; Middle Aged; Mutation; Quinolones; Young Adult

Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis.. We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)).. The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%).. Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 ClinicalTrials.gov number, NCT00909532.).

Topics: Administration, Oral; Adolescent; Adult; Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Synergism; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Mutation; Quinolones; Young Adult

A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro.. We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study).. At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3.5 mV (range, -8.3 to 0.5; P=0.02 for the within-subject comparison, P=0.13 vs. placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P=0.008 within-subject, P=0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P=0.008 for the within-subject comparison, P=0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770.. This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.).

Topics: Adult; Aminophenols; Chlorides; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Ion Channels; Male; Membrane Potentials; Middle Aged; Mutation; Nasal Mucosa; Quinolones; Sweat; Young Adult

Lumacaftor/Ivacaftor (LUM/IVA) is an approved combination therapy for cystic fibrosis (CF) patients homozygous for F508del.. This study aimed to detect changes in liver stiffness measurement (LSM) in patients under this treatment.. The study population consisted of CF patients homozygous for F508del, 6 to 11 years old, who had been treated for six months with LUM/IVA. Shear wave elastography (SWE) was performed in all of them, before and 6 months after the commencement of treatment.. Thirty-one patients were included in the study. LSM values after treatment were significantly higher than the values before treatment (medians and interquartile ranges of LSM values before and after treatment: 5.6, 5.3-6.3 kPa and, 6.4, 6.0-7.6 kPa, respectively, p<0.001).. SWE can detect early changes in LSM in some CF patients treated with LUM/IVA.

Topics: Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Elasticity Imaging Techniques; Humans; Mutation

Topics: Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Quality of Life

CHEC-SC is an ongoing epidemiologic study characterizing modulator-induced sweat chloride (SC) responses across the CF population, with interim results available prior to the availability of triple combination modulator therapy.. Eligible participants had been prescribed a modulator for ≥90 days with re-enrollment allowed upon establishment of a new modulator. Pre-modulator SC values were obtained from chart review; post-modulator sweat was collected and analyzed locally. SC changes were descriptively summarized with biologic sex effects adjusted for age, weight, and CFTR genotype. Heterogeneity in ivacaftor SC response was characterized in relation to published CFTR functional responses.. 1848 participants provided 2004 SC measurements, 26.2% on ivacaftor, 39.1% on lumacaftor/ivacaftor, and 34.7% on tezacaftor/ivacaftor. Average SC changes for all modulators were consistent with those reported in previous clinical studies, with greater variation in SC response observed among rarer mutations and notable shifts in the proportion with SC <60mmol/L independent of the magnitude of SC change. Ivacaftor induced in vitro CFTR functional change was significantly correlated with ivacaftor-modulated SC response (Pearson correlation= ‒0.52, 95% CI: ‒0.773, ‒0.129). Average SC change from ivacaftor to tezacaftor/ivacaftor was ‒4.9 mmol/L (n=17,95% CI:‒9.3, ‒0.5) and differed from those switching from lumacaftor/ivacaftor (10.0 mmol/L, n=139, 95% CI:7.8,12.3). Sex at birth was not associated with SC response.. CHEC-SC is the largest study characterizing modulator-induced SC changes across the CF population. There was a strong association between ivacaftor induced in vitro CFTR function and SC response across a genotypically heterogenous cohort. Biological sex was not associated with SC response.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Sweat

Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes.. Clinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12 months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed.. ETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1 s (+10%) and body mass index (+1.0 kg·m. ETI is associated with unique changes in innate immune function and clinical outcomes.

Topics: Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Macrophages; Mutation

Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.. PROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex.. 438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change.. After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.

Topics: Aminophenols; Benzodioxoles; Constipation; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pancreatic Elastase; Prospective Studies; Quality of Life

We report a case series of four patients with cystic fibrosis (CF) and previous solid organ transplantation (SOT) receiving elexacaftor/tezacaftor/ivacaftor therapy for 6 months or more. Data was collected retrospectively. The treatment was well tolerated and all patients reported subjective improvements.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Drug Combinations; Humans; Mutation; Organ Transplantation; Retrospective Studies

In vitro studies have demonstrated rescue of CFTR function with Elexacaftor/Tezacaftor/Ivacaftor (ETI) in several mutations other than F508del. However, clinical efficacy was not tested in vivo in people with CF (pwCF) carrying mutations other than F508del. We report effects of treatment with ETI in pwCF with non-F508del mutations.. We retrospectively analyzed pwCF with non-F508del mutations who received treatment with ETI. We evaluated sweat chloride, nutritional status, spirometry, antibiotic treatment, and pulmonary exacerbations (PEx), at baseline and 3-6 months after commencing treatment with ETI.. We demonstrate the clinical efficacy of ETI in pwCF carrying CFTR processing non-F508del mutations which are predicted to respond by in vitro studies. Our results support routine clinical use of ETI in this patient group.

Topics: Aminophenols; Anti-Bacterial Agents; Benzodioxoles; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Retrospective Studies

Cystic fibrosis (CF) is a multisystem disease with progressive deterioration. Recently, CF transmembrane conductance regulator (CFTR) modulator therapies were introduced that repair underlying protein defects. Objective of this study was to determine the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on clinical parameters and inflammatory responses in people with CF (pwCF).. Lung function (FEV. Sample size was 48 pwCF, 28 (58.3%) males with a mean age of 28.8 ± 10.7 years. Significant increases in %predicted FEV. In pwCF, ETI significantly improved clinical outcomes, reduced systemic pro-inflammatory cytokines, and restored circulating immune cell composition after 6 months of therapy.

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Female; Humans; Interleukin-17; Interleukin-8; Male; Mutation; Young Adult

A new treatment for cystic fibrosis combining 3 CFTR modulators-elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA)-has recently been approved for cystic fibrosis treatment. The cutaneous adverse effects following treatment with this combination are poorly described in the literature.. To describe the clinicopathological features and treatment response of ELX-TEZ-IVA-associated acneiform eruptions in patients with cystic fibrosis.. This case series study was conducted in the Dermatology Department of Cochin Hospital, Paris, France, from July 2021 to June 2022 in collaboration with the Cochin Reference Center for Cystic Fibrosis. Referred patients were examined by senior dermatologists. All patients with cystic fibrosis treated with ELX-TEZ-IVA and referred for an acneiform rash were included.. Treatment with ELX-TEZ-IVA.. Onset of acneiform rash, type of lesions, and degree of severity, as well as treatments initiated and response, were evaluated. When performed, skin biopsies were reviewed.. This study included 16 patients (11 women [68.7%]) with a median (range) age of 27 (22-38) years. Six patients (37.5%) developed new-onset acneiform rashes, whereas 10 patients (62.5%) had a relapse (5 patients) or worsening (5 patients) of previous acne. The median (range) onset of acneiform rash was 45 (15-150) days. At inclusion, 11 patients (68.7%) had facial hyperseborrhea, 15 patients (93.7%) had noninflammatory lesions, and 14 (87.5%) had inflammatory lesions of seborrheic regions. Four patients (25.0%) had severe acne with deep inflammatory lesions and pitted scars. A specific pathological pattern of necrotizing infundibular crystalline folliculitis was observed in 4 patients. Topical acne treatments, antibiotics, and isotretinoin were used successfully in these patients, resulting in partial or complete remission in 12 patients (85.7% of patients reevaluated).. This case series study found that acneiform eruption is an adverse event associated with ELX-TEZ-IVA treatment in patients with cystic fibrosis. Most patients developed mild lesions. However, isotretinoin treatment may be necessary in some patients. The mechanism of ELX-TEZ-IVA-associated acneiform eruption is currently unknown, but the observation of necrotizing infundibular crystalline folliculitis in biopsied patients may guide further exploration.

Topics: Acne Vulgaris; Acneiform Eruptions; Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Exanthema; Female; Folliculitis; Humans; Isotretinoin; Male; Mutation; Young Adult

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Neutrophils

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and show robust treatment effects at group level. The individual effect however, is variable which might be (partially) related to differences in drug exposure. The profound influence of fat containing food compared to fasting on drug exposure gives need to investigate if the exocrine pancreatic function changes the degree and rate of absorption of ivacaftor and thereby may contribute to differences in drug exposure.. Pharmacokinetic parameters of ivacaftor were measured in 10 pancreatic sufficient (PS) and 10 pancreatic insufficient (PI) patients with CF on current treatment with tezacaftor/ivacaftor and compared between both groups. In PI patients pharmacokinetic parameters were investigated with and without the use pancreatic enzymes and compared in each individual.. We demonstrated that the pharmacokinetic parameters of ivacaftor did not differ significantly between PS and PI people with CF (pwCF). Pancreatic enzymes did not significantly change the absorption or exposure to ivacaftor in PI pwCF using tezacaftor/ivacaftor.. The exocrine pancreatic function of pwCF does not significantly influence the absorption and exposure of ivacaftor. The use of pancreatic enzymes in PI pwCF does not change the absorption and exposure of ivacaftor. Therefore, the dosing advice as mentioned in the SmPC for ivacaftor can be maintained independent of the exocrine pancreatic function.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation

Cystic fibrosis is a severe monogenic disease that affects around 7400 patients in France. More than 2100 mutations in the cystic fibrosis conductance transmembrane regulator (CFTR), the gene encoding for an epithelial ion channel that normally transports chloride and bicarbonate, lead to mucus dehydration and impaired bronchial clearance. Systematic neonatal screening in France since 2002 has enabled early diagnosis of cystic fibrosis. Although highly demanding, supportive treatments including daily chest physiotherapy, inhaled aerosol therapy, frequent antibiotic courses, nutritional and pancreatic extracts have improved the prognosis. Median age at death is now beyond 30 years. Ivacaftor was the first CFTR modulator found to both reduce sweat chloride concentration and improve pulmonary function in the rare CFTR gating mutations. Combinations of modulators such as lumacaftor + ivacaftor or tezacaftor + ivacaftor were found to improve pulmonary function both in patients homozygous for the F508del mutation characterized by the lack of CFTR protein and those heterozygous for F508del with minimal CFTR activity. The triple combination of ivacaftor + tezacaftor + elexacaftor was recently shown to significantly improve pulmonary function and quality of life, to normalize sweat chloride concentration, and to reduce the need for antibiotic therapy in patients with at least one F508del mutation (83% in France). These impressive data, however, need to be confirmed in the long term. Nevertheless, it is encouraging to hear treated patients testify about their markedly improved quality of life and to observe that the number of lung transplants for cystic fibrosis decreased dramatically in France after 2020, despite the COVID pandemic, with no increase in deaths without lung transplant.

Topics: Adult; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Infant, Newborn; Mutation; Quality of Life

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung Transplantation; Mutation

In the past decade, the medical management of people with cystic fibrosis (pwCF) has changed with the development of small molecules that partially restore the function of the defective CF transmembrane conductance regulator (CFTR) protein and are called CFTR modulators. Ivacaftor (IVA), a CFTR potentiator with a large effect on epithelial ion transport, was the first modulator approved in pwCF carrying gating mutations. Because IVA was unable to restore sufficient CFTR function in pwCF with other mutations, two CFTR correctors (lumacaftor and tezacaftor) were developed and used in combination with IVA in pwCF homozygous for F508del, the most common CFTR variant. However, LUM/IVA and TEZ/IVA were only moderately effective in F508del homozygous pwCF and had no efficacy in those with F508del and minimal function mutations. Elexacaftor, a second-generation corrector, was thus developed and combined to tezacaftor and ivacaftor (ELX/TEZ/IVA) to target pwCF with at least one F508del variant, corresponding to approximately 85% of pwCF. Both IVA and ELX/TEZ/IVA are considered highly effective modulator therapies (HEMTs) in eligible pwCF and are now approved for nearly 90% of the CF population over 6 years of age. HEMTs are responsible for rapid improvement in respiratory manifestations, including improvement in symptoms and lung function, and reduction in the rate of pulmonary exacerbations. The impact of HEMT on extrapulmonary manifestations of CF is less well established, although significant weight gain and improvement in quality of life have been demonstrated. Recent clinical trials and real-world studies suggest that benefits of HEMT could even prove greater when used earlier in life (i.e., in younger children and infants). This article shortly reviews the past 10 years of development and use of CFTR modulators. Effects of HEMT on extrapulmonary manifestations and on CF demographics are also discussed.

Topics: Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Mutation; Quality of Life

Cystic fibrosis is caused by mutations impairing expression, trafficking, stability and/or activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The G1244E mutation causes a severe gating defect that it is not completely rescued by ivacaftor but requires the use of a second compound (a co-potentiator). Recently, it has been proposed that the corrector elexacaftor may act also as a co-potentiator.. By using molecular, biochemical and functional analyses we performed an in-depth characterization of the G1244E-CFTR mutant in heterologous and native cell models.. Our studies demonstrate that processing and function of the mutant protein, as well as its pharmacological sensitivity, are markedly dependent on cell background. In heterologous expression systems, elexacaftor mainly acted on G1244E-CFTR as a co-potentiator, thus ameliorating the gating defect. On the contrary, in the native nasal epithelial cell model, elexacaftor did not act as a co-potentiator, but it increased mature CFTR expression possibly by improving mutant's defective stability at the plasma membrane.. Our study highlights the importance of the cell background in the evaluation of CFTR modulator effects. Further, our results draw attention to the need for the development of novel potentiators having different mechanisms with respect to ivacaftor to improve channel activity for mutants with severe gating defect.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation

Elexacaftor-tezacaftor-ivacaftor (ETI) represents a significant step forward in cystic fibrosis (CF) care and could change the course of CF lung disease and quality of life for many people with CF (PwCF). However, several PwCF cannot benefit from these modulators because their rare mutations are not eligible for treatment. This study aimed to investigate the lived experiences of PwCF who are not eligible for ETI.. Data were collected through semi-structured interviews with 13 individuals with CF that were not eligible for ETI. Thematic analysis was used to identify the key themes of their experiences.. Two main themes and six subthemes were identified. The first main theme (being deemed ineligible for ETI) had four subthemes (disappointment, information, happiness, and concerns). The second main theme (coping with a life without ETI) had two subthemes (lack of hope and continued hope).. PwCF who are not eligible for ETI experience intense disappointment and conflicting emotions that can influence their decision-making linked to diminishing/renewal hope. Integrated care, including mental health monitoring programs, should be provided to these patients to aid them in overcoming their disappointment and to improve their coping.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quality of Life

Topics: Aminophenols; Cystic Fibrosis; Female; Humans; Pregnancy

With improvement in supportive therapies and the introduction of cystic fibrosis transmembrane conductance regulator (CFTR)-modulator treatment in patients with cystic fibrosis (CF), milder disease courses are expected. Therefore, sensitive parameters are needed to monitor disease course and effects of CFTR-modulators. Functional lung MRI using matrix-pencil decomposition (MP-MRI) is a promising tool for assessing ventilation and perfusion quantitatively. This study aimed to assess the treatment effect of elexacaftor/tezacaftor/ivacaftor combination regimen (ELX/TEZ/IVA) on measures of structural and functional lung abnormalities.. 24 children with CF underwent lung function tests (multiple breath washout, spirometry), functional and structural MRI twice (one year apart) before and once after at least two weeks (mean 4.7 ± 2.6 months) on ELX/TEZ/IVA. Main outcomes were changes (Δ) upon ELX/TEZ/IVA in lung function, defect percentage of ventilation (VDP) and perfusion (QDP), defect distribution index of ventilation and perfusion (DDI. We observed a significant improvement in lung function, structural and functional MRI parameters upon ELX/TEZ/IVA treatment (mean; 95%-CI): ΔLCI. Besides lung function tests, functional and structural MRI is a suitable tool to monitor treatment response of ELX/TEZ/IVA therapy, and seems promising as outcome marker in the future.

Topics: Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Magnetic Resonance Imaging; Mutation; Respiratory Function Tests; Spirometry

Limited published research is available on the impact of elexacaftor/tezacaftor/ivacaftor (ETI) beyond the initial few months postdrug initiation, especially for those who initiated therapy via individual investigational new drug application. The experiences of patients with cystic fibrosis (CF) experiencing severe lung disease were reviewed for significant improvements in clinical symptoms and quality of life.. To examine clinical outcomes 2 years post-ETI in patients with CF and advanced lung disease.. This single center institutional review board-approved, retrospective chart review assessed clinical markers (percent predicted forced expiratory volume in 1 s, weight, sweat chloride), quality of life and computed tomography scans in patients with advanced lung disease who met criteria for compassionate use/expanded access program due to high risk of death or transplant need within 2 years.. Eighteen identified patients (ages 15-49 years) initiated drug between July and September 2019. Clinical markers indicated that therapy was well tolerated, not discontinued by any participant, and lab values did not indicate medical concern or discontinuation. Monitoring results indicated the safety of modulator therapy as there were no adverse clinical occurrences and all patients presented universal stabilization. There were no deaths and no transplants by the end of the study.. This study focused on patients with CF eligible for modulator therapy and were initiated due to advanced lung disease. Initiation of modulator therapy was deemed safe and resulted in objective positive changes in nutrition, cough, FEV

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Middle Aged; Mutation; Quality of Life; Retrospective Studies; Young Adult

The cystic fibrosis (CF) transmembrane conductance regulator corrector/potentiator combinations lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor improve sweat chloride, pulmonary function, and nutrition. Yet it is unclear whether they may also impact the progression of liver fibrosis, which is a substantial source of morbidity and mortality for patients with CF. We conducted a retrospective, single-center analysis of children and adolescents with CF treated with lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor therapy, focusing on alterations in liver function tests and fibrosis indices using previously-established thresholds that corresponded with increased liver elastography. In pairwise comparisons of before and during treatment timepoints, we found that those with CF-associated liver involvement experienced significant decreases in gamma-glutamyl transferase, aspartate aminotransferase-to-platelet index, and gamma-glutamyl transferase-to-platelet ratio while on lumacaftor/ivacaftor. These differences were not observed in patients treated with elexacaftor/tezacaftor/ivacaftor, nor were they observed in patients without underlying CF-associated liver disease. These results provide the first evidence that lumacaftor/ivacaftor may improve liver fibrosis in children and adolescents with CF and suggest it may be beneficial in the treatment of CF-associated liver disease.

Topics: Adolescent; Biomarkers; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Liver Cirrhosis; Retrospective Studies; Transferases

The novel triple CFTR modulator therapy Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) improves lung function, body mass index (BMI), sinus clearance, and quality of life in patients with cystic fibrosis. Whether treatment with ELX/TEZ/IVA is associated with improved glucose tolerance is unknown.. This cohort study included adults with CF and at least one copy of F508del.. Study assessments before treatment and at least 3 months after ELX/TEZ/IVA initiation included an oral glucose tolerance test (OGTT) with glucose and insulin measurements, BMI, lung function test, and sweat chloride levels. We used an analysis of response profiles to calculate changes in outcomes.. In adult patients with CF and at least one copy of F508del, treatment with the triple CFTR modulator was associated with possible improvement of glucose tolerance without increases of insulin secretion. Early initiation of treatment as assessed through long-term prospective trials is mandatory to demonstrate if decreased glucose control is preventable or even reversible.

Topics: Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Glucose; Humans; Male; Mutation; Prospective Studies; Quality of Life

Elexacaftor/tezacaftor/ivacaftor (E/T/I) therapy has resulted in substantial improvements in health status for many with cystic fibrosis. Monitoring of liver tests is recommended due to observed rises in transaminases in trials and cases of hepatotoxicity. Comprehensive data in large populations of unselected individuals and those with established CF related liver disease (CFLD) is lacking.. Patients prescribed E/T/I at a large, adult centre had liver tests monitored at least 3 monthly for 12 months. Changes in individual liver tests were analysed and abnormalities were compared in those with and without CFLD.. 255 of 267 eligible patients were included. Mild rises in median ALT, AST and bilirubin from baseline to 3 months (all p < 0.001) within normal limits were noted which were sustained. There were no differences in changes in liver tests between those with or without CFLD. There was a significant difference in alkaline phosphatase for those with raised levels at baseline versus those with normal baseline level (-18.5 vs +2.0 IU/L, p = 0.002). Clinically significant rises in ALT and AST occurred in 8 (3.1%) and 6 (2.4%) cases respectively, with derangements in 2 individuals attributed to therapy.. E/T/I leads to a mild, likely clinically insignificant increase in ALT, AST and bilirubin after 3 months which is sustained but does not appear to increase further in the vast majority. Underlying CFLD should not be a barrier to treatment. Although there was a reduction in ALP when elevated at baseline, this was not unique to those with pre-existing CFLD.

Topics: Adult; Aminophenols; Benzodioxoles; Bilirubin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Liver; Mutation

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Pyridines

Cystic-fibrosis-related liver disease (CFLD) is a variable phenotype of CF. The severe CFLD variant with cirrhosis or portal hypertension has a poor prognosis and life expectancy. CFTR modulator therapies are now available for people with CF and eligibility for such treatment is based on their CFTR genotype. We evaluated the genetic eligibility for elexacaftor, tezacaftor, ivacaftor (ETI), and ivacaftor (IVA) monotherapy in a previously reported CF cohort of 1591 people with CF of whom 171 with severe CFLD. Based on their CFTR mutations, 13% (N=184/1420) of subjects without CFLD and 11% (N=19/171) of those with severe CFLD are not eligible for either ETI or IVA therapy. The non-eligible patients without CFLD or with severe CFLD can currently not take advantage of the potential benefits of these new treatments. Although this study cannot provide any data regarding the effect of ETI or IVA on the progression of severe CFLD, the consequences for ineligibility of patients with extreme liver phenotype may be even more significant because of their poorer disease risk profile.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Hypertension, Portal; Mutation

Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a recently approved cystic fibrosis (CF) transmembrane conductance regulator modulator therapy that has shown promising clinical and laboratory improvements on multiple organ systems in people with CF (pwCF). While original clinical trials found little to no effect on depression and anxiety, many post-marketing reports have suggested that ETI may be associated with adverse mental health effects. Here we report on two pwCF with adverse mental health effects shortly after starting ETI. Although many factors such as the burden of living with a chronic disease or widespread effects of the Covid-19 pandemic may have contributed to these events, similar reports have led to mounting concern that ETI may be the cause of such events. Regular mental health screening before the initiation of ETI and monitoring for signs and symptoms of mental diseases afterward should be a routine part of care, given the gravity of possible outcomes.

Topics: Adolescent; Aminophenols; Benzodioxoles; COVID-19; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pandemics; Suicide, Attempted

A retrospective chart review of the electronic medical record at the University of Iowa was completed for individuals 12 years and older taking ELX/TEZ/IVA for at least 12 months. The primary outcome was determined by assessing bacterial cultures pre- and postinitiation of ELX/TEZ/IVA. Baseline demographic and clinical characteristics were summarized using mean and standard deviation for continuous outcomes and count and percentage for categorical outcomes. Culture positivity for Pa, MSSA, and MRSA was compared among enrolled subjects between pre- and posttriple combination therapy periods using an exact McNemar's test.. One hundred and twenty-four subjects prescribed ELX/TEZ/IVA for at least 12 months met the requirements for inclusion within our analysis. Culture positivity for Pa, MSSA, and MRSA was approximately 54%, 33%, and 31%, respectively, for the pre-ELX/TEZ/IVA period. Prevalence decreased to approximately 30%, 32%, and 24% (-24.2% [p < 0.0001], -0.7% [p = 1.00], and -6.5% [p = 0.0963], respectively) post-ELX/TEZ/IVA. The source of bacterial culture was predominantly sputum (70.2%) in the pre-ELX/TEZ/IVA group, whereas a throat source (66.1%) was more common post-ELX/TEZ/IVA.. ELX/TEZ/IVA treatment has an appreciable impact on the detection of common bacterial pathogens in CF respiratory cultures. While previous studies have found a similar effect with single and double CFTR modulator therapies, this is the first single-center study to show the impact of triple therapy, ELX/TEZ/IVA, on bacterial isolation from airway secretions.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pseudomonas aeruginosa; Retrospective Studies

To evaluate the effectiveness of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and to characterize its safety profile in cystic fibrosis (CF) patients in a real-world clinical setting.. This was a prospective observational study carried out in a CF referral center in Portugal involving adult CF patients who started treatment with ELX/TEZ/IVA. Clinical characteristics of the patients were collected, and effectiveness and safety data were evaluated.. Of the 56 patients followed in the center at the time of the study, 28 were eligible for ELX/TEZ/IVA treatment in accordance with the Portuguese National Authority for Medicines and Health Products at the time of the study. Of these, 24 met the follow-up time requirement to be included in the clinical effectiveness analysis. The mean follow-up time was 167.3 ± 96.4 days. Adverse events were generally mild and self-limited. Significant improvements in lung function, BMI, sweat chloride concentration, and number of pulmonary exacerbations were observed. No significant differences in outcomes between F508del homozygous and heterozygous patients were found. The effectiveness of this new CFTR modulator combination also applied to patients with advanced lung disease.. Treatment with ELX/TEZ/IVA showed effective improvement in real-world clinical practice, namely in lung function, BMI, sweat chloride concentration, and number of pulmonary exacerbations, with no safety concerns.

Topics: Adult; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Portugal; Treatment Outcome

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators represent targeted therapies directly acting on the CFTR channel. The triple therapy Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) has been demonstrated to improve lung function and quality of life in cystic fibrosis (CF) patients. However, the effects of ELX/TEZ/IVA on sleep-disordered breathing (SDB) and respiratory muscle strength are poorly studied. The aim of this study was to assess the effects of ELX/TEZ/IVA in patients with CF and severe lung disease on cardiorespiratory polygraphy parameters, maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) measures.. patients with CF aged ≥ 12 who started treatment in a compassionate use program were retrospectively studied through the evaluation of nocturnal cardiorespiratory polygraphy parameters, MIP and MEP; and six-minute walk test (6MWT) at baseline and at months 3, 6, and 12 of treatment.. Nine patients (mean age 30.3 ± 6.5 years) with severe CF (mean baseline ppFEV1 34.6 ± 5.1%) were evaluated. A significant improvement in nocturnal oxygenation measured by mean SpO. We provide further evidence on the efficacy of the CFTR modulators ELX/TEZ/IVA, adding information about their effect on the respiratory muscles' performance and cardiorespiratory polygraphy parameters in CF patients with severe lung disease.

Topics: Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Quality of Life; Respiratory Muscles; Respiratory Rate; Retrospective Studies; Young Adult

A series of phase 3 clinical trials have demonstrated that elexacaftor plus tezacaftor plus ivacaftor (ELX/TEZ/IVA) is safe and efficacious in people with cystic fibrosis (pwCF) aged ≥12 years with ≥1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impact of this treatment on lifetime clinical outcomes and survival, however, has yet to be assessed.. We used a person-level microsimulation model to estimate the survival and lifetime clinical benefits of ELX/TEZ/IVA treatment versus other CFTR modulator combinations (tezacaftor plus ivacaftor [TEZ/IVA] or lumacaftor plus ivacaftor [LUM/IVA]) or best supportive care (BSC) alone in pwCF aged ≥12 years who are homozygous for F508del-CFTR. Disease progression inputs were derived from published literature; clinical efficacy inputs were derived from an indirect treatment comparison conducted using relevant phase 3 clinical trial data and extrapolations of clinical data.. The median projected survival for pwCF homozygous for F508del-CFTR treated with ELX/TEZ/IVA was 71.6 years. This was an increase of 23.2 years versus TEZ/IVA, 26.2 years versus LUM/IVA, and 33.5 years versus BSC alone. Treatment with ELX/TEZ/IVA also reduced disease severity as well as the number of pulmonary exacerbations and lung transplants. In a scenario analysis, the median projected survival for pwCF initiating ELX/TEZ/IVA between the ages of 12 and 17 years was 82.5 years, an increase of 45.4 years compared with BSC alone.. The results from our model suggest ELX/TEZ/IVA treatment may substantially increase survival for pwCF, with early initiation potentially allowing pwCF to achieve near-normal life expectancy.

Topics: Adolescent; Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Treatment Outcome

Elexacaftor/tezacaftor/ivacaftor (ETI) treatment is associated with significant improvement in lung function in people with cystic fibrosis (pwCF); however, some patients experience adverse effects (AEs) including hepatotoxicity. One potential strategy is dose reduction in ETI with the goal of maintaining therapeutic efficacy while resolving AEs. We report our experience of dose reduction in individuals who experienced AEs following ETI therapy. We provide mechanistic support for ETI dose reduction by exploring predicted lung exposures and underlying pharmacokinetics-pharmacodynamics (PK-PD) relationships.. Adults prescribed ETI who underwent dose reduction due to the AEs were included in this case series, and their percent predicted forced expiratory volume in 1 s (ppFEV. Fifteen patients underwent dose reduction in ETI due to AEs. Clinical stability without significant changes in ppFEV. Albeit in a small number of patients, this study provides evidence that reduced ETI doses in pwCF who have experienced AEs may be effective. The PBPK models enable exploration of a mechanistic basis for this finding by simulating target tissue concentrations of ETI that can be compared with drug efficacy in vitro.

Topics: Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Tapering; Humans; Mutation

Topics: Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Sputum

Cystic fibrosis (CF), especially CF lung disease, is characterized by chronic infection, immune dysfunction including impairment of regulatory T cells (Tregs) and an exaggerated inflammatory response. CF transmembrane conductance regulator (CFTR) modulators have shown to improve clinical outcomes in people with CF (PwCF) with a wide range of CFTR mutations. However, it remains unclear whether CFTR modulator therapy also affects CF-associated inflammation. We aimed to examine the effect of elexacaftor/tezacaftor/ivacaftor therapy on lymphocyte subsets and systemic cytokines in PwCF.. Peripheral blood mononuclear cells and plasma were collected before and at three and six months after the initiation of elexacaftor/tezacaftor/ivacaftor therapy; lymphocyte subsets and systemic cytokines were determined using flow cytometry.. Elexacaftor/tezacaftor/ivacaftor treatment was initiated in 77 PwCF and improved percent predicted FEV1 by 12.5 points (p<0.001) at 3 months. During elexacaftor/tezacaftor/ivacaftor therapy, percentages of Tregs were enhanced (+18.7%, p<0.001), with an increased proportion of Tregs expressing CD39 as a marker of stability (+14.4%, p<0.001). Treg enhancement was more pronounced in PwCF clearing Pseudomonas aeruginosa infection. Only minor, non-significant shifts were observed among Th1-, Th2- and Th17-expressing effector T helper cells. These results were stable at 3- and 6-month follow-up. Cytokine measurements showed a significant decrease in interleukin-6 levels during treatment with elexacaftor/tezacaftor/ivacaftor (-50.2%, p<0.001).. Treatment with elexacaftor/tezacaftor/ivacaftor was associated with an increased percentage of Tregs, especially in PwCF clearing Pseudomonas aeruginosa infection. Targeting Treg homeostasis is a therapeutic option for PwCF with persistent Treg impairment.

Topics: Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Humans; Leukocytes, Mononuclear; Pseudomonas Infections; T-Lymphocytes, Regulatory

Cystic fibrosis transmembrane regulator (CFTR) modulators treat defective CFTR protein. Our objective is to describe the course of children with cystic fibrosis treated with lumacaftor/ivacaftor. This is a case series of 13 patients aged 6 to 18 years with ≥ 6 months of treatment. Forced expiratory volume in the first second (FEV1), body mass index (BMI) Z-score, antibiotic therapy/year, before treatment and for 24 months after treatment were analyzed. At 12 months (9/13) and 24 months (5/13), the median change in the percent predicted FEV1 (ppFEV1) was 0.5 pp (-2-12) and 15 pp (8.7-15.2) and the BMI Z-score was 0.32 points (-0.2-0.5) and 1.23 points (0.3-1.6). In the first year, in 11/13 patients, the median number of days of antibiotic use decreased from 57 to 28 (oral) and from 27 to 0 (intravenous). Two children had associated adverse events.. Los moduladores de la proteína reguladora transmembrana de fibrosis quística (CFTR) tratan el defecto de esta proteína. El objetivo es describir la evolución de niños con fibrosis quística tratados con lumacaftor/ivacaftor. Se trata de una serie de 13 pacientes de 6 a 18 años con ≥ 6 meses de tratamiento. Se analizaron el volumen espiratorio forzado en el primer segundo (VEF1), puntaje Z del índice de masa corporal (IMC), antibioticoterapia/año, antes del tratamiento y durante 24 meses posteriores. A los 12 meses (9/13) y 24 meses (5/13), la mediana de cambio del porcentaje del predicho VEF1 (ppVEF1) fue de 0,5 pp [-2-12] y 15 pp [8,7-15,2], y del puntaje Z de IMC de 0,32 puntos [-0,2-0,5] y 1,23 puntos [0,3-1,6]. El primer año (11/13) la mediana de días de uso de antibiótico disminuyó de 57 a 28 (oral) y de 27 a 0 (intravenoso). Dos niños evidenciaron eventos adversos asociados.

Topics: Aminophenols; Anti-Bacterial Agents; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forced Expiratory Volume; Hospitals; Humans; Mutation

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have changed the clinical landscape of cystic fibrosis (CF) by improving clinically significant outcome measures and quality of life of people with CF (pwCF). There are now long-term data showing improved 5-year survival with the use of ivacaftor, and the field continues to evolve at a rapid pace with the continued development of highly effective CFTR modulators. While the randomized controlled trials of CFTR modulators excluded patients with severe lung disease (forced expiratory volume in 1 second <40% predicted), observational data based on case reports and registry data show similar benefits in those with advanced lung disease. This has altered clinical practice particularly as it pertains to the role of lung transplantation in CF. This article describes the impact of highly effective modulator therapy (HEMT) on the natural history of CF and the influence on the timing of referral and consideration of listing for lung transplantation. CF clinicians play a pivotal role to ensure that the impetus of the CF foundation consensus guidelines to facilitate timely referral for lung transplantation is not lost among the excitement of anticipated sustained benefit from HEMT. While the widespread availability of elexacaftor/tezacaftor/ivacaftor over the past 2 years has been associated with a sharp drop in the number of people referred for consideration for lung transplantation and the number of people wait-listed for lung transplantation, it is difficult to accurately determine the true impact due to the confounding effect of the coronavirus disease 2019 pandemic. It is expected that lung transplantation will remain an important treatment for a smaller number of pwCF. Lung transplantation offers survival benefits in CF, and there remains an imperative to ensure timely consideration of lung transplantation in patients with advanced disease to further reduce the number of pwCF dying without consideration of lung transplant.

Topics: COVID-19; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung Transplantation; Mutation; Quality of Life

Cystic fibrosis transmembrane conductance regulator modulator therapy is associated with substantial clinical benefit and improved quality of life in patients with cystic fibrosis (CF). While their effect on lung function has been clearly reported, we are still in the process of unraveling the full impact they have on the pancreas. We present two cases of pancreatic-insufficient CF patients who presented with acute pancreatitis shortly after commencing elexacaftor/tezacaftor/ivacaftor modulator therapy. Both patients were treated with ivacaftor for 5 years prior to elexacaftor/tezacaftor/ivacaftor initiation, but had no previous episodes of acute pancreatitis. We suggest that highly effective modulator combination therapy may restore additional pancreatic acinar activity, resulting in the development of acute pancreatitis in the interim until ductal flow is improved. This report adds to the growing evidence for possible restoration of pancreatic function in patients receiving modulator therapy, and highlights that treatment with elexacaftor/tezacaftor/ivacaftor may be associated with acute pancreatitis until ductal flow is restored, even in pancreatic-insufficient CF patients.

Topics: Acute Disease; Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pancreatitis; Quality of Life

The effects of elexacaftor-tezacaftor-ivacaftor (ETI) on body composition in people with CF (pwCF) are unknown.. Dual-energy X-ray absorptiometry fat-free mass and fat mass adjusted for height (FMI) as well as oral glucose tolerance test derived measures of insulin secretion and sensitivity were compared before and after ETI initiation in eight pwCF.. Patients median age: 22 years interquartile range (IQR: 16-28), 87.5% male, median time on ETI:11 months. Weight z-score increased from -0.52 to 0.18 (p = 0.014); FMI increased from 4.12 to 6.29 (p = 0.014). Insulin secretion (C pep iAUC/Gluc iAUC) increased from 8.71 to 14.21 (p = 0.021), insulin resistance (HOMA2 IR) increased from 0.73 to 1.25 (p = 0.014) and insulin sensitivity decreased (Matsuda) 8.88 to 5.58 (p = 0.036).. ETI resulted in increased weight and fat mass. BMI and muscle mass did not change. Both insulin secretion and insulin resistance increased. Longer-term metabolic consequences of ETI need further investigation.

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Body Composition; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Insulin Resistance; Male; Mutation; Young Adult

Topics: Cholecystitis, Acute; Cystic Fibrosis; Drug Combinations; Humans; Mutation; Pyrrolidines

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Lung; Mutation

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Allosteric Regulation; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Electric Conductivity; Electrophysiology; Fluorescence Resonance Energy Transfer; Humans; Ion Channel Gating; Protein Multimerization

Topics: Alleles; Benzodioxoles; Colforsin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Middle Aged; Mutation

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelium; Humans; Macrophages

Acquired cystic fibrosis transmembrane regulator (CFTR) dysfunctions have been associated with several conditions, including myocardial infarction (MI). Here, CFTR is downregulated in brain, heart, and lung tissue and associates with inflammation and degenerative processes. Therapeutically increasing CFTR expression attenuates these effects. Whether potentiating CFTR function yields similar beneficial effects post-MI is unknown. The CFTR potentiator ivacaftor is currently in clinical trials for treatment of acquired CFTR dysfunction associated with chronic obstructive pulmonary disease and chronic bronchitis. Thus, we tested ivacaftor as therapeutic strategy for MI-associated target tissue inflammation that is characterized by CFTR alterations. MI was induced in male C57Bl/6 mice by ligation of the left anterior descending coronary artery. Mice were treated with ivacaftor starting ten weeks post-MI for two consecutive weeks. Systemic ivacaftor treatment ameliorates hippocampal neuron dendritic atrophy and spine loss and attenuates hippocampus-dependent memory deficits occurring post-MI. Similarly, ivacaftor therapy mitigates MI-associated neuroinflammation (i.e., reduces higher proportions of activated microglia). Systemically, ivacaftor leads to higher frequencies of circulating Ly6C

Topics: Animals; Brain; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Inflammation; Lung; Male; Mice; Mutation; Myocardial Infarction

Cystic fibrosis (CF) is a rare genetic disease characterized by life-shortening lung function decline. Ivacaftor, a CF transmembrane conductance regulator modulator (CFTRm), was approved in 2012 for people with CF with specific gene mutations. We used real-world evidence of 5-year mortality impacts of ivacaftor in a US registry population to validate a CF disease-progression model that estimates the impact of ivacaftor on survival.. The model projects the impact of ivacaftor vs. standard care in people with CF aged ≥6 years with CFTR gating mutations by combining parametric equations fitted to historical registry survival data, with mortality hazards adjusted for fixed and time-varying person-level characteristics. Disease progression with standard care was derived from published registry studies and the expected impact of ivacaftor on clinical characteristics was derived from clinical trials. Individual-level baseline characteristics of the registry ivacaftor-treated population were entered into the model; 5-year model-projected mortality with credible intervals (CrIs) was compared with registry mortality to evaluate the model's validity.. Post-calibration 5-year mortality projections closely approximated registry mortality in populations treated with standard care (6.4% modeled [95% CrI: 5.3% to 7.6%] vs. 6.0% observed) and ivacaftor (3.4% modeled [95% CrI: 2.7% to 4.4%] vs. 3.1% observed). The model accurately predicted 5-year relative risk of mortality (0.53 modeled [0.47 to 0.60] vs. 0.51 observed) in people treated with ivacaftor vs. standard care.. Modeled 5-year survival projections for people with CF initiating ivacaftor vs. standard care align closely with real-world registry data. Findings support the validity of modeling CF to predict long-term survival and estimate clinical and economic outcomes of CFTRm.

Topics: Aminophenols; Calibration; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Routinely Collected Health Data; United States

We present the case of a girl (now 11 years and 9 months old) with cystic fibrosis (F508del homozygote), who developed pruritic rash and urticaria six days after the first dose of the CFTR modulators lumacaftor/ivacaftor. The treatment was paused and had to be interrupted due to an immediate recurrence of the urticarial rash after rechallenge. We developed a drug desensitization protocol, aligned to protocols used for desensitization against oral antibiotics. In contrast to other published protocols, it was performed by rapidly increasing the dose of lumacaftor/ivacaftor granulate at 15 min intervals. The medication was continued without interruption, the rash did not reappear during follow-up of two years. This drug desensitization protocol provides a potential new therapeutic option for patients with drug hypersensitivity reactions to CFTR modulators, especially when there are no alternative treatments. Lumacaftor/ivacaftor is available as granulate, doses can be titrated during desensitization and used for long-term treatment.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Drug Tolerance; Exanthema; Female; Forced Expiratory Volume; Humans; Infant; Mutation

Since patients with cystic fibrosis with different Cystic Fibrosis Transmembrane Regulator (CFTR) genotypes present a wide response variability for modulator drugs such as Orkambi®, it is important to screen variants in candidate genes with an impact on precision and personalized medicine, such as Solute Carrier Family 26, member 9 (SLC26A9) gene.. Sanger sequencing for the exons and intron-exon boundary junctions of the SLC26A9 gene was employed in nine individuals with p.Phe508del homozygous genotype for the CFTR gene who were not under CFTR modulators therapy. The sequencing variants were evaluated by in silico prediction tools. The CFTR function was measured by cAMP-stimulated current (ΔIsc-eq-FSK) in polarized CFTR of human nasal epithelial cells cultured in micro-Ussing chambers with Orkambi®.. We found 24 intronic variants, three in the coding region (missense variants - rs74146719 and rs16856462 and synonymous - rs33943971), and three in the three prime untranslated region (3' UTR) region in the SLC26A9 gene. Twenty variants were considered benign according to American College of Medical Genetics and Genomics guidelines, and ten were classified as uncertain significance. Although some variants had deleterious predictions or possible alterations in splicing, the majority of predictions were benign or neutral. When we analyzed the ΔIsc-eq-FSK response to Orkambi®, there were no significant differences within the genotypes and alleles for all 30 variants in the SLC26A9 gene.. Among the nine individuals with p.Phe508del homozygous genotype for the CFTR gene, no pathogenic SLC26A9 variants were found, and we did not detect associations from the 30 SLC26A9 variants and the response to the Orkambi® in vitro.

Topics: Antiporters; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Nucleotides; Sulfate Transporters

We previously documented that elevated HE4 plasma concentration decreased in people with CF (pwCF) bearing the p.Gly551Asp-CFTR variant in response to CFTR modulator (CFTRm) ivacaftor (IVA), and this level was inversely correlated with the FEV1% predicted values (ppFEV1). Although the effectiveness of lumacaftor (LUM)/IVA in pwCF homozygous for the p.Phe508del-CFTR variant has been evaluated, plasma biomarkers were not used to monitor treatment efficacy thus far.. Plasma HE4 concentration was examined in 68 pwCF drawn from the PROSPECT study who were homozygous for the p.Phe508del-CFTR variant before treatment and at 1, 3, 6 and 12 months after administration of LUM/IVA therapy. Plasma HE4 was correlated with ppFEV1 using their absolute and delta values. The discriminatory power of delta HE4 was evaluated for the detection of lung function improvements based on ROC-AUC analysis and multiple regression test.. HE4 plasma concentration was significantly reduced below baseline following LUM/IVA administration during the entire study period. The mean change of ppFEV1 was 2.6% (95% CI, 0.6 to 4.5) by 6 months of therapy in this sub-cohort. A significant inverse correlation between delta values of HE4 and ppFEV1 was observed especially in children with CF (r=-0.7053; p<0.0001). Delta HE4 predicted a 2.6% mean change in ppFEV1 (AUC: 0.7898 [95% CI 0.6823-0.8972]; P < 0.0001) at a cut-off value of -10.7 pmol/L. Moreover, delta HE4 independently represented the likelihood of being a responder with ≥ 5% delta ppFEV1 at 6 months (OR: 0.89, 95% CI: 0.82-0.95; P = 0.001).. Plasma HE4 level negatively correlates with lung function improvement assessed by ppFEV1 in pwCF undergoing LUM/IVA CFTRm treatment.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Homozygote; Humans; Mutation

We report here how the triple combination of drugs elexacaftor/tezacaftor/ivacaftor (ETI) alters the balance of the de-novo synthethic pathway of sphingolipids in primary cells of human bronchial epithelium. The treatment with ETI roughly doubles the levels of dihydrosphingolipids, possibly by modulating the delta(4)-desaturase enzymes that convert dihydroceramides into ceramides. This appears to be an off-target effect of ETI, since it occurs in a genotype-independent manner, for both cystic fibrosis (CF) and non-CF subjects.

Topics: Aminophenols; Benzodioxoles; Ceramides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Humans; Mutation

To assess the feasibility of enrolling people with CF (pwCF) taking the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) in clinical trials of a new modulator.. PwCF receiving ETI at CHEC-SC study (NCT03350828) enrollment were surveyed for interest in 2-week to 6-month placebo- (PC) and active-comparator (AC) modulator studies. Those taking inhaled antimicrobials (inhABX) were surveyed for interest in PC inhABX studies.. Of 1791 respondents, 75% [95% CI 73, 77] would enroll in a 2-week PC modulator study versus 51% [49, 54] for a 6-month study; 82% [81, 84] and 63% [61, 65] would enroll in 2-week and 6 month AC studies; 77% [74, 80] of 551 taking inhABX would enroll in a 2-week PC inhABX study versus 59% [55, 63] for a 6-month study. Previous clinical trial experience increased willingness.. Study designs will affect feasibility of future clinical trials of new modulators and inhABX in people receiving ETI.

Topics: Aminophenols; Anti-Infective Agents; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation

Cystic fibrosis is a severe, autosomal recessive disease that shortens life expectancy. According to studies, approximately 27% of patients with CF aged 2-5 years and 60 to 70% of adult patients are infected with P. aeruginosa. The patients experience bronchospasm leading to a persistent contracted state of the airways.. The current work explores the possibility of combining ivacaftor and ciprofloxacin to combat the bacteria. A third drug L-salbutamol would be coated onto the surface of the drug-entrappped microparticles to instantaneously provide relief from bronchoconstriction.. The microparticles were prepared using bovine serum albumin and L-leucine using the freeze-drying approach. The process and formulation parameters were optimized. The prepared microparticles were surface coated by L-salbutamol using the dry-blending method. The microparticles were subjected to rigorous in-vitro characterization for entrapment, inhalability, antimicrobial activity, cytotoxicity study and safety. The performance of the microparticles to be loaded into a inhaler was checked by the Anderson cascade impactor.. The freeze-dried microparticles had a particle size of 817.5 ± 5.6 nm with a polydispersity ratio of 0.33. They had a zeta potential of -23.3 ± 1.1 mV. The mass median aerodynamic diameter of the microparticles was 3.75 ± 0.07 μm, and the geometric standard diameter was 1.66 ± 0.033 μm. The microparticles showed good loading efficiency for all three drugs. DSC, SEM, XRD, and FTIR studies confirmed the entrapment of ivacaftor and ciprofloxacin. SEM and TEM scans observed the shape and the smooth surface. Antimicrobial synergism was proven by the agar broth, and dilution technique and the formulation was deemed safe by the results of the MTT assay.. Freeze-dried microparticles of ivacaftor, ciprofloxacin, and L-salbutamol could pave way to a hitherto unexplored combination of drugs as a novel approach to treat P. aeruginosa infcetions and bronchoconstriction commonly associated with cystic fibrosis.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Ciprofloxacin; Cystic Fibrosis; Dry Powder Inhalers; Humans; Particle Size

Children with cystic fibrosis are at risk of fat-soluble vitamin deficiency. CFTR modulators positively effect nutritional status. This study aimed to assess changes in serum vitamins A, D & E after starting ETI therapy to ensure levels were not abnormally high.. Retrospective review of annual assessment data over 3½ years, before and after starting ETI in a specialist paediatric CF centre, including vitamin levels.. 54 eligible patients were included, aged 5-15 yrs (median age 11.5). Median time to post measurements was 171 days. Median vitamin A was increased (1.38 to 1.63 µmol/L, p<0.001). Three patients (6%) had high vitamin A post-ETI, compared with none at baseline; and 2 (4%) had low levels compared to 4 (8%) at baseline. No changes in vitamins D&E.. This study found increased vitamin A, sometimes to high levels. We recommend testing levels within 3 months of starting ETI.

Topics: Aminophenols; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Vitamin A; Vitamins

Topics: Aminophenols; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Intracranial Pressure; Mutation

Topics: Alleles; Child; Cystic Fibrosis; Humans; Iodine

Cystic fibrosis (CF) is a genetic disease that results in dysfunction of the CF transmembrane conductance regulator (CFTR) protein, which is a chloride and bicarbonate channel expressed in the apical portion of epithelial cells of various organs. Dysfunction of that protein results in diverse clinical manifestations, primarily involving the respiratory and gastrointestinal systems, impairing quality of life and reducing life expectancy. Although CF is still an incurable pathology, the therapeutic and prognostic perspectives are now totally different and much more favorable. The purpose of these guidelines is to define evidence-based recommendations regarding the use of pharmacological agents in the treatment of the pulmonary symptoms of CF in Brazil. Questions in the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) format were employed to address aspects related to the use of modulators of this protein (ivacaftor, lumacaftor+ivacaftor, and tezacaftor+ivacaftor), use of dornase alfa, eradication therapy and chronic suppression of Pseudomonas aeruginosa, and eradication of methicillin-resistant Staphylococcus aureus and Burkholderia cepacia complex. To formulate the PICO questions, a group of Brazilian specialists was assembled and a systematic review was carried out on the themes, with meta-analysis when applicable. The results obtained were analyzed in terms of the strength of the evidence compiled, the recommendations being devised by employing the GRADE approach. We believe that these guidelines represent a major advance to be incorporated into the approach to patients with CF, mainly aiming to favor the management of the disease, and could become an auxiliary tool in the definition of public policies related to CF.

Topics: Brazil; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Methicillin-Resistant Staphylococcus aureus; Mutation; Quality of Life

Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to improve lung function in people with cystic fibrosis (PWCF). However, its biological effects remain incompletely understood. Here we describe alterations in pulmonary and systemic inflammation in PWCF following initiation of ETI. To address this, we collected spontaneously expectorated sputum and matching plasma from PWCF (n=30) immediately prior to ETI therapy, then again at 3 and 12 months. Within 3 months, PWCF demonstrated reduced activity of neutrophil elastase, proteinase three and cathepsin G, and decreased concentrations of interleukin (IL)-1β and IL-8 in sputum, accompanied by decreased

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Inflammation; Mutation

In people with cystic fibrosis (pwCF), the impact of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, such as Elexacaftor-Tezacaftor-Ivacaftor (ETI), on structural changes in the lungs is unclear.. To determine the impact of ETI on clinical parameters and on structural lung disease as measured by the changes in the chest computed tomography (CT) scans in pwCF.. Percent predicted forced expiratory volume in one second (ppFEV1), body mass index (BMI), and microbiologic data were collected at initiation and 3-month intervals for 1 year. Chest CT scans before starting ETI therapy (baseline) and at 1-year on ETI therapy were compared by two pulmonologists independently.. The sample size was 67 pwCF, 30 (44.8%) males, median age of 25 (16, 33.5) years. Significant increases in ppFEV1 and BMI observed by 3 months of ETI therapy persisted throughout 1 year of ETI therapy (p < 0.001 at all-time points for both). After 1 year on ETI, pwCF had significant reductions in Pseudomonas aeruginosa (-42%) and MRSA (-42%) positivity. None of the pwCF had worsening of chest CT parameters during 1 year of ETI therapy. Comparing chest CT findings at baseline and at 1-year follow-up, bronchiectasis was present in 65 (97%) pwCF and at 1-year follow-up decreased in 7 (11%). Bronchial wall thickening 64 (97%), decreased in 53 (79%). Mucous plugging in 63 (96%), absent in 11 (17%), and decreased in 50 (77%). Hyperinflation/air trapping in 44 (67%), decreased in 11 (18%), absent in 27 (44%) CONCLUSIONS: ETI significantly improved clinical outcomes and lung disease as documented by improvement in chest CT scans.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Mutation; Pyrazoles

Ivacaftor approval was extended to people with cystic fibrosis (CF) and an. Key outcomes were evaluated in ivacaftor-treated people with CF and an. The ivacaftor cohort included 369 people with CF and an. The results support the clinical effectiveness of ivacaftor in people with CF and an

Topics: Adult; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Registries

Elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with unprecedented clinical improvements, transforming the management of cystic fibrosis (CF). However, side effects with implications for safety and well-being have been reported, including neuropsychiatric changes. This study aimed to better characterize the emerging positive and negative impacts of ETI.. The Cystic Fibrosis Foundation's Mental Health Advisory Committee distributed a 26-item survey to US CF care teams to assess clinician observations of patient-reported experiences with ETI. Survey responses measured the prevalence of these effects in five domains: (1) positive physical and psychological effects, (2) sleep difficulties, (3) cognitive difficulties, (4) worsening mental health, and (5) concerns about the future and finances.. Seventy-five healthcare providers responded from a pediatric, adult, and combined centers. Positive physical effects of ETI and increased optimism were reported in the upper quartiles (50%-100%) and rated as having a significant impact on daily functioning. Sleep and cognitive difficulties were reported in 1%-24%, with slight impacts on functioning, and psychological symptoms (e.g., increased stress, depression, anxiety) and new psychiatric medications were reported in 1%-24%, with moderate impacts. Concerns about the future were reported in 1%-24%, with minimal impacts.. Across US centers, providers most often observed positive physical effects of ETI. However, a variety of negative side effects were also reported, including sleep disruptions and worsening psychological functioning, which should be systematically monitored by CF teams. These national-level data are a first step in evaluating the prevalence and consequences of these side effects and can directly inform future studies.

Topics: Adult; Aminophenols; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug-Related Side Effects and Adverse Reactions; Health Personnel; Humans; Mutation

The introduction of the novel therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been effective in improving weight gain in both clinical trials and real-world studies. However, the magnitude of this effect appears to be heterogeneous across patient subgroups. This study aims to identify potential determinants of heterogeneity in weight gain following 6-month ETI therapy.. We conducted a multicenter, prospective cohort study enrolling 92 adults with CF at two major CF centers in Italy with follow-up visit at one month and six months from ETI initiation. The treatment's effect on weight changes was evaluated using mixed effect regression models that included subject-specific random intercepts and fixed effects for potential predictors of treatment response, time and a predictor-by-time interaction term.. The mean weight gain at six months from the start of treatment was 4.6 kg (95% CI: 2.3-6.9) for the 10 patients with underweight, 3.2 kg (95% CI: 2.3-4.0) for the 72 patients with normal weight, and 0.7 kg (95% CI: -1.6-3.0) for the 10 patients with overweight. After six months of ETI treatment, 8 (80%) of the patients with underweight transitioned to the normal weight category, while 11 (15.3%) of the normal-weight patients became overweight. The major determinants of heterogeneity in weight gain were the baseline BMI and the presence of at least one CFTR residual function mutation, explaining 13% and 8% of the variability, respectively.. Our results indicate that ETI is highly effective in improving weight gain in underweight subjects with CF. However, our data also suggests the need for close monitoring of excess weight gain to prevent potential cardiometabolic complications.

Topics: Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Overweight; Prospective Studies; Thinness; Weight Gain

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA.. Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment.. Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m. This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation

Life expectancy for people with CF (PwCF) continues to increase. However, a trend of overweight and obesity is emerging along with concern of developing comorbitities. Body composition (BC) is associated with several health indices. However, body mass index (BMI) does not provide information on BC.. BMI, fat mass (FM), fat free mass (FFM), using bioelectrical impedance, lung function and sweat chloride (SwCl) were assessed in adult PwCF in routine clinic before and after commencement of the CFTR modulator Elexacaftor/Tezacaftor/Ivacaftor.. 109 PwCF (76 male) underwent assessments at both time points. In all PwCF a significant upward trend in BMI was observed (p < 0.001). Males significantly gained more FFM compared to females (p0.03), whilst prevalence of normal weight obesity increased primarily in females (25-38%).. Routine BC assessment identifies individuals with elevated FM or depleted FFM enabling individualised care with the focus of optimising BC.

Topics: Adult; Aminophenols; Benzodioxoles; Body Composition; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Mutation; Obesity

Despite the promising results of new CFTR targeting drugs designed for the recovery of F508del- and class III variants activity, none of them have been approved for individuals with selected rare mutations, because uncharacterized CFTR variants lack information associated with the ability of these compounds in recovering their molecular defects. Here we used both rectal organoids (colonoids) and primary nasal brushed cells (hNEC) derived from a CF patient homozygous for A559T (c.1675G>A) variant to evaluate the responsiveness of this pathogenic variant to available CFTR targeted drugs that include VX-770, VX-809, VX-661 and VX-661 combined with VX-445. A559T is a rare mutation, found in African-Americans people with CF (PwCF) with only 85 patients registered in the CFTR2 database. At present, there is no treatment approved by FDA (U.S. Food and Drug Administration) for this genotype. Short-circuit current (Isc) measurements indicate that A559T-CFTR presents a minimal function. The acute addition of VX-770 following CFTR activation by forskolin had no significant increment of baseline level of anion transport in both colonoids and nasal cells. However, the combined treatment, VX-661-VX-445, significantly increases the chloride secretion in A559T-colonoids monolayers and hNEC, reaching approximately 10% of WT-CFTR function. These results were confirmed by forskolin-induced swelling assay and by western blotting in rectal organoids. Overall, our data show a relevant response to VX-661-VX-445 in rectal organoids and hNEC with CFTR genotype A559T/A559T. This could provide a strong rationale for treating patients carrying this variant with VX-661-VX-445-VX-770 combination.

Topics: Benzodioxoles; Colforsin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Humans; Mutation; Organoids

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Gilbert Disease; Humans; Hyperbilirubinemia; Mutation

Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease.. Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations.. Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV. ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug.

Topics: Adult; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quality of Life; Young Adult

Background The triple combination of the cystic fibrosis transmembrane regulator (CFTR) modulators elexacaftor, tezacaftor, and ivacaftor (hereafter, elexacaftor/tezacaftor/ivacaftor) has a positive effect on lung function in patients with cystic fibrosis (CF). Purpose To compare three-dimensional (3D) ultrashort echo time (UTE) MRI functional lung data to common functional lung parameters in assessing lung function in patients with CF undergoing elexacaftor/tezacaftor/ivacaftor therapy. Materials and Methods In this prospective feasibility study, 16 participants with CF consented to undergo pulmonary MRI with a breath-hold 3D UTE sequence at baseline (April 2018-June 2019) and follow-up (April-July 2021). Eight participants received elexacaftor/tezacaftor/ivacaftor after baseline, and eight participants with unchanged treatment served as the control group. Lung function was assessed with body plethysmography and lung clearance index (LCI). Image-based functional lung parameters, such as ventilation inhomogeneity and ventilation defect percentage (VDP), were calculated from signal intensity change between MRI scans at inspiration and expiration. Metrics at baseline and follow-up were compared within groups (permutation test), correlation was tested (Spearman rank correlation), and 95% CIs were calculated (bootstrapping technique). Results MRI ventilation inhomogeneity correlated with LCI at baseline (

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Magnetic Resonance Imaging; Mutation; Prospective Studies

Pulmonary exacerbations (PEx) remain a major cause of morbidity and mortality in people with cystic fibrosis (PWCF). Although the combination cystic fibrosis transmembrane conductance regulator (CFTR) modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor have been shown to reduce PEx frequency, their influence on clinical and biochemical responses to acute PEx treatment is unknown.. We performed a secondary analysis of STOP2, a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx. Propensity score matching was used to compare outcomes in antibiotic-treated F508del/F508del PWCF receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor with those observed in antibiotic-treated F508del/F508del controls not receiving CFTR modulator therapy. The primary outcome measure was the change in percent predicted FEV. Among 982 PEx events in randomized PWCF, 480 were homozygous for F508del, of whom 289 were receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor at initiation of antibiotic therapy. Modulator-treated F508del/F508del PWCF did not demonstrate greater improvements in ppFEV. In the acute setting, CFTR modulator therapy with lumacaftor/ivacaftor or tezacaftor/ivacaftor does not convey additional clinical or biochemical advantage above standardized PEx treatment in F508del/F508del PWCF.

Topics: Adult; Aminophenols; Anti-Bacterial Agents; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Female; Humans; Male; Multicenter Studies as Topic; Mutation; Randomized Controlled Trials as Topic

Recent studies demonstrated that the triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in cystic fibrosis (CF) patients with at least one. In this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ETI.. In total, 79 patients with CF and at least one. Our data demonstrate that restoration of CFTR function by ETI improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Proteome; Sputum

Highly effective CFTR modulators improve nutritional status and are of particular importance among younger children experiencing rapid growth. This study was designed to examine CFTR modulator associated changes in nutritional and other extrapulmonary outcomes in children 4-24 months of age with ivacaftor treatment over 12 weeks.. Children 4-24 months were recruited from US and Canadian CF Centers. Eligible children were ivacaftor naïve and approved to start therapy. Anthropometrics, diet, sleeping energy expenditure (SEE), nutrition biomarkers, pancreatic status, serum and fecal calprotectin, serum bile acids, plasma fatty acids were measured. Changes from baseline at 6 and 12 weeks were examined using mixed effects linear regression modeling.. Fifteen participants enrolled (40% male). Weight-for-age z-scores increased at 6 (p = 0.03) and 12 weeks ivacaftor therapy (p<0.001) compared to baseline. Plasma docosatetraenoic acid (DTA), total saturated fatty acids increased at 6 weeks (p = 0.02) and 12 weeks (p = 0.009). At 12 weeks, serum CO. Overall, younger children experienced favorable changes in nutritional and growth status in the first 12 weeks of ivacaftor therapy.

Topics: Aminophenols; Bile Acids and Salts; Canada; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Fatty Acids; Female; Humans; Infant; Male; Mutation; Nutritional Status

Topics: Blood Platelets; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Granulocytes; Humans; Monocytes

Cystic fibrosis (CF) is a disease caused by mutations in the gene located on chromosome 7 that encodes the CF transmembrane conductance regulator protein. Several trials have demonstrated the efficacy and safety of the ELE/TEZ/IVA combination in patients who have at least one F508del mutation. The main objective of the study was to evaluate the safety at 3 and 6 months of treatment with ELE/TEZ/IVA in adult patients with CF.. This is a real-life, prospective, single-center, cross-sectional study that included adult patients from the CF multidisciplinary unit. The demographic and clinical characteristics of all patients were recorded. During the time of the study, 3 visits were carried out (baseline, at 3 and at 6 months). Side effects were recorded during the follow-up time.. 3 months after the start of treatment, a statistically significant improvement was observed. of lung function, BMI, pulmonary exacerbations and energy level, as well as in all the categories of the CFQ-R questionnaire except in the digestive domain. This improvement was maintained, but not increased at 6 months in all variables, except BMI, where differences were observed between 3 and 6 months of treatment.. In the cohort studied, treatment with ELE/TEZ/IVA has a good safety profile. and produces an early improvement in lung function, BMI, quality of life and the "energy level" of adult patients with CF, which is maintained at 6 months of treatment.

Topics: Adult; Cross-Sectional Studies; Cystic Fibrosis; Humans; Mutation; Prospective Studies; Quality of Life

Cystic fibrosis (CF) causes infertility and subfertility due to various factors, including altered cervical mucus, delayed puberty, and hormonal imbalances. With the introduction of the CFTR modulator therapy elexacaftor-tezacaftor-ivacaftor, we have observed an increase in unplanned pregnancies among women undergoing ETI treatment in our CF center, despite repeated recommendations for strict fertility monitoring. It appears that these pregnancies are more likely attributed to reduced attention to the possibility of conception rather than contraceptive failure. The perception of subfertility developed by women with CF over time, before the era of modulators, can influence their long-term habits and lead to the underuse of contraceptive methods. While further research is needed to fully understand the effects of ETI on fertility, healthcare providers should be attentive to the fertility concerns of women with CF, particularly those treated with modulators in adulthood.

Topics: Chloride Channel Agonists; Cystic Fibrosis; Female; Humans; Infertility; Mutation; Pregnancy; Pregnancy, Unplanned; Pyrazoles

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a group of new drugs for the treatment of cystic fibrosis (CF) and elexacaftor + tezacaftor + ivacaftor (ETI) triple combination therapy has been approved as first choice therapy in the treatment of patients with at least 1 copy of F508del variation. Data on the effects of CFTR modulators on glucose metabolism are limited to small studies with conflicting results. We conducted a prospective observational study on 24 CF patients with CF-related diabetes requiring insulin therapy, with the aim to evaluate the effectiveness of ETI on glucose metabolism, glucose variability and body composition. After six months of treatment, HbA1c and coefficient of variation, measured through flash or continuous glucose monitoring, significantly decreased (median changes: -0.5, P = 0.029 and -6.3, P = 0.008, respectively), despite unchanged insulin requirements. Over the treatment period, percent of fat mass increased by a median value of 3% (p = 0.029).

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Body Composition; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Glycemic Control; Humans; Insulin; Mutation

Topics: Cystic Fibrosis; Humans; Inflammation; Sputum

The drug combination elexacaftor-tezacaftor-ivacaftor (ETI) proved highly effective in the improvement of the respiratory symptoms, the percentage of predicted forced expiratory volume in 1 s (FEV1), and to reduce rates of pulmonary exacerbations in people with cystic fibrosis (CF) with at least one F508del mutation. The objectives of the study were to evaluate the impact of ETI on the daily treatment burden due to patient decision and the evolution of lung function parameters at 6 months of treatment in real life.. A single-center observational study was realized including adult patients starting ETI therapy from March 10, 2020 to April 5, 2022. Clinical characteristics were collected at initiation (T0) and at 6 months (T6) of treatment. Outcome measures included names and number of chronic daily medications, respectively lung function parameters: FEV1, forced vital capacity (FVC), FEV1/FVC ratio, peak expiratory flow (PEF), forced expiratory flow at 25-75% of FVC (FEF25-75), β-angle and FEF50/PEF ratio.. Sixty-five patients were included with a mean age of 29.4 ± 8.5 years old, 48% of them F508del homozygous previously treated by lumacaftor-ivacaftor. At T6, the median number of daily medications decreased from 13 [2-24] to 9 [1-19] (p < 0.001). All the studied functional respiratory parameters were improved: FEV1 +18%, FVC +14%, FEF25-75% + 18% (all p < 0.001), as well the airflow obstruction: FEV1/FVC +6%, FEF50/PEF by 0.1 ± 0.1 and β-angle by 10° ± 13° (all p ≤ 0.007).. ETI therapy can reduce the daily treatment burden in real-life at 6 months of treatment, increase a large number of lung function parameters and improve airflow obstruction.

Topics: Adult; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Lung; Mutation; Pulmonary Disease, Chronic Obstructive; Young Adult

While elexacaftor/tezacaftor/ivacaftor (ETI) has improved the pulmonary health of many people with cystic fibrosis (PwCF), less is known about ETI effectiveness for extra-pulmonary manifestations, including fat-soluble vitamin malabsorption. This study aims to evaluate ETI's impact on vitamin A, D, E, and international normalized ratio (INR, an indirect marker for Vitamin K) serum levels.. Retrospective cohort study of PwCF ≥12 years receiving ETI. Vitamin levels up to four years preceding and up to two years following ETI initiation were collected. Pairwise comparisons of vitamin levels pre/post-ETI initiation were made using Wilcoxon signed rank and McNemar's tests. Linear mixed effect models were used to regress vitamin levels on time since starting ETI, ETI use (yes/no), the interaction between time and ETI use, and age.. Two hundred and sixty-four participants met study inclusion, and 169 (64%) had post-ETI initiation vitamin levels. Median vitamin A levels increased from 422.0 to 471.0 mcg/L (p < 0.001), median vitamin D levels increased from 28.5 to 30.8 ng/mL (p = 0.003), and there were no significant changes in median vitamin E or INR. Vitamin A levels rose at a rate of 40.7 mcg/L/year (CI 11.3, 70.2) after ETI start.. ETI initiation is associated with increased median vitamin A and vitamin D levels, but no change in median vitamin E or INR levels. Ongoing monitoring of vitamin levels after ETI initiation is needed to screen for potential deficiencies and toxicities, particularly in light of case reports of hypervitaminosis A following ETI initiation.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Retrospective Studies; Vitamin A; Vitamin D; Vitamin E; Vitamins

Recent advances in CFTR modulator therapy have the potential to change the face of cystic fibrosis (CF). This retrospective observational study describes real world experience of the four available CFTR modulators in adults and children with CF in a single centre in Melbourne, Australia.. Data were collected for all patients treated with CFTR modulators at MonashCF between May 2012 and September 2020. Primary outcomes included lung function, admission days and BMI/BMI centile over time. Adverse events and reasons for changing or ceasing medications were also analysed.. 55% (74/133) adult and 46% (55/119) paediatric patients were treated with CFTR modulators. FEV1 increased in adults treated with ivacaftor (IVA) and elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) by 4.73% and 10.07% respectively, and BMI also improved in these groups. Nutrition improved in adults and children treated with lumacaftor/ivacaftor (LUM/IVA). There was no significant improvement in FEV1 or admission days with LUM/IVA or tezacaftor/ivacaftor (TEZ/IVA). 36% (31/85) ceased LUM/IVA, due to adverse effects in 81% (25/31). Of these, 92% (23/25) changed to TEZ/IVA, 78% (18/23) without significant adverse effects.. Our findings for LUM/IVA and TEZ/IVA are less encouraging than those seen in clinical trials, with no significant improvement in lung function or admission days and a higher rate of adverse effects with LUM/IVA compared with phase 3 clinical trials. TEZ/IVA was generally well tolerated by those who experienced side effects with LUM/IVA. The small number of patients treated with ELX/TEZ/IVA had improvements in all parameters. These findings support ongoing use of IVA for individuals with gating mutations, and transition to ELX/TEZ/IVA once available for patients with at least one Phe508del mutation.

Topics: Adult; Aminophenols; Australia; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation

Treatment, prognosis, and quality of life for people with cystic fibrosis (CF) have improved steadily since the initial description of the disease, but most dramatically in the past decade. In 2021, the median predicted survival increased to 53 years, compared with 17 years in 1970. The recent improvement in outcomes is attributable to the advent of cystic fibrosis transmembrane regulator (CFTR) modulators, small molecules that enhance the function of defective CFTR protein. The first CFTR modulator, ivacaftor, received Food and Drug Administration approval in 2011 to treat a single CFTR variant, comprising only 4% of those affected by CF. With the demonstration of efficacy, drug approval has been expanded to other variants. Multiple CFTR modulators used in combination with ivacaftor augment efficacy and increase the number of CFTR variants amenable to therapy. Approval of elexecaftor/tezecaftor/ivacaftor in 2019 increased the number of individuals who could benefit from highly effective modulator therapy (HEMT) to ∼90% of the CF population in the United States. HEMT has been dramatically effective, with overall improvements in lung function, quality of life, nutritional status, and, in women, increased fertility. HEMT may delay the onset of other CF-related comorbidities. Although off-target effects, including hepatotoxicity, drug-drug interactions, and putative mental health issues can complicate use, modulator therapy has been generally well tolerated. Ten percent of people with CF have variants that are not amenable to modulator treatment. HEMT, despite its great cost and limited global access, has brought legitimate hope and changed the lives of a significant majority of individuals and families affected by CF in North America.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Mutation; Quality of Life

Cystic fibrosis (CF) is caused by defects of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR-modulating drugs may overcome specific defects, such as the case of Trikafta, which is a clinically approved triple combination of Elexacaftor, Tezacaftor and Ivacaftor (ETI) that exhibited a strong ability to rescue the function of the most frequent F508del pathogenic variant even in genotypes with the mutated allele in single copy. Nevertheless, most rare genotypes lacking the F508del allele are still not eligible for targeted therapies. Via the innovative approach of using nasal conditionally reprogrammed cell (CRC) cell-based models that mimic patient disease in vitro, which are obtainable from each patient due to the 100% efficiency of the cell culture establishment, we theratyped orphan CFTR mutation L1077P. Protein studies, Forskolin-induced organoid swelling, and Ussing chamber assays congruently proved the L1077P variant function rescue by ETI. Notably, this rescue takes place even in the context of a single-copy L1077P allele, which appears to enhance its expression. Thus, the possibility of single-allele treatment also arises for rare genotypes, with an allele-specific modulation as part of the mechanism. Of note, besides providing indication of drug efficacy with respect to specific CFTR pathogenic variants or genotypes, this approach allows the evaluation of the response of single-patient cells within their genetic background. In this view, our studies support in vitro guided personalized CF therapies also for rare patients who are nearly excluded from clinical trials.

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans

Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (. CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (Δ. 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved. Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dimethyl Sulfoxide; Humans; Mutation

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Pyrazoles

Cystic fibrosis arthropathy (CFA) is a transient, intermittent form of arthritis that cannot be associated with any other disease other than CF thus making CFA a diagnosis of exclusion. NSAIDs, short-term intermittent splinting, glucocorticoids, and disease-modifying anti-rheumatic drugs are treatment options for CFA. Currently, there is no consensus on how to best treat CFA. Diagnosis and treatment of CFA remain a challenge for physicians and people with CF. The newest CFTR modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), was approved by the FDA recently for children over the age of 6 with at least one Phe508del allele in the CFTR gene. Multiple clinical benefits of ETI in pulmonary functions and overall disease burden have been reported since its approval, however, the data on the musculoskeletal therapeutic benefits of ETI has been limited. In this report, we present a 7-year-old female with CF whose CFA symptoms resolved after starting ETI therapy.

Topics: Aminophenols; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Joint Diseases; Mutation

Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface.. To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation.. Clinical variables (body mass index [BMI], pulmonary exacerbations, sweat test, and pulmonary function) were analyzed in 30 CF patients homozygous for the Phe508del CFTR mutation, treated with lumacaftor-ivacaftor for 12 months, at the Respiratory Center of Hospital de Niños Ricardo Gutiérrez. These clinical variables were compared with those before the use of modulators.. A total of 30 patients with CF homozygous for the Phe508del CFTR mutation receiving lumacaftor-ivacaftor therapy were included in this study. The median (interquartile range [IQR]) age at the start of treatment was 10.79 (7.08-14.05) years. Nineteen patients were male. Before treatment, median (IQR) sweat chloride concentration was 80 (72-92) mEq/L, and it had decreased to 74 (68-78) mEq/L (p = .05) 12 months after treatment. Median (IQR) BMI z-score improved from -0.33 (-0.86 to 0.21) to -0.13 (-0.66 to 0.54) (p = .003). A spirometry was performed in 28 of 30 patients. Median (IQR) ppFEV. The use of a generic formulation of lumacaftor-ivacaftor in patients homozygous for the Phe508del CFTR mutation was associated with improvement in nutritional status and respiratory symptoms, and a significant reduction in severe pulmonary exacerbations.

Topics: Adolescent; Aminophenols; Aminopyridines; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Female; Humans; Male; Mutation

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Prevalence

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Humans; Lung; Tomography, X-Ray Computed

Risk of cardiovascular disease (CVD) may be changing in people with cystic fibrosis (pwCF) with widespread use of highly effective modulator therapy (HEMT). We performed a retrospective analysis of patients who had lipids checked before and after initiation of ivacaftor or elexacaftor/tezacaftor/ivacaftor. We hypothesized that HEMT negatively impacts lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL], TC/HDL ratio). 41 adult patients were included. Paired t-tests showed statistically significant increases in TC (mean difference 16.3 mg/dL, p = 0.007, n = 40), LDL (mean difference 17.1 mg/dL, p < 0.001, n = 35), and TC/HDL ratio (mean difference 0.40, p = 0.014, n = 39) after HEMT initiation. HDL was unchanged (mean difference -1.5 mg/dL, p = 0.69, n = 39). Linear mixed models showed CF liver disease was associated with significantly blunted changes in TC and LDL. Family history of CVD risk factors was associated with significantly accentuated increases in TC and LDL. These data suggest a role for more lipid screening in pwCF.

Topics: Adult; Aminophenols; Benzodioxoles; Cardiovascular Diseases; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lipoproteins, LDL; Mutation; Retrospective Studies

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans

Malnutrition and cystic fibrosis related diabetes (CFRD) are common comorbidities in cystic fibrosis (CF). Cystic fibrosis transmembrane regulator (CFTR) modulators have shown beneficial effects on respiratory status. This study aims to determine the effect of elexacaftor-tezacaftor-ivacaftor (ETI) on body mass index (BMI) and glycemic control.. A retrospective, observational study of a cohort of 17 adult CF patients was conducted at the CF reference center of Ghent University Hospital. BMI evolution was analyzed 18 months before and 0, 3, 6, 12 and 18 months after the start of ETI. The evolution of insulin dependence and the 2 h oral glucose tolerance test (OGTT) results were described until 36 months after start of ETI, in a small subgroup of ten patients with CFRD or impaired glucose tolerance (IGT).. A significant increase in mean BMI of 1.2 kg/m. After initiation of ETI an increase in BMI was observed in adults with CF. ETI can have a beneficial impact on glucose metabolism in patients with CFRD, leading to a possible need for reduction or cessation of insulin therapy.

Topics: Adult; Body Mass Index; Cystic Fibrosis; Glycemic Control; Humans; Insulin; Retrospective Studies

In late 2012, ivacaftor became available in the UK for people with cystic fibrosis (CF) aged 6 years and over with a G551D mutation. Long-term changes in treatment patterns have not previously been reported. We investigated long-term treatment patterns in people with CF with a G551D mutation who took ivacaftor and compared these with non-ivacaftor-treated cohorts using the UK Cystic Fibrosis Registry.. Using 2007-2018 data we compared treatment patterns between four cohorts: 1: ivacaftor-treated; 2: ivacaftor era (2013-2018), ineligible genotype (no G551D mutation); 3: pre-ivacaftor era (2007-2012), eligible genotype (G551D mutation); 4: pre-ivacaftor era, ineligible genotype. Treatments included: inhaled antibiotics, dornase alfa, hypertonic saline, chronic oral antibiotics and supplementary feeding.. Up to 2012 the percentages of people taking each treatment were similar between the two cohorts defined by genotype and tended to increase by year with a similar slope. Once ivacaftor was introduced, the use of other treatments tended to decrease or remain stable by year for the ivacaftor-treated cohort, whereas it remained stable or increased in the non-ivacaftor-treated cohort. This led to differences in treatment use between the two cohorts in the ivacaftor-era, which became more marked over time.. We have shown a clear divergence in treatment patterns since the introduction of ivacaftor in a number of key treatments widely used in CF. Further research is needed to investigate whether the differences in treatment patterns are associated with changes in health outcomes.

Topics: Aminophenols; Anti-Bacterial Agents; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Quinolones

Cystic fibrosis related diabetes (CFRD) is associated with pulmonary decline and compromised nutritional status. Emerging data suggest that CFTR dysfunction may play a direct role in the pathogenesis of CFRD; however, studies investigating the effect of CFTR modulators on glycemic outcomes in patients with cystic fibrosis (CF) have shown mixed results. The impact of elexacaftor-tezacaftor-ivacaftor (ETI) on glycemic control is currently unknown. Our objective was to investigate the effect of ETI initiation on glycemia in adults with CF using continuous glucose monitoring (CGM).. In this prospective observational study, 34 adults with CF and at least one F508del CFTR mutation wore CGM sensors for 14 days prior to starting ETI and again 3-12 months after ETI initiation. Hypoglycemia symptoms were queried at each visit, and most recent anthropometric measures and spirometry data were obtained by chart review.. Twenty-three participants completed the study. Compared to baseline, average glucose (AG), standard deviation (SD), % time >200 mg/dL, and peak sensor glucose decreased with ETI treatment, and % time in target range 70-180 mg/dL increased. Improvements in glycemic parameters were most notable in individuals with CFRD. There was no significant change in CGM-measured or self-reported hypoglycemia before and after ETI initiation.. Initiation of ETI in adults with CF was associated with improvement CGM-derived measures of hyperglycemia and glycemic variability with no effect on hypoglycemia. Further studies are needed to investigate underlying etiology of these changes and the long-term impact of ETI on glycemic control in patients with CF.

Topics: Adult; Aminophenols; Benzodioxoles; Blood Glucose; Blood Glucose Self-Monitoring; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Hypoglycemia; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Precision Medicine; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Uncertainty

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators have revolutionized the therapeutic landscape in CF treatment. These vital drugs are extensively metabolized via CYP3A, so caution must be exercised in multimodal CF therapy because of the risk of adverse drug interactions. Our goal was to develop a highly sensitive assay for the purpose of therapeutic drug monitoring (TDM) in diagnostic laboratories.. After protein precipitation, the CFTR modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their metabolites ivacaftor-M1, ivacaftor-M6, and tezacaftor-M1 were separated with a two-dimensional chromatography setup within 5 min, and quantified with stable isotope-labeled internal standards. The method was validated according to the European Medicines Agency (EMA) guideline on bioanalytical method validation and applied to CF patient samples.. Inaccuracy was ≤7.0% and the imprecision coefficient of variation (CV) was ≤8.3% for all quality controls (QCs). The method consistently compensated for matrix effects, recovery, and process efficiency were 105-115 and 96.5-103%, respectively. Analysis of CF serum samples provided concentrations comparable to the pharmacokinetic profile data reported in the EMA assessment report for the triple combination therapy Kaftrio.. We hereby present a robust and highly selective isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) assay for the simultaneous quantification of the so far approved CFTR modulators and their metabolites in human serum. The assay is suitable for state-of-the-art pharmacovigilance of CFTR modulator therapy in CF patients, in order to maximize safety and efficacy, and also to establish dose-response relationships in clinical trials.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chromatography, Liquid; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Isotopes; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Tandem Mass Spectrometry

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Smell

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA, Trikafta) is the newest Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator drug approved by the Food and Drug Administration. Post-marketing reports with earlier CFTR modulators suggest these medications can impact mood, and in clinical trials an adverse effect of headache was reported with all currently approved CFTR modulators. However, there are no other documented reports of mental status changes during clinical trials or in post-marketing reports with elexacaftor/tezacaftor/ivacaftor. In this case series, we describe 6 patients who reported "mental fogginess" or other mental status changes shortly after initiation of this drug. The mechanism of this patient-reported side effect is still unclear. All patients noticed a change within the first 3 months of therapy. The management differed in each case, with all four cystic fibrosis (CF) care teams utilizing a patient-centered decision-making approach to address this concern.

Topics: Affect; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mental Fatigue; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Somatoform Disorders

When an entire cohort of patients receives a treatment, it is difficult to estimate the treatment effect in the treated because there are no directly comparable untreated patients. Attempts can be made to find a suitable control group (e.g., historical controls), but underlying differences between the treated and untreated can result in bias. Here we show how negative control outcomes combined with difference-in-differences analysis can be used to assess bias in treatment effect estimates and obtain unbiased estimates under certain assumptions. Causal diagrams and potential outcomes are used to explain the methods and assumptions. We apply the methods to UK Cystic Fibrosis Registry data to investigate the effect of ivacaftor, introduced in 2012 for a subset of the cystic fibrosis population with a particular genotype, on lung function and annual rate (days/year) of receiving intravenous (IV) antibiotics (i.e., IV days). We consider 2 negative control outcomes: outcomes measured in the pre-ivacaftor period and outcomes among persons ineligible for ivacaftor because of their genotype. Ivacaftor was found to improve lung function in year 1 (an approximately 6.5-percentage-point increase in ppFEV1), was associated with reduced lung function decline (an approximately 0.5-percentage-point decrease in annual ppFEV1 decline, though confidence intervals included 0), and reduced the annual rate of IV days (approximately 60% over 3 years).

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

The cystic fibrosis (CF) sweat gland is defective in β-adrenergically-stimulated sweat secretion in the coil and chloride reabsorption in the duct. Whereas chloride reabsorption is regularly assessed by quantitative pilocarpine iontophoresis (QPIT), the measurement of β-adrenergic sweat secretion is not yet established in clinical practice.. A novel sweat bubble imaging protocol was developed that determines sweat secretion rates by automatic recording, processing and quality control of the kinetics of sweat droplet formation.. Treatment of CF patients with the CFTR modulators elexacaftor, tezacaftor and ivacaftor reduced the sweat chloride concentration measured in QPIT in the majority of patients to values in the intermediate or normal range. In contrast, the β-adrenergically-stimulated sweat secretion rate assayed by the automated bubble sweat test was normalized in only 3 patients, slightly increased in 12 patients and remained undetectable in 8 patients.. β-adrenergic sweat stimulation in the coil is apparently rather stringent in its requirements for a wild type CFTR conformation whereas chloride reabsorption in the duct tolerates residual structural and functional deficits of native or pharmacologically rescued mutant CFTR in the apical membrane.

Topics: Adrenergic Agents; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Sweat

Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy is showing promising efficacy for treatment of cystic fibrosis (CF) and is becoming more widely available since recent FDA approval. However, little is known about how these drugs will affect lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF).. We analyzed sputum microbiome and metabolome data from pwCF (n=24) before and after ETI therapy using 16S rRNA gene sequencing and untargeted metabolomics.. The sputum microbiome diversity, particularly its evenness, was increased (p=0.036) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes remained more similar within an individual than across the sampled population. No specific microbial taxa differed in relative abundance before and after therapy, but the collective log-ratio of classic CF pathogens to anaerobes significantly decreased (p=0.013). The sputum metabolome also showed changes associated with ETI (PERMANOVA F=4.22, p=0.002) and was characterized by greater variation across subjects while on treatment. Changes in the metabolome were driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway, which were associated with a decrease in CF pathogens. Metabolism of the three small molecules that make up ETI was extensive, including previously uncharacterized structural modifications.. ETI therapy is associated with a changing microbiome and metabolome in airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche space for microbial residency in lung mucus as the drug's effects take hold.. This project was funded by a National Institute of Allergy and Infectious Disease Grant R01AI145925.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Microbiota; RNA, Ribosomal, 16S

Cystic fibrosis (CF)-related liver disease (CFLD) manifests as a wide spectrum of hepatobiliary disease and can progress to need liver transplantation. Elexacaftor/tezacaftor/ivacaftor (elx/tez/iva) is a cystic fibrosis transmembrane conductance regulator modulator that has superior efficacy compared to previously approved modulators. Use of elx/tez/iva, should be approached with caution in individuals with CFLD or following liver transplantation due to possible increases in liver function tests (LFTs) and drug-drug interactions with several immunosuppressant medications.. The purpose of this case series is to explore if the use of elx/tez/iva is safe and tolerable in patients with CF postliver transplantation.. A retrospective case series including patients prescribed elx/tez/iva following liver transplantation and an immunosuppressive regimen consisting of drug therapy metabolized by P-glycoprotein was completed.. Ten patients at six CF centers with a median age of 22.1 years (range 14-43.4 years) and the median time from the transplant of 6.9 years (range 0.6-22 years) were included. Most patients (8, 80%) received a reduced or full dose of elx/tez/iva for a mean duration of 10.4 months (range 7-12 months). Fluctuations in LFTs occurred in all patients (10, 100%) and led to therapy discontinuation in two patients (20%). Elx/tez/iva initiation resulted in elevations in tacrolimus trough concentration in seven patients (70%). Most patients who tolerated elx/tez/iva had symptomatic and quality of life improvement, increased body mass index, and maintained or improved lung function.. Initiation of elx/tez/iva in patients with CF who received liver transplantation may be safe with clinical benefits.

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quality of Life; Quinolones; Retrospective Studies; Young Adult

Cystic fibrosis (CF) is a multisystem disorder that results in the buildup of mucus in various organs. Ninety percent of CF patients are classified as pancreatic insufficient, leading to malabsorption of nutrients and fat-soluble vitamins without the assistance of exogenous pancreatic enzymes. This study was designed to determine if serum 25-hydroxyvitamin D concentrations were impacted by initiation of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA).. Serum 25-hydroxyvitamin D concentrations were measured before and 1 year post-ELX/TEZ/IVA initiation. A Wilcoxon signed-rank test was used to compare values.. Seventy-six patients were included in the final analysis. The average age of our population was 25.8 years (SD = 13.2 years) with a majority being male, homozygous F508del, pancreatic insufficient, and not modulator-naive. The median increase of serum vitamin D concentration after initiating ELX/TEZ/IVA was 5 ng/ml (interquartile range = -4, 13; p = .0035).. We suggest that ELX/TEZ/IVA may improve fat-soluble vitamin absorption, specifically serum 25-hydroxyvitamin D. These results may lead to adjustments in vitamin supplementation in patients receiving cystic fibrosis transmembrane conductance regulator modulator therapy.

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Indoles; Male; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Vitamin D; Vitamins; Young Adult

Though weight gain has been reported in some clinical trials of CFTR modulators, the effect of elexacaftor-tezacaftor-ivacaftor on body weight, body mass index (BMI), blood pressure, lipids and glycemic control in the real-world setting remains incompletely described.. We performed a single-center, retrospective, observational analysis of the effect of elexacaftor-tezacaftor-ivacaftor on body weight and cardiometabolic parameters in 134 adult CF patients of the Washington University Adult Cystic Fibrosis Center. Body weight, BMI, and blood pressure were extracted from outpatient clinic visits for the year preceding and the period following the initiation of elexacaftor-tezacaftor-ivacaftor. Other metabolic parameters were extracted at baseline and at latest available follow-up.. In this single-center, retrospective, observational study of 134 adults with CF, initiation of elexacaftor-tezacaftor-ivacaftor was associated with increases in BMI at a mean follow up of 12.2 months. Changes in other cardiometabolic risk factors were also observed. Widespread use of elexacaftor-tezacaftor-ivacaftor may be expected to increase the incidence of overnutrition in the CF population.

Topics: Adult; Aminophenols; Benzodioxoles; Body Weight; Cardiometabolic Risk Factors; Chloride Channel Agonists; Cholesterol; Cystic Fibrosis; Humans; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Retrospective Studies

In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR)-dependent bicarbonate secretion precipitates the accumulation of viscous mucus in the lumen of respiratory and gastrointestinal epithelial tissues. We investigated whether the combination of elexacaftor (ELX), ivacaftor (IVA) and tezacaftor (TEZ), apart from its well-documented effect on chloride transport, also restores Phe508del-CFTR-mediated bicarbonate transport.. Epithelial monolayers were cultured from intestinal and biliary (cholangiocyte) organoids of homozygous Phe508del-CFTR patients and controls. Transcriptome sequencing was performed, and bicarbonate and chloride transport were assessed in the presence or absence of ELX/IVA/TEZ, using the intestinal current measurement technique.. ELX/IVA/TEZ markedly enhanced bicarbonate and chloride transport across intestinal epithelium. In biliary epithelium, it failed to enhance CFTR-mediated bicarbonate transport but effectively rescued CFTR-mediated chloride transport, known to be requisite for bicarbonate secretion through the chloride-bicarbonate exchanger AE2 (SLC4A2), which was highly expressed by cholangiocytes. Biliary but not intestinal epithelial cells expressed an alternative anion channel, anoctamin-1/TMEM16A (ANO1), and secreted bicarbonate and chloride upon purinergic receptor stimulation.. ELX/IVA/TEZ has the potential to restore both chloride and bicarbonate secretion across CF intestinal and biliary epithelia and may counter luminal hyper-acidification in these tissues.

Topics: Aminophenols; Benzodioxoles; Bicarbonates; Chloride Channel Agonists; Chloride-Bicarbonate Antiporters; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Epithelial Cells; Humans; Indoles; Organoids; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Elexacaftor, tezacaftor, ivacaftor (ETI) have been associated with marked clinical improvements in adults with CF, which appears to be associated with increased fertility. However, maternal and fetal effects of therapy continued during pregnancy are not well understood. We collected maternal blood, infant blood, cord blood, and breast milk from 3 mother-infant pairs from women who elected to remain on ETI therapy while pregnant. Our results demonstrated relatively high levels of ETI in cord blood, suggesting placental transfer of these compounds, as well as low levels of ETI in breast milk and infant blood, suggesting further transfer of these compounds to breast-fed infants in the postnatal period. These data underscore the need for larger studies on the effects of modulator surrounding reproduction.

Topics: Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Female; Humans; Indoles; Infant; Maternal Exposure; Mothers; Placenta; Pregnancy; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

CFTR mutation carriers, numbering 1 in 25 among Caucasians, have an increased risk of developing chronic pancreatitis due to the underlying dysfunction of ion channels created by the mutant allele. Carriers do not frequently manifest disease due to the remaining wild-type CFTR protein sufficiently maintaining normal pancreatic homeostasis. However, additional risk factors for pancreatitis, such as organic acidemias (as seen in our patient) that further impact function of pancreatic acinar cells can result in the precipitation of CFTR related pancreatitis. Here we report a CFTR carrier with methylmalonic acidemia who was treated with ivacaftor and subsequently experienced resolution of her chronic pancreatitis. Our report suggests that ivacaftor may rescue the function of mutant CFTR in carriers and treat pancreatitis caused by CFTR dysfunction in situations where there are additional precipitating factors.

Topics: Amino Acid Metabolism, Inborn Errors; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Mutation; Pancreatitis, Chronic; Quinolones

Aquagenic wrinkling of palms (AWP) in cystic fibrosis (CF) patients and common CFTR mutations is recognized as a frequent symptom of the disease. The long-term effect of CFTR targeting therapy on AWP has not been studied. AWP was monitored in 16 CF patients (8 children and 8 adults) before and for 6 months after initiation of ivacaftor therapy. Thirteen (81.3%) patients had at least mild and 8/16 (50%) moderate-to-severe AWP at baseline. AWP improved with ivacaftor therapy. This observation suggests that AWP is also common in individuals with CF and relatively rare mutations and is directly related to CFTR function.

Topics: Adult; Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones; Skin Aging; Water

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Drug Combinations; Humans; Quinolones; Tomography, X-Ray Computed; Unsupervised Machine Learning

Topics: Aminophenols; Aminopyridines; Artificial Intelligence; Benzodioxoles; Cystic Fibrosis; Humans; Quinolones; Tomography, X-Ray Computed; Unsupervised Machine Learning

Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates.. Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021.. Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV. In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Lung Transplantation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Hypervitaminosis A; Indoles; Intracranial Hypertension; Precision Medicine; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

People with cystic fibrosis (CF) routinely suffer from recurrent sinopulmonary infections. Such infections require frequent courses of antimicrobials and often involve multidrug-resistant organisms. The goal of this study was to identify real-world evidence for the effectiveness of elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) in decreasing infection-related visits and antimicrobial use in people with CF.. Using IBM MarketScan data, we identified 389 enrollees with CF who began taking ELX/TEZ/IVA before 1 December 2019 and were enrolled from 1 July 2019 to 14 March 2020. We also identified a comparison population who did not begin ELX/TEZ/IVA during the study period. We compared the following outcomes in the 15 weeks before and after medication initiation: total healthcare visits, inpatient visits, infection-related visits, and antimicrobial prescriptions. We analyzed outcomes using both a case-crossover analysis and a difference-in-differences analysis, to control for underlying trends.. For the case-crossover analysis, ELX/TEZ/IVA initiation was associated with the following changes over a 15-week period: change in overall healthcare visit dates, -2.5 (95% confidence interval, -3.31 to -1.7); change in inpatient admissions, -0.16 (-.22 to -.10); change in infection-related visit dates, -0.62 (-.93 to -.31); and change in antibiotic prescriptions, -0.78 (-1.03 to -.54). Results from the difference-in-differences approach were similar.. We show a rapid reduction in infection-related visits and antimicrobial use among people with CF after starting a therapy that was not explicitly designed to treat infections. Currently, there are >30 000 people living with CF in the United States alone. Given that this therapy is effective for approximately 90% of people with CF, the impact on respiratory infections and antimicrobial use may be substantial.

Topics: Aminophenols; Anti-Bacterial Agents; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

A decrease in the lumacaftor-mediated increase in F508del-CFTR function and expression upon prolonged exposure to ivacaftor (VX-770) has previously been described. However, the efficacy observed with ivacaftor-containing CFTR modulator therapies in vivo is in conflict with these reports. We hypothesized that a portion of the apparent decrease in CFTR function observed after prolonged ivacaftor exposure in vitro was due to an increase in constitutive CFTR-mediated ion transport.. Human nasal epithelial (HNE) cells were obtained by brushings from three CF individuals homozygous for the F508del CFTR mutation. Differentiated epithelia were pre-treated with prolonged (24 h) exposure to either lumacaftor (VX-809; 3 µM), tezacaftor (VX-661; 3 µM), elexacaftor (VX-445; 3 µM), and/or ivacaftor (0.1-6.4 µM) or DMSO (vehicle control), and CFTR function was assayed by Ussing chamber electrophysiology.. In cells treated with lumacaftor, constitutive CFTR activity was not increased at any concentration of co-treatment with ivacaftor. Constitutive CFTR activity was also unchanged in cells treated with the combination of tezacaftor and elexacaftor. An increase in constitutive CFTR activity above the DMSO controls was only observed in cells treated with the combination of tezacaftor and elexacaftor and co-treated with at least 0.1 µM ivacaftor.. These results demonstrate that ivacaftor is a critical component in the triple combination therapy along with tezacaftor and elexacaftor to increase constitutive CFTR function. This work further elucidates the mechanism of action of the effective triple combination therapeutic that is now the primary clinical tool in treating CF.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dimethyl Sulfoxide; Drug Combinations; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

The advent of Trikafta (Kaftrio in Europe) (a triple-combination therapy based on two correctors-elexacaftor/tezacaftor-and the potentiator ivacaftor) has represented a revolution for the treatment of patients with cystic fibrosis (CF) carrying the most common misfolding mutation, F508del-CFTR. This therapy has proved to be of great efficacy in people homozygous for F508del-CFTR and is also useful in individuals with a single F508del allele. Nevertheless, the efficacy of this therapy needs to be improved, especially in light of the extent of its use in patients with rare class II CFTR mutations. Using CFBE41o- cells expressing F508del-CFTR, we provide mechanistic evidence that targeting the E1 ubiquitin-activating enzyme (UBA1) by TAK-243, a small molecule in clinical trials for other diseases, boosts the rescue of F508del-CFTR induced by CFTR correctors. Moreover, TAK-243 significantly increases the F508del-CFTR short-circuit current induced by elexacaftor/tezacaftor/ivacaftor in differentiated human primary airway epithelial cells, a gold standard for the pre-clinical evaluation of patients' responsiveness to pharmacological treatments. This new combinatory approach also leads to an improvement in CFTR conductance on cells expressing other rare CF-causing mutations, including N1303K, for which Trikafta is not approved. These findings show that Trikafta therapy can be improved by the addition of a drug targeting the misfolding detection machinery at the beginning of the ubiquitination cascade and may pave the way for an extension of Trikafta to low/non-responding rare misfolded CFTR mutants.

Topics: Aminophenols; Benzodioxoles; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Indoles; Mutation; Protein Folding; Pyrazoles; Pyridines; Pyrimidines; Pyrrolidines; Quinolones; Sequence Deletion; Sulfides; Sulfonamides; Ubiquitin-Activating Enzymes

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies, including elexacaftor-tezacaftor-ivacaftor, are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A-mediated DDI of elexacaftor-tezacaftor-ivacaftor was evaluated using a physiologically-based pharmacokinetic modeling approach. Modeling was performed incorporating physiological information and drug-dependent parameters of elexacaftor-tezacaftor-ivacaftor to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on the pharmacokinetics of elexacaftor-tezacaftor-ivacaftor. The elexacaftor-tezacaftor-ivacaftor models were verified using independent clinical pharmacokinetic and DDI data of elexacaftor-tezacaftor-ivacaftor with a range of CYP3A modulators. When ritonavir was administered on Days 1 through 5, the predicted area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate) on Day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of elexacaftor-tezacaftor-ivacaftor should be reduced when coadministered with nirmatrelvir-ritonavir to elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg on Days 1 and 5, with delayed resumption of full-dose elexacaftor-tezacaftor-ivacaftor on Day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of elexacaftor-tezacaftor-ivacaftor administered concomitantly with nirmatrelvir-ritonavir in people with CF that will likely decrease the impact of the drug interaction.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; COVID-19 Drug Treatment; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytochrome P-450 CYP3A; Drug Combinations; Drug Interactions; Humans; Indoles; Lactams; Leucine; Mutation; Nitriles; Proline; Pyrazoles; Pyridines; Pyrrolidines; Quinolines; Quinolones; Ritonavir

The triple-combination cystic fibrosis transmembrane conductance regulator modulator elexacaftor/- tezacaftor/ivacaftor is known to improve lung function and have extrapulmonary benefits in people with cystic fibrosis. However, there is limited evidence for its use in patients with cystic fibrosis after lung transplant, where the donor lung expresses normal levels of the cystic fibrosis transmembrane conductance regulator. We describe the use of elexacaftor/tezacaftor/ivacaftor as a bridge to potential lung retransplant in a 37-year-old man with cystic fibrosis and chronic lung allograft dysfunction. Although forced expiratory volume in 1 second did not improve, the patient had decreased sputum volume, no pulmonary exacerbations of cystic fibrosis, and no longer required continuous antibiotic therapy. Pancreatic function, revised Cystic Fibrosis Questionnaire scores, sinus symptoms, weight, and corticosteroid dependence significantly improved. There were no reported side effects attributable to elexacaftor/tezacaftor/ivacaftor. However, the patient exhibited declined renal function, which had been initially attributed to lability in cyclosporin levels but which were corrected after lithotripsy for renal calculi. Triple-combination modulators of the cystic fibrosis transmembrane conductance regulator may offer benefits to carefully selected individuals awaiting retransplant, balanced against the risk of worsened immunosuppressant level control.

Topics: Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Lung; Male; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Treatment Outcome

Many individuals with cystic fibrosis (CF) have chronic rhinosinusitis resulting in nasal obstruction, sinus infections, and repeated surgeries. Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator therapy approved for individuals aged 6 years or older with CF who have at least one F508del allele or other responsive mutation. The current study tests the hypothesis that ELX/TEZ/IVA improves sinonasal disease in CF.. The study was a pre/post, observational cohort study conducted at two sites. Participants underwent a study visit prior to starting ELX/TEZ/IVA and a second visit at a median of 9 months on therapy. Each visit included sinus CT scan, rigid nasal endoscopy, and sweat chloride measurement. Symptoms were measured with the 22 item Sinonasal Outcome Test at scheduled intervals during the study. Regression models were used to test for improvement in symptoms, endoscopy, and CT scales.. The study enrolled 34 individuals, with a median age of 27 years (range 12-60). Symptoms improved within 7 days of therapy and plateaued by day 28. Endoscopic crusting resolved and nasal polyposis improved, with a decrease in size or resolution of polyps. Sinus opacification and mucosal thickening improved on CT radiographs with treatment.. Sinonasal symptoms improved rapidly and durably for at least 180 days on ELX/TEZ/IVA therapy. Objective measures of disease including endoscopic and CT findings improved with ELX/TEZ/IVA.

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Middle Aged; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Sinusitis; Young Adult

The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl-]; 87-105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl-] (75-123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o-) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.

Topics: Aminophenols; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Phenotype; Quinolones

Topics: Alleles; Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) was recently approved for adult cystic fibrosis (CF) patients with at least one F508del mutation. However, its effects on structural and functional lung abnormalities and chronic rhinosinusitis have not been studied by imaging.. 19 adults with CF (mean age 31±9y, range 19-55y) underwent standardized chest magnetic resonance imaging (MRI), and nine also same-session sinonasal MRI, before (MRI1) and after (MRI2) at least one month (mean duration 5 ± 3mon) on ETI. 24 control CF patients (30±7y, range 20-44y) without ETI underwent longitudinal chest MRI, and eleven also sinonasal MRI, twice (mean interval 40±15mon). MRI was assessed using the validated chest MRI score and chronic rhinosinusitis (CRS)-MRI score. Forced expiratory volume in 1 s percent predicted (FEV1%) was measured in all patients.. In controls, the chest MRI global score and CRS-MRI sum score were stable from MRI1 to MRI2. In patients under ETI, the chest MRI global score improved (-11.4 ± 4.6, P<0.001), mainly due to reduction of bronchiectasis/wall thickening and mucus plugging subscores (-3.3 ± 2.2 and -5.2 ± 1.5, P<0.001, respectively). The improvement in chest MRI score correlated well with improved FEV1% (r=-0.703, P<0.001). The CRS-MRI sum score also improved in patients under ETI (-6.9 ± 3.0, P<0.001), mainly due to a reduction of mucopyoceles in the maxillary and ethmoid sinus (-50% and -39%, P<0.05, respectively).. MRI detects improvements of chest MRI and CRS-MRI scores in adult CF patients who first received ETI, demonstrating reversibility of structural lung and paranasal sinus abnormalities in patients with established disease.

Topics: Adult; Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Magnetic Resonance Imaging; Mutation; Young Adult

While the clinical benefits of CFTR modulators are clear, their high prices render them inaccessible outside of the world's richest countries. Despite this, there is currently limited evidence regarding global access to these transformative therapies. Therefore, this study aims to estimate the minimum costs of production of CFTR modulators, assuming robust generic competition, and to compare them with current list prices to evaluate the feasibility of increased global access to treatment.. Minimum costs of production for CFTR modulators were estimated via an algorithm validated in previous literature and identification of cost-limiting key starting materials from published routes of chemical synthesis. This algorithm utilised per kilogram active pharmaceutical ingredient costs obtained from global import/export data. Estimated production costs were compared with published list prices in a range of countries.. Costs of production for elexacaftor/tezacaftor/ivacaftor are estimated at $5,676 [$4,628-6,723] per year, over 90% lower than the US list price. Analysis of chemical structure and published synthetic pathways for elexacaftor/tezacaftor/ivacaftor revealed relatively straightforward routes of synthesis related to currently available products. Total cost of triple therapy for all eligible diagnosed CF patients worldwide would be $489 million per year. Comparatively, the annual cost at US list price would be $31.2 billion.. Elexacaftor/tezacaftor/ivacaftor could be produced via generic companies for a fraction of the list price. The current pricing model restricts access to the best available therapy, thereby exacerbating existing inequalities in CF care. Urgent action is needed to increase the availability of triple combination treatment worldwide. One strategy based on previous success is originator-issued voluntary licenses.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Quinolones

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment.. Blood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed.. Significant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight.. Ivacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation.

Topics: Aminophenols; Calreticulin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Granulocyte Colony-Stimulating Factor; HMGB Proteins; Humans; Inflammation; Insulin-Like Growth Factor I; Leptin; Leukocyte L1 Antigen Complex; Lipids; Mutation; Proteome; Proteomics; Respiratory System Agents

Alteration of the airway microbiota is a hallmark of cystic fibrosis (CF) pulmonary disease. Dysfunction of cystic fibrosis transmembrane regulator (CFTR) in the intestine also promotes changes in local microbiota such as small intestinal bacterial overgrowth (SIBO), which is common in CF. We evaluated whether therapy with the CFTR modulator combination lumacaftor/ivacaftor (luma/iva) has a beneficial impact on SIBO as measured by breath testing (BT).. A multicenter longitudinal study of CFTR-dependent disease profiling (NCT02477319) included a prospective evaluation for SIBO by BT. Tidal breath samples were collected after fasting and 15, 30, 45, 60, 90, and 120 minutes after ingestion of glucose, before and 1 month after subjects initiated luma + iva.. Forty-two subjects enrolled in the sub-study (mean age = 23.3 years; 51% female; 9.5% Latinx); 38 completed a hydrogen BT at both time points, of which 73.7% had a positive BT before luma/iva (baseline) and 65.8% had a positive test after luma/iva ( P = 0.44); shifts from negative to positive were also seen. Use of azithromycin (63.1%) and inhaled antibiotics (60.5%) were not associated with positive BT. Acid-blocking medications were taken by 73% of those with a negative BT at baseline and by 35% with a positive baseline BT ( P = 0.04).. We found a high rate of positive hydrogen breath tests in individuals with CF, confirming that SIBO is common. One month of luma/iva did not significantly change the proportion of those with positive breath hydrogen measurements.

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Breath Tests; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Glucose; Humans; Hydrogen; Longitudinal Studies; Male; Mutation; Quinolones; Young Adult

Elexacaftor/tezacaftor/ivacaftor (ETI) is associated with major improvements in respiratory outcomes of individuals with cystic fibrosis (CF) and at least one Phe508del mutation. Although ETI was well tolerated in registration studies, the attention on adverse events not previously described is very high in the post-marketing phase. In this case series we report the onset of systemic arterial hypertension in 4 individuals with CF within the first weeks of starting therapy. All patients needed cardiac evaluation and started chronic anti-hypertensive therapy. Until more data is available, this report could foster the attention of CF physicians towards careful monitoring of cardiovascular parameters in patients starting ETI.

Topics: Adult; Aminophenols; Antihypertensive Agents; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Hypertension; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

As elexacaftor/tezacaftor/ivacaftor has proven to have robust clinical efficacy for eligible persons with cystic fibrosis, desensitization should be offered to those with maculopapular eruption hypersensitivity reactions to achieve tolerance. As presented in this case, if provided with tools for crushing and mixing the medication, a successful escalation protocol can be completed at home without coordinating the help of a compound pharmacy.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Exanthema; Humans; Hypersensitivity, Delayed; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Cystic fibrosis (CF) lung transplant (LT) recipients may warrant treatment with elexacaftor/tezacaftor/ivacaftor (ETI) to improve extrapulmonary manifestations of CF. Our objectives were to identify reasons for prescribing ETI after LT and evaluate changes in body mass index (BMI), hemoglobin A1c, hemoglobin, and liver enzymes.. This was an electronic health record-based cohort study, October 2019-September 2020, at 14 CF LT Consortium sites in North America. The study included CF LT recipients prescribed ETI after transplant. Differences in BMI, A1c, and hemoglobin were assessed with paired t-tests.. ETI is rarely prescribed for non-pulmonary indications after LT for CF. Further study is needed to determine the risks and benefits of ETI in the CF lung transplant population given the potential for drug interactions, side effects leading to discontinuation of ETI, and the possible mechanisms for ETI to positively impact long-term post-transplant outcomes.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Glycated Hemoglobin; Humans; Indoles; Lung; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Transaminases; Transplant Recipients

Topics: Alleles; Aminophenols; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Alleles; Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Lung; Magnetic Resonance Imaging; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Pyrazoles

Deterioration in mental health has been reported in a minority of individuals with cystic fibrosis starting elexacafor/tezacaftor/ivacaftor (ELX/TEZ/IVA). We report our experience of using sweat chloride and markers of clinical stability to titrate dose reduction with the aim of minimising adverse events and maintaining clinical stability.. Adults (n = 266) prescribed ELX/TEZ/IVA, were included. Adverse events, sweat chloride, lung function and clinical data were collected.. Nineteen (7.1%) individuals reported anxiety, low mood, insomnia and "brain fog" with reduced attention and concentration span. Thirteen underwent dose reduction with sweat chloride remained normal (<30 mmol l-1) or borderline (30-60 mmol l-1) in six (46.2%) and seven (53.2%) cases respectively. Improvement or resolution of AEs occurring in 10 of the 13 cases.. Dose adjustment of ELX/TEZ/IVA was associated with improvement in mental health AEs without significant clinical deterioration. Sweat chloride concentration may prove useful as a surrogate marker of CFTR function.

Topics: Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mental Health; Mutation

Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective cystic fibrosis transmembrane conductance regulator modulator. It has been shown to improve lung function and decrease pulmonary exacerbations in short-term clinical trials. The effect of ETI on hospitalization and intravenous (IV) antibiotic rates is not known. We performed a single-institution, retrospective review comparing these rates before and after the initiation of ETI.. Among patients taking the cystic fibrosis modulator ETI, we compared the cumulative number of days per month hospitalized and cumulative number of days per month on IV antibiotics before and after the initiation of ETI. Electronic medical records from 37 patients were reviewed from 2016 through 2020 to identify demographic data, hospitalizations, and antibiotic use. Results were then stratified by severity of lung disease.. Following the initiation of ETI, there was a decline in days per month hospitalized and on IV antibiotics. The cumulative average number of days per month patients were hospitalized decreased 86% from 27 to 4 after starting ETI. The cumulative average number of days per month on IV antibiotics decreased by 80% (32.5 to 6.4). Most of these reductions occurred among patients with severe lung disease.. At our institution, we saw a decline in cystic fibrosis-related hospitalizations and in the use of outpatient IV antibiotics following the initiation of ETI. These reductions were most pronounced among patients with severe lung disease.. The initiation of ETI was associated with a decline in days hospitalized and days on IV antibiotics.

Topics: Aminophenols; Anti-Bacterial Agents; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Hospitalization; Humans; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Improved methods are needed to risk-stratify patients with cystic fibrosis (CF) and reduced FEV. What are the predictors of death or lung transplantation (LTx) within 2 years among patients with CF whose FEV. Patients with CF, age ≥ 6 years with FEV. FEV. Among individuals with CF and FEV

Topics: Aminophenols; Anti-Bacterial Agents; Child; Cystic Fibrosis; Hemoglobins; Humans; Lung Transplantation; Oxygen; Probability; Prognosis; Quinolones

Since 2015, when the first cystic fibrosis transmembrane conductance regulator (CFTR) modulators were approved for people with cystic fibrosis (CF) homozygous for F508del-CFTR, studies have shown improved lung function after initiation of the treatment and patients experience improved physical capacity. The aim of this study was to investigate change in exercise capacity after initiation of Lumacaftor/Ivacaftor and Tezacaftor/Ivacaftor treatment (LUM/IVA, TEZ/IVA).. We performed a single group prospective observational cohort study with follow-up at six and 12 months. The study examined change in exercise capacity in people with CF initiating treatment with LUM/IVA and TEZ/IVA, measured by cardio-pulmonary exercise testing (CPET). Inclusion criteria were people with CF homozygous for F508del-CFTR aged 12 years or older eligible for LUM/IVA and TEZ/IVA treatment from June 2017 until June 2019. Primary outcomes were change in VO

Topics: Aminophenols; Aminopyridines; Bacterial Toxins; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Denmark; Drug Combinations; Exercise Test; Exercise Tolerance; Humans; Indoles; Mutation; Prospective Studies; Quinolones

A 29 year old woman with cystic fibrosis (CF) presented to CF clinic following the sudden development of over 200 pigmented naevi located predominately on the trunk and limbs 3 months after commencing elexacaftor/tezacaftor/ivacaftor, a novel triple-therapy CFTR modulator therapy for CF. Skin biopsy confirmed benign naevi and the clinical presentation was consistent with eruptive melanocytic naevi. Elexacaftor/tezacaftor/ivacaftor received marketing authorisation in August 2020 and this is the first report of associated naevi. The individual described here remains clinically well, and continues on elexacaftor/tezacaftor/ivacaftor with dermatology follow-up.

Topics: Adult; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Mutation; Nevus, Pigmented; Skin Neoplasms

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Drug Combinations; Humans; Mutation; Quinolones; T-Lymphocytes

Cystic Fibrosis (CF) has prominent gastrointestinal and pancreatic manifestations. The aim of this study was to determine the effect of Cystic fibrosis transmembrane conductance regulator (CFTR) modulation on, gastrointestinal inflammation, pancreatic function and gut microbiota composition in people with cystic fibrosis (CF) and the G551D-CFTR mutation.. Fourteen adult patients with the G551D-CFTR mutation were assessed clinically at baseline and for up to 1 year after treatment with ivacaftor. The change in gut inflammatory markers (calprotectin and lactoferrin), exocrine pancreatic status and gut microbiota composition and structure were assessed in stool samples.. There was no significant change in faecal calprotectin nor lactoferrin in patients with treatment while all patients remained severely pancreatic insufficient. There was no significant change in gut microbiota diversity and richness following treatment.. There was no significant change in gut inflammation after partial restoration of CFTR function with ivacaftor, suggesting that excess gut inflammation in CF is multi-factorial in aetiology. In this adult cohort, exocrine pancreatic function was irreversibly lost. Longer term follow-up may reveal more dynamic changes in the gut microbiota and possible restoration of CFTR function.

Topics: Adult; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Inflammation; Lactoferrin; Leukocyte L1 Antigen Complex; Microbiota; Mutation; Prospective Studies; Quinolones

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Pneumonia; Quinolones

The triple combination of Elexacaftor-Tezacaftor-Ivacaftor (ELX-TEZ-IVA) has been shown to markedly improve lung function in persons with cystic fibrosis (pwCF). An important adverse effect of the drug is rash, which was reported in clinical trials and highlighted in case reports. Our report demonstrates a similar adverse event with the drug in one of our patients with spontaneous resolution of the rash not necessitating cessation of treatment or desensitization to the drug as were done in other cases. We highlight through our report the heterogeneity of the clinical presentation of the rash when on triple therapy and the need for further studies to understand the immunological mechanism of this adverse event.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Exanthema; Humans; Mutation

Topics: Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Infant

The association of certain disease processes with digital clubbing is well documented. Digital clubbing is often reversible after successful treatment of the underlying pathology, for example, after lung transplantation in patients with cystic fibrosis (CF). We examined the effect of highly effective Cystic Fibrosis Transmembrane Regulator (CFTR) modulators, defined for the purposes of this study as ivacaftor or the combination of ivacaftor, tezacaftor, and elexacaftor (ETI), on digital clubbing.. Clubbing index was measured on plaster of Paris casts of right index fingers obtained from 15 patients with cystic fibrosis, before and after initiation of CFTR modulator therapy. Similar measurements were made on casts for 9 cystic fibrosis patients who underwent lung transplantation. Measurements were made on the most recent casts available before treatment and the first cast available at least 3 months after initiation of treatment. The Wilcoxon signed-rank text was used to detect any significant difference in the pre- and post-treatment casts for each individual.. A significant decrease in the clubbing index was found after both lung transplantation and treatment with highly effective CFTR modulator therapy.. These results add to the body of evidence demonstrating the efficacy of highly effective CFTR modulator therapy, the first agents that act directly at the dysfunctional chloride channel responsible for CF. By demonstrating that CFTR modulator therapy is capable of reversing digital clubbing, this study suggests a beneficial effect on lung pathology aside from air flow and gas transfer.

Topics: Aminophenols; Benzodioxoles; Calcium Sulfate; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

Access to cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been gradually increasing for people with cystic fibrosis, the first of which was ivacaftor, a CFTR potentiator that is part of all clinically available modulator treatments. In this study, we hypothesized that the steady-state concentrations in blood and tissue are highly variable in patients taking ivacaftor in a real-world context, which may have an impact on the treatment approach. We collected nasal epithelial cells to estimate target site concentrations and blood samples to estimate pharmacokinetic parameters at a steady state. We found that patients on ivacaftor monotherapy have variable concentrations well above the maximal effective concentration and may maintain concentrations necessary for the clinical benefit even if dosing is reduced. We also are the first to provide detailed target site concentration data over time, which shows that tissue concentrations do not fluctuate significantly and do not correlate with plasma concentrations. These findings show that some patients may have higher-than-expected concentrations and may benefit from tailored dosing to balance clinical response with side effects or adherence needs.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

Topics: Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation

Topics: Adolescent; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Female; Humans; Mutation; Pyrazoles

Clinical trials for CFTR modulators consider mean changes of clinical status at the cohort level, and thus fail to assess the heterogeneity of the response. We aimed to study the different response profiles to lumacaftor-ivacaftor according to age in children with cystic fibrosis (CF).. A mathematical framework, including principal component analysis, data clustering, and data completion, was applied to a multicenter cohort of 112 children aged 6-18 years, treated with lumacaftor-ivacaftor. Studied parameters at baseline and 6 months included body mass index (BMI), number of days of antibiotics (ATB), Sweat test (ST), forced expiratory volume in 1 s expressed in percentage predicted (ppFEV. Change in ppFEV

Topics: Adolescent; Aminophenols; Aminopyridines; Anti-Bacterial Agents; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Fibrosis; Forced Expiratory Volume; Humans; Mutation

Elexacaftor/tezacaftor/ivacaftor (ELX-TEZ-IVA) is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator shown to improve lung function and reduce sweat chloride in people with Cystic Fibrosis (CF). The only commonly reported dermatologic adverse effect with CFTR modulators including ELX-TEZ-IVA is rash. In this case series, we describe 19 patients who reported new onset or worsening of acne after initiation of this drug to their CF pharmacist or another member of their CF care team. The mechanism and frequency of this adverse effect is unknown.

Topics: Acne Vulgaris; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation

Triple-combination therapy with elexacaftor, tezacaftor and ivacaftor has been recently approved for cystic fibrosis patients with at least one F508

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Female; Folliculitis; Humans; Malassezia; Mutation; Quinolones

Topics: Aminophenols; Aspergillus; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation

Topics: Adolescent; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Metagenome; Mutation; Quality of Life

Semistructured qualitative interviews were performed with 10 children with CF, 7 parents/carers and 10 HCPs. Audio recordings were transcribed and analysed using reflexive thematic analysis.. Four main themes were identified: 'Kaftrio changed my life', 'Your entire life is dictated by the CF timetable', 'Simplifying treatment-hopes and fears' and 'Kaftrio is a game-changer' along with several subthemes and an overarching theme of 'I still can't get my head around how three tablets can do what Kaftrio done'.. Despite the highly positive impact of ETI on the health of children with CF some concerns remain about the longer-term outcomes of reducing ACTs or nebulised treatments. ETI has prompted a shift in treatment for many and offers an opportunity to personalise approaches.

Topics: Aged; Aminophenols; Benzodioxoles; Child; Cyclic N-Oxides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Delivery of Health Care; Humans; Indoles; Mutation; Nebulizers and Vaporizers; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a plasma membrane protein expressed on the apical surface of secretory epithelia of the airways. In the airways, defective or absent function of the CFTR protein determines abnormalities of chloride and bicarbonate secretion and, in general, of the transepithelial homeostasis that lead to alterations of airway surface liquid (ASL) composition and properties. The reduction of ASL volume impairs ciliary beating with the consequent accumulation of a sticky mucus. This situation prevents normal mucociliary clearance, favoring the survival and proliferation of bacteria and contributing to the genesis of the CF pulmonary disease. We explored the potential of some CFTR modulators, namely ivacaftor, tezacaftor, elexacaftor and their combination Kaftrio

Topics: Aminophenols; Benzodioxoles; Bicarbonates; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Phenylalanine; Quinolones

The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo-electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function.

Topics: Cryoelectron Microscopy; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Synergism; Humans; Phenylalanine; Protein Conformation; Sequence Deletion

Elexacaftor-tezacaftor-ivacaftor (ETI) is known to pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of ivacaftor in rats demonstrated infant cataracts, but cataracts were not reported in human infants exposed to ivacaftor. We describe 3 cases of infants exposed to elexacaftor-tezacaftor-ivacaftor (ETI) in utero and while breast feeding who were found to have bilateral congenital cataracts within six months of birth. None of the infants had significant visual impairment from the cataracts nor any report of elevated liver function testing. These data highlight the need to counsel females who continue ETI throughout pregnancy and while breast feeding to consider cataract screen for their infants.

Topics: Aminophenols; Animals; Benzodioxoles; Breast Feeding; Cataract; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Female; Humans; Infant, Newborn; Mutation; Rats

Lumacaftor/Ivacaftor (LUM-IVA), a cystic fibrosis transmembrane conductance regulator (CFTR) protein corrector-potentiator combination, improves lung function and reduces pulmonary exacerbations (PEx) in F508del homozygous CF patients. However, the systemic effects of LUM-IVA outside the respiratory system have not yet been thoroughly investigated.. A prospective, real-world, yearlong study was performed on F508del homozygous adult CF patients who commenced treatment with LUM-IVA. Pancreatic function, bone metabolism, fertility status, nutritional and pulmonary factors were evaluated.. Twelve patients, mean age 28.3 years (18.6-43.9) were recruited. Following 12 months of treatment, no changes were detected in glucose, insulin, c-peptide or BMI values. A significant relative decrease in mean alkaline-phosphatase levels (122.8 U/L vs 89.4, p = 0.002) and a trend toward an increase in calcium levels (9.5 vs 9.9 mg/dL, p = 0.074) were observed. A non-significant improvement in mean DEXA spine t-score after a year of treatment (-2.1 vs -1.6, n = 4, p = 0.11) was detected. Sweat chloride concentrations decreased significantly (-21.4 mEq/L; p = 0.003). Pulmonary outcome revealed improvement in spirometry values during the first three months (FEV. After one year of treatment, stabilization was observed in the pancreatic indices, nutritional status, structure and function of the lungs, with a beneficial effect on bone mineral metabolism and CFTR function. Additional studies should investigate the effect of CFTR modulators on extra-pulmonary manifestations.

Topics: Adolescent; Adult; Anti-Bacterial Agents; C-Peptide; Calcium; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Glucose; Humans; Mutation; Prospective Studies; Young Adult

Topics: Anti-Bacterial Agents; Benzodioxoles; Clarithromycin; Clofazimine; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytochrome P-450 CYP3A; Drug Interactions; Humans; Nontuberculous Mycobacteria; Pyrrolidines; Rifabutin

In cystic fibrosis (CF), renal base excretion is impaired. Accordingly, challenged urine bicarbonate excretion may be an in vivo biomarker of cystic fibrosis transmembrane conductance regulator (CFTR) function.. To evaluate the association between challenged bicarbonate excretion and clinical characteristics at baseline, quantify the CFTR modulator drug elexacaftor/tezacaftor/ivacaftor-induced changes of challenged bicarbonate excretion after 6 months of treatment, and characterize the intraindividual variation in healthy adults.. Prospective observational study.. Cystic fibrosis clinic, Aarhus University Hospital, Denmark.. Fifty adult patients with CF starting CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor between May 2020 and June 2021.. Quantification of urine bicarbonate excretion after an acute oral sodium bicarbonate challenge before and 6 months after elexacaftor/tezacaftor/ivacaftor treatment.. At baseline, challenged urine bicarbonate excretion was associated with several CF disease characteristics. Bicarbonate excretion was higher in patients with residual function mutations. A higher bicarbonate excretion was associated with better lung function, pancreatic sufficiency, and lower relative risk for chronic pseudomonas infections. Elexacaftor/tezacaftor/ivacaftor treatment increased bicarbonate excretion by 3.9 mmol/3 h (95% CI, 1.6 to 6.1 mmol/3 h), reaching about 70% of that seen in healthy control participants. In healthy control participants, individual bicarbonate excretion at each visit correlated with the individual mean bicarbonate excretion. The median coefficient of variation was 31%.. Single-center study without a placebo-controlled group.. Although further studies are needed to address the performance and sensitivity of this approach, this early-stage evaluation shows that challenged urine bicarbonate excretion may offer a new, simple, and safe quantification of CFTR function and the extent of its pharmacologic improvement. Elexacaftor/tezacaftor/ivacaftor partially restores renal CFTR function in patients with CF, likely resulting in decreased risk for electrolyte disorders and metabolic alkalosis.. Innovation Fund Denmark.

Topics: Adult; Bicarbonates; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation

This short report documented cystic fibrosis transmembrane conductance regulator (CFTR) variants in 37 patients with cystic fibrosis (CF) in the Rio Grande do Norte region of Northeast Brazil. The high-throughput sequencing technology (HTS) genetic testing provided a definitive molecular diagnosis in 31 patients (83.8%). Among them, 25 patients' carriers of the c.1521_1523delCTT variant, categorized as a class 2 mutation, can be currently treated with CFTR modulator drugs. Five children aged 2-5 years could benefit from double lumacaftor/ivacaftor therapy, and 20 patients aged >6 years could be treated with the triple-combination elexacaftor/tezacaftor/ivacaftor therapy. Thus, the identification of pathogenic variants associated with the development of this disease allows for the introduction of therapy with CFTR modulators that favour better patient management.

Topics: Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; High-Throughput Nucleotide Sequencing; Humans; Mutation

Topics: Cystic Fibrosis; Humans; Pyrazoles

The triple combination modulator therapy (ETI, elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA)) is a recent advancement for the care of patients with cystic fibrosis. To aid in the development of clinical pharmacokinetics studies of this treatment, we developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for quantifying the component compounds in human plasma and cell lysate. This assay was optimized for small volumes (10 µL), uses stably labeled isotopes of the ETI compounds as internal standards, and employs a simple methanol protein precipitation method. Chromatography was performed on an ACE Excel C18, 2.1 × 50 mm, reversed phase analytical column, using a step or bump isocratic method, with mobile phases consisting of 0.1% formic acid in water for A, and 0.1% formic acid in acetonitrile for B. Analyte and internal standard detection was conducted with ESI positive ionization tandem mass spectrometry. The precursor/product transitions (m/z) monitored were 598.0/422.0 for ELX, 521.0/449.0 for TEZ, 393.0/172.0 for IVA, 601.0/422.0 for IS-ELX, 525.0/453.0 for IS-TEZ, and 399.0/178.0 for IS-IVA, respectively. The assay has a dynamic range of 10 to 10,000 ng/mL, with a mean coefficient of determination (r

Topics: Aminophenols; Benzodioxoles; Chromatography, Liquid; Cystic Fibrosis; Humans; Tandem Mass Spectrometry

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Drug Combinations; Exanthema; Humans; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Drug Combinations; Humans; Hypervitaminosis A; Indoles; Mutation; Papilledema; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

The CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) is a genetic mutation-targeted treatment in cystic fibrosis that results in profound improvements in clinical outcomes. Each of the compounds are substrates of CYP3A4/5, the cytochrome P450 enzyme family for which tacrolimus is also a substrate. The use of these compounds in an individual with a solid organ transplant has not been previously studied and there is potential for a drug interaction. In this report, we describe a pediatric liver transplant recipient with clinical decline related to cystic fibrosis who improved substantially with ETI, without significant impact on the systemic exposure of either ETI or tacrolimus.

Topics: Adolescent; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Indoles; Liver Transplantation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Tacrolimus

Topics: Aminophenols; Benzodioxoles; Chemical and Drug Induced Liver Injury; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Superior efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) over tezacaftor/ivacaftor (TEZ/IVA) in people with cystic fibrosis (CF) and Phe508del/Phe508del genotype was shown in clinical trials. We utilized intestinal organoid approach to compare in vitro responses to these 2 CFTR modulator drug combinations and to check potential inter-individual variability in therapeutic response to the triple combination. Organoids from 17 subjects with Phe508del/Phe508del were screened with forskolin induced swelling assay. Significantly larger swelling, when exposed to ELX/TEZ/IVA as compared to TEZ/IVA, was observed in 16 of them. However, 1 sample showed no additional effect of ELX. The finding of unique CFTR variants in this sample indicates that genetic traits other than CF-causing CFTR mutation are worth exploring as they may have an impact on the definitive modulator drug response.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mutation; Organoids; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Liver Transplantation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

The effects of lumacaftor-ivacaftor on cystic fibrosis transmembrane conductance regulator (CFTR)-associated liver disease remain unclear. The objective of the study was to describe the effect of this treatment on features of liver involvement in a cystic fibrosis (CF) adolescent population homozygous for F508del.. Clinical characteristics, liver blood tests, abdominal ultrasonography (US), and pancreas and liver proton density fat fraction (PDFF) by magnetic resonance imaging, were obtained at treatment initiation and at 12 months for all patients. Biomarkers of CFTR activity (sweat chloride test, nasal potential difference, and intestinal current measurement) were assessed at initiation and at 6 months therapy.. Of the 37 patients who started ivacaftor/lumacaftor treatment, 28 were eligible for analysis. In this group, before treatment initiation, 4 patients were diagnosed with multinodular liver and portal hypertension, 19 with other forms of CF liver involvement, and 5 with no signs of liver involvement. During treatment, no hepatic adverse reactions were documented, and no patient developed liver failure. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyl transferase (GGT) decreased significantly following initiation of lumacaftor-ivacaftor, and remained so after 12 months treatment. This was not correlated with changes in clinical status, liver and pancreas US and PDFF, fecal elastase, or lumacaftor-ivacaftor serum levels. The most "responsive" patients demonstrated a significant increase in biomarkers of CFTR activity.. These results may suggest a potential beneficial effect of CFTR modulators on CF liver disease and warrant further investigation in larger, prospective studies.

Topics: Adolescent; Aminophenols; Aminopyridines; Benzodioxoles; Biomarkers; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Liver; Mutation; Prospective Studies; Quinolones

Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, we describe the discovery and optimization of a novel potentiator series. Scaffold hopping, focusing on retaining the different intramolecular contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clinical candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.

Topics: Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Discovery; Humans; Pyridines; Rats

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit

Topics: Administration, Oral; Aminopyridines; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Deletion; Half-Life; Humans; Protein Binding; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Solubility; Structure-Activity Relationship

Topics: Adolescent; Adult; Age Factors; Aminophenols; Chloride Channel Agonists; Cohort Studies; Cystic Fibrosis; Diabetes Mellitus; Female; Forced Expiratory Volume; Humans; Male; Quinolones; Young Adult

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Insurance Coverage; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Acneiform Eruptions; Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Drug Eruptions; Humans; Indoles; Male; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

The c.3700A>G mutation, a rare cystic fibrosis (CF)-causing CFTR mutation found mainly in the Middle East, produces full-length transcript encoding a missense mutation (I1234V-CFTR), and a cryptic splice site that deletes 6 amino acids in nucleotide binding domain 2 (I1234del-CFTR).. FRT cell models expressing I1234V-CFTR and I1234del-CFTR were generated. We also studied an I1234del-CFTR-expressing gene-edited human bronchial (16HBE14o-) cell model, and primary cultures of nasal epithelial cells from a c.3700A>G homozygous subject. To identify improved mutation-specific CFTR modulators, high-throughput screening was done using I1234del-CFTR-expressing FRT cells. Motivated by the in vitro findings, Trikafta was tested in two c.3700A>G homozygous CF subjects.. FRT cells expressing full-length I1234V-CFTR had similar function to that of wildtype CFTR. I1234del-CFTR showed reduced activity, with modest activation seen with potentiators VX-770 and GLPG1837, correctors VX-809, VX-661 and VX-445, and low-temperature incubation. Screening identified novel arylsulfonyl-piperazine and spiropiperidine-quinazolinone correctors, which when used in combination with VX-445 increased current ~2-fold compared with the VX-661/VX-445 combination. The combination of VX-770 with arylsulfonamide-pyrrolopyridine, piperidine-pyridoindole or pyrazolo-quinoline potentiators gave 2-4-fold greater current than VX-770 alone. Combination potentiator (co-potentiator) efficacy was also seen in gene-edited I1234del-CFTR-expressing human bronchial epithelial cells. In two CF subjects homozygous for the c.3700A>G mutation, one subject had a 27 mmol/L decrease in sweat chloride and symptomatic improvement on Trikafta, and a second subject showed a small improvement in lung function.. These results support the potential benefit of CFTR modulators, including co-potentiators, for CF caused by the c.3700A>G mutation.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cells, Cultured; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Mutant Proteins; Mutation, Missense; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Aberrant responses by the cystic fibrosis airway epithelium during viral infection may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with ivacaftor (Iva) or ivacaftor/lumacaftor (Iva/Lum) would improve control of rhinovirus infection.. Nineteen CF epithelial cultures (10 homozygous for p.Phe508del as CFTR Class 2, 9 p.Phe508del/p.Gly551Asp as Class 3) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 h. Culture RNA and supernatants were harvested to assess gene and protein expression respectively.. RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated with CFTR modulators and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3 and only 68 genes for Class 2. Changes were predominantly related to regulators of lipid metabolism and inflammation, aspects of epithelial biology known to be dysregulated in CF. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection.. Though long-term clinical data is not yet available, results presented here suggest that first generation CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection. Future work should investigate the latest triple modulation therapies.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cells, Cultured; Common Cold; Cystic Fibrosis; Drug Combinations; Humans; Quinolones; Respiratory Mucosa; Rhinovirus

Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator for cystic fibrosis (CF) patients homozygous or heterozygous for F508del. Effects of the drug on sinonasal symptoms have not been studied.. Adult participants were prospectively evaluated at baseline and after three months of treatment using validated questionnaires assessing sinonasal symptoms (SNOT-22) and CF-related quality of life (CFQ-R).. Forty-three participants completed the study; 23 were taking other CF transmembrane conductance (CFTR) modulators at the time of study participation. There was a significant improvement in mean SNOT-22 from 34.8 (29.4-40, 95% confidence interval) to 24.4 (19.9-29.0) (p = 0.000003) and in the Respiratory domain of the CFQR from 60.6 (57.1-64.1) to 83.3 (79.4-87.2) (p = 0.0000002), both achieving a minimal clinically important difference. Patients previously taking CFTR modulators experienced a greater benefit in sinonasal and respiratory symptoms.. Elexacaftor-tezacaftor-ivacaftor is associated with significant improvement in sinonasal symptoms; previous use of CFTR modulators is associated with greater benefit.

Topics: Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Female; Humans; Indoles; Male; Paranasal Sinus Diseases; Prospective Studies; Pyrazoles; Pyridines; Pyrrolidines; Quality of Life; Quinolones

Individuals with cystic fibrosis (CF) have an increased risk for gallbladder abnormalities and biliary tract disease, but the reported incidence of these manifestations of CF varies widely in the literature. With the approval of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), increasing numbers of CF patients have been initiated on highly effective cystic fibrosis transmembrane regulator (CFTR) modulator therapy. While elevations in hepatic panel are known potential side effects of CFTR modulators, there have been no published cases of biliary disease or acute cholecystitis attributed to these medications. In this case series, we describe seven patients at two adult CF centers with biliary colic shortly after initiation with ELX/TEZ/IVA, six of whom required cholecystectomy.

Topics: Adult; Aminophenols; Benzodioxoles; Biliary Tract Diseases; Chloride Channel Agonists; Cholecystectomy; Cystic Fibrosis; Drug Combinations; Female; Humans; Indoles; Male; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Therapies that target the underlying defect in Cystic Fibrosis (CF) will likely impact the future characteristics of the CF population and healthcare utilization. The objectives of this study were to estimate the potential impact of elexacaftor/tezacaftor/ivacaftor on morbidity and mortality, and the impact of delayed access.. A microsimulation transition model was applied to Canadian CF Registry data to forecast lung disease severity, pulmonary exacerbations, deaths and transplants to 2030 under three scenarios: 1) no availability of elexacaftor/tezacaftor/ivacaftor, 2) availability in 2021 ('early') or 3) availability in 2025 ('delayed'). Published Phase III data on treatment effects were used to estimate transition rates between disease severity states.. Under specific assumptions regarding disease state and treatment effect applied to the Canadian CF population it is projected that by 2030, early introduction of elexacaftor/tezacaftor/ivacaftor is expected to reduce the number of individuals with severe lung disease by 60% (95% CI 55.3; 63.9), increase the number of individuals with mild lung disease by 18% (95%CI 18.2; 19.0) and reduce the number of pulmonary exacerbations by 19% (95%CI 18.9; 19.5). Earlier introduction of elexacaftor/tezacaftor/ivacaftor could reduce deaths by 15% (95% 13.2; 18.4) and improve the median age of survival by 9.2 years (7.5; 10.8) over a 10-year period. The expected benefits of therapy are cumulative, therefore delayed access to elexacaftor/tezacaftor/ivacaftor will result in preventable health care utilization and deaths.. Delayed access to elexacaftor/tezacaftor/ivacaftor will have a negative impact on lung health and survival in the CF population.

Topics: Adolescent; Adult; Aminophenols; Benzodioxoles; Canada; Child; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Health Services Accessibility; Humans; Indoles; Middle Aged; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Registries

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Neutrophils; Phenotype; Quinolones

Topics: Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Enzyme Replacement Therapy; Humans; Mutation; Pancreas; Quinolones

We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC

Topics: Aminophenols; Animals; Cell Line; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Models, Molecular; Mutation; Piperidines; Quinolones; Rats; Structure-Activity Relationship

Topics: Aminophenols; Child; Child, Preschool; Cystic Fibrosis; Humans; Infant; Mutation; Precision Medicine; Quinolones

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

The novel cystic fibrosis transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, and tezacaftor, are the first drugs directly targeting the underlying pathophysiological mechanism in cystic fibrosis (CF); however, independent studies describing their pharmacokinetics are lacking. The aim of this study was to develop a quantification method for ivacaftor and its 2 main metabolites, lumacaftor and tezacaftor, in plasma and sputum using liquid chromatography with tandem mass spectrometry.. The developed method used a small sample volume (20 µL) and simple pretreatment method; protein precipitation solution and internal standard were added in one step to each sample. Liquid chromatography with tandem mass spectrometry was performed for a total run time of 6 minutes. The method was validated by assessing selectivity, carryover, linearity, accuracy and precision, dilution, matrix effects, and stability.. The selectivity was good as no interference from matrices was observed. In the concentration range from 0.01 to 10.0 mg/L, calibration curves were linear with a correlation coefficient >0.9997 for all compounds. The within-run and between-run accuracy were between 99.7% and 116% at the lower limit of quantitation (LLOQ) and between 95.8% and 112.9% for all concentrations above LLOQ for all analytes in plasma and sputum. Within-run and between-run precisions were <12.7% for LLOQ and <6.7% for the higher limit of quantitation. Samples were stable, with no significant degradation at examined temperatures and time points. Clinical applicability was revealed by analyzing samples from 2 patients with CF.. The presented method enables simultaneous quantification of ivacaftor, lumacaftor, and tezacaftor in plasma and sputum and is an improvement over previous methods because it uses smaller sample volumes, a simple pretreatment protocol, and includes tezacaftor. In future studies, it can be applied for examining pharmacokinetics characteristics of new CF transmembrane conductance regulator modulators.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chromatography, Liquid; Cystic Fibrosis; Drug Combinations; Humans; Indoles; Mutation; Plasma; Quinolones; Sputum; Tandem Mass Spectrometry

The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, ivacaftor, was first approved for people with CF and the G551D CFTR mutation. This study describes the long-term clinical effectiveness of ivacaftor in this population.. We conducted a multicenter, prospective, longitudinal, observational study of people with CF ages ≥6 years with at least one copy of the G551D CFTR mutation. Measurements of lung function, growth, quality of life, and sweat chloride were performed after ivacaftor initiation (baseline, 1 month, 3 months, 6 months, and annually thereafter until 5.5 years).. Ninety-six participants were enrolled, with 81% completing all study measures through 5.5 years. This cohort experienced significant improvements in percent predicted forced expiratory volume in 1 second (ppFEV1) of 4.8 [2.6, 7.1] (p < 0.001) at 1.5 years, that diminished to 0.8 [-2.0, 3.6] (p = 0.57) at 5.5 years. Adults experienced larger improvements in ppFEV1 (7.4 [3.6, 11.3], p < 0.001 at 1.5 years and 4.3 [0.6, 8.1], p = 0.02 at 5.5 years) than children (2.8 [0.1, 5.6], p = 0.04 at 1.5 years and -2.0 [-5.9, 2.0], p = 0.32 at 5.5 years). Rate of lung function decline for the overall study cohort from 1 month after ivacaftor initiation through 5.5 years was estimated to be -1.22 pp/year [-1.70, -0.73]. Significant improvements in growth, quality of life measures, sweat chloride, Pseudomonas aeruginosa detection, and pulmonary exacerbation rates requiring antimicrobial therapy persisted through five years of therapy.. These findings demonstrate the long-term benefits and disease modifying effects of ivacaftor in children and adults with CF and the G551D mutation.

Topics: Adolescent; Adult; Aminophenols; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Longitudinal Studies; Male; Mutant Proteins; Mutation; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Quality of Life; Quinolones; Respiratory Function Tests; United States

Cystic fibrosis (CF) transmembrane conductance (CFTR) dysfunction may play a role in CF-related bone disease (CFBD). Ivacaftor is a CFTR potentiator effective in improving pulmonary and nutritional outcomes in patients with the G551D-CFTR mutation. The effects of ivacaftor on bone health are unknown.. To determine the impact of ivacaftor on bone density and microarchitecture in children and adults with CF.. Prospective observational multiple cohort study.. Outpatient clinical research center within a tertiary academic medical center.. Three cohorts of age-, race-, and gender-matched subjects were enrolled: 26 subjects (15 adults and 11 children) with CF and the G551D-CFTR mutation who were planning to start or had started treatment with ivacaftor within 3 months (Ivacaftor cohort), 26 subjects with CF were not treated with ivacaftor (CF Control cohort), and 26 healthy volunteers.. All treatments, including Ivacaftor, were managed by the subjects' pulmonologists.. Bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT), areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) and bone turnover markers at baseline, 1, and 2 years.. Cortical volume, area, and porosity at the radius and tibia increased significantly in adults in the Ivacaftor cohort. No significant differences were observed in changes in aBMD, trabecular microarchitecture, or estimated bone strength in adults or in any outcome measures in children.. Treatment with ivacaftor was associated with increases in cortical microarchitecture in adults with CF. Further studies are needed to understand the implications of these findings.

Topics: Adolescent; Adult; Aged; Amino Acid Substitution; Aminophenols; Bone and Bones; Bone Density; Case-Control Studies; Child; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Middle Aged; Mutation, Missense; Quinolones; United States; Young Adult

Positive results in pre-clinical studies of the triple combination of elexacaftor, tezacaftor and ivacaftor, performed in airway epithelial cell cultures obtained from patients harbouring the class II cystic fibrosis transmembrane conductance regulator (CFTR) mutation F508del-CFTR, translated to impressive clinical outcomes for subjects carrying this mutation in clinical trials and approval of Trikafta.Encouraged by this correlation, we were prompted to evaluate the effect of the elexacaftor, tezacaftor and ivacaftor triple combination on primary nasal epithelial cultures obtained from individuals with rare class II CF-causing mutations (G85E, M1101K and N1303K) for which Trikafta is not approved.Cultures from individuals homozygous for M1101K responded better than cultures harbouring G85E and N1303K after treatment with the triple combination with respect to improvement in regulated channel function and protein processing. A similar genotype-specific effect of the triple combination was observed when the different mutations were expressed in HEK293 cells, supporting the hypothesis that these modulators may act directly on the mutant proteins. Detailed studies in nasal cultures and HEK293 cells showed that the corrector, elexacaftor, exhibited dual activity as both corrector and potentiator, and suggested that the potentiator activity contributes to its pharmacological activity.These pre-clinical studies using nasal epithelial cultures identified mutation genotypes for which elexacaftor, tezacaftor and ivacaftor may produce clinical responses that are comparable to, or inferior to, those observed for F508del-CFTR.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; HEK293 Cells; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolines; Quinolones

Infertility and subfertility are commonly faced by females with cystic fibrosis (FwCF) and resulting in decreased contraceptive use and increased utilization of reproductive technologies. Elexacaftor-tezacaftor-ivacaftor (ETI) is a CFTR modulator that affects common causes of subfertility. Two CF centers conducted a retrospective chart review on females with CF who were receiving ETI and became pregnant. We analyzed obstetrical-gynecological history, genotype, and clinical response to ETI therapy. Fourteen FwCF on ETI became pregnant. Half (7) of the FwCFs were previously attempting to conceive, but only three were using contraceptives. Four FwCF had a history of infertility; two were reconsidering use of reproductive technologies (IUI). Patients achieved conception at mean 8 weeks after initiating ETI. ETI may lessen CF-associated factors that affect fertility; however, its exact mechanism is unknown. This warrants counseling on contraceptive use and family planning prior to initiation of therapy and at routine intervals while utilizing ETI.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Female; Humans; Indoles; Infertility; Pregnancy; Pregnancy Rate; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Retrospective Studies

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones; Treatment Outcome

Studies have demonstrated that people with CF with pancreatic insufficiency (PI) have fecal dysbioses. Evidence suggests the causes of these dysbioses are multifactorial, and that important drivers include antibiotic exposure, dietary intake, and CF gastrointestinal tract dysfunction, including nutrient malabsorption. In this pilot study, we tested whether initiation of the CFTR modulator treatments ivacaftor (in a cohort of pancreatic sufficient (PS) people with CF and an R117H CFTR variant) or lumacaftor/ivacaftor (in a cohort of PI people with CF and an F508del variant) changed fecal measures of malabsorption or fecal microbiomes. While we identified no statistically significant fecal changes with either treatment, we detected trends in the PI cohort when initiating lumacaftor/ivacaftor towards decreased fecal fat content and towards fecal microbiomes that more closely resembled the fecal microbiota of people without PI. While these findings support a model in which nutrient malabsorption resulting from CF-induced PI drives fecal dysbiosis, they must be validated in future, larger studies of fecal microbiome and malabsorption outcomes with highly effective CFTR modulator therapies.

Topics: Adolescent; Adult; Aminophenols; Anti-Bacterial Agents; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Exocrine Pancreatic Insufficiency; Feces; Humans; Microbiota; Pilot Projects; Quinolones; Young Adult

Cystic fibrosis (CF) is a genetic disease characterized by CF transmembrane regulator (CFTR) dysfunction. With over 2000 CFTR variants identified, in addition to known patient to patient variability, there is a need for personalized treatment. The discovery of CFTR modulators has shown efficacy in certain CF populations, however there are still CF populations without valid therapeutic options. With evidence suggesting that single drug therapeutics are insufficient for optimal management of CF disease, there has been an increased pursuit of combinatorial therapies. Our aim was to test cyclic AMP (cAMP) modulation, through ATP Binding Cassette Transporter C4 (ABCC4) and phosphodiesterase-4 (PDE-4) inhibition, as a potential add-on therapeutic to a clinically approved CFTR modulator, VX-770, as a method for increasing CFTR activity. Human airway epithelial cells (Calu-3) were used to test the efficacy of cAMP modulation by ABCC4 and PDE-4 inhibition through a series of concentration-response studies. Our results showed that cAMP modulation, in combination with VX-770, led to an increase in CFTR activity via an increase in sensitivity when compared to treatment of VX-770 alone. Our study suggests that cAMP modulation has potential to be pursued as an add-on therapy for the optimal management of CF disease.

Topics: Aminophenols; Bronchi; Cell Line; Cells, Cultured; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Epithelial Cells; Humans; Multidrug Resistance-Associated Proteins; Phosphodiesterase 4 Inhibitors; Quinolones

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mutation; Precision Medicine; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Combinations; Drug Costs; Humans; Indoles; Medical Assistance; Mutation; Pyrazoles; Pyridines; Quinolines; Quinolones; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Adolescent; Aminophenols; Aminopyridines; Benzodioxoles; Child; Chloride Channel Agonists; Cost-Benefit Analysis; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Combinations; Drug Costs; Health Policy; Humans; Indoles; Models, Economic; Mutation; Pyrazoles; Pyridines; Quinolines; Quinolones; Treatment Outcome; United States; United States Food and Drug Administration

Treatment with Ivacaftor provides a significant clinical benefit in people with cystic fibrosis (PWCF) with the class III G551D-CFTR mutation. This study determined the effect of CFTR modulation with ivacaftor on the lung microbiota in PWCF.. Using both extended-culture and culture-independent molecular methods, we analysed the lower airway microbiota of 14 PWCF, prior to commencing ivacaftor treatment and at the last available visit within the following year. We determined total bacterial and Pseudomonas aeruginosa densities by both culture and qPCR, assessed ecological parameters and community structure and compared these with biomarkers of inflammation and clinical outcomes.. Significant improvement in FEV. Following treatment with ivacaftor, significant improvements in clinical parameters were seen. Despite modest changes in overall microbial community composition, there was a shift towards a bacterial ecology associated with less severe CF lung disease. Furthermore, a significant correlation was observed between richness and diversity and levels of circulating inflammatory markers.

Topics: Adolescent; Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Microbiota; Quinolones; Respiratory Function Tests; Sputum; Young Adult

Half of adults with cystic fibrosis (CF) develop CF-related diabetes (CFRD). CFRD contributes to worsened pulmonary function and malnutrition. We undertook this study to determine the effect of cystic fibrosis transmembrane regulator (CFTR) modulators on CRFD.. We reviewed the medical records of adults with CF who followed in the CF clinic at Oklahoma University Medical Center. We collected data for age at diagnosis of CF and CFRD, CF mutations present, first date of ivacaftor therapy either alone or in combination, insulin use, pulmonary function, body mass index data, and home glucose monitoring results. Clinical resolution of CFRD was taken as discontinuation of routine insulin and resolution of high interstitial home glucose values.. We identified 69 adult CF patients, of whom 31 had CFRD. Among these 14 CFRD patients taking ivacaftor alone or in combination, four patients completely stopped using insulin. Another patient went from three times a day pre-prandial insulin to using insulin once a week. Home blood glucose and hemoglobin A1c values supported resolution of CFRD. Three patients continued to have hypoglycemia despite stopping insulin. No CFRD patient not taking CFTR modulators markedly changed the insulin regimen. Pulmonary function was preserved in those patients with resolved CFRD (FEV. About one-third of patients on CFTR modulator therapy had resolution or near resolution of CFRD.

Topics: Adult; Aminophenols; Blood Glucose; Blood Glucose Self-Monitoring; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Humans; Insulin; Quinolones

Ivacaftor was the first therapy licensed to address the underlying defect in cystic fibrosis (CF). The improvements in lung function, nutritional status and pulmonary exacerbations in patients carrying a. We conducted a 5-year single-centre retrospective study of people with CF carrying the. 35 people were included. After commencing ivacaftor, FEV. The addition of ivacaftor provides acute benefits for people with the

Topics: Adolescent; Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Mutation; Quinolones; Retrospective Studies

The question whether the new cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs aimed at restoring CFTR protein function might improve glucose metabolism is gaining attention, but data on the effect of lumacaftor/ivacaftor treatment (LUMA/IVA) on glucose tolerance are limited. We evaluated the variation in glucose metabolism and insulin secretion in CF patients homozygous for Phe508del CFTR mutation after one-year treatment with LUMA/IVA in comparison to patients with the same genotype who did not receive such treatment.. We performed a retrospective case-control study on 13 patients with a confirmed diagnosis of CF, homozygous for the Phe508del CFTR mutation, who received LUMA/IVA for one year (cases) and 13 patients with identical genotype who did not receive this treatment (controls). At the beginning and conclusion of the follow-up, all subjects received a modified 3 h OGTT, sampling at baseline, and at 30 min intervals for plasma glucose, serum insulin, and c-peptide concentrations to evaluate glucose tolerance, and quantify by modeling beta-cell insulin secretion responsiveness to glucose, insulin clearance and insulin sensitivity.. LUMA/IVA did not produce differences in glucose tolerance, insulin secretory parameters, clearance and sensitivity with respect to matched controls over one-year follow-up.. We found no evidence of improvements in glucose tolerance mechanisms in patients with CF after one-year treatment with LUMA/IVA.

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Blood Glucose; Case-Control Studies; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Follow-Up Studies; Homozygote; Humans; Insulin Secretion; Male; Mutation; Prognosis; Quinolones; Retrospective Studies; Young Adult

Topics: Aminophenols; Aminopyridines; Animals; Benzoates; Benzodioxoles; Benzopyrans; Cell Line; Chlorides; Codon, Nonsense; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Ion Transport; Protein Biosynthesis; Pyrans; Pyrazoles; Quinolones; Rats; Recovery of Function; Thyroid Epithelial Cells

The CFTR modulator ivacaftor has been variably effective in treating individuals with cystic fibrosis (CF) who harbor CFTR gating variants such as G551D, as well as other classes of CFTR variants when used with other modulators. Because CFTR genotype does not fully explain this variability, defining genetic modifiers of response to modulator therapy is of particular interest to the field of individualized CF drug therapy. Previous studies have proposed that a variant in SLC26A9 (rs7512462) is associated with lung disease severity and with response to treatment with ivacaftor in individuals with CF who carry G551D or gating variants.. Given the implications for CF treatment, we re-examined the reported associations in three cohorts; patients enrolled in the Twin and Siblings study at Johns Hopkins University, the CF modifier study at the University of North Carolina at Chapel Hill, and the prospective G551D Observational (GOAL) study. The GOAL study was specifically designed to measure lung function response to ivacaftor.. We find no association between SLC26A9 (rs7512462) genotype and lung disease severity (n = 272) or change in lung function at one-, three-, and six-month intervals following ivacaftor treatment(n = 141) in individuals with CF who carry at least one G551D variant.. Our inability to replicate this association indicates that rs7512462 genotype should not be used in treatment decisions.

Topics: Aminophenols; Antiporters; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Male; Polymorphism, Single Nucleotide; Prospective Studies; Quinolones; Respiratory Function Tests; Severity of Illness Index; Sulfate Transporters; Young Adult

New drugs that target the basic defect in cystic fibrosis (CF) patients may now be used in a large number of patients carrying responsive mutations. Nevertheless, further research is needed to extend the benefit of these treatments to patients with rare mutations that are still uncharacterized in vitro and that are not included in clinical trials. For this purpose, ex vivo models are necessary to preliminary assessing the effect of CFTR modulators in these cases.. We report the clinical effectiveness of lumacaftor/ivacaftor therapy prescribed to a CF child with a rare genetic profile (p.Phe508del/p.Gly970Asp) after testing the drug on nasal epithelial cells. We observed a significant drop of the sweat chloride value, as of the lung clearance index. A longer follow-up period is needed to define the effects of therapy on pancreatic status, although an increase of the fecal elastase values was found.. Drug response obtained on nasal epithelial cells correlates with changes in vivo therapeutic endpoints and can be a predictor of clinical efficacy of novel drugs especially in pediatric patients.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cells, Cultured; Child, Preschool; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Female; Genotype; Humans; Mutation, Missense; Nasal Mucosa; Pancreatic Elastase; Quinolones

With the improved health afforded by cystic fibrosis transmembrane conductance regulator (CFTR) modulators, pregnancy rates are increasing in women with CF. In animal reproductive models, the three components of elexacaftor-tezacaftor-ivacaftor (ETI) did not cause teratogenicity at normal human doses. Although the limited human data available in the literature for previously approved modulators did not suggest cause for concern, there is currently no data in the literature regarding use of ETI in pregnant women. Thus, the decision to continue therapy during pregnancy (with the associated unknown fetal impact) versus discontinuing therapy (with the known risk of maternal health decline) is challenging.. CF Center staff completed an anonymous questionnaire regarding pregnancy and infant outcomes for women who used ETI during pregnancy and/or lactation.. Of 45 ETI-exposed pregnancies reported to date, complications in 2 mothers and in 3 infants (2 born to mothers with poorly controlled diabetes) were rated by clinicians as unknown (possible) or suspected relatedness to ETI use. Two women terminated unplanned pregnancies. Miscarriage rates were consistent with that known in the general U.S.. Five of the six women who discontinued ETI out of concern for unknown fetal risk restarted because of clinical deterioration. No infant cataracts were reported though only two infants were formally evaluated.. In the context of the known increased rate of complications in women with CF and their infants, data from this retrospective survey is reassuring for women who choose to continue ETI during pregnancy. However, a large, multi-center prospective study is needed to assess impact of use of ETI in pregnancy.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Female; Humans; Indoles; Lactation; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Rate; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Surveys and Questionnaires

Ivacaftor is a CFTR potentiator with demonstrated efficacy in clinical trials and has been rapidly adopted within the CF community. Given the uptake of ivacaftor in eligible people, identifying a comparator group not on modulators to measure effectiveness is difficult. We evaluated health outcomes in individuals with G551D and non-G551D genotypes on ivacaftor using real-world longitudinal data.. This population-based observational study compared clinical trajectories pre-post ivacaftor using the Canadian CF Registry from 2006 to 01-01 through 2018-12-31. Piece-wise linear mixed-effects models were used to compare lung function, nutritional status, pulmonary exacerbations, and Pseudomonas colonization pre- and post-ivacaftor. Multivariable models were used to adjust for confounding factors.. Forced expiratory volume in 1 second (FEV1) increased significantly by 5.7 percent predicted (95% confidence interval (CI) 3.9, 7.5; p<0.001) after initiation of ivacaftor. FEV1 decline rate was attenuated to -0.30% (95% CI -0.9, 0.29; p = 0.32) predicted/year post-ivacaftor, compared with -0.75% (95% CI -1.12, -0.37; p<0.001) predicted/year pre-ivacaftor, although this difference did not reach statistical significance. BMI percentiles also increased post-ivacaftor (6.57 percentiles, 95% CI 3.91, 9.24; p<0.001). Pulmonary exacerbations showed a nonsignificant reduction of 18% (RR 0.82, 95% CI 0.61, 1.11; p = 0.19) and the odds of a positive sputum culture for Pseudomonas aeruginosa decreased in the post-ivacaftor period (odds ratio 0.44, 95% CI 0.30, 0.63; p<0.001).. This real-world, observational study demonstrated improvement in health outcomes in a broad population of people with CF. Additional studies are needed to evaluate the impact of ivacaftor on quality of life and survival.

Topics: Adolescent; Adult; Aminophenols; Canada; Child; Chloride Channel Agonists; Cystic Fibrosis; Female; Humans; Longitudinal Studies; Male; Middle Aged; Pseudomonas Infections; Quinolones; Registries; Retrospective Studies

Animal models have been highly informative for understanding the pathogenesis and progression of cystic fibrosis (CF) lung disease. In particular, the CF rat models recently developed have addressed mechanistic causes of the airway mucus defect characteristic of CF, and how these may change when cystic fibrosis transmembrane conductance regulator (CFTR) activity is restored using new modulator therapies. We hypothesized that inflammatory changes to the airway would develop spontaneously and progressively, and that these changes would be resolved with modulator therapy. To test this, we used a humanized-CFTR rat expressing the G551D variant that responds to the CFTR modulator ivacaftor. Markers typically found in the CF lung were assessed, including neutrophil influx, small airway histopathology, and inflammatory cytokine concentration. Young hG551D rats did not express inflammatory cytokines at baseline but did upregulate these in response to inflammatory trigger. As the hG551D rats aged, histopathology worsened, accompanied by neutrophil influx into the airway and increasing concentrations of TNF-α, IL-1α, and IL-6 in the airways. Ivacaftor administration reduced concentrations of these cytokines when administered to the rats at baseline but was less effective in the rats that had also received inflammatory stimulus. Therefore, we conclude that administration of ivacaftor resulted in an incomplete resolution of inflammation when rats received an external trigger, suggesting that CFTR activation may not be enough to resolve inflammation in the lungs of patients with CF.

Topics: Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Inflammation; Ion Transport; Lung; Molecular Targeted Therapy; Mucociliary Clearance; Quinolones; Rats, Transgenic

The aim of this study was the identification of specific proteomic profiles, related to a restored cystic fibrosis transmembrane conductance regulator (CFTR) activity in cystic fibrosis (CF) leukocytes before and after ex vivo treatment with the potentiator VX770. We used leukocytes, isolated from CF patients carrying residual function mutations and eligible for Ivacaftor therapy, and performed CFTR activity together with proteomic analyses through micro-LC-MS. Bioinformatic analyses of the results obtained revealed the downregulation of proteins belonging to the leukocyte transendothelial migration and regulation of actin cytoskeleton pathways when CFTR activity was rescued by VX770 treatment. In particular, we focused our attention on matrix metalloproteinase 9 (MMP9), because the high expression of this protease potentially contributes to parenchyma lung destruction and dysfunction in CF. Thus, the downregulation of MMP9 could represent one of the possible positive effects of VX770 in decreasing the disease progression, and a potential biomarker for the prediction of the efficacy of therapies targeting the defect of Cl

Topics: Actin Cytoskeleton; Adult; Aminophenols; Biomarkers; Cell Movement; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Gene Expression Regulation; Humans; Leukocytes, Mononuclear; Male; Matrix Metalloproteinase 9; Proteome; Quinolones

Cystic fibrosis is a deadly multiorgan disorder caused by loss of function mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride/bicarbonate ion channel. More than 1,700

Topics: Aminophenols; Animals; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mice; Mutation; Organoids; Precision Medicine; Quinolones

A previous phase 3 study showed that lumacaftor-ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor-ivacaftor in a rollover study of children who participated in this previous phase 3 study.. In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor-ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115). The study was done at 20 cystic fibrosis care centres in the USA and Canada. Children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation who completed 24 weeks of lumacaftor-ivacaftor treatment in study 115 received weight-based and age-based doses of oral lumacaftor-ivacaftor: children weighing less than 14 kg and aged younger than 6 years at study 116 screening received lumacaftor 100 mg-ivacaftor 125 mg every 12 h; children weighing 14 kg or more and aged younger than 6 years at screening received lumacaftor 150 mg-ivacaftor 188 mg every 12 h; and children aged 6 years or older received lumacaftor 200 mg-ivacaftor 250 mg every 12 h. Children received treatment for up to 96 weeks, equivalent to up to 120 weeks of treatment in total from the start of study 115 to completion of study 116. The primary endpoint was the safety and tolerability of the study drug in all participants who had received lumacaftor-ivacaftor for 24 weeks in study 115 and had received at least one dose in study 116. Secondary endpoints included change from baseline in study 115 at week 96 of study 116 in sweat chloride concentration, growth parameters, markers of pancreatic function, and lung clearance index (LCI) parameters in all children who received at least one dose of lumacaftor-ivacaftor in study 116. This study is registered with ClinicalTrials.gov, NCT03125395.. This extension study ran from May 12, 2017, to July 17, 2019. Of 60 participants enrolled and who received lumacaftor-ivacaftor in study 115, 57 (95%) were included in study 116 and continued to receive the study drug. A total of 47 (82%) of 57 participants completed 96 weeks of treatment. Most participants (56 [98%] of 57) had at least one adverse event during study 116, most of which were mild (19 [33%] participants) or moderate (29 [51%] participants) in severity. The most common adverse events were cough (47 [82%] participants), nasal congestion (25 [44%] participants), pyrexia (23 [40%] participants), rhinorrhoea (18 [32%] participants), and vomiting (17 [30%] participants). A total of 15 (26%) participants had at least one serious adverse event; most were consistent with underlying cystic fibrosis or common childhood illnesses. Respiratory adverse events occurred in five (9%) participants, none of which were serious or led to treatment discontinuation. Elevated aminotransferase concentrations, most of which were mild or moderate in severity, occurred in ten (18%) participants. Three (5%) participants discontinued treatment due to adverse events (two due to increased aminotransferase concentrations [one of whom had concurrent pancreatitis], considered as possibly related to study drug; and one due to gastritis and metabolic acidosis, considered unlikely to be related to study drug). No clinically significant abnormalities or changes were seen in electrocardiograms, vital signs, pulse oximetry, ophthalmological examinations, or spirometry assessments. Improvements in secondary endpoints observed in study 115 were generally maintained up to week 96 of study 116, including improvements in sweat chloride concentration (mean absolute change from study 115 baseline at week 96 of study 116 -29·6 mmol/L [95% CI -33·7 to -25·5]), an increase in growth parameters and pancreatic function, and stable lung function relative to baseline, as measured by the LCI.. Lumacaftor-ivacaftor was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor-ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older homozygous for the F508del-CFTR mutation.. Vertex Pharmaceuticals Incorporated.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Ivacaftor is currently the only CFTR potentiator approved and is increasingly used since the development of CFTR correctors. Ivacaftor is metabolized by CYP3A4 and therefore dose reduction is required when treating patients on ivacaftor with CYP3A4 inhibiting drugs. As this advice is based on studies in healthy volunteers and not in cystic fibrosis (CF) patients, we need to investigate this in both groups to be able to extrapolate these data to CF.. A cohort of CF patients and healthy subjects were exposed to a single dose of ivacaftor in combination with a strong (ritonavir), moderate (clarithromycin) and mild (azithromycin) CYP3A4 inhibitor. Ivacaftor concentrations were measured in all blood samples in order to calculate the pharmacokinetic parameters for ivacaftor.. We found that exposure to ivacaftor was higher in healthy volunteers than in subjects with CF. However this difference was not statistically significant. No differences were observed in the interaction potential of CYP3A4 inhibitors between both study groups. The strong CYP3A4 inhibitor ritonavir, increased exposure to ivacaftor 7 times.. Our data support current recommendations for dose adjustment of ivacaftor in case of co-treatment with CYP3A4 inhibitors in people with CF. However, exposure to ivacaftor was higher in healthy subjects than in CF patients. Further study is needed to investigate the cause and implication of this difference.

Topics: Adult; Aminophenols; Azithromycin; Case-Control Studies; Chloride Channel Agonists; Cystic Fibrosis; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Quinolones; Ritonavir

In vitro biomarkers to assess cystic fibrosis transmembrane conductance regulator activity are desirable for precision modulator selection and as a tool for clinical trials. Here, we describe an organoid swelling assay derived from human nasal epithelia using commercially available reagents and equipment and an automated imaging process. Cells were collected in nasal brush biopsies, expanded in vitro, and cultured as spherical organoids or as monolayers. Organoids were used in a functional swelling assay with automated measurements and analysis, whereas monolayers were used for short-circuit current measurements to assess ion channel activity. Clinical data were collected from patients on modulators. Relationships between swelling data and short-circuit current, as well as between swelling data and clinical outcome measures, were assessed. The organoid assay measurements correlated with short-circuit current measurements for ion channel activity. The functional organoid assay distinguished individual responses as well as differences between groups. The organoid assay distinguished incremental drug responses to modulator monotherapy with ivacaftor and combination therapy with ivacaftor, tezacaftor, and elexacaftor. The swelling activity paralleled the clinical response. In conclusion, an in vitro biomarker derived from patients' cells can be used to predict responses to drugs and is likely to be useful as a preclinical tool to aid in the development of novel treatments and as a clinical trial outcome measure for a variety of applications, including gene therapy or editing.

Topics: Aminophenols; Benzodioxoles; Case-Control Studies; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Ion Transport; Mutation; Nasal Mucosa; Organoids; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators varies between people with cystic fibrosis (CF) of the same genotype, in part through the action of solute carriers encoded by modifier genes. Here, we investigate whether phosphate transport by SLC34A2 modulates the function of F508del-CFTR after its rescue by CFTR correctors.. With Fischer rat thyroid (FRT) cells heterologously expressing wild-type and F508del-CFTR and fully-differentiated CF and non-CF human airway epithelial cells, we studied SLC34A2 expression and the effects of phosphate on CFTR-mediated transepithelial ion transport. F508del-CFTR was trafficked to the plasma membrane by incubation with different CFTR correctors (alone or in combination) or by low temperature.. Quantitative RT-PCR demonstrated that both FRT and primary airway epithelial cells express SLC34A2 mRNA and no differences were found between cells expressing wild-type and F508del-CFTR. For both heterologously expressed and native F508del-CFTR rescued by either VX-809 or C18, the magnitude of CFTR-mediated Cl. Extracellular phosphate modulates the magnitude of CFTR-mediated Cl

Topics: Aminophenols; Animals; Benzodioxoles; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Indoles; Ion Transport; Phosphates; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Rats; Rats, Inbred F344; Sodium-Phosphate Cotransporter Proteins, Type IIb

Elexacaftor-tezacaftor-ivacaftor partially restores cystic fibrosis transmembrane conductance regulator function, and has been shown to induce significant clinical improvement in patients with at least one Phe508del allele. Yet little data exist on patient perspectives following elexacaftor-tezacaftor-ivacaftor initiation.. A mixed methods study was conducted using an online 13-item questionnaire (including 9 closed questions and 4 open questions), submitted from July 10. Of 245 patients who started elexacaftor-tezacaftor-ivacaftor in France, 101 (41%) participated. Median [IQR] age was 35 [28-41] years and duration of elexacaftor-tezacaftor-ivacaftor treatment was 4.3 [3.0-5.6] months. Patients generally reported a rapid impact on respiratory symptoms, sleep quality, general well-being and physical self-esteem, and a reduction in overall treatment burden. The majority of patients contrasted treatment burden, symptom severity, depression and a closed future marked by death or transplantation before elexacaftor-tezacaftor-ivacaftor, to renewed and unexpected physical strength, leading to greater self-confidence, autonomy and long-term planning, after treatment initiation. A small number of patients expressed concerns, mainly regarding changes in body representation and/or the fear of becoming dependent on the treatment.. After initiation of elexacaftor-tezacaftor-ivacaftor, CF patients with advanced disease reported rapid and positive physical, psychological and social effects, which translated into improved quality of life and the formulation of new life goals.

Topics: Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quality of Life; Quinolones; Sleep Quality

Topics: Adult; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cohort Studies; Cystic Fibrosis; Drug Therapy, Combination; Female; Humans; Indoles; Lung Transplantation; Male; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Respiratory Function Tests; Retrospective Studies

Substantial progress has been made in the treatment of Cystic fibrosis due to introduction of CFTR modulators. However, little is known about the long term side effects of treatment with these drugs. We here present a 7 year old girl with CF who presented with breast development as a rare dose dependent side effect of treatment with ivacaftor and we report data on the correlation between drug plasma concentration and clinical effect, bodyweight, and BSA in 16 patients. Higher plasma concentrations did not correlate with clinical effect, as change in FEV1 and sweat chloride concentration. Patients with low bodyweight or BSA tended to have higher plasma concentrations. This might indicate that the current recommended dose of ivacaftor is at the top of the dose-response curve and that some patients can be treated with lower doses of ivacaftor with similar clinical effect.

Topics: Aminophenols; Breast; Child; Chloride Channel Agonists; Cystic Fibrosis; Female; Humans; Puberty, Precocious; Quinolones

The potential effects of ivacaftor during pregnancy and breastfeeding on the offspring are still unknown. This study aimed to investigate pre-/postnatal age-related entry into the brain and lungs and transfer of maternally administered drug by the placental and via the milk.. In acute experiments Sprague Dawley rats at embryonic day (E) 19, postnatal days (P) 4, 9, 16, and adult were administered an intraperitoneal injection of ivacaftor (40 mg/kg) traced with [3H] ivacaftor. To determine tissue entry, plasma, cerebrospinal fluid (CSF), lungs and brains were collected, and radioactivity measured using liquid scintillation counting. For long term experiments pregnant dams were orally treated at 25 mg/kg/day for 7 days and pups collected at E19. For postnatal pups, dams received treatment for 7 or 14 days and pups were collected at P6, 9, 13 and 16. To estimate placental and milk transfer concentration of ivacaftor in pup & maternal plasma was determined by liquid chromatography-mass spectrometry.. At all ages, entry of ivacaftor into lungs, following either acute or prolonged exposure, was much higher than into brain & CSF. Brain entry appeared higher at earlier ages. Transfer across the placenta and breast milk. was estimated to be around ~40% of maternal plasma.. Fetal and postnatal rats were exposed to maternally administered ivacaftor via placental and milk transfer. Preferential entry in the lungs at all ages suggests the possibility that exposing CF babies to maternally administered ivacaftor could be beneficial for limiting progression of CF pathology in early development.

Topics: Aminophenols; Animals; Brain; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Lung; Milk; Placenta; Pregnancy; Quinolones; Rats; Rats, Sprague-Dawley

Cystic fibrosis is a genetic disease caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator gene, encoding for CFTR protein. The most frequent mutation is the deletion of phenylalanine at position 508 (F508del), which leads to distinct defects in channel gating and cellular processing. In last years, several thiazole containing small molecules, endowed with dual F508del-CFTR modulator activity, proved to be able to target these defects. In search of new chemical entities able to restore CFTR function, we designed and synthesized a small series of sixteen thiazole derivatives. The designed compounds were studied as correctors and potentiators of F508del-CFTR. Although none of the molecules showed significant corrector activity, compounds 10 and 11 exhibited potentiator effects, thus allowing to determine some basic structural features which enable to obtain F508del-CFTR potentiator activity. In silico ADME studies showed that these derivatives obey Lipinski's rule of five and are expected to be orally bioavailable. Therefore, these molecules may represent a good starting point for the design of analogues endowed with improved CFTR potentiator activity and a good pharmacokinetic profile.

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Humans; Molecular Structure; Structure-Activity Relationship; Thiazoles

Topics: Adolescent; Adult; Aminophenols; Biomarkers; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Humans; Longitudinal Studies; Lung; Male; Microbiota; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Respiratory System Agents; Sputum; Sweat; Treatment Outcome; Young Adult

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Humans; Quinolones

The potentiator ivacaftor (VX-770) has been approved for therapy of 38 cystic fibrosis (CF) mutations (∼10% of the patient population) associated with a gating defect of the CF transmembrane conductance regulator (CFTR). Despite the success of VX-770 treatment of patients carrying at least one allele of the most common gating mutation G551D-CFTR, some lung function decline and P. aeruginosa colonization persist. This study aims at identifying potentiator combinations that can considerably enhance the limited channel activity of a panel of CFTR gating mutants over monotherapy.. The functional response of 13 CFTR mutants to single potentiators or systematic potentiator combinations was determined in the human bronchial epithelial cell line CFBE41o- and a subset of them was confirmed in primary human nasal epithelia (HNE).. In six out of thirteen CFTR missense mutants the fractional plasma membrane (PM) activity, a surrogate measure of CFTR channel gating, reached only ∼10-50% of WT channel activity upon VX-770 treatment, indicating incomplete gating correction. Combinatorial potentiator profiling and cluster analysis of mutant responses to 24 diverse investigational potentiators identified several compound pairs that improved the gating activity of R352Q-, S549R-, S549N-, G551D-, and G1244E-CFTR to ∼70-120% of the WT. Similarly, the potentiator combinations were able to confer WT-like function to G551D-CFTR in patient-derived human nasal epithelia.. This study suggests that half of CF patients with missense mutations approved for VX-770 administration, could benefit from the development of dual potentiator therapy.

Topics: Aminophenols; Cells, Cultured; Chloride Channel Agonists; Cluster Analysis; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Synergism; Drug Therapy, Combination; Humans; Ion Channel Gating; Ion Transport; Mutation, Missense; Nasal Mucosa; Precision Medicine; Pyrans; Pyrazoles; Quinolones

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Eligibility Determination; Female; Humans; Medication Therapy Management; Mutation; Quality of Life; Quinolones; Respiratory Function Tests; Respiratory Tract Infections; Treatment Outcome

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Combinations; Humans; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolines; Quinolones; United States; United States Food and Drug Administration

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

Topics: Adolescent; Adult; Age Factors; Aminophenols; Body Mass Index; Body Weight; Child; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Disease Progression; Female; Forced Expiratory Volume; Humans; Male; Quinolones; Sex Factors; Sweat; Young Adult

Topics: Adult; Aminophenols; Bronchiectasis; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Delivery, Obstetric; Drug Dosage Calculations; Exocrine Pancreatic Insufficiency; Female; Gestational Age; Humans; Infant, Newborn; Lung Diseases; Monitoring, Physiologic; Mutation; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pseudomonas; Quinolones

Methicillin-resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients have greatly increased in prevalence in the past two decades and may lead to a more rapid rate of lung function decline. The objective of this study was to determine the impact of a MRSA eradication protocol on long-term culture results and clinical outcomes of pediatric CF patients in a real-world setting.. This was a single-center, retrospective study of children age 30 days to 17 years. Eradication followed the STAR-too study protocol. The primary outcome was the percent of patients with MRSA-negative cultures at 12 months. Secondary outcomes were the percent of patients with negative cultures at 3, 6, and greater than 12 months and changes in clinical outcomes compared to individual baseline.. Of the 55 patients who met inclusion criteria, 10 received protocol eradication. Baseline characteristics were similar between eradication and control groups except more eradication patients were on ivacaftor (30% vs 4%; P = .037). Two eradication patients did not receive rifampin due to ivacaftor use. Eradication did not significantly increase the percent of MRSA-negative cultures at 3 months (P = .122), 6 months (P = .058), or 12 months (P = .108); however, did increase culture negativity at greater than 12 months (P = .008). Eradication resulted in no significant differences in clinical outcomes compared to control.. An extensive eradication protocol may lead to an increased clearance rate of long-term CF respiratory cultures but does not appear to affect clinical outcomes. Eradication may be reasonable to attempt; however, more data is needed before routine recommendation in all patients.

Topics: Adolescent; Aminophenols; Anti-Bacterial Agents; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Quinolones; Retrospective Studies; Rifampin; Staphylococcal Infections

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Drug Approval; Drug Combinations; Humans; Indoles; Pyrazoles; Pyridines; Pyrrolidines; Quinolines; Quinolones; United States; United States Food and Drug Administration

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Administration Schedule; Drug Combinations; Drug Interactions; Forced Expiratory Volume; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Randomized Controlled Trials as Topic; Treatment Outcome

The development of CFTR modulators has transformed the care of patients with cystic fibrosis (CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. We developed assays to quantitate ivacaftor in cells and plasma from patients on modulator therapy, and our analyses revealed that cellular ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of ivacaftor in the cells of patients. While the nature of this study is exploratory and limited by a small number of patients, these findings suggest that techniques to measure modulator concentrations in vivo will be essential to interpreting their clinical impact, particularly given the evidence that ivacaftor concentrations influence the activity and stability of restored CFTR protein.

Topics: Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Epithelial Cells; Feasibility Studies; Humans; Pilot Projects; Quinolones

Topics: Alleles; Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Mutation; Quinolones

Variability in disease severity and CFTR modulator responses exists between patients with identical CFTR genotypes. Here, we characterized transcription, translation and function of R117H-CFTR using intestinal organoids and correlated them with in vitro responses to ivacaftor (VX-770).. Organoids were generated from individuals possessing at least one R117H-CFTR allele. The forskolin-induced swelling (FIS) assay was used to measure CFTR function and response to VX-770 treatment. R117H-CFTR protein and mRNA expression levels were determined in parallel and Pearson's correlation coefficients were assessed.. Variability in R117H-CFTR FIS responses was observed and correlated significantly with mRNA and protein expression. Response to VX-770 treatment in organoids correlated with mRNA and protein expression as well.. Our results indicate that gene expression, protein expression and CFTR function are strongly correlated in organoids from people with CFTR-R117H-7T/9T, which may suggest that CFTR gene expression may have consequences for CF diagnosis, prognosis and therapeutic benefit.

Topics: Aminophenols; Cell Culture Techniques; Chloride Channel Agonists; Colon; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Organoids; Quinolones; RNA, Messenger

Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Down-Regulation; Drug Therapy, Combination; Female; Humans; Indoles; Inflammation; Interleukin-18; Interleukin-1beta; Male; Monocytes; Quinolones; Tumor Necrosis Factor-alpha; Young Adult

Since the cloning of the CFTR gene 30 years ago, research aiming at understanding how CFTR mutations translate to abnormal synthesis or function of the CFTR protein has opened the way to genomically-guided therapy to improve CFTR function. A CFTR potentiator to enhance CFTR channel function has been approved in 2012 for specific and quite rare mutations. Subsequently, combinations of a corrector to increase CFTR expression at the cell membrane, plus a potentiator, have been approved for patients homozygous for the p.Phe508del mutation. To obtain robust correction of CFTR, new combinations of drugs are being studied. A triple combination associating two correctors and one potentiator is very promising and if data of clinical trials are confirmed, it could be a robust and well tolerated CFTR modulator for patients bearing at least one p.Phe508del mutation. Many other strategies are also in development to make these genomically-guided treatments available to all patients with CF. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Genetic Therapy; Humans; Indoles; Mutation; Precision Medicine; Quinolones; Respiratory System Agents

To describe the long-term effects of ivacaftor (Kalydeco®) in individuals with cystic fibrosis (CF) on body mass index (BMI), body composition (BC), pulmonary function (PF), resting energy expenditure (REE), and exercise capacity (EC) after ≥12 months of treatment.. BMI, lean and fat mass, PF, and EC will increase and REE will decrease after treatment.. Observational study.. Seven individuals with CF (mean age 15.4 ± 5.8 years) heterozygous for S1251N mutation, starting with ivacaftor, were included. Paired t tests were performed to assess the effects of ivacaftor. Height and weight were used to calculate BMI and BMI Z-scores. Dual-energy X-ray absorptiometry was used to assess BC. Spirometry and body plethysmography were used to assess PF. Indirect calorimetry was used to measure REE and cardiopulmonary exercise testing (CPET) was used to measure oxygen uptake (VO. After a median of 15 (interquartile range: 13-16) months of treatment, BMI increased significantly (P = .03), but not BMI Z-score (P = .23) or BC. Significant improvements were found for several PF variables, especially measures of hyperinflation (P = .02). Absolute VO. The results showed that long-term treatment of ivacaftor is associated with improvement of BMI and PF, but not of BC and REE. Oxygen uptake reduced after treatment, which may be due to a decrease in work of breathing.

Topics: Adolescent; Adult; Aminophenols; Body Composition; Body Mass Index; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Energy Metabolism; Female; Heterozygote; Humans; Lung; Male; Mutation; Quinolones; Spirometry; Young Adult

In this paper the innovative approach of nano into micro dry powders (NiM) was applied to incorporate into mannitol or mannitol/cysteamine micromatrices ivacaftor-loaded nanoparticles for pulmonary delivery in CF. Nanoparticles composed by a mixture of two polyhydrohydroxyethtylaspartamide copolymers containing loaded with ivacaftor at 15.5% w/w were produced. The nanoparticles were incorporated into microparticles to obtain NiM that were fully characterized in terms of size, morphology, interactions with artificial Cf mucus (CF-AM) as well as for aerodynamic behaviour. Finally the activity of ivacaftor-containing NiM was evaluated by in vitro preliminary experiments. NiM at matrix composed by a mixture of mannitol:cysteamine showed greater ability to reduce CF-AM viscosity whereas that based on just mannitol showed better aerodynamic properties with a FPF of about 25%. All produced NiM showed very good cytocompatibility and the released ivacaftor was able to restore the chroride transport in vitro.

Topics: Administration, Inhalation; Aminophenols; Animals; Cells, Cultured; Chloride Channel Agonists; Cysteamine; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Compounding; Drug Liberation; Expectorants; Mannitol; Mutation; Nanoparticles; Peptides; Powders; Quinolones; Rats, Inbred F344

Topics: Adult; Aminophenols; Codon, Nonsense; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Female; Humans; Oxadiazoles; Quinolones; Treatment Outcome

Cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators have revolutionized care for individuals with cystic fibrosis (CF) with positive effects on the gastrointestinal (GI) tract. There is emerging evidence linking CFTR dysfunction to celiac disease (CD). We present 3 cases of patients with CF, genotype F508del/G551D, treated with CFTR modulator, ivacaftor, and diagnosed with CD. These patients tested for CD because they had persistent GI symptoms that had partially improved with ivacaftor. This case series highlights the importance of a better understanding of how CFTR modulators impact the GI tract, their possible link to CD, and the importance of considering CD when evaluating GI symptoms in individuals with CF.

Topics: Aminophenols; Benzodioxoles; Celiac Disease; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive genetic disorder among Caucasian populations. The majority of CF cases are diagnosed in childhood; however, increasing numbers of adults are being diagnosed with the condition. We present the case of a 65-year-old Irish woman presenting with a chronic cough and a history of recurrent respiratory tract infections.

Topics: Aged; Aminophenols; Bronchoalveolar Lavage Fluid; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genetic Testing; Humans; Mutation; Quinolones; Scedosporium; Staphylococcus aureus; Stenotrophomonas maltophilia

Although the 1,2,3-triazole is a commonly used amide bioisostere in medicinal chemistry, the structural implications of this replacement have not been fully studied. Employing X-ray crystallography and computational studies, we report the spatial and electronic consequences of replacing an amide with the triazole in analogues of cystic fibrosis drugs in the VX-770 and VX-809 series. Crystallographic analyses quantify subtle differences in the relative positions and conformational preferences of the R

Topics: Amides; Aminophenols; Aminopyridines; Benzodioxoles; Crystallography, X-Ray; Cystic Fibrosis; Humans; Models, Molecular; Molecular Structure; Quantum Theory; Quinolones; Triazoles

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Glucose; Humans; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Lung; Proof of Concept Study; Quinolones

In epithelial cells, the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-regulated Cl- channel, plays a key role in water and electrolytes secretion. A dysfunctional CFTR leads to the dehydration of the external environment of the cells and to the production of viscous mucus in the airways of cystic fibrosis patients. Here, we applied the quadriwave lateral shearing interferometry (QWLSI), a quantitative phase imaging technique based on the measurement of the light wave shift when passing through a living sample, to study water transport regulation in human airway epithelial CFBE and CHO cells expressing wild-type, G551D- and F508del-CFTR. We were able to detect phase variations during osmotic challenges and confirmed that cellular volume changes reflecting water fluxes can be detected with QWLSI. Forskolin stimulation activated a phase increase in all CFBE and CHO cell types. This phase variation was due to cellular volume decrease and intracellular refractive index increase and was completely blocked by mercury, suggesting an activation of a cAMP-dependent water efflux mediated by an endogenous aquaporin (AQP). AQP3 mRNAs, not AQP1, AQP4 and AQP5 mRNAs, were detected by RT-PCR in CFBE cells. Readdressing the F508del-CFTR protein to the cell surface with VX-809 increased the detected water efflux in CHO but not in CFBE cells. However, VX-770, a potentiator of CFTR function, failed to further increase the water flux in either G551D-CFTR or VX-809-corrected F508del-CFTR expressing cells. Our results show that QWLSI could be a suitable technique to study water transport in living cells. We identified a CFTR and cAMP-dependent, mercury-sensitive water transport in airway epithelial and CHO cells that might be due to AQP3. This water transport appears to be affected when CFTR is mutated and independent of the chloride channel function of CFTR.

Topics: Aminophenols; Animals; Aquaporin 3; Biological Transport, Active; Biophysical Phenomena; Bronchi; Cell Line; Chloride Channel Agonists; CHO Cells; Colforsin; Cricetulus; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Microscopy, Interference; Mutant Proteins; Osmosis; Quinolones; Respiratory Mucosa; RNA, Messenger; Water

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Glucose; Humans; Quinolones

The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV

Topics: Adolescent; Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Middle Aged; Mutation; Quinolones; Respiratory Function Tests; United States

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding an anion channel that conducts chloride and bicarbonate across epithelial membranes. Mutations that disrupt pre-mRNA splicing occur in >15% of CF cases. One common CFTR splicing mutation is CFTR c.3718-2477C>T (3849+10 kb C>T), which creates a new 5' splice site, resulting in splicing to a cryptic exon with a premature termination codon. Splice-switching antisense oligonucleotides (ASOs) have emerged as an effective therapeutic strategy to block aberrant splicing. We test an ASO targeting the CFTR c.3718-2477C>T mutation and show that it effectively blocks aberrant splicing in primary bronchial epithelial (hBE) cells from CF patients with the mutation. ASO treatment results in long-term improvement in CFTR activity in hBE cells, as demonstrated by a recovery of chloride secretion and apical membrane conductance. We also show that the ASO is more effective at recovering chloride secretion in our assay than ivacaftor, the potentiator treatment currently available to these patients. Our findings demonstrate the utility of ASOs in correcting CFTR expression and channel activity in a manner expected to be therapeutic in patients.

Topics: Aminophenols; Bronchi; Cell Line, Tumor; Cells, Cultured; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Ion Transport; Mutation; Oligodeoxyribonucleotides, Antisense; Quinolones; RNA Splicing

Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment.. CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with ivacaftor plus lumacaftor or ivacaftor plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting.. During treatment, ivacaftor accumulated in CF-HBEs to a much greater extent than either lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further ivacaftor accumulation, though remained above baseline even after washout.. Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Bronchi; Cell Culture Techniques; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Epithelial Cells; Humans; Indoles; Quinolones; Respiratory Mucosa

Topics: Aminophenols; Animals; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Models, Animal; Mucus; Quinolones; Rats

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization. Since ganglioside GM1 is involved in the functional stabilization of transmembrane proteins, we investigated its role as an adjuvant to increase the effectiveness of CFTR modulators. According to our results, we found that GM1 resides in the same PM microenvironment as CFTR. In CF cells, the expression of the mutated channel is accompanied by a decrease in the PM GM1 content. Interestingly, by the exogenous administration of GM1, it becomes a component of the PM, reducing the destabilizing effect of the potentiator VX-770 on rescued CFTR protein expression/function and improving its stabilization. This evidence could represent a starting point for developing innovative therapeutic strategies based on the co-administration of GM1, correctors and potentiators, with the aim of improving F508del CFTR function.

Topics: Adjuvants, Immunologic; Aminophenols; Aminopyridines; Benzodioxoles; Bronchi; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; G(M1) Ganglioside; Humans; Mutation; Quinolones; Therapies, Investigational

Cystic Fibrosis (CF) is caused by mutations in the CF Transmembrane conductance Regulator (CFTR), the only ATP-binding cassette (ABC) transporter functioning as a channel. Unique to CFTR is a regulatory domain which includes a highly conformationally dynamic region-the regulatory extension (RE). The first nucleotide-binding domain of CFTR contains another dynamic region-regulatory insertion (RI). Removal of RI rescues the trafficking defect of CFTR with F508del, the most common CF-causing mutation. Here we aimed to assess the impact of RE removal (with/without RI or genetic revertants) on F508del-CFTR trafficking and how CFTR modulator drugs VX-809/lumacaftor and VX-770/ivacaftor rescue these variants. We generated cell lines expressing ΔRE and ΔRI CFTR (with/without genetic revertants) and assessed CFTR expression, stability, plasma membrane levels, and channel activity. Our data demonstrated that ΔRI significantly enhanced rescue of F508del-CFTR by VX-809. While the presence of the RI seems to be precluding full rescue of F508del-CFTR processing by VX-809, this region appears essential to rescue its function by VX-770, suggesting some contradictory role in rescue of F508del-CFTR by these two modulators. This negative impact of RI removal on VX-770-stimulated currents on F508del-CFTR can be compensated by deletion of the RE which also leads to the stabilization of this mutant. Despite both regions being conformationally dynamic, RI precludes F508del-CFTR processing while RE affects mostly its stability and channel opening.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cell Line; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Protein Domains; Quinolones; Regulatory Sequences, Nucleic Acid; Signal Transduction

Cystic Fibrosis is a lethal monogenic autosomal recessive disease linked to mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The most frequent mutation is the deletion of phenylalanine at position 508 of the protein. This F508del-CFTR mutation leads to misfolded protein that is detected by the quality control machinery within the endoplasmic reticulum and targeted for destruction by the proteasome. Modulating quality control proteins as molecular chaperones is a promising strategy for attenuating the degradation and stabilizing the mutant CFTR at the plasma membrane. Among the molecular chaperones, the small heat shock protein HspB1 and HspB4 were shown to promote degradation of F508del-CFTR. Here, we investigated the impact of HspB5 expression and phosphorylation on transport to the plasma membrane, function and stability of F508del-CFTR. We show that a phosphomimetic form of HspB5 increases the transport to the plasma membrane, function and stability of F508del-CFTR. These activities are further enhanced in presence of therapeutic drugs currently used for the treatment of cystic fibrosis (VX-770/Ivacaftor, VX-770+VX-809/Orkambi). Overall, this study highlights the beneficial effects of a phosphorylated form of HspB5 on F508del-CFTR rescue and its therapeutic potential in cystic fibrosis.

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Cell Line; Cell Membrane; Crystallins; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Heat-Shock Proteins; HEK293 Cells; Humans; Male; Mice; Molecular Chaperones; Mutation; Phenylalanine; Phosphorylation; Proteasome Endopeptidase Complex; Protein Transport; Quinolones

In recent years, a number of drugs have been approved for the treatment of cystic fibrosis (CF). Among them, newly released Trikafta, a combination of 3 drugs (VX-661/VX-445/VX-770), holds great promise to radically improve the quality of life for a large portion of patients with CF carrying 1 copy of F508del, the most frequent CF transmembrane conductance regulator (CFTR) mutation. Currently available disease-modifying CF drugs work by rescuing the function of the mutated CFTR anion channel. Recent research has shown that membrane lipids, and the cell lipidome in general, play a significant role in the mechanism of CFTR-defective trafficking and, on the other hand, its rescue. In this paper, by using untargeted lipidomics on CFBE41o- cells, we identified distinctive changes in the bronchial epithelial cell lipidome associated with treatment with Trikafta and other CF drugs. Particularly interesting was the reduction of levels of ceramide, a known molecular player in the induction of apoptosis, which appeared to be associated with a decrease in the susceptibility of cells to undergo apoptosis. This evidence could account for additional beneficial roles of the triple combination of drugs on CF phenotypes.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Bronchi; Cells, Cultured; Ceramides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Epithelial Cells; Humans; Indoles; Lipid Metabolism; Lipidomics; Pyrazoles; Pyridines; Quinolines; Quinolones; Spectrometry, Mass, Electrospray Ionization

Topics: Adolescent; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Gastrointestinal Microbiome; Humans; Quinolones

Sinonasal symptoms in patients suffering from cystic fibrosis can negatively influence the quality of life and sinuses can be a niche for pathogens causing infection and inflammation leading to a decrease of lung function. Ivacaftor, a potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator protein, has shown improvement in pulmonary function in cystic fibrosis patients with different forms of class III gating mutations. However, the effects of ivacaftor on sinonasal pathology have hardly been studied.. To determine the impact of ivacaftor therapy on sinonasal pathology in patients with cystic fibrosis with an S1251N mutation.. Prospective observational mono-center cohort study, between June 2015 and December 2016.. A tertiary referral center in Utrecht, The Netherlands.. Eight patients with cystic fibrosis with an S1251N mutation, treated with the potentiator ivacaftor were investigated.. Ivacaftor (Kalydeco, VX-770) therapy. Computed tomography imaging of paranasal sinuses. Nasal nitric oxide concentration measurements and nasal endoscopy.. Primary outcome is opacification of paranasal sinuses examined with computed tomography scan analysis and scaled by the modified Lund-Mackay score before and one year after treatment. Secondary outcomes are nasal nitric oxide concentration levels, sinonasal symptoms and nasal endoscopic findings before and approximately two months and in some cases one year after treatment.. Computed tomography scan analysis showed a significant decrease in opacification of the majority of paranasal sinuses comparing the opacification score per paranasal sinus before and after one year of treatment with ivacaftor. Median nasal nitric oxide levels significantly improved from 220.00 (IQR:136.00-341.18) to 462.84 (IQR:233.17-636.25) (p = 0.017) parts per billion. Likewise, the majority of sinonasal symptoms and nasal endoscopic pathology decreased or resolved at two months after the use of ivacaftor.. Ivacaftor appears to improve sinonasal outcome parameters and thereby sinonasal health in patients with cystic fibrosis with an S1251N mutation.

Topics: Adolescent; Adult; Aminophenols; Chloride Channel Agonists; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Male; Nitric Oxide; Paranasal Sinuses; Polymorphism, Single Nucleotide; Prospective Studies; Quinolones; Tertiary Care Centers; Tomography, X-Ray Computed; Young Adult

Topics: Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Mucus; Quinolones; Rats

For most of the >2000 CFTR gene variants reported, neither the associated disease liability nor the underlying basic defect are known, and yet these are essential for disease prognosis and CFTR-based therapeutics. Here we aimed to characterize two ultra-rare mutations - 1717-2A > G (c.1585-2A > G) and S955P (p.Ser955Pro) - as case studies for personalized medicine.. Patient-derived rectal biopsies and intestinal organoids from two individuals with each of these mutations and F508del (p.Phe508del) in the other allele were used to assess CFTR function, response to modulators and RNA splicing pattern. In parallel, we used cellular models to further characterize S955P independently of F508del and to assess its response to CFTR modulators.. Results in both rectal biopsies and intestinal organoids from both patients evidence residual CFTR function. Further characterization shows that 1717-2A > G leads to alternative splicing generating <1% normal CFTR mRNA and that S955P affects CFTR gating. Finally, studies in organoids predict that both patients are responders to VX-770 alone and even more to VX-770 combined with VX-809 or VX-661, although to different levels.. This study demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs to patients with rare mutations.

Topics: Alleles; Aminophenols; Aminopyridines; Benzodioxoles; Blotting, Western; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Electrophysiology; Fluorescent Antibody Technique; Genotype; Humans; Indoles; Mutation; Precision Medicine; Quinolones

A chronic intestinal inflammation may occur in patients with cystic fibrosis (CF), while no therapeutic management is proposed. Although Lumacaftor/Ivacaftor is well-known to modulate the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in lungs, no data are available on the impact of this treatment on CF intestinal disorders. We, therefore, investigated the evolution of intestinal inflammation after initiation of Lumacaftor/Ivacaftor in CF adolescents (median of follow-up: 336 days [IQR: 278;435]). Median fecal calprotectin concentrations decreased significantly after Lumacaftor/Ivacaftor initiation (102 μg/g [IQR: 69-210]) compared with the baseline (713 μg/g (IQR:148-852), P = 0.001). To our knowledge, this study showed for the first time that CF-related intestinal inflammation is improved by Lumacaftor/Ivacaftor treatment.

Topics: Adolescent; Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Inflammation; Lung; Mutation; Quinolones

Ivacaftor is an innovative treatment for CF. Ivacaftor monotherapy in a phase III trial for patients with F508del and a residual function (RF) mutation showed improvement in lung function. We evaluated the effectiveness and safety of ivacaftor in patients with severe CF carrying RF mutations.. Data were collected from Italian CF centers with patients enrolled in an ivacaftor compassionate use program. Data were collected 1 year before and 1 year after commencement of ivacaftor.. In patients with CFTR mutations that confer RF with severe lung disease, treatment with Ivacaftor is safe and results in a clinically significant improvement that was evident at 1 month and maintained at 12 months.

Topics: Adult; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Lung; Lung Diseases; Male; Middle Aged; Mutation; Quinolones; Respiratory Function Tests; Retrospective Studies; Treatment Outcome; Young Adult

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Double-Blind Method; Humans; Indoles; Mutation; Quinolones

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Double-Blind Method; Humans; Indoles; Mutation; Quinolones

Exocrine pancreatic insufficiency (EPI), which leads to malabsorption and poor weight gain, is seen in 85% of patients with cystic fibrosis (CF). EPI is treated with pancreatic enzyme replacement therapy taken with each meal. The highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator, ivacaftor, restores CFTR function in patients with responsive mutations. It is a widely held view that EPI in CF is irreversible due to the complete destruction of pancreatic ducts and acinar cells. We describe three pediatric CF patients with EPI who were started on ivacaftor, and subsequently showed evidence of restored exocrine pancreatic function with clinical and biochemical parameters.

Topics: Aminophenols; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Exocrine Pancreatic Insufficiency; Female; Humans; Male; Mutation; Pancreas; Quinolones

Cystic fibrosis (CF) is a rare genetic disease with no cure. Until recently, treatment has targeted symptoms of the disease and not the disease-causing genetic defect. Ivacaftor is included in a new class of breakthrough drugs targeting the genetic defects of CF. We sought to estimate the long-term cost-effectiveness of ivacaftor from a US payer perspective.. We developed an individual-level microsimulation model that followed a cohort of heterogeneous US CF patients over a lifetime. The primary outcome of interest was quality-adjusted life years (QALYs). We also compared unadjusted life years, count of acute pulmonary exacerbations, and count of lung transplants over a lifetime between patients treated with ivacaftor plus best supportive care and patients treated with best supportive care alone. We conducted one-way and probabilistic sensitivity analyses to test the impact of various model inputs and uncertainties.. We found a substantial increase in QALYs, life years, and treatment costs over a lifetime for patients treated with ivacaftor plus best supportive care versus best supportive care alone. Discounted results for ivacaftor were 22.92 QALYs and $8 797 840 in total lifetime costs compared to 16.12 QALYs and $2 336 366 lifetime costs for best supportive care alone. The incremental cost-effectiveness ratios (ICERs) were $950 217 per QALY. Results from the probabilistic sensitivity analysis indicated a 0% chance that ivacaftor was cost-effective at a willingness-to-pay (WTP) threshold of $500 000 per QALY.. Treatment with ivacaftor plus best supportive care versus best supportive care alone is not cost-effective at or near commonly accepted WTP thresholds.

Topics: Aminophenols; Chloride Channel Agonists; Cost-Benefit Analysis; Cystic Fibrosis; Drug Costs; Female; Health Care Costs; Humans; Male; Mutation; Quality-Adjusted Life Years; Quinolones; Time Factors

A 48-year-old woman sought a second opinion for dyspnea and chronic productive cough; she was a never smoker. Mild respiratory symptoms persisted since childhood and had progressively worsened over the previous decade. In addition, an unintentional 30-pound weight loss had occurred over several years. Six years previously, a diagnosis of hypersensitivity pneumonitis was made following right upper lobe wedge resection that revealed chronic bronchiolitis with interstitial pneumonia and non-necrotizing granulomatous inflammation. Subsequent use of prednisone elicited mild intermittent improvement. She had used feather pillows in the past without any other significant exposures. There were no reports of sinus or GI symptoms.

Topics: Alveolitis, Extrinsic Allergic; Aminophenols; Anti-Bacterial Agents; Bronchiectasis; Bronchoscopy; Cefazolin; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diagnosis, Differential; Female; Genetic Testing; Humans; Late Onset Disorders; Middle Aged; Quinolones; Staphylococcal Infections; Staphylococcus aureus; Tomography, X-Ray Computed; Treatment Outcome

Topics: Aminophenols; Cystic Fibrosis; Forced Expiratory Volume; Humans; Liver Cirrhosis; Mutation; Nutritional Status; Quinolones

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Lung; Mutation; Pregnancy; Pregnancy Outcome; Quinolones

Lumacaftor/ivacaftor (LUM/IVA) is indicated for patients with cystic fibrosis (CF) homozygous for the F508del mutation in the CFTR gene. In clinical trials, LUM/IVA decreased pulmonary exacerbation rates. To our knowledge, there is no published data evaluating real-world outcomes for Medicaid patients receiving LUM/IVA.. To compare CF pulmonary exacerbation rates before and after initiation of LUM/IVA in 1 state's Medicaid program.. This pre-post claims analysis screened fee-for-service and managed Medicaid members who had ≥ 1 pharmacy claim for LUM/IVA between July 2, 2015, and September 30, 2016. Members were included if they were aged ≥ 6 years with a CF diagnosis and homozygous for the F508del mutation, consistent with the indication at study initiation. Exclusion criteria included Medicaid as a secondary payer or any break in coverage during the study. The index date was defined as the first claim for LUM/IVA. Demographics and outcomes were derived from pharmacy and medical claims. Outcomes included overall rate of pulmonary exacerbations (reported as the total events for the study population 6 months before and after the index date and average annualized rate). Pulmonary exacerbation was defined as any combination of medical claims for an emergency room (ER) visit or inpatient hospitalization with a CF pulmonary exacerbation or respiratory infection (ICD-9/10-CM codes) or pharmacy claims for an oral or intravenous antibiotic (excluding macrolides). A gap of > 7 days was considered a new pulmonary exacerbation. Paired t-test was used to test significance.. 21 patients met inclusion criteria with an average age at treatment initiation of 20.1 years. Average proportion of days covered (SD) was 0.62 (0.29). The number of pulmonary exacerbations increased from 45 to 48 during the 6 months before and after the index date, respectively, and the annualized rate increased from 4.37 to 4.66 (. This analysis did not find a decrease in pulmonary exacerbation rate for Medicaid members receiving LUM/IVA; however, adherence was low. Further study of similar populations is needed to better understand the long-term effect of treatment.. No outside funding supported this study. The authors have nothing to disclose. A poster of this project was presented at the Academy of Managed Care Pharmacy Managed Care & Specialty Pharmacy Annual Meeting 2018 in Boston, MA, on April 23-26, 2018.

Topics: Adolescent; Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Female; Humans; Lung; Male; Medicaid; Middle Aged; Mutation; Quinolones; United States; Young Adult

VX-770 (ivacaftor) is approved for clinical use in CF patients bearing multiple CFTR mutations. VX-770 potentiated wildtype CFTR and several disease mutants expressed in oocytes in a manner modulated by PKA-mediated phosphorylation. Potentiation of some other mutants, including G551D-CFTR, was less dependent upon the level of phosphorylation, likely related to the severe gating defects in these mutants exhibited in part by a shift in PKA sensitivity to activation, possibly due to an electrostatic interaction of D551 with K1250. Phosphorylation-dependent potentiation of wildtype CFTR and other variants also was observed in epithelial cells. Hence, the efficacy of potentiators may be obscured by a ceiling effect when drug screening is performed under strongly phosphorylating conditions. These results should be considered in campaigns for CFTR potentiator discovery, and may enable the expansion of VX-770 to CF patients bearing ultra-orphan CFTR mutations.

Topics: Aminophenols; Animals; Cell Line; Cyclic AMP-Dependent Protein Kinases; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Mutation; Oocytes; Phosphorylation; Quinolones; Rats; Xenopus laevis

Approximately 1 in 5 patients with pancreas sufficient cystic fibrosis (PS-CF) will develop acute pancreatitis (AP). It is not known whether ivacaftor alone or in combination with other CFTR (cystic transmembrane regulator) modulators (tezacaftor or lumacaftor) can reduce the risk of AP in patients with PS-CF and AP history.. We retrospectively queried the CF registry at our institution for adult patients with PS-CF, a documented history of AP and initiation of CFTR modulators for pulmonary indications. Patient characteristics including demographics, CFTR genotype, pancreatitis risk factors, pancreatic exocrine function and other relevant laboratory, imaging parameters were obtained from the time of the sentinel AP episode through the follow-up period.. A total of 15 adult CF patients were identified with mean age of 44.1 years (SD ± 13.8). In the 24 months preceding CFTR modulator initiation, six of these patients had at least 1 episode of AP with median of 2 episodes [1.75, 2.5]. None of the patients had evidence of pancreatic calcifications or exocrine pancreas insufficiency at the time of CFTR modulator initiation. The mean duration of follow-up after CFTR modulator initiation was 36.7 months (SD ± 21.5). None of the patients who remained on CFTR modulators developed an episode of AP or required hospitalization for AP related abdominal pain during follow-up.. CFTR modulators, alone or in combination, substantially reduce the risk of recurrent AP over a mean follow-up period of 3 years in adult patients with PS-CF and a history of prior AP. These data suggest that any augmentation of CFTR function can reduce the risk of pancreatitis.

Topics: Adult; Aged; Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Exocrine Pancreatic Insufficiency; Female; Humans; Indoles; Male; Middle Aged; Quinolones; Retrospective Studies

Topics: Aminophenols; Cohort Studies; Cystic Fibrosis; Humans; Infections; Pseudomonas; Quinolones; Registries

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Humans; Indoles; Mutation; Quinolones; Safety

In patients with cystic fibrosis (CF), ivacaftor treatment results in significant weight gain and the impact on diet has not been explored.. A study in 22 subjects (6.1-61.6 years) compared diet, energy balance, weight gain, and body composition, before and after three months of treatment in Italians and North Americans with CFTR gating mutations.. With no differences between groups in energy or macronutrient intake at baseline, fat intake increased in all subjects, and both fat and energy intake increased in Italians. Height, weight, BMI, lean and fat mass, and % body fat increased and resting energy expenditure decreased after treatment. Weight gain was associated with energy and fat intake.. Fat intake increased with treatment, possibly due to the recommendation to take ivacaftor with high fat meals. Increased energy and fat intake correlated with weight gain. Regional dietary patterns differed.

Topics: Adolescent; Adult; Aminophenols; Child; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diet; Dietary Supplements; DNA; DNA Mutational Analysis; Energy Intake; Energy Metabolism; Female; Humans; Italy; Male; Middle Aged; Morbidity; Mutation; North America; Quinolones; Young Adult

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has been shown to improve the nutritional status and lung function of cystic fibrosis patients with the G551D mutation in clinical trials. The objective of this study was to describe the real-world progress of children receiving ivacaftor.. We describe the real-world progress of four children with cystic fibrosis and the F508del/G551D genotype comparing data during ivacaftor treatment with baseline and with the year before commencing treatment.. Our sample comprised 4 children aged between 6 and 14 years and including one with a recent diagnosis of CF and other with persistent Mycobacterium abscessus (M. abscessus) and recurrent allergic bronchopulmonary aspergillosis. The baseline FEV1 was 58.5% to 81.8% of the predicted value, and ivacaftor was taken for a mean 24 months (range, 12-30 months). All patients experienced a significant and sustained improvement in lung function. Compared to baseline, the weight z-score improved by 1.53 points, and the BMI z-score by 1.6 points. Compared to the year before starting ivacaftor, the frequency of Pseudomonas aeruginosa (P. aeruginosa) isolates decreased (-0.4/patient/year), as did the number of respiratory exacerbations (-1.8/patient/year). The weight-adjusted dose of lipase per kilogram decreased progressively in all patients. In 1 patient, a previously persistent M. abscessus infection and recurrent allergic bronchopulmonary aspergillosis resolved during treatment.. Children with cystic fibrosis and the F508del/G551D genotype receiving treatment with ivacaftor experienced a real-world improvement in lung function, nutritional status, respiratory exacerbations, isolation of P. aeruginosa, and dose of pancreatic enzymes.

Topics: Adolescent; Aminophenols; Aspergillosis, Allergic Bronchopulmonary; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Male; Mutation; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Nutritional Status; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Treatment Outcome

Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF.. To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion.. Oral glucose tolerance tests, mixed-meal tolerance tests, and glucose-potentiated arginine tests were compared preivacaftor initiation and 16 weeks postivacaftor initiation in CF participants with at least one CFTR gating or conductance mutation. Meal-related 30-minute (early phase) and 180-minute incremental area under the curves were calculated as responses for glucose, insulin, C-peptide, and incretin hormones; glucagon-like peptide-1; and glucose-dependent insulinotropic polypeptide. First-phase insulin secretion, glucose potentiation of arginine-induced insulin secretion, and disposition index were characterized by glucose-potentiated arginine stimulation tests.. Insulin secretion improved following 4 months of clinically indicated ivacaftor therapy in this relatively young group of patients with CF with normal to mildly impaired glucose tolerance, whereas incretin secretion remained unchanged.

Topics: Adolescent; Adult; Aminophenols; Blood Glucose; C-Peptide; Child; Cystic Fibrosis; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Quinolones; Young Adult

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Humans; Incretins; Insulin Secretion; Quinolones

We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy.. In this retrospective clinical study, 3 independent CF patient cohorts (US-American: 29, Australian: 12 and Irish: 19 cases) were enrolled carrying at least one Class III CFTR CF-causing mutation (p.Gly551Asp) and being treated with CFTR potentiator ivacaftor. Plasma HE4 was measured by immunoassay before treatment (baseline) and 1-6 months after commencement of ivacaftor, and were correlated with FEV. After 1 month of therapy, HE4 levels were significantly lower than at baseline and remained decreased up to 6 months. A significant inverse correlation between absolute and delta values of HE4 and FEV. This study shows that plasma HE4 levels inversely correlate with lung function improvement in CF patients receiving ivacaftor. Overall, this potential biomarker may be of value for routine clinical and laboratory follow-up of CFTR modulating therapy.

Topics: Adult; Aminophenols; Biomarkers; Body Mass Index; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Monitoring; Female; Forced Expiratory Volume; Humans; Male; Mutation; Quinolones; Respiratory Function Tests; Retrospective Studies; Sweat; WAP Four-Disulfide Core Domain Protein 2

Disruption of the enterohepatic circulation of bile acids (BAs) is part of the gastrointestinal phenotype of cystic fibrosis (CF). Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, improves pulmonary function in CF patients with class III gating mutations. We studied the effect of ivacaftor on the enterohepatic circulation by assessing markers of BA homeostasis and their changes in CF patients.. In CF patients with an S1251N mutation (N = 16; age 9-35 years S125N study/NTR4873) or a G551D mutation (N = 101; age 10-24 years; GOAL study/ NCT01521338) we analyzed plasma fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) levels, surrogate markers for intestinal BA absorption and hepatic synthesis, respectively, before and after treatment with ivacaftor.. At baseline, median FGF19 was lower (52% and 53%, P < .001) and median C4 higher (350% and 364%, P < .001), respectively, for the S1251 N and G551D mutation patient groups compared to healthy controls. Treatment with ivacaftor significantly increased FGF19 and reduced C4 levels towards normalization in both cohorts but this did not correlate with CFTR function in other organs, as measured by sweat chloride levels or pulmonary function.. We demonstrate that patients with CFTR gating mutations display interruption of the enterohepatic circulation of BAs reflected by lower FGF19 and elevated C4 levels. Treatment with ivacaftor partially restored this disruption of BA homeostasis. The improvement did not correlate with established outcome measures of CF, suggesting involvement of modulating factors of CFTR correction in different organs.

Topics: Adolescent; Adult; Aminophenols; Bile Acids and Salts; Biological Availability; Child; Chloride Channel Agonists; Cholestenones; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Enterohepatic Circulation; Female; Fibroblast Growth Factors; Homeostasis; Humans; Male; Mutation; Netherlands; Quinolones

Cystic fibrosis (CF) is the most common life-limiting genetic disease in Caucasian patients. Continued advances have led to improved survival, and adults with CF now outnumber children. As our understanding of the disease improves, new therapies have emerged that improve the basic defect, enabling patient-specific treatment and improved outcomes. However, recurrent exacerbations continue to lead to morbidity and mortality, and new pathogens have been identified that may lead to worse outcomes. In addition, new complications, such as CF-related diabetes and increased risk of gastrointestinal cancers, are creating new challenges in management. For patients with end-stage disease, lung transplantation has remained one of the few treatment options, but challenges in identifying the most appropriate patients remain.

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Chronic Disease; Combined Modality Therapy; Comprehension; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Management; Disease Progression; Drug Approval; Female; Genetic Predisposition to Disease; Humans; Lung Transplantation; Male; Prognosis; Quinolones; Risk Assessment; Severity of Illness Index; Survival Analysis; United States; United States Food and Drug Administration

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Monitoring; Humans; Male; Mutation; Quinolones; Respiratory Function Tests; Sweat; Treatment Outcome

Electrophysiological characterization of Q1412X-CFTR, a C-terminal truncation mutation of cystic fibrosis transmembrane conductance regulator (CFTR) associated with the severe form of cystic fibrosis (CF), reveals a gating defect that has not been reported previously. Mechanistic investigations of the gating deficit in Q1412X-CFTR suggest that the reduced open probability in Q1412X-CFTR is the result of a disruption of the function of the second ATP binding site (or site 2) in the nucleotide binding domains (NBDs). Detailed comparisons of several mutations with different degrees of truncation in the C-terminal region of NBD2 reveal the importance of the last two beta-strands in NBD2 for maintaining proper gating functions. The results of the present study also show that the application of clinically-approved drugs (VX-770 and VX-809) can greatly enhance the function of Q1412X, providing in vitro evidence for a therapeutic strategy employing both reagents for patients bearing Q1412X or similar truncation mutations.. Cystic fibrosis (CF) is caused by loss-of-function mutations of cystic fibrosis transmembrane conductance regulator (CFTR), a phosphorylation-activated but ATP-gated chloride channel. Based on the molecular mechanism of CF pathogenesis, disease-associated mutations are categorized into six classes. Among them, Class VI, whose members include some of the C-terminal truncation mutations such as Q1412X, is defined as decreased membrane expression because of a faster turnover rate. In the present study, we characterized the functional properties of Q1412X-CFTR, a severe-form premature stop codon mutation. We confirmed previous findings of a ∼90% decrease in membrane expression but found a ∼95% reduction in the open probability (P

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Chloride Channel Agonists; CHO Cells; Cricetulus; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Ion Channel Gating; Mutation; Protein Conformation; Quinolones

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that improves pulmonary function in cystic fibrosis (CF) patients with at least 1 copy of the G551D CFTR mutation. The purpose of this study is to evaluate the impact of ivacaftor on chronic rhinosinusitis (CRS) symptoms in this population.. The G551D Observational (GOAL) study was a multicenter prospective cohort study enrolling CF patients ≥6 years with at least 1 G551D mutation. Subjects were provided 20-item Sino-Nasal Outcome Test (SNOT-20) questionnaires prior to ivacaftor therapy and at 1, 3, and 6 months afterward. The impact on rhinologic (R), psychological (P), sleep (S), and ear/facial (E) quality of life (QOL) domains was evaluated separately.. Of 153 subjects, 129 (84%) completed all questionnaires. Typical baseline symptom burden was low (75% with scores <1) and degree of improvement (ie, reduced scores) was greater with higher baseline scores. SNOT-20 decreased, reflecting improvement, at all follow-up intervals (1 month: [mean change ± standard deviation] -0.25 ± 0.53, p < 0.01; 3 months; -0.29 ± 0.58, p < 0.01; 6 months: -0.21 ± 0.58, p = 0.02), but less than the prespecified minimal clinically important difference (0.8). Significant improvement was observed at 1, 3, and 6 months in the R domain (1 month: -0.24, p < 0.01; 3 months: -0.34, p < 0.01; 6 months: -0.25, p < 0.01) and P domain (1 month: -0.25, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.26, p < 0.01), and 1 and 3 months in the S domain (1 months: -0.35, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.18, p = 0.07). There was no improvement in the E domain at any time point.. Ivacaftor improves QOL in the R, P, and S domains in G551D CF patients, although QOL instruments validated for CRS may not translate well to CF CRS patients because symptom burden was surprisingly low.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminophenols; Child; Chronic Disease; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Mental Health; Middle Aged; Mutation; Prospective Studies; Quality of Life; Quinolones; Rhinitis; Sinusitis; Sleep; Surveys and Questionnaires; Young Adult

Topics: Alleles; Aminophenols; Benzodioxoles; Cystic Fibrosis; Humans; Indoles; Organothiophosphorus Compounds; Quinolones

Cystic fibrosis is caused by mutations in the

Topics: Alleles; Aminophenols; Aminopyridines; Benzodioxoles; Biopsy; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; HEK293 Cells; Humans; Mutation; Organoids; Protein Folding; Protein Structure, Tertiary; Quinolones; Rectum; Transfection

Cystic fibrosis (CF), a most deadly genetic disorder, is caused by mutations of CF transmembrane receptor (CFTR) - a chloride channel present at the surface of epithelial cells. In general, two steps have to be involved in treatment of the disease: correction of cellular defects and potentiation to further increase channel opening. Consequently, a combinatorial simultaneous treatment with two drugs with different mechanisms of action, lumacaftor and ivacaftor, has been recently proposed. While lumacaftor is used to correct p.Phe508del mutation (the loss of phenylalanine at position 508) and increase the amount of cell surface-localized CFTR protein, ivacaftor serves as a CFTR potentiator that increases the open probability of CFTR channels. Since the main organ that is affected by cystic fibrosis is the lung, the delivery of drugs directly to the lungs by inhalation has a potential to enhance the efficacy of the treatment of CF and limit adverse side effects upon healthy tissues and organs. Based on our extensive experience in inhalation delivering of drugs by different nanocarriers, we selected nanostructured lipid carriers (NLC) for the delivery both drugs directly to the lungs by inhalation and tested NLC loaded with drugs in vitro (normal and CF human bronchial epithelial cells) and in vivo (homozygote/homozygote bi-transgenic mice with CF). The results show that the designed NLCs demonstrated a high drug loading efficiency and were internalized in the cytoplasm of CF cells. It was found that NLC-loaded drugs were able to restore the expression and function of CFTR protein. As a result, the combination of lumacaftor and ivacaftor delivered by lipid nanoparticles directly into the lungs was highly effective in treating lung manifestations of cystic fibrosis.

Topics: Administration, Inhalation; Aminophenols; Aminopyridines; Animals; Benzodioxoles; Cell Line; Chloride Channel Agonists; Cystic Fibrosis; Drug Carriers; Drug Combinations; Humans; Lipids; Lung; Mice, Transgenic; Nanostructures; Quinolones

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones

Topics: Aminophenols; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Ireland; Quinolones; Registries

Topics: Adult; Aminophenols; Bias; Chloride Channel Agonists; Cystic Fibrosis; Humans; Quinolones; Research Design; Time Factors

Topics: Aminophenols; Bias; Cystic Fibrosis; Humans; Quinolones

We analyzed the CFTR response to VX-809/VX-770 drugs in conditionally reprogrammed cells (CRC) of human nasal epithelium (HNE) from F508del/F508del patients based on SNP rs7512462 in the Solute Carrier Family 26, Member 9 (SLC26A9; MIM: 608481) gene.. The CRC-HNE cells from F508del/F508del patients evidenced high variability in the basal levels of CFTR function. Also, the rs7512462*C allele showed an increased basal CFTR function and higher responses to VX-809 + VX-770. The rs7512462*CC + CT genotypes together evidenced CFTR function levels of 14.89% relatively to wt/wt (rs7512462*CT alone-15.29%) i.e., almost double of rs7512462*TT (7.13%). Furthermore, sweat [Cl. The CFTR function can be performed in F508del/F508del patient-derived CRC-HNEs and its function and responses to VX-809 + VX-770 combination as well as clinical data, are all associated with the rs7512462 variant, which partially sheds light on the generally inter-individual phenotypic variability and in personalized responses to CFTR modulator drugs.

Topics: Alleles; Aminophenols; Aminopyridines; Antiporters; Base Sequence; Benzodioxoles; Body Mass Index; Case-Control Studies; Cellular Reprogramming; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diffusion Chambers, Culture; Epithelial Cells; Gene Expression; Genotype; Humans; Models, Biological; Nasal Mucosa; Polymorphism, Single Nucleotide; Primary Cell Culture; Quinolones; Sequence Deletion; Sulfate Transporters; Sweat

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Breath Tests; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Drug Combinations; Exhalation; Female; Humans; Male; Nitric Oxide; Prospective Studies; Quinolones; Young Adult

Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (

Topics: Aminophenols; Animals; Animals, Genetically Modified; Animals, Newborn; Blood Glucose; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Disease Progression; Female; Ferrets; Gene Knock-In Techniques; Genitalia, Male; Gestational Age; Humans; Male; Mutation; Pancreas, Exocrine; Pregnancy; Quinolones; Respiratory Tract Infections; Translational Research, Biomedical

CFTR modulator therapy with ivacaftor is a treatment option for Cystic Fibrosis (CF) patients with at least one copy of a R117H-7T mutation in the CFTR gene. Desirable effects of this therapy are improvement of lung function, decrease in exacerbation rate, normalization or reduction of sweat chloride and weight gain. Monogenetic CF-twins carry identical genetic information, so therapy response and side effects are expected to be nearly identical under this specific therapy.. In monozygotic twins, at the age of 55, two pathogenic variants in the CFTR gene (F508del and R117H-7T) were detected. Both patients presented with a borderline sweat test (30-59 mmol/L) and despite the same genetic information and similar life circumstances the disease proceeds completely different. While one patient has severe pulmonary involvement with chronic P. aeruginosa infection, her twin sister is almost unimpaired. Liver or pancreatic involvement was not seen in either patient. Due to the presence of one copy of a R117H-7T mutation, CFTR modulator therapy with ivacaftor was initiated in both. Response and side effects were significantly different. In the less affected patient, we observed an improvement in lung function and a normalization of sweat chloride. In the severely affected patient, no functional response to treatment was seen, but stabilization of the disease state with a decrease in exacerbation and hospitalization rate and weight gain as well as a normalization of sweat chloride. There was an increase in liver enzymes in the less affected patient, which normalized after halving the dose of ivacaftor, while the therapeutic effect was maintained.. Despite nearly identical genetic information, as in monogenetic twins, therapy response and onset of side effects of CFTR modulating therapy are very different. In patients with late diagnosis and severe pulmonary involvement, ivacaftor does not seem to improve lung function, whereas in patients with late diagnosis and low disease severity a relevant therapy response was obtained. In addition to lung function, additional clinical parameters such as reduction of exacerbation and hospitalization rate and weight gain should be used to assess therapy response, especially in severely affected patients.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Heterozygote; Humans; Lung; Middle Aged; Mutation; Quinolones; Twins, Monozygotic

Personalized approaches for systematically assessing ciliary beat dynamics and for drug testing would improve the challenging task of diagnosing and treating respiratory disorders. In this pilot study, we show how multiscale differential dynamic microscopy (multi-DDM) can be used to characterize collective ciliary beating in a non-biased automated manner. We use multi-DDM to assess the efficacy of different CFTR-modulating drugs in human airway epithelial cells derived from subjects with cystic fibrosis (ΔF508/ΔF508 and ∆F508/-) based on ciliary beat frequency and coordination. Similar to clinical observations, drug efficacy is variable across donors, even within the same genotype. We show how our assay can quantitatively identify the most efficient drugs for restoring ciliary beating for each individual donor. Multi-DDM provides insight into ciliary beating responses following treatment with drugs, and has application in the broader context of respiratory disease and for drug screening.

Topics: Algorithms; Aminophenols; Aminopyridines; Benzodioxoles; Bronchi; Cilia; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Epithelial Cells; Genotype; Humans; Microscopy; Oscillometry; Phenotype; Quinolones; Video Recording

Ivacaftor is a drug that was recently approved by the U.S. Food and Drug Administration for the treatment of patients with cystic fibrosis (CF) and at least one copy of the G511D mutation in the CFTR (CF transmembrane conductance regulator) gene. The transcriptomic effect of ivacaftor in patients with CF remains unclear. Here, we sought to examine whether and how the transcriptome of patients is influenced by ivacaftor treatment, and to determine whether these data allow prediction of ivacaftor responsiveness. Our data originated from the G551D Observational Study (GOAL). We performed RNA sequencing (RNA-seq) on peripheral blood mononuclear cells (PBMCs) from 56 patients and compared the transcriptomic changes that occurred before and after ivacaftor treatment. We used consensus clustering to stratify patients into subgroups based on their clinical responses after treatment, and we determined differences between subgroups in baseline gene expression. A random forest model was built to predict ivacaftor responsiveness. We identified 239 genes (false discovery rate < 0.1) that were significantly influenced by ivacaftor in PBMCs. The functions of these genes relate to cell differentiation, microbial infection, inflammation, Toll-like receptor signaling, and metabolism. We classified patients into "good" and "moderate" responder groups based on their clinical response to ivacaftor. We identified a panel of signature genes and built a statistical model for predicting CFTR modulator responsiveness. Despite a limited sample size, adequate prediction performance was achieved with an accuracy of 0.92. In conclusion, for the first time, the present study demonstrates profound transcriptomic impacts of ivacaftor in PBMCs from patients with CF, and provides a pilot statistical model for predicting clinical responsiveness to ivacaftor before treatment.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Leukocytes, Mononuclear; Mucociliary Clearance; Mutation; Quinolones; Transcriptome

Pancreatic exocrine insufficiency in cystic fibrosis is genetically determined and generally felt to be irreversible. However, recent studies in young children started on cystic fibrosis transmembrane conductance regulator (CFTR) modulators have suggested improvement of pancreatic functioning over time. Here, we present the case of a 10-year-old child with pancreatic exocrine insufficiency since birth who regained pancreatic functioning after 4 years on the CFTR corrector drug, ivacaftor.

Topics: Aminophenols; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Exocrine Pancreatic Insufficiency; Humans; Male; Quinolones; Treatment Outcome

Topics: Aminophenols; Aminopyridines; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Benzodioxoles; Cystic Fibrosis; Female; Humans; Male; Nitriles; Pyridines; Quinolones; Triazoles

The devastating inherited disease cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel. The recent approval of the CFTR potentiator drug ivacaftor (Vx-770) for the treatment of CF patients has marked the advent of causative CF therapy. Currently, thousands of patients are being treated with the drug, and its molecular mechanism of action is under intensive investigation. Here we determine the solubility profile and true stimulatory potency of Vx-770 towards wild-type (WT) and mutant human CFTR channels in cell-free patches of membrane. We find that its aqueous solubility is ~200 fold lower (~60 nanomolar), whereas the potency of its stimulatory effect is >100 fold higher, than reported, and is unexpectedly fully reversible. Strong, but greatly delayed, channel activation by picomolar Vx-770 identifies multiple sequential slow steps in the activation pathway. These findings provide solid guidelines for the design of

Topics: Aminophenols; Animals; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Ion Channel Gating; Ion Transport; Mutation; Oocytes; Quinolones; Solubility; Solvents; Xenopus laevis

Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo-electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)-approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.

Topics: Aminophenols; Binding Sites; Chloride Channel Agonists; Cryoelectron Microscopy; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drugs, Investigational; HEK293 Cells; Humans; Hydrogen Bonding; Mutagenesis; Protein Domains; Protein Folding; Pyrans; Pyrazoles; Quinolones

Ivacaftor is a significant innovation in the treatment of cystic fibrosis (CF) with gating mutations. A substantial percentage of patients with CF have severe lung involvement, but these patients are usually excluded from phase III clinical trials. Thus, the effectiveness of ivacaftor in this population has not been fully determined.. Data were collected from Italian CF centers with patients enrolled in an ivacaftor compassionate use programme (percent predicted [pp] forced expiratory volume in 1 second [FEV. Ivacaftor was safe and effective in patients with CF with severe lung disease and non-G551D gating mutations.

Topics: Adolescent; Adult; Aminophenols; Child; Chloride Channel Agonists; Chlorides; Compassionate Use Trials; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Humans; Ion Channel Gating; Lung; Male; Middle Aged; Mutation; Quinolones; Respiratory Function Tests; Retrospective Studies; Sweat

Cystic fibrosis (CF) is a genetic disorder of the epithelial CFTR apical chloride channel resulting in multi-organ manifestations, including pancreatic exocrine secretion. In the pancreas, CFTR abnormality results in abnormally viscous secretions that obstruct proximal ducts leading to fibrotic injury and ultimately pancreatic insufficiency in 85% of the CF population. CFTR modulators, including the potentiator ivacaftor, augment channel gating to restore 30-50% of CFTR-mediated anion transport. While CFTR modulation has been shown to alkalinize the pH of the alimentary tract and potentially augment pancreatic enzyme activity, the effect of ivacaftor on recurrent pancreatitis is emerging. Here we describe a case of a patient with CF (R117H/7 T/F508del) who presented with recurrent pancreatitis who was effectively treated with ivacaftor in the absence of respiratory symptoms.. A 24-year-old white male with past medical history of recurrent acute pancreatitis presented for evaluation following a referral from an outside hospital. The patient reported a lifetime of gastrointestinal symptoms requiring over 20 hospitalizations for pancreatitis in the last 10 years. Prior U/S and CT imaging for pancreatitis ruled out gallstones or anatomical etiologies. Family history included a brother with CF carrier status who suffered from recurrent acute pancreatitis. Sweat chloride testing was suggestive of CFTR dysfunction (57 mmol/L). Genetic testing demonstrated disease causing CFTR mutations: R1117H/7 T/F508del. Patient was prescribed pancrelipase, however, he reported worsened gas and diarrhea symptoms. Pancrelipase was discontinued and the patient was prescribed ivacaftor 150 mg BID. After 6 weeks of ivacaftor treatment, patient reported improved gastrointestinal symptoms. For an additional 19 months, patient reported no episodes of pancreatitis until he discontinued ivacaftor. Over the next 3 weeks, patient experienced progressive nausea and sharp epigastric pain and laboratory studies confirmed pancreatitis. Patient was subsequently lost to follow up.. These findings support a possible relationship between the use of CFTR modulators, such as ivacaftor, in the management of recurrent pancreatitis in the setting of patients with cystic fibrosis and a CFTR mutation with residual CFTR activity or otherwise known to be responsive in vitro. Ivacaftor may be useful for recurrent pancreatitis, even in the absence of respiratory morbidity.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Male; Pancreatitis, Chronic; Quinolones; Recurrence; Treatment Outcome; Young Adult

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Drug Industry; England; Humans; Negotiating; Quinolones; State Medicine

Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described.

Topics: Aminophenols; Animals; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Discovery; Humans; Mutant Proteins; Mutation; Pyrazoles; Quinolones; Rats; Structure-Activity Relationship

The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity.

Topics: Aminopyridines; Benzodioxoles; Cell Line; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quantitative Structure-Activity Relationship; Thiazoles

Pulmonary exacerbations (PEx) are associated with acute loss of lung function that is often not recovered after treatment. We investigated lung function recovery following PEx for ivacaftor- and placebo-treated subjects.. Short- and long-term pulmonary function recovery data after PEx were summarized from a placebo-controlled trial in 161 cystic fibrosis patients≥12years old with the G551D-CFTR mutation (NCT00909532). Short-term recovery was measured 2 to 8weeks after treatment, and long-term recovery was determined at the end-of-study, both compared with baseline measured just prior to the PEx.. Fewer patients receiving ivacaftor experienced a PEx than patients receiving placebo (33.7% vs. 56.4%; P=0.004) and had a lower adjusted incidence rate of PEx (0.589 vs. 1.382; P<0.001). The proportion of PEx followed by full short-term recovery of percent predicted forced expiratory volume in 1s was similar (ivacaftor vs. placebo, 57.1% vs. 53.7), as was the proportion of patients having long-term recovery (46.4% vs. 47.7%).. Ivacaftor treatment reduces the frequency of PEx but does not improve on the rate of complete lung function recovery after PEx when compared with placebo.

Topics: Adolescent; Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Female; Humans; Male; Mucociliary Clearance; Mutation; Outcome Assessment, Health Care; Quinolones; Recovery of Function; Respiratory Function Tests

Ivacaftor has been shown to improve lung function and body weight in patients with CF and a gating mutation. Real-world evaluation is warranted to examine its safety and effectiveness over the long term.. A retrospective observational multicentre study collected clinical data in the year before and the 2years after ivacaftor initiation in patients with CF and a Gly551Asp-CFTR mutation.. Fifty-seven patients were included. Mean absolute change in FEV. The clinical benefits of ivacaftor reported in previous clinical trials were confirmed in a real-world setting two years post-initiation, also reducing treatment burden.

Topics: Adolescent; Adult; Aminophenols; Anti-Bacterial Agents; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; France; Humans; Male; Pseudomonas aeruginosa; Quinolones; Respiratory Function Tests; Respiratory System; Staphylococcus aureus; Time

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Drug Combinations; Drug Therapy, Combination; Forced Expiratory Volume; Homozygote; Humans; Italy; Mutation; Quinolones; Surveys and Questionnaires; Treatment Outcome

Cystic fibrosis transmembrane conductance regulator (CFTR), the channel mutated in cystic fibrosis (CF), is expressed by the biliary epithelium (i.e., cholangiocytes) of the liver. Progressive clinical liver disease (CF-associated liver disease; CFLD) occurs in around 10% of CF patients and represents the third leading cause of death. Impaired secretion and inflammation contribute to CFLD; however, the lack of human-derived experimental models has hampered the understanding of CFLD pathophysiology and the search for a cure. We have investigated the cellular mechanisms altered in human CF cholangiocytes using induced pluripotent stem cells (iPSCs) derived from healthy controls and a ΔF508 CFTR patient. We have devised a novel protocol for the differentiation of human iPSC into polarized monolayers of cholangiocytes. Our results show that iPSC-cholangiocytes reproduced the polarity and the secretory function of the biliary epithelium. Protein kinase A/cAMP-mediated fluid secretion was impaired in ΔF508 cholangiocytes and negligibly improved by VX-770 and VX-809, two small molecule drugs used to correct and potentiate ΔF508 CFTR. Moreover, ΔF508 cholangiocytes showed increased phosphorylation of Src kinase and Toll-like receptor 4 and proinflammatory changes, including increased nuclear factor kappa-light-chain-enhancer of activated B cells activation, secretion of proinflammatory chemokines (i.e., monocyte chemotactic protein 1 and interleukin-8), as well as alterations of the F-actin cytoskeleton. Treatment with Src inhibitor (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyramidine) decreased the inflammatory changes and improved cytoskeletal defects. Inhibition of Src, along with administration of VX-770 and VX-809, successfully restored fluid secretion to normal levels.. Our findings have strong translational potential and indicate that targeting Src kinase and decreasing inflammation may increase the efficacy of pharmacological therapies aimed at correcting the basic ΔF508 defect in CF liver patients. These studies also demonstrate the promise of applying iPSC technology in modeling human cholangiopathies. (Hepatology 2018;67:972-988).

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Biliary Tract; Cell Culture Techniques; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Cytoskeleton; Epithelial Cells; Fluorescent Antibody Technique; Humans; Induced Pluripotent Stem Cells; Inflammation; Mice; Microscopy, Confocal; Pyrimidines; Quinolones; Signal Transduction; src-Family Kinases

Air pollution stimulates airway epithelial secretion through a cholinergic reflex that is unaffected in cystic fibrosis (CF), yet a strong correlation is observed between passive smoke exposure in the home and impaired lung function in CF children. Our aim was to study the effects of low smoke concentrations on cystic fibrosis transmembrane conductance regulator (CFTR) function in vitro. Cigarette smoke extract stimulated robust anion secretion that was transient, mediated by CFTR, and dependent on cAMP-dependent protein kinase activation. Secretion was initiated by reactive oxygen species (ROS) and mediated by at least two distinct pathways: autocrine activation of EP4 prostanoid receptors and stimulation of Ca

Topics: Aminophenols; Aminopyridines; Autocrine Communication; Benzodioxoles; Bronchi; Calcium Signaling; Cell Line; Cyclic AMP; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Mutation; Oxidative Stress; Quinolones; Reactive Oxygen Species; Receptors, Prostaglandin E, EP4 Subtype; Second Messenger Systems; Secretory Pathway; Tobacco Smoke Pollution

On May 17, 2017, the U.S. Food and Drug Administration expanded the patient population for use of ivacaftor to include patients with cystic fibrosis with relatively rare mutations in the cystic fibrosis transmembrane conductance regulator gene. The label expansion is unique in that clinical efficacy was not based on clinical data but on in vitro assay data demonstrating increased chloride ion transport across cells in response to ivacaftor. Such an approach provides a pathway for adding difficult-to-study mutation-based cystic fibrosis subpopulations to the indication as well as defining mutations unresponsive to ivacaftor and has important implications for cystic fibrosis drug development and other rare genetic diseases whose genetics and disease pathophysiology are well understood.

Topics: Aminophenols; Chloride Channel Agonists; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Development; Humans; Mutation; Quinolones; Sweat; United States; United States Food and Drug Administration

Using planar gamma scintigraphy of inhaled radioaerosols, we have developed new analytical methods for assessing homogeneity of aerosol deposition and time-dependent particle clearance on a pixel-by-pixel basis, and applied them to a therapeutic cystic fibrosis (CF) study.. At baseline and 1 month after beginning treatment with ivacaftor, a cystic fibrosis transmembrane regulator modulator for CF patients with at least one copy of the G551D mutation (n = 13), initial deposition and subsequent mucociliary clearance (MCC) of radiolabeled particles (. Improved homogeneity of deposition, that is, decreased areas of higher and lower particle deposition in the lungs, was observed following ivacaftor treatment. The mean number ratio (NR) of pixels with higher deposition, relative to lung size, decreased from 0.14 to 0.09 (p = 0.003) and mean NR of colder pixels decreased from 0.23 to 0.19 (p = 0.004). Particle clearance was also improved following treatment, with mean MCC through 60 minutes equal to 12% versus 24%, without and with treatment, respectively (p = 0.010). Pixel-level analysis of MCC showed that (1) the fraction of pixels clearing >30% at 60 minutes was increased from 0.13 to 0.32 (p = 0.007); and (2) the fraction of pixels clearing <5% at 60 minutes was decreased from 0.54 to 0.37 (p = 0.014), indicating an overall recruitment of more fast-clearing lung regions with ivacaftor treatment.. These detailed pixel analyses of deposition and clearance homogeneity may supplement traditional methods that use large regions of interest for assessing efficacy and mechanisms of therapeutic intervention in patients with airways disease.

Topics: Administration, Inhalation; Adolescent; Adult; Aerosols; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Mucociliary Clearance; Quinolones; Young Adult

Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment.. Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed.. Significant improvements in FEV. Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota.

Topics: Adolescent; Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Humans; Male; Prospective Studies; Quinolones; Radiography, Thoracic; Saliva; Tomography, X-Ray Computed; Young Adult

The effect of ivacaftor in patients with cystic fibrosis (CF) with recurrent pancreatitis is unknown. We conducted a multicenter retrospective study of patients with CF taking ivacaftor who had a history of recurrent pancreatitis. During the first 3 months of therapy, only 1 of the 6 patients had an episode of pancreatitis, which was managed on an outpatient basis. Between 3 and 12 months on ivacaftor therapy, none of the patients had recurrence of pancreatitis or required hospitalization. The use of ivacaftor was associated with a reduced frequency and recurrence rate of pancreatitis in patients with CF.

Topics: Adolescent; Adult; Aminophenols; Child; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pancreatitis, Chronic; Quinolones; Recurrence; Retrospective Studies; Secondary Prevention; Treatment Outcome; Young Adult

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Quinolones

Ivacaftor use can lead to dramatic health improvements in cystic fibrosis (CF) patients with gating mutations. Here, we report five instances of dramatic clinical decline following withdrawal of ivacaftor in three individuals with the G551D-CFTR mutation. In each case, the patient's lung function and symptoms rapidly deteriorated after cessation of treatment. Awareness of this phenomenon should inform both clinical practices as well as the design of future clinical trials of highly active CFTR modulators.

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Humans; Male; Mutation; Quinolones; Substance Withdrawal Syndrome; Young Adult

Topics: Adolescent; Aminophenols; Child, Preschool; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Ion Transport; Male; Mutation, Missense; Pancreas; Quinolones; Sequence Deletion; Treatment Outcome

Here, mucus-penetrating nanoparticles (NPs) for pulmonary administration of ivacaftor in patients with cystic fibrosis (CF) were produced with the dual aim of enhancing ivacaftor delivery to the airway epithelial cells, by rapid diffusion through the mucus barrier, and at the same time, promoting ivacaftor lung cellular uptake. Pegylated and Tat-decorated fluorescent nanoparticles (FNPs) were produced by nanoprecipitation, starting from two synthetic copolymers, and showed nanometric sizes (∼70 nm), a slightly negative ζ potential, and high cytocompatibility toward human bronchial epithelium cells. After having showed the significant presence of poly(ethylene glycol) chains and Tat protein onto the FNP surface, the FNP mucus-penetrating ability, ivacaftor release profile, and lung cellular uptake were studied in the presence of CF-artificial mucus as a function of the FNP surface chemical composition. Moreover, microparticle-based pulmonary drug-delivery systems composed of mucus-penetrating FNPs loaded with ivacaftor and mannitol were prepared by using the nano-into-micro strategy and realized by spray-drying, thereby providing optimal preservation and stabilization of FNP technological and fluorescence properties.

Topics: Aminophenols; Cystic Fibrosis; Drug Carriers; Humans; Mucus; Nanoparticles; Quinolones

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Heterozygote; Humans; Indoles; Mutation; Quinolones

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminophenols; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Follow-Up Studies; Humans; Male; Middle Aged; Quinolones; Time Factors; Treatment Outcome; Young Adult

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Gastrointestinal Diseases; Humans; Pancreatitis; Quinolones

To determine in vivo effects of CFTR modulators on mutation S945L.. We measured effects of CFTR modulators on CFTR-dependent sweating ('C-sweat') in two pancreatic sufficient cystic fibrosis (CF) subjects. S1 (S945L/G542X) took ivacaftor and S2 (S945L/F508del) took ivacaftor+tezacaftor. Sweating was stimulated pharmacologically to produce sequentially both CFTR-independent (methacholine stimulated) M-sweat and C-sweat; and the ratio of these was compared. Sweat secretion was measured with two methods: real time secretory rate quantitative recording and by optically measuring the growth of sweat bubbles under oil from multiple identified glands.. Using the quantitative recorder, we saw zero C-sweat secretion off-drug, but when on-drug the C-sweat responses for both subjects were comparable to those seen in carriers. The on-drug response was further quantified using the sweat bubble method. Each subject again showed robust C-sweat responses, with C-sweat/M-sweat ratios~half of the ratio determined for a cohort of 40 controls tested under identical conditions.. These in vivo results, consistent with prior in vitro findings, indicate that the drug treatments restore near-normal function to S945L-CFTR, and support the use of ivacaftor as a treatment for CF patients who carry this allele.

Topics: Adult; Alleles; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Male; Mutation; Quinolones; Sweat Glands; Sweating

The CFTR potentiator, ivacaftor (IVA), has been widely used in the treatment of cystic fibrosis (CF) patients with the G551D mutation. To date, there has been limited information on the microbiological status of patients on this therapy and no data on the effect (if any) on the in vivo antibiotic susceptibility of Pseudomonas aeruginosa isolated from patients on therapy. Although IVA intervention is not designed per se as anti-infective, the effect (if any) of this molecule to CF patients' microbiological status merits careful monitoring. Therefore, it was the aim of this observational study to examine the effect in patients, both before and after commencement of IVA therapy, on several commonly reported microbiological markers in CF patients, including (i) bacterial density, (ii) frequency (rate) of isolation of bacterial pathogens, particularly P. aeruginosa, and (iii) antimicrobial susceptibility of these isolates to commonly prescribed oral and iv antibiotics. In addition, we wished to examine the requirements for these antibiotics in CF patients, before and after commencement of IVA therapy.. Archived data from 15 adult cystic fibrosis patients with the c.1652G›A (G551D) mutation were followed from two years pre-IVA therapy to two years after commencement of IVA therapy. The microbiological parameters examined included (i) oral antibiotic courses taken, (ii) intravenous (iv) antibiotic courses taken, (iii) rate of isolation of non-mucoid Pseudomonas aeruginosa (NM-PA) and mucoid P. aeruginosa (M-PA), (iv) density of NM-PA and M-PA and (v) antimicrobial susceptibility of NM-PA and M-PA to 11 antibiotics [aminoglycosides, beta-lactams, polymyxin and fluoroquinolone].. Following commencement of IVA therapy, patients required less iv antibiotic courses but no change in number of oral antibiotics courses. There was significant reduction in both the rate of isolation and density of M-PA (P = .02; P = .006, respectively). In contrast, there was no significant reduction in both the rate of isolation and density of NM-PA (P = .90; P = .07, respectively). Antimicrobial susceptibility in NM-PA and M-PA was not significantly reduced within any of the antibiotics classes or individual antibiotics examined. Increased susceptibility was noted in the beta-lactam class for NM-PA and M-PA, in particular with ceftazidime.. Overall, (i) the requirement for less iv antibiotic therapy, (ii) a reduction in the rate and density of M-PA and (iii) no reduction in antibiotic susceptibility indicate that microbiological parameters with patients on IVA therapy were not detrimentally affected.

Topics: Adolescent; Adult; Aminophenols; Anti-Bacterial Agents; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Retrospective Studies; Young Adult

Cystic fibrosis patients exhibit chronic Pseudomonas aeruginosa respiratory infections and sustained proinflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with MAPK hyperactivation and increased cytokines expression, such as interleukin-8 [chemoattractant chemokine (C-X-C motif) ligand 8 (CXCL8)]. Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed, and ORKAMBI (Vx-809/Vx-770 combination) is the only Food and Drug Administration-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Bronchi; Cells, Cultured; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Interleukin-8; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones

Topics: Adenoviridae; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Genomics; Hemophilia A; Humans; Molecular Targeted Therapy; Motor Neuron Disease; Mutation; Nucleic Acids; Oligonucleotides, Antisense; Precision Medicine; Quinolones; United Kingdom

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Biomarkers; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones

Traditional pulmonary therapies for cystic fibrosis (CF) target the downstream effects of CF transmembrane conductance regulator (CFTR) dysfunction (the cause of CF). Use of one such therapy, β-adrenergic bronchodilators (such as albuterol), is nearly universal for airway clearance. Conversely, novel modulator therapies restore function to select mutant CFTR proteins, offering a disease-modifying treatment. Recent trials of modulators targeting F508del-CFTR, the most common CFTR mutation, suggest that chronic β-agonist use may undermine clinical modulator benefits. We therefore sought to understand the impact of chronic or excess β-agonist exposure on CFTR activation in human airway epithelium. The present studies demonstrate a greater than 60% reduction in both wild-type and modulator-corrected F508del-CFTR activation following chronic exposure to short- and long-acting β-agonists. This reduction was due to reduced cellular generation of cAMP downstream of the β-2 adrenergic receptor-G protein complex. Our results point towards a posttranscriptional reduction in adenylyl cyclase function as the mechanism of impaired CFTR activation produced by prolonged β-agonist exposure. β-Agonist-induced CFTR dysfunction was sufficient to abrogate VX809/VX770 modulation of F508del-CFTR in vitro. Understanding the clinical relevance of our observations is critical for CF patients using these drugs, and for investigators to inform future CFTR modulator drug trials.

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Aminophenols; Aminopyridines; Benzodioxoles; Cell Line; Cilia; Cyclic AMP; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Interactions; Epithelial Cells; Humans; Mutation; Quinolones; Respiratory Mucosa; Time Factors

The CFTR potentiator ivacaftor is responsible for significant clinical improvements among a subset of patients with cystic fibrosis. Because it is a substrate of the cytochrome P450 system, specifically CYP3A4/5, ivacaftor is subject to significant drug-drug interactions, including due to commonly used antimicrobials such as rifampin. While the interaction of rifampin and ivacaftor has been examined in vitro, severe adverse events resulting from this interaction have not been reported in the literature. In this report, we describe the termination of steady, long-term improvement in a patient taking ivacaftor, resulting from the use of rifampin and precipitating a significant pulmonary exacerbation.

Topics: Adult; Aminophenols; Anti-Bacterial Agents; Chloride Channel Agonists; Cystic Fibrosis; Cytochrome P-450 CYP3A; Drug Interactions; Female; Humans; Medication Adherence; Methicillin-Resistant Staphylococcus aureus; Quinolones; Rifampin; Staphylococcal Infections; Treatment Outcome

Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Male; Mutation; Precision Medicine; Quinolones

Topics: Aminophenols; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Female; Humans; Lung; Male; Quinolones; Treatment Outcome

Cystic fibrosis is a life-threatening genetic disease that causes severe damage to the lungs. Ivacaftor, the first drug that targeted the underlying defect of the disease caused by specific mutations, is a sterling example of the potential of precision medicine. Clinical trial and registry studies showed that ivacaftor improved outcomes and reduced hospitalizations. Our study used US administrative claims data to assess the real-world effectiveness of ivacaftor. Comparing twelve-month rates before and after starting the use of ivacaftor among people who initiated therapy during 2012-2015, we found that overall and cystic fibrosis-related inpatient admissions fell by 55 percent and 81 percent, respectively. There was a comparable reduction in inpatient spending. Ivacaftor appears to be effective for multiple mutations that cause the disease, as suggested by the fact that during the study period, ivacaftor's use was extended to nine additional mutations in 2014. Examination of evidence from clinical trial, clinical care, and administrative data sources is important for understanding the real-world effectiveness of precision medicines such as ivacaftor.

Topics: Adolescent; Adult; Age Factors; Aminophenols; Child; Cohort Studies; Cost Savings; Cystic Fibrosis; Databases, Factual; Female; Hospitalization; Humans; Male; Middle Aged; Precision Medicine; Prescriptions; Quinolones; Retrospective Studies; Risk Assessment; Sex Factors; Treatment Outcome; United States; United States Food and Drug Administration; Young Adult

Ivacaftor is the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator demonstrating clinical benefit in patients with cystic fibrosis (CF). As ivacaftor is intended for chronic, lifelong use, understanding long-term effects is important for patients and healthcare providers.. This ongoing, observational, postapproval safety study evaluates clinical outcomes and disease progression in ivacaftor-treated patients using data from the US and the UK CF registries following commercial availability.. Annual analyses compare ivacaftor-treated and untreated matched comparator patients for: risks of death, transplantation, hospitalisation, pulmonary exacerbation; prevalence of CF-related complications and microorganisms and lung function changes in a subset of patients who initiated ivacaftor in the first year of commercial availability. Results from the 2014 analyses (2 and 3 years following commercial availability in the UK and USA, respectively) are presented here.. Analyses included 1256 ivacaftor-treated and 6200 comparator patients from the USA and 411 ivacaftor-treated and 2069 comparator patients from the UK. No new safety concerns were identified based on the evaluation of clinical outcomes included in the analyses. As part of safety evaluations, ivacaftor-treated US patients were observed to have significantly lower risks of death (0.6% vs 1.6%, p=0.0110), transplantation (0.2% vs 1.1%, p=0.0017), hospitalisation (27.5% vs 43.1%, p<0.0001) and pulmonary exacerbation (27.8% vs 43.3%, p<0.0001) relative to comparators; trends were similar in the UK. In both registries, ivacaftor-treated patients had a lower prevalence of CF-related complications and select microorganisms and had better preserved lung function.. While general limitations of observational research apply, analyses revealed favourable results for clinically important outcomes among ivacaftor-treated patients, adding to the growing body of literature supporting disease modification by CFTR modulation with ivacaftor.. EUPAS4270.

Topics: Adolescent; Adult; Aminophenols; Child; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Disease Progression; Female; Humans; Infant; Male; Quinolones; Registries; Respiratory Function Tests; Treatment Outcome; United Kingdom; United States

Topics: Aminophenols; Chloride Channel Agonists; Contraindications, Drug; Cost-Benefit Analysis; Cystic Fibrosis; Dose-Response Relationship, Drug; Double-Blind Method; Evidence-Based Medicine; Forced Expiratory Volume; Humans; Mutation; Patient Education as Topic; Practice Guidelines as Topic; Quinolones; Randomized Controlled Trials as Topic; Respiratory Function Tests; Treatment Outcome

To develop an automated density-based computed tomography (CT) score evaluating high-attenuating lung structural abnormalities in patients with cystic fibrosis (CF).. Seventy adult CF patients were evaluated. The development cohort comprised 17 patients treated with ivacaftor, with 45 pre-therapeutic and follow-up chest CT scans. Another cohort of 53 patients not treated with ivacaftor was used for validation. CT-density scores were calculated using fixed and adapted thresholds based on histogram characteristics, such as the mode and standard deviation. Visual CF-CT score was also calculated. Correlations between the CT scores and forced expiratory volume in 1 s (FEV. On cross-sectional evaluation, the correlation coefficients between FEV. The developed CT-density score reliably quantifies high-attenuating lung structural abnormalities in CF.. • Automated CT score shows moderate to good cross-sectional correlations with FEV

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cross-Sectional Studies; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Lung; Male; Observer Variation; Quinolones; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Tomography, Spiral Computed; Young Adult

Topics: Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Infant; Mutation; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diagnosis, Differential; Humans; Male; Middle Aged; Pancreatitis; Quinolones; Recurrence

Current modulator therapies for some cystic fibrosis-causing CFTR mutants, including N1303K, have limited efficacy. We provide evidence here to support combination potentiator (co-potentiator) therapy for mutant CFTRs that are poorly responsive to single potentiators.. Functional synergy screens done on N1303K and W1282X CFTR, in which small molecules were tested with VX-770, identified arylsulfonamide-pyrrolopyridine, phenoxy-benzimidazole and flavone co-potentiators.. A previously identified arylsulfonamide-pyrrolopyridine co-potentiator (ASP-11) added with VX-770 increased N1303K-CFTR current 7-fold more than VX-770 alone. ASP-11 increased by ~65% of the current of G551D-CFTR compared to VX-770, was additive with VX-770 on F508del-CFTR, and activated wild-type CFTR in the absence of a cAMP agonist. ASP-11 efficacy with VX-770 was demonstrated in primary CF human airway cell cultures having N1303K, W1282X and G551D CFTR mutations. Structure-activity studies on 11 synthesized ASP-11 analogs produced compounds with EC. These studies support combination potentiator therapy for CF caused by some CFTR mutations that are not effectively treated by single potentiators.

Topics: Aminophenols; Animals; Cell Line; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Synergism; Humans; Ion Channel Gating; Mutant Proteins; Mutation; Quinolones; Structure-Activity Relationship; Sulfonamides

Deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) is the most common cystic fibrosis (CF)-causing mutation. Recently, ORKAMBI, a combination therapy that includes a corrector of the processing defect of F508del-CFTR (lumacaftor or VX-809) and a potentiator of channel activity (ivacaftor or VX-770), was approved for CF patients homozygous for this mutation. However, clinical studies revealed that the effect of ORKAMBI on lung function is modest and it was proposed that this modest effect relates to a negative impact of VX-770 on the stability of F508del-CFTR. In the current studies, we showed that this negative effect of VX-770 at 10

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cell Line; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Freeze Drying; HEK293 Cells; Humans; Microscopy, Fluorescence; Mutation; Protein Stability; Quinolones; Sulfate Transporters

Topics: Aminophenols; Cells, Cultured; Chloride Channel Agonists; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Gene Expression Regulation; Humans; Male; Monocytes; Mutation; Prognosis; Quinolones; Receptor Activator of Nuclear Factor-kappa B; Receptor, Macrophage Colony-Stimulating Factor

Ivacaftor is a novel potentiator of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein, which corrects the gating defect and increases ion-function of activated cell-surface CFTR. Bacteria also regulate their physiology through ion channels. However, little is known about the potential effects of ivacaftor on bacterial ion channels, which, in turn, may have a potential effect on transport across the bacterial cell membrane. Therefore, any change in the ability to transport molecules across cell membranes in bacteria could have an important impact on bacterial transport physiology. One area where this could be particularly important is in the movement of antibiotics, both into and out of the bacterial cell. An in vitro study was therefore performed to examine the influence of ivacaftor at therapeutic concentration on antibiotic susceptibility of 11 commonly used anti-pseudomonal antibiotics against a population of clinical Pseudomonas aeruginosa [PA], from CF and non-CF sources.. Pseudomonas aeruginosa (n = 80; including 70 ivacaftor-naïve clinical PA from sputa from adult CF patients and 10 control PA from non-CF clinical blood culture sources) were examined. Antibiotic susceptibility was determined by standard disc diffusion assay using CLSI criteria and measuring zone size (mm), against four classes of anti-pseudomonal antibiotics, including beta-lactams (temocillin, ceftazidime, piperacillin/tazobactam, imipenem, meropenem and aztreonam), aminoglycosides (gentamicin, tobramycin, amikacin), fluoroquinolone (ciprofloxacin) and polymyxin (colistin), in the absence and presence of ivacaftor (5 μmol/L), as previously determined. In addition, all CF and non-CF PA were examined phenotypically in vitro, as previously described, for changes linked to bacterial virulence, including (i) growth density (ii) pigmentation, (iii) presence of adhesins and (iv) change to mucoidy, in the presence/absence of ivacaftor at therapeutic concentration.. Antibiotic susceptibility did not decrease significantly with any of the antibiotics examined with CF PA isolates or with non-CF PA control organisms. There was a statistically significant increase in zone size (CF PA and amikacin, gentamicin, temocillin and ciprofloxacin; Non-CF PA and amikacin, gentamicin and aztreonam). However, at a population level, this did not translate into a shift in CLSI category to a more susceptible phenotype. None of the PA isolates examined were susceptible to ivacaftor alone, and additionally, no changes were noted with the four phenotypic parameters examined in the presence of ivacaftor.. This study showed that antibiotic susceptibility of commonly used anti-pseudomonal antibiotics was not negatively affected by ivacaftor, in a population of ivacaftor-naive P. aeruginosa.

Topics: Adult; Aminophenols; Anti-Bacterial Agents; Case-Control Studies; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Interactions; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones

To determine if ivacaftor treatment results in weight gain and improved pulmonary function in people with cystic fibrosis transmembrane conductance regulator gating mutations.. Children and adults with cystic fibrosis and at least 1 cystic fibrosis transmembrane conductance regulator gating mutation were evaluated in this observational study before and after 3 months of ivacaftor treatment. Body size and composition, total energy expenditure, resting energy expenditure (REE%) as percent predicted, coefficient of fat absorption (CFA%), fecal calprotectin, fecal elastase, and quality of life were assessed. Some outcomes were explored by pancreatic status.. There were 23 patients (5-61 years of age) who completed the study; 70% had pancreatic insufficiency (PI). Patients gained 2.5 ± 2.2 kg (P < .001) with increased (P < .05) fat-free mass (0.9 ± 1.9 kg) and fat mass (1.6 ± 1.5 kg). REE% decreased by 5.5 ± 12.0% (P < .05), fecal calprotectin decreased by 30 ± 40 µg/g stool (P < .01), and total energy expenditure was unchanged. Improvements were greater for PI than patients who were pancreatic-sufficient. CFA% increased significantly only with PI. The change (Δ) in weight was positively correlated with the percent change in forced expiratory volume at 1 second (r = 0.46; P = .028) and ΔCFA% (r = 0.47; P = .032) and negatively with ΔREE% (r = -0.50; P = .017). Together, ΔREE%, ΔCFA%, and the percent change in forced expiratory volume at 1 second explained 58% of the variance in weight gain (adjusted R. Mechanisms identified for ivacaftor-associated weight gain were decreased REE, gut inflammation, and fat malabsorption (CFA).. ClinicalTrials.gov: NCT02141464.

Topics: Adolescent; Adult; Aminophenols; Child; Child, Preschool; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; DNA Mutational Analysis; Energy Metabolism; Female; Humans; Male; Middle Aged; Mutation; Quality of Life; Quinolones; Treatment Outcome; Weight Gain; Young Adult

Treatment of individuals with cystic fibrosis (CF) has been transformed by small molecule therapies that target select pathogenic variants in the CF transmembrane conductance regulator (CFTR). To expand treatment eligibility, we stably expressed 43 rare missense CFTR variants associated with moderate CF from a single site in the genome of human CF bronchial epithelial (CFBE41o-) cells. The magnitude of drug response was highly correlated with residual CFTR function for the potentiator ivacaftor, the corrector lumacaftor, and ivacaftor-lumacaftor combination therapy. Response of a second set of 16 variants expressed stably in Fischer rat thyroid (FRT) cells showed nearly identical correlations. Subsets of variants were identified that demonstrated statistically significantly higher responses to specific treatments. Furthermore, nearly all variants studied in CFBE cells (40 of 43) and FRT cells (13 of 16) demonstrated greater response to ivacaftor-lumacaftor combination therapy than either modulator alone. Together, these variants represent 87% of individuals in the CFTR2 database with at least 1 missense variant. Thus, our results indicate that most individuals with CF carrying missense variants are (a) likely to respond modestly to currently available modulator therapy, while a small fraction will have pronounced responses, and (b) likely to derive the greatest benefit from combination therapy.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Drug Therapy, Combination; HEK293 Cells; Humans; Mutation; Quinolones

Disruption of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function causes cystic fibrosis (CF), and lung disease produces most of the mortality. Loss of CFTR-mediated HCO3- secretion reduces the pH of airway surface liquid (ASL) in vitro and in neonatal humans and pigs in vivo. However, we previously found that, in older children and adults, ASL pH does not differ between CF and non-CF. Here, we tested whether the pH of CF ASL increases with time after birth. Finding that it did suggested that adaptations by CF airways increase ASL pH. This conjecture predicted that increasing CFTR activity in CF airways would further increase ASL pH and also that increasing CFTR activity would correlate with increases in ASL pH.. To test for longitudinal changes, we measured ASL pH in newborns and then at 3-month intervals. We also studied people with CF (bearing G551D or R117H mutations), in whom we could acutely stimulate CFTR activity with ivacaftor. To gauge changes in CFTR activity, we measured changes in sweat Cl- concentration immediately before and 48 hours after starting ivacaftor.. Compared with that in the newborn period, ASL pH increased by 6 months of age. In people with CF bearing G551D or R117H mutations, ivacaftor did not change the average ASL pH; however reductions in sweat Cl- concentration correlated with elevations of ASL pH. Reductions in sweat Cl- concentration also correlated with improvements in pulmonary function.. Our results suggest that CFTR-independent mechanisms increase ASL pH in people with CF. We speculate that CF airway disease, which begins soon after birth, is responsible for the adaptation.. Vertex Inc., the NIH (P30DK089507, 1K08HL135433, HL091842, HL136813, K24HL102246), the Cystic Fibrosis Foundation (SINGH17A0 and SINGH15R0), and the Burroughs Wellcome Fund.

Topics: Adult; Aminophenols; Animals; Bicarbonates; Biological Transport, Active; Bronchoalveolar Lavage Fluid; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Female; Humans; Hydrogen-Ion Concentration; Infant; Infant, Newborn; Ion Transport; Longitudinal Studies; Lung; Male; Middle Aged; Mutation; Quinolones; Respiratory Mucosa; Sweat; Young Adult

Ivacaftor is the first drug to target directly defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which causes cystic fibrosis (CF). To understand better how ivacaftor potentiates CFTR channel gating, here we investigated the effects of temperature on its action. As a control, we studied the benzimidazolone UC

Topics: Aminophenols; Animals; Benzodioxoles; Cell Line; Cricetinae; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Ion Channel Gating; Ion Transport; Mice; Mice, Inbred CFTR; Mutation; Quinolones; Temperature

Cystic fibrosis (CF), the most common inherited disease in Caucasians, is caused by mutations in the CFTR chloride channel, the most frequent of which is Phe508del. Phe508del causes not only intracellular retention and premature degradation of the mutant CFTR protein, but also defective channel gating and decreased half-life when experimentally rescued to the plasma membrane (PM). Despite recent successes in the functional rescue of several CFTR mutations with small-molecule drugs, the folding-corrector/gating-potentiator drug combinations approved for Phe508del-CFTR homozygous patients have shown only modest benefit. Several factors have been shown to contribute to this outcome, including an unexpected intensification of corrector-rescued Phe508del-CFTR PM instability after persistent co-treatment with potentiator drugs. We have previously shown that acute co-treatment with hepatocyte growth factor (HGF) can significantly enhance the chemical correction of Phe508del-CFTR. HGF coaxes the anchoring of rescued channels to the actin cytoskeleton via induction of RAC1 GTPase signalling. Here, we demonstrate that a prolonged, 15-day HGF treatment also significantly improves the functional rescue of Phe508del-CFTR by the VX-809 corrector/VX-770 potentiator combination, in polarized bronchial epithelial monolayers. Importantly, we found that HGF treatment also prevented VX-770-mediated destabilization of rescued Phe508del-CFTR and enabled further potentiation of the rescued channels. Most strikingly, prolonged HGF treatment prevented previously unrecognized epithelial dedifferentiation effects of sustained exposure to VX-809. This was observed in epithelium-like monolayers from both lung and intestinal origin, representing the two systems most affected by adverse symptoms in patients treated with VX-809 or the VX-809/VX-770 combination. Taken together, our findings strongly suggest that co-administration of HGF with corrector/potentiator drugs could be beneficial for CF patients.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cell Line; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Hepatocyte Growth Factor; Humans; Models, Biological; Mutant Proteins; Quinolones; Treatment Outcome

Lumacaftor/ivacaftor was approved by the Food and Drug Administration (FDA) as a combination treatment for Cystic Fibrosis (CF) patients who are homozygous for the F508del mutation. The objective of this study was to assess the cost-effectiveness of lumacaftor/ivacaftor combination for the treatment of CF homozygous for F508del CF Transmembrane Conductance Regulator (CFTR) mutation.. A Markov-state transition model following a cohort of 12 year-old CF patients homozygous for F508del CFTR mutation in the United States (US) over two, four, six, eight and ten years from a payer's perspective was developed using TreeAge Pro 2016. Markov states included: mild (percentage of predicted forced expiratory volume in 1 s or FEV1 > 70%), moderate (FEV1 40-70%), severe (FEV1 < 40%) disease, post-transplant, and death. Pulmonary exacerbation and lung transplant were included as transition states. All the input parameters were estimated from the literature. A 1-year cycle length and 3% discount rate were applied. To assess uncertainty in long-term treatment effects, several scenarios were modelled: 100% long-term effectiveness (base-case), defined as improvement in FEV1 in the first year followed by no annual FEV1 decline and a constant reduction in pulmonary exacerbations throughout, 75%, 50%, 25% and 0% (worst case) long-term effectiveness, where treatment effects were intermediate from the second year of treatment until the end of the time horizon. Other scenarios included changing the starting age of the cohort to 6 and 25 years. Primary outcome included incremental cost-effectiveness ratio (ICER) in terms of cost per quality adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were performed to determine uncertainty.. Under the base-case, Lumacaftor/ivacaftor resulted in higher QALYs (7.29 vs 6.84) but at a very high cost ($1,778,920.88) compared to usual care ($116,155.76) over a 10-year period. The ICER for base-case and worst-case scenarios were $3,655,352 / QALY, and $8,480,265/QALY gained, respectively. In the base-case, lumacaftor/ivacaftor was cost-effective at a threshold of $150,000/QALY-gained when annual drug costs were lower than $4153. The results were not substantially affected by the sensitivity analyses.. The intervention produces large QALY gains but at an extremely high cost, resulting in an ICER that would not typically be covered by any insurer. Lumacaftor/ivacaftor's status as an orphan drug complicates coverage decisions.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child; Cost-Benefit Analysis; Cystic Fibrosis; Female; Humans; Male; Quality-Adjusted Life Years; Quinolones; United States

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Bronchi; Cell Line; Colforsin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Inflammation; Mutation; Quinolones; Respiratory System

Topics: Administration, Oral; Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Administration Schedule; Drug Combinations; Drug Interactions; Humans; Indoles; Lung; Membrane Transport Modulators; Mutation; Quinolones; Treatment Outcome

The most common cystic fibrosis (CF)-causing mutation is deltaF508 (F508del), which is present in 28% of CF Spanish patients. While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor/ivacaftor is limited, it demonstrates the need for better strategies to prevent related adverse events (AEs) as well as the development of newer drugs.. We conducted a multicenter, retrospective, observational study to describe the effects of lumacaftor/ivacaftor treatment in real-life in Spain. 20 CF patients were included, all aged 6 and upwards and presented with ppFEV1<40%, chosen from CF units country-wide. For the purposes of the study, they were treated with lumacaftor/ivacaftor 200/125mg two tablets twice a day on a compassionate use programme throughout 2016. The primary endpoint was measured in all of the sample patients. Data were analysed from ppFEV1 at baseline and was measured every 6 months.. While treatment with lumacaftor/ivacaftor resulted in an improvement in the number of pulmonary severe exacerbations, no improvement in ppFEV1 or BMI was found.

Topics: Adolescent; Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Chloride Channel Agonists; Compassionate Use Trials; Cystic Fibrosis; Drug Combinations; Female; Humans; Male; Middle Aged; Quinolones; Retrospective Studies; Spain; Young Adult

The ability to restore cystic fibrosis transmembrane regulator (CFTR) function with effective small molecule modulators in patients with cystic fibrosis provides an opportunity to study relationships between CFTR ion channel function, organ level physiology, and clinical outcomes.. We performed a multisite, prospective, observational study of ivacaftor, prescribed in patients with the G551D-CFTR mutation. Measurements of lung mucociliary clearance (MCC) were performed before and after treatment initiation (1 and 3 months), in parallel with clinical outcome measures.. Marked acceleration in whole lung, central lung, and peripheral lung MCC was observed 1 month after beginning ivacaftor and was sustained at 3 months. Improvements in MCC correlated with improvements in forced expiratory volume in the first second (FEV1) but not sweat chloride or symptom scores.. Restoration of CFTR activity with ivacaftor led to significant improvements in MCC. This physiologic assessment provides a means to characterize future CFTR modulator therapies and may help to predict improvements in lung function.. ClinicialTrials.gov, NCT01521338.. CFF Therapeutics (GOAL11K1).

Topics: Adolescent; Adult; Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Humans; Longitudinal Studies; Male; Mucociliary Clearance; Mutation; Prospective Studies; Quinolones; Respiratory Function Tests; Treatment Outcome; Young Adult

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders worldwide. The incidence of CF depends on the prevalence of CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations in the population, which is determined by genetic diversity and ethnicity. Over 2 000 CFTR mutation variants, divided into six distinct functional classes, are now identified, but not all cause CF disease. Advancements in the molecular diagnosis of CF and recognition of a wider spectrum of CF severity have led to recent revision of CF diagnostic nomenclature and criteria. Identifying which CFTR mutations people with CF carry is important, as novel treatments that target the specific CFTR dysfunction at a molecular level are now available, and many new drugs are in the pipeline. These and other advancements in CF are comprehensively covered in the revised 5th edition of the South African Cystic Fibrosis Consensus Guidelines, published in 2017. In addition, the South African Cystic Fibrosis Registry Initiative (SACFRI) was launched in April 2018. SACFRI is a multicentre public-private collaboration of CF healthcare providers across South Africa (SA), which will prospectively collect data relating to CF diagnosis and outcomes in SA. Local SA registry data are critical to understanding the epidemiology of CF in SA, and SACFRI will be an important tool to identify and prioritise areas of CF care that require intervention.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Testing; Humans; Indoles; Molecular Diagnostic Techniques; Mutation; Practice Guidelines as Topic; Prospective Studies; Public-Private Sector Partnerships; Quinolones; Registries; South Africa

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones

Ivacaftor was approved for rarer class-III CFTR mutations including S549N in 2014. Since these mutations are uncommon, ongoing reports of patient experiences with Ivacaftor and these mutations are important. This case series describes the clinical effectiveness (including airway infection status, lung function, and growth) of Ivacaftor therapy in four pediatric Hispanic patients with S549N and F508del over 24 months. In these patients, Ivacaftor was highly efficacious with no further Pseudomonas-positive cultures despite prior chronic colonization in three patients as well as notable improvements in lung function and growth. The remarkable improvements in lung function and growth were similar to G551D patients with more striking changes in airway infection status. Pediatr Pulmonol 2017;52:E37-E39. © 2017 Wiley Periodicals, Inc.

Topics: Adolescent; Adolescent Development; Aminophenols; Child; Child Development; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Hispanic or Latino; Humans; Mutation; Pseudomonas; Pseudomonas Infections; Quinolones; Treatment Outcome

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Quinolones

Topics: Aminophenols; Aminopyridines; Anniversaries and Special Events; Anti-Bacterial Agents; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Enzyme Replacement Therapy; History, 20th Century; History, 21st Century; Mutation; Periodicals as Topic; Pulmonary Medicine; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Drug Approval; Drug Labeling; Humans; Quinolones; United States; United States Food and Drug Administration

Topics: Aminophenols; Cystic Fibrosis; Drug Evaluation, Preclinical; History, 20th Century; History, 21st Century; Humans; Intestines; Organoids; Quinolones

Topics: Aminophenols; Aminopyridines; Anti-Bacterial Agents; Benzodioxoles; Chloride Channel Agonists; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Expectorants; Genetic Therapy; Humans; Indoles; Mutation; Patient Selection; Quality of Life; Quinolones

Topics: Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Humans; Mutation; Quinolones; United States; United States Food and Drug Administration

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Drug Combinations; Humans; Quinolones

Ivacaftor is a drug that increases the probability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel remaining open. Information about the efficacy of ivacaftor in patients carrying the rare p.Ser549Arg (S549R) CFTR mutation is sparse.. Efficacy of ivacaftor treatment in patients carrying the p.Ser549Arg (S549R) CFTR mutation.. Data obtained from CF patients receiving ivacaftor for one year.. Ivacaftor therapy resulted in significant clinical improvement in patients carrying the p.Ser549Arg (S549R) CFTR mutation.

Topics: Adolescent; Adult; Aminophenols; Blood Glucose; Body Mass Index; Child; Chloride Channel Agonists; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Glucose Tolerance Test; Humans; Israel; Male; Mutation; Quinolones; Retrospective Studies; Sweat; Treatment Outcome; Vital Capacity; Young Adult

Approximately 50% of cystic fibrosis (CF) patients are heterozygous with a rare mutation on at least one allele. Several mutants exhibit functional defects, correctable by gating potentiators. Long-term exposure (≥24 h) to the only available potentiator drug, VX-770, leads to the biochemical and functional downregulation of F508del-CFTR both in immortalized and primary human airway cells, and possibly other CF mutants, attenuating its beneficial effect. Based on these considerations, we wanted to determine the effect of chronic VX-770 exposure on the functional and biochemical expression of rare CF processing/gating mutants in human airway epithelia. Expression of CFTR2 mutants was monitored in the human bronchial epithelial cell line (CFBE41o-) and in patient-derived conditionally reprogrammed bronchial and nasal epithelia by short-circuit current measurements, cell surface ELISA and immunoblotting in the absence or presence of CFTR modulators. The VX-770 half-maximal effective (EC50) concentration for G551D-CFTR activation was ∼0.63 μM in human nasal epithelia, implying that comparable concentration is required in the lung to attain clinical benefit. Five of the twelve rare CFTR2 mutants were susceptible to ∼20-70% downregulation by chronic VX-770 exposure with an IC50 of ∼1-20 nM and to destabilization by other investigational potentiators, thereby diminishing the primary functional gain of CFTR modulators. Thus, chronic exposure to VX-770 and preclinical potentiators can destabilize CFTR2 mutants in human airway epithelial models in a mutation and compound specific manner. This highlights the importance of selecting potentiator drugs with minimal destabilizing effects on CF mutants, advocating a precision medicine approach.

Topics: Aminophenols; Bronchi; Cell Line; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Down-Regulation; Drug Synergism; Epithelial Cells; Humans; Ion Channel Gating; Lung; Models, Molecular; Mutation; Quinolones; Respiratory Mucosa

Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening pulmonary manifestations. Ivacaftor (IVA) and ivacaftor-lumacaftor (LUMA) combination are two new breakthrough CF drugs that directly modulate the activity and trafficking of the defective CFTR-protein. However, there is still a dearth of understanding on pharmacokinetic/pharmacodynamic parameters and the pharmacology of ivacaftor and lumacaftor. The HPLC-MS technique for the simultaneous analysis of the concentrations of ivacaftor, hydroxymethyl-ivacaftor, ivacaftor-carboxylate, and lumacaftor in biological fluids in patients receiving standard ivacaftor or ivacaftor-lumacaftor combination therapy has previously been developed by our group and partially validated to FDA standards. However, to allow the high-throughput analysis of a larger number of patient samples, our group has optimized the reported method through the use of a smaller pore size reverse-phase chromatography column (2.6 µm, C8 100 Å; 50 x 2.1 mm) and a gradient solvent system (0-1 min: 40% B; 1-2 min: 40-70% B; 2-2.7 min: held at 70% B; 2.7-2.8 min: 70-90% B; 2.8-4.0 min: 90% B washing; 4.0-4.1 min: 90-40% B; 4.1-6.0 min: held at 40% B) instead of an isocratic elution. The goal of this study was to reduce the HPLC-MS analysis time per sample dramatically from ~15 min to only 6 min per sample, which is essential for the analysis of a large amount of patient samples. This expedient method will be of considerable utility for studies into the exposure-response relationships of these breakthrough CF drugs.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Case-Control Studies; Chromatography, Liquid; Cystic Fibrosis; High-Throughput Screening Assays; Humans; Quinolones; Tandem Mass Spectrometry

In Ireland, Ivacaftor is reimbursed, on the High-Tech Drug Scheme, for the treatment of cystic fibrosis in patients age 6 years and older who have the G551D mutation. The aim of this study was to analyse the utilisation and expenditure of Ivacaftor on this scheme in the 12 month period post-reimbursement. All patients who had received Ivacaftor (regardless of General Medical Services Scheme eligibility/ineligibility) were included. A total of 140 individuals (male=74; 53%) received Ivacaftor over the defined 12 month study period (from January 2015 to December 2015 inclusive). The cohort ranged in age from 6 years to 61 years. The mean age was 22 years; a positive skew in age distribution indicated that a greater number of the cohort were in the younger age groups. No statistically significant difference was detected in the mean ages of the male and female subgroups. Drug acquisition expenditure by the Health Services Executive on Ivacaftor over the 12 month study period was €29.81 million.

Topics: Adolescent; Adult; Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Health Expenditures; Humans; Ireland; Male; Mutation; Quinolones; Young Adult

Expansion of novel therapeutics to all patients with cystic fibrosis (CF) requires personalized CFTR modulator therapy. We have developed nasospheroids, a primary cell culture-based model derived from individual CF patients and healthy subjects by a minimally invasive nasal biopsy. Confocal microscopy was utilized to measure CFTR activity by analyzing changes in cross-sectional area over time that resulted from CFTR-mediated ion and fluid movement. Both the rate of change over time and AUC were calculated. Non-CF nasospheroids with active CFTR-mediated ion and fluid movement showed a reduction in cross-sectional area, whereas no changes were observed in CF spheroids. Non-CF spheroids treated with CFTR inhibitor lost responsiveness for CFTR activation. However, nasospheroids from F508del CF homozygotes that were treated with lumacaftor and ivacaftor showed a significant reduction in cross-sectional area, indicating pharmacologic rescue of CFTR function. This model employs a simple measurement of size corresponding to changes in CFTR activity and is applicable for detection of small changes in CFTR activity from individual patients in vitro. Advancements of this technique will provide a robust model for individualized prediction of CFTR modulator efficacy.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Biological Transport; Colforsin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Mutation; Nasal Mucosa; Particle Size; Precision Medicine; Quinolones; Spheroids, Cellular

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Genetic Variation; Humans; Quinolones

The tumor suppressor PTEN controls cell proliferation by regulating phosphatidylinositol-3-kinase (PI3K) activity, but the participation of PTEN in host defense against bacterial infection is less well understood. Anti-inflammatory PI3K-Akt signaling is suppressed in patients with cystic fibrosis (CF), a disease characterized by hyper-inflammatory responses to airway infection. We found that Ptenl

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Gene Expression Regulation; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Monocytes; Phosphatidylinositol 3-Kinases; Protein Binding; Protein Conformation; Protein Transport; Proto-Oncogene Proteins c-akt; Pseudomonas aeruginosa; Pseudomonas Infections; PTEN Phosphohydrolase; Quinolones; Signal Transduction

This project aimed to explore the attitudes of prenatal genetic counselors toward discussion of novel approved and experimental CF treatments in the prenatal setting, and to assess how knowledge of genotype-specific, targeted treatments may influence their current practices. Targeted treatments have the potential to impact the health-related quality of life of individuals affected with CF and therefore, knowledge of the availability of such treatments may influence the decision-making process of parents who receive a fetal diagnosis of CF. Using the 2012 FDA approval and introduction of ivacaftor into CF clinical practice as a case study, a survey was designed to explore the opinions and practices of prenatal genetic counselors with regard to counseling for a prenatal diagnosis of CF, and how those practices might be impacted by the availability of a new genotype-specific treatment. Approximately 800 genetic counselors were sent questionnaires in January of 2013. Respondents were provided information about this treatment and were asked to rate its perceived benefits, along with the likelihood that they would discuss potential benefits and limitations with parents receiving a prenatal diagnosis of CF. One-hundred sixty-nine prenatal genetic counselors (21.1 %) responded to the survey. Results indicated that 80 % of respondents 'never heard of the drug', or they were 'not exactly sure' what it was. After reading the materials provided, counselors felt the new treatment would have 'some' or a 'significant' impact on an affected individual's life. Their opinions varied on what information about this treatment they would choose to discuss with their patients; even if the treatment is currently FDA approved and clinically available for affected individuals with the genotype of the fetus. However, they would 'definitely' refer these patients to a specialist to discuss targeted treatments further. Most prenatal genetic counselors indicated there are certain scenarios in the prenatal setting which warrant a discussion of targeted treatments for CF, at least on some level. Counselor's views on sharing information about new treatment options are shaped by their familiarity with the treatment and their perception of its benefits and limitations, their comfort discussing these subjects, and their interpretation of the genetic counselor's role. Most genetic counselors had never heard of ivacaftor or Kalydeco™ prior to taking the survey. Therefore, counselors need to be

Topics: Aminophenols; Attitude to Health; Chloride Channel Agonists; Counselors; Cystic Fibrosis; Decision Making; Female; Genetic Counseling; Genetic Testing; Humans; Mutation; Parents; Precision Medicine; Pregnancy; Prenatal Diagnosis; Quality of Life; Quinolones; Surveys and Questionnaires; Therapies, Investigational

Ivacaftor has produced significant improvement in certain individuals with cystic fibrosis (CF), though the full metabolic effects of treatment remain unknown. Abnormalities in fatty acid metabolism have previously been shown to be a characteristic of CFTR dysfunction. We hypothesized that as a reflection of this clinical improvement, ivacaftor would improve plasma fatty acid levels and decrease urine prostaglandin E metabolite levels.. This study analyzed plasma fatty acid levels and urine prostaglandin E metabolites (PGE-M) in 40 subjects with CF participating in the G551D observational (GOAL) study who demonstrated response to the medication by a significant decrease in sweat Cl levels. Paired samples were analyzed before and after 6months of ivacaftor treatment.. Linoleic acid and docosahexaenoic acid levels, which are typically low in individuals with CF, did not significantly increase with ivacaftor treatment. However, arachidonic acid levels did decrease with ivacaftor treatment and there was a significant decrease in the arachidonic acid metabolite PGE-M as measured in the urine [median: before treatment 17.03ng/mg Cr; after treatment 9.06ng/mg Cr; p<0.001]. Furthermore, there were fatty acid age differences observed, including pediatric participants having significantly greater linoleic acid levels at baseline.. Ivacaftor reduces inflammatory PGE without fully correcting the plasma fatty acid abnormalities of CF. Age-related differences in fatty acid levels were observed, that may be a result of other clinical factors, such as diet, clinical care, or drug response.

Topics: Adult; Aminophenols; Arachidonic Acid; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Monitoring; Fatty Acids, Monounsaturated; Female; Humans; Inflammation Mediators; Linoleic Acid; Lipid Metabolism; Male; Mutation; Pilot Projects; Prostaglandins E; Quinolones

Extra-oesophageal reflux (EOR) may lead to microaspiration in patients with cystic fibrosis (CF), a probable cause of deteriorating lung function. Successful clinical trials of ivacaftor highlight opportunities to understand EOR in a real world study.. Data from 12 patients with CF and the G551D mutation prescribed ivacaftor (150mg bd) was collected at baseline, 6, 26 and 52weeks. The changes in symptoms of EOR were assessed by questionnaire (reflux symptom index (RSI) and Hull airway reflux questionnaire (HARQ)).. Six patients presented EOR at baseline (RSI >13; median 13; range 2-29) and 5 presented airway reflux (HARQ >13; median 12; range 3 to 33). Treatment with ivacaftor was associated with a significant reduction of EOR symptoms (P<0∙04 versus baseline) denoted by the reflux symptom index and Hull airway reflux questionnaire.. Ivacaftor treatment was beneficial for patients with symptoms of EOR, thought to be a precursor to microaspiration.

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Monitoring; Female; Gastroesophageal Reflux; Humans; Lung; Male; Mutation; Quinolones; Respiratory Aspiration; Respiratory Function Tests; Treatment Outcome; United Kingdom

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones

Ivacaftor, a CFTR potentiator, has been found to improve CFTR function and clinical outcomes in patients with cystic fibrosis (CF) gating mutations. We investigated the effects of ivacaftor on CFTR functional measurement in CF patients carrying gating mutations other than p.Gly551Asp. Two siblings aged 13 and 12 carrying the p.Ser549Asn mutation, two sisters (45 and 43years old) compound heterozygotes for p.Asp1152His and p.Gly1244Glu, a 37year old man homozygous for the p.Gly1244Glu mutation, and a 7year old girl with p.Arg352Gln and p.Gly1244Glu mutations commenced treatment with ivacaftor. NPD was performed in all the patients and approached normal for four patients who had also clinical improvement (p.Ser549Asn compound heterozygotes, and p.Asp1152His/p.Gly1244Glu siblings). Beta-adrenergic sweat chloride secretion performed in thep.Asp1152His/p.Gly1244Glu patients improved significantly. The p.Gly1244Glu mutation homozygous patient, who had undergone an ileal resection with ileostomy and enterocutaneous fistula, did not respond clinically to ivacaftor and did not modify his sweat test. These results highlight the importance of different CFTR activity measurements to explore CFTR modulator efficacy.

Topics: Adolescent; Adult; Aminophenols; Child; Chloride Channel Agonists; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Membrane Potentials; Middle Aged; Mutation; Nasal Mucosa; Outcome Assessment, Health Care; Quinolones; Sweat; Treatment Outcome

Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) gene result in nonfunctional CFTR protein and are the proximate cause of ~11% of CF causing alleles. Aminoglycosides and other novel agents are known to induce translational readthrough of PTCs, a potential therapeutic approach. Among PTCs, W1282X CFTR is unique, as it is a C-terminal CFTR mutation that can exhibit partial activity, even in the truncated state. The potentiator ivacaftor (VX-770) is approved for treating CF patients with G551D and other gating mutations. Based on previous studies demonstrating the beneficial effect of ivacaftor for PTC mutations following readthrough in vitro, we hypothesized that ivacaftor may enhance CFTR activity in CF patients expressing W1282X CFTR, and could be further enhanced by readthrough. Ivacaftor significantly increased CFTR activity in W1282X-expressing cells compared to R1162X CFTR cells, and was further enhanced by readthrough with the aminoglycoside G418. Primary nasal epithelial cells from a W1282X homozygous patient showed improved CFTR function in the presence of ivacaftor. Upon ivacaftor administration to the same patient, there was significant improvement in pulmonary exacerbation frequency, BMI, and insulin requirement, whereas FEV

Topics: Aminophenols; Chloride Channel Agonists; Codon, Nonsense; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Homozygote; Humans; Ion Transport; Quinolones; Treatment Outcome

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Early Diagnosis; Genetic Therapy; Humans; Quinolones; Survival Rate

Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV

Topics: Aminophenols; Biomarkers; Chloride Channel Agonists; Chlorides; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forced Expiratory Volume; Humans; Mutation; Predictive Value of Tests; Quinolones; Sweat; Treatment Outcome

Topics: Aged; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Male; Polymorphism, Genetic; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Helium; Humans; Isotopes; Magnetic Resonance Imaging; Quinolones

ABCB4 (MDR3) is an adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene are responsible for several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ABCB4 missense variations that reside in the highly conserved motifs of ABC transporters, involved in ATP binding. Five disease-causing variations in these motifs have been identified in ABCB4 (G535D, G536R, S1076C, S1176L, and G1178S), three of which are homologous to the gating mutations of cystic fibrosis transmembrane conductance regulator (CFTR or ABCC7; i.e., G551D, S1251N, and G1349D), that were previously shown to be function defective and corrected by ivacaftor (VX-770; Kalydeco), a clinically approved CFTR potentiator. Three-dimensional structural modeling predicted that all five ABCB4 variants would disrupt critical interactions in the binding of ATP and thereby impair ATP-induced nucleotide-binding domain dimerization and ABCB4 function. This prediction was confirmed by expression in cell models, which showed that the ABCB4 mutants were normally processed and targeted to the plasma membrane, whereas their PC secretion activity was dramatically decreased. As also hypothesized on the basis of molecular modeling, PC secretion activity of the mutants was rescued by the CFTR potentiator, ivacaftor (VX-770).. Disease-causing variations in the ATP-binding sites of ABCB4 cause defects in PC secretion, which can be rescued by ivacaftor. These results provide the first experimental evidence that ivacaftor is a potential therapy for selected patients who harbor mutations in the ATP-binding sites of ABCB4. (Hepatology 2017;65:560-570).

Topics: Adenosine Triphosphate; Adolescent; Aminophenols; ATP Binding Cassette Transporter, Subfamily B; Binding Sites; Cells, Cultured; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Hep G2 Cells; Humans; Male; Mutagenesis; Mutation, Missense; Phosphatidylcholines; Quinolones; Sampling Studies; Transfection; Young Adult

Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Cell Line; Cell Membrane; Cell-Free System; Chromatography; Cricetinae; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Hot Temperature; Humans; Mutation; Patch-Clamp Techniques; Protein Denaturation; Quinolones

Little is known about how new therapies that partially correct the basic cystic fibrosis (CF) defect (ivacaftor and lumacaftor) might alter hormonal contraceptive effectiveness, impact pregnancy outcomes, or affect pregnancy timing. Examination of pregnancy rates among CF women during periods of CFTR modulator therapy initiation will provide foundation for further research in this area.. The Cystic Fibrosis Foundation Patient Registry was used to examine pregnancy rates and outcomes by genotype class before, during, and after the introduction of CFTR modulator therapies between 2005 and 2014.. Among women with CF, ages 15-44years, there was a slight downward trend in annual pregnancy rates from 2005 to 2014 (2% reduction per year, p=0.041). Among women with G551D, pregnancy rates during phase 3 ivacaftor trial years was 14.4/1000 women-years compared to 34.0/1000 prior to the trial period (relative risk [RR]=0.65; 95% CI=0.43-0.96; p=0.011) and 38.4/1000 after drug approval in June 2012 (RR=1.52 post-approval compared to trial period; 95% CI=1.26, 1.83; p<0.001). Pregnancy outcomes did not significantly change between 2005 and 2014 for any genotype class.. Evidence of significantly increased numbers of pregnancies among women taking approved CFTR modulators is important because of the unknown risk to pregnancy and fetal outcomes. Increases may be temporary following pregnancy prevention during controlled clinical trials, or from altered perceptions about maternal survival with new approved treatments. As more women with CF become eligible to receive modulators, the CF community must study their effect on contraceptive efficacy and safety during pregnancy. With increased health and survival due to modulation, family planning topics will become more common in CF.

Topics: Adolescent; Adult; Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Rate; Pregnancy, High-Risk; Quinolones; Risk Adjustment; United States

Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established.. To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections.. We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans.. Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging.. Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments.

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Inflammation; Lung; Male; Quinolones; Respiratory Tract Infections; Sputum; Tomography, X-Ray Computed

Ivacaftor improves clinical outcome by potentiation of mutant G551D CFTR. Due to the presence of CFTR in monocytes and polymorphonuclear neutrophils (PMNs), we hypothesized that ivacaftor may impact leukocyte activation.. We examined blood leukocytes from G551D CF subjects prior to and at one and six months after receiving ivacaftor. Blood leukocytes from ivacaftor-naïve G551D, F508del, and healthy controls were also treated with ivacaftor ex vivo to assess mutation-specific effects.. Compared to healthy controls, G551D CF subjects had significantly higher expression of active CD11b on PMNs and of CD63 on monocytes, which were normalized by in vivo ivacaftor treatment. Ex vivo exposure to ivacaftor of blood cells from G551D, but not F508del and healthy subjects, resulted in changes in CXCR2 and CD16 expression on PMNs.. In vivo and ex vivo exposure of G551D CF leukocytes to ivacaftor resulted in an altered activation profile, suggesting mutation-specific leukocyte modulation.

Topics: Adult; Aminophenols; CD11b Antigen; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Monocytes; Mutation; Neutrophils; Quinolones; Statistics as Topic; Tetraspanin 30

The most common cystic fibrosis (CF) mutation F508del inhibits the gating and surface expression of CFTR, a plasma membrane anion channel. Optimal pharmacotherapies will probably require both a 'potentiator' to increase channel open probability and a 'corrector' that improves folding and trafficking of the mutant protein and its stability at the cell surface. Interaction between CF drugs has been reported but remains poorly understood.. CF bronchial epithelial cells were exposed to the corrector VX-809 (lumacaftor) and potentiator VX-770 (ivacaftor) individually or in combination. Functional expression of CFTR was assayed as the forskolin-stimulated short-circuit current (Isc ) across airway epithelial monolayers expressing F508del CFTR.. The potentiated Isc response during forskolin stimulation was increased sixfold after pretreatment with VX-809 alone and reached ~11% that measured across non-CF monolayers. VX-770 (100 nM) and genistein (50 μM) caused similar levels of potentiation, which were not additive and were abolished by the CFTR inhibitor CFTRinh -172. The unbound fraction of VX-770 in plasma was 0.13 ± 0.04%, which together with previous measurements in patients given 250 mg p.o. twice daily, suggests a peak free plasma concentration of 1.5-8.5 nM. Chronic exposure to high VX-770 concentrations (>1 μM) inhibited functional correction by VX-809 but not in the presence of physiological protein levels (20-40 mg·mL(-1) ). Chronic exposure to a low concentration of VX-770 (100 nM) together with VX-809 (1 μM) also did not reduce the forskolin-stimulated Isc , relative to cells chronically exposed to VX-809 alone, provided it was assayed acutely using the same, clinically relevant concentration of potentiator.. Chronic exposure to clinically relevant concentrations of VX-770 did not reduce F508del CFTR function. Therapeutic benefit of VX-770 + VX-809 (Orkambi) is probably limited by the efficacy of VX-809 rather than by inhibition by VX-770.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Bronchi; Cell Line; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Interactions; Epithelial Cells; Humans; Mutation; Quinolones

To investigate the effect of treatment with ivacaftor on insulin secretion in patients with cystic fibrosis (CF) (ΔF508\\S549R) having CFRD/impaired insulin secretion.. A standard OGTT was performed before and after 16weeks of treatment with ivacaftor in 2 sibling patients with CF carrying the S549R gating mutation. The area under the curve (AUC) for glucose and insulin was calculated using the trapezoidal estimation.. Before treatment, the OGTT of case 1 showed indeterminate glycemia; the OGTT of case 2 indicated CFRD. After ivacaftor treatment the OGTT demonstrated improved insulin secretion pattern mainly by increased first phase early insulin secretion, resulting in reduction of the AUC of glucose in both cases.. The treatment with ivacaftor in patients with CF carrying gating mutation can ameliorate impaired insulin secretion. Further studies and larger cohorts are needed to evaluate the impact of ivacaftor on insulin secretion in patients with CF carrying gating or other mutations.

Topics: Aminophenols; Blood Glucose; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Insulin; Insulin Secretion; Male; Mutation; Quinolones; Siblings; Treatment Outcome; Young Adult

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR), leading to significant morbidity and mortality. CFTR is a chloride and bicarbonate channel at the epithelial cell membrane. The most common CFTR mutation is F508del, resulting in minimal CFTR at the plasma membrane. Current disease management is supportive, whereas an ultimate goal is to develop therapies to restore CFTR activity. We summarize experience with lumacaftor, a small molecule that increases F508del-CFTR levels at the plasma membrane. Lumacaftor in combination with ivacaftor, a modulator of CFTR gating defects, improves clinical outcome measures in patients homozygous for the F508del mutation. Lumacaftor represents a significant advancement in the treatment of biochemical abnormalities in CF. Further development of CFTR modulators will improve upon current therapies, although it remains unclear whether this approach will provide therapies for all CFTR mutations.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones; Randomized Controlled Trials as Topic

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Quinolones; Respiratory Function Tests

Topics: Aminophenols; Child; Cystic Fibrosis; Duodenum; Humans; Mucus; Quinolones; Treatment Outcome

Topics: Adult; Alleles; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forced Expiratory Volume; Humans; Maximal Midexpiratory Flow Rate; Mutation; Quinolones; Saline Solution, Hypertonic; Severity of Illness Index; Spirometry; Treatment Outcome

Recently approved therapies that modulate CFTR function have shown significant clinical benefit, but recent investigations regarding their molecular mechanism when used in combination have not been consistent with clinical results. We employed micro-optical coherence tomography as a novel means to assess the mechanism of action of CFTR modulators, focusing on the effects on mucociliary clearance. Primary human airway monolayers from patients with a G551D mutation responded to ivacaftor treatment with increased ion transport, airway surface liquid depth, ciliary beat frequency, and mucociliary transport rate, in addition to decreased effective viscosity of the mucus layer, a unique mechanism established by our findings. These endpoints are consistent with the benefit observed in G551D patients treated with ivacaftor, and identify a novel mechanism involving mucus viscosity. In monolayers derived from F508del patients, the situation is more complicated, compounded by disparate effects on CFTR expression and function. However, by combining ion transport measurements with functional imaging, we establish a crucial link between in vitro data and clinical benefit, a finding not explained by ion transport studies alone. We establish that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen. We further show that improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponds to changes in sweat chloride. Functional imaging reveals insights into clinical efficacy and CFTR biology that significantly impact our understanding of novel therapies.

Topics: Amiloride; Aminophenols; Animals; Cells, Cultured; Chloride Channel Agonists; Colforsin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Membrane Potentials; Mice; Mutation, Missense; NIH 3T3 Cells; Quinolones

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Drug Combinations; Humans; Quinolones; Randomized Controlled Trials as Topic

Topics: Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Monocytes; Proteome; Quinolones

Ivacaftor was approved in 2012 to treat patients with cystic fibrosis (CF) with specific CFTR gene mutations. The objective of this analysis was to analyze the impact of ivacaftor on health resource utilization through analysis of claims data.. Patients diagnosed with CF aged ≥6 years prescribed ivacaftor between January 1, 2012 and July 31, 2014 with ≥12 months of continuous insurance coverage prior to and following the prescription were identified. All-cause and CF-specific healthcare resource utilization during the pre- and post-prescription periods and ivacaftor adherence levels were studied.. The 79 identified patients had a mean age of 20.8 years, and 54% were female. The proportion of patients with inpatient admissions (all-cause and CF-related) was significantly higher in the pre index compared to post index period (p ≤ 0.05). Mean ivacaftor medication possession ratio was 0.8 (SD = 0.3), and 73% of patients had a medication possession ratio >0.80.. Only a small number of patients met the inclusion criteria. Additionally, claims data may contain errors or inconsistencies and cannot be used to determine if medications were taken as prescribed.. Ivacaftor therapy was associated with significant reductions in hospitalizations along with high rates of adherence to treatment over 12 months.

Topics: Adolescent; Adult; Age Factors; Aminophenols; Child; Chloride Channel Agonists; Costs and Cost Analysis; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Health Expenditures; Health Services; Humans; Insurance, Health; Male; Middle Aged; Mutation; Quinolones; Retrospective Studies; Sex Factors; Young Adult

Ivacaftor, a breakthrough treatment for cystic fibrosis (CF) patients with the G551D genetic mutation, lacks long-term clinical and cost projections. This study forecasted outcomes and cost by comparing ivacaftor plus usual care versus usual care alone.A lifetime Markov model was conducted from a US payer perspective. The model consisted of five health states: 1) forced expiratory volume in 1 s (FEV1) % pred ≥70%, 2) 40%≤ FEV1 % pred <70%, 3) FEV1 % pred <40%, 4) lung transplantation and 5) death. All inputs were extracted from published literature. Budget impact was also estimated. We estimated ivacaftor's improvement in outcomes compared with a non-CF referent population.Ivacaftor was associated with 18.25 (95% credible interval (CrI) 13.71-22.20) additional life-years and 15.03 (95% CrI 11.13-18.73) additional quality-adjusted life-years (QALYs). Ivacaftor was associated with improvements in survival and QALYs equivalent to 68% and 56%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $3 374 584. The budget impact was $0.087 per member per month.Ivacaftor increased life-years and QALYs in CF patients with the G551D mutation, and moved morbidity and mortality closer to that of their non-CF peers. Ivacaftor costs much more than usual care, but comes at a relatively limited budget impact.

Topics: Aminophenols; Cohort Studies; Computer Simulation; Cost-Benefit Analysis; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy; Forced Expiratory Volume; Forecasting; Health Status; Humans; Lung Transplantation; Markov Chains; Monte Carlo Method; Mutation; Quality-Adjusted Life Years; Quinolones; Respiratory Function Tests; Treatment Outcome; United States

The potentiator VX-770 (ivacaftor/KALYDECO™) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities. Results indicated that all possible combinations of VX-770, genistein and curcumin synergistically repaired CFTR-dependent forskolin-induced swelling of organoids with CFTR-S1251N or CFTR-G551D, even under suboptimal CFTR activation and compounds concentrations, conditions that may predominate in vivo. Genistein and curcumin also enhanced forskolin-induced swelling of F508del homozygous organoids that were treated with VX-770 and the prototypical CFTR corrector VX-809. These results indicate that VX-770, genistein and curcumin in double or triple combinations can synergize in restoring CFTR-dependent fluid secretion in primary CF cells and support the use of multiple potentiators for treatment of CF.

Topics: Aminophenols; Chloride Channel Agonists; Curcumin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Genistein; Humans; Models, Theoretical; Molecular Targeted Therapy; Mutation; Organoids; Quinolones; Rectum

The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to deletion of the phenylalanine at position 508 (ΔF508) in the CFTR protein and causes multiple folding and functional defects. Contrary to large-scale efforts by industry and academia, no significant therapeutic benefit has been achieved with a single "corrector". Therefore, investigations concentrate on drug combinations. Orkambi (Vertex Pharmaceuticals), the first FDA-approved drug for treatment of cystic fibrosis (CF) caused by this mutation, is a combination of a corrector (VX-809) that facilitates ΔF508 CFTR biogenesis and a potentiator (VX-770), which improves its function. Yet, clinical trials utilizing this combination showed only modest therapeutic benefit. The low efficacy Orkambi has been attributed to VX-770-mediated destabilization of VX-809-rescued ΔF508 CFTR. Here we report that the negative effects of VX-770 can be reversed by increasing the half-life of the endoplasmic reticulum (ER) form (band B) of ΔF508 CFTR with another corrector (Corr-4a.) Although Corr-4a alone has only minimal effects on ΔF508 CFTR rescue, it increases the half-life of ΔF508 CFTR band B when it is present during half-life measurements. Our data shows that stabilization of band B ΔF508 CFTR with Corr-4a and simultaneous rescue with VX-809, leads to a >2-fold increase in cAMP-activated, CFTRinh-172-inhibited currents compared to VX-809 alone, or VX-809+VX-770. The negative effects of VX-770 and the Corr-4a protection are specific to the native I507-ATT ΔF508 CFTR without affecting the inherently more stable, synonymous variant I507-ATC ΔF508 CFTR. Our studies emphasize that stabilization of ΔF508 CFTR band B in the ER might improve its functional rescue by Orkambi.

Topics: Aminophenols; Aminopyridines; Benzamides; Benzodioxoles; Cell Line; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Endoplasmic Reticulum; Gene Expression Regulation; Half-Life; HEK293 Cells; Humans; Mutation; Quinolones; Thiazoles

Ivacaftor is a revolutionary treatment option for cystic fibrosis (CF) patients with G551D and other gating mutations. The aim of this study was to evaluate the clinical status of patients on ivacaftor who were followed for up to 6 years together with an evaluation of ivacaftor therapy in one patient with an initial FEV1 less than 40% of predicted value.. Data on development of clinical status and sinopulmonary-related therapies were obtained from patient health records during ivacaftor treatment lasting for up to six years and were compared with an equivalent period before ivacaftor administration.. Five CF adults with a median age 28.6 years (range 21.4-35.6 years) with median FEV1 45% pred. (range 16-85% pred.) were included in the study. Four subjects were also participants in the STRIVE and PERSIST studies. Altogether, twenty-four patient-years of ivacaftor treatment were analyzed. The median FEV1 decline per year decreased from -4.5 to -0.9% pred. (P = 0.043). Reduction in number of days on antibiotic treatment and hospital stays was 21% (P < 0.001) and 75% (P = 0.003), respectively. Improvement and stabilization of lung function was observed for up to six years of treatment. In a patient with severe airway obstruction, an increase in the FEV1 value (30.4% from baseline) was documented during the first twelve months of treatment.. Ivacaftor therapy resulted in improved and stabilized lung function in up to six years of treatment with a reduction in number of days on antibiotic treatment and hospital stays. Its efficiency was also displayed in a patient with severe airway obstruction.

Topics: Adult; Aftercare; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Male; Quinolones; Treatment Outcome; Young Adult

Topics: Adult; Aminophenols; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Monitoring; Female; France; Humans; Lung; Male; Middle Aged; Quinolones; Retrospective Studies; Time; Tomography, X-Ray Computed

VX-770 (Ivacaftor) has been approved for clinical usage in cystic fibrosis patients with several CFTR mutations. Yet the binding site(s) on CFTR for this compound and other small molecule potentiators are unknown. We hypothesize that insight into this question could be gained by comparing the effect of potentiators on CFTR channels from different origins, e.g., human, mouse, and Xenopus (frog). In the present study, we combined this comparative molecular pharmacology approach with that of computer-aided drug discovery to identify and characterize new potentiators of CFTR and to explore possible mechanism of action. Our results demonstrate that 1) VX-770, NPPB, GlyH-101, P1, P2, and P3 all exhibited ortholog-specific behavior in that they potentiated hCFTR, mCFTR, and xCFTR with different efficacies; 2) P1, P2, and P3 potentiated hCFTR in excised macropatches in a manner dependent on the degree of PKA-mediated stimulation; 3) P1 and P2 did not have additive effects, suggesting that these compounds might share binding sites. Also 4) using a pharmacophore modeling approach, we identified three new potentiators (IOWH-032, OSSK-2, and OSSK-3) that have structures similar to GlyH-101 and that also exhibit ortholog-specific potentiation of CFTR. These could potentially serve as lead compounds for development of new drugs for the treatment of cystic fibrosis. The ortholog-specific behavior of these compounds suggest that a comparative pharmacology approach, using cross-ortholog chimeras, may be useful for identification of binding sites on human CFTR.

Topics: Amino Acid Sequence; Aminophenols; Animals; Cells, Cultured; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Evaluation, Preclinical; Glycine; Hydrazines; Membrane Potentials; Mice; Nitrobenzoates; Patch-Clamp Techniques; Quinolones; Sequence Deletion; Xenopus laevis

Topics: Aminophenols; Anemia, Sickle Cell; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biotechnology; Cystic Fibrosis; Drug Costs; Drug Industry; Genetic Therapy; Humans; Insurance, Health; Neoplasms; Quinolones; Sofosbuvir

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cost-Benefit Analysis; Cystic Fibrosis; Humans; Quinolones; Respiratory System Agents

Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Biological Assay; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Humans; In Vitro Techniques; Mutation; Organoids; Quinolones

Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cell Line; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Evaluation, Preclinical; Humans; Mutation, Missense; Protein Folding; Quinolones; Sequence Deletion

Remarkable advances in the management of individuals born with cystic fibrosis (CF) would not have been realized without empiric trial and error by CF clinicians with treatments developed and available for other purposes. As the testing and registration of CF-specific treatments have increased, so too have associated health care costs, particularly those of chronic medications. The transition of CF from a lethal pediatric disease to a life-shortening one with an adult majority, concurrent with sharp increases in chronic medication costs, has placed many CF treatments under increased scrutiny by third-party payers, particularly when prescribed to individuals from CF subpopulations that may not have been included in registration trials. Despite overall health improvements in the CF cohort and the increasing availability of CF-specific therapies, many physicians remain tasked with managing the health of patients from subpopulations that may be too young, too sick, or too complicated to have been included in clinical trials. An understanding of why particular CF subpopulations may have been excluded from registration trials, as well as consideration of a treatment's described mechanism of action, can support assessment for the potential for benefit (and risk) in these populations and help physicians advocate for patient access to treatments.

Topics: Aminophenols; Clinical Trials as Topic; Cystic Fibrosis; Health Care Costs; Humans; Off-Label Use; Patient Selection; Quinolones; Risk Assessment

Novel combination therapies are desperately needed for combating lung infections caused by bacterial "superbugs". This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the cystic fibrosis (CF) drugs KALYDECO (ivacaftor) and ORKAMBI (ivacaftor + lumacaftor) against Gram-negative pathogens that commonly colonize the CF lung, in particular, the problematic Pseudomonas aeruginosa. The in vitro synergistic activity of polymyxin B combined with ivacaftor or lumacaftor was assessed using checkerboard and static time-kill assays against a panel of polymyxin-susceptible and polymyxin-resistant P. aeruginosa isolates from the lungs of CF patients. Polymyxin B, ivacaftor, and lumacaftor were ineffective when used individually against polymyxin-resistant (MIC ≥ 4 mg/L) isolates. However, when used together, the combination of clinically relevant concentrations of polymyxin B (2 mg/L) combined with ivacaftor (8 mg/L) or ivacaftor (8 mg/L) + lumacaftor (8 mg/L) displayed synergistic killing activity against polymyxin-resistant P. aeruginosa isolates as demonstrated by a 100-fold decrease in the bacterial count (CFU/mL) even after 24 h. The combinations also displayed excellent antibacterial activity against P. aeruginosa under CF relevant conditions in a sputum medium assay. The combination of lumacaftor (alone) with polymyxin B showed additivity against P. aeruginosa. The potential antimicrobial mode of action of the combinations against P. aeruginosa was investigated using different methods. Treatment with the combinations induced cytosolic GFP release from P. aeruginosa cells and showed permeabilizing activity in the nitrocefin assay, indicating damage to both the outer and inner Gram-negative cell membranes. Moreover, scanning and transmission electron micrographs revealed that the combinations produce outer membrane damage to P. aeruginosa cells that is distinct from the effect of each compound per se. Ivacaftor was also shown to be a weak inhibitor of the bacterial DNA gyrase and topoisomerase IV with no effect on either human type I or type IIα topoisomerases. Lumacaftor displayed the ability to increase the cellular production of damaging reactive oxygen species. In summary, the combination of polymyxin B with KALYDECO or ORKAMBI exhibited synergistic activity against highly polymyxin-resistant P. aeruginosa CF isolates and can be potentially useful for otherwise untreatable CF lung infections.

Topics: Aminophenols; Aminopyridines; Anti-Bacterial Agents; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Synergism; Drug Therapy, Combination; Humans; Polymyxin B; Pseudomonas aeruginosa; Quinolones

Low bone mineral density (BMD) is a common problem in adults with cystic fibrosis (CF), the etiology of which is multifactorial. In this study, we provide the first evidence that ivacaftor improves BMD in CF patients carrying the p.Gly551Asp mutation. Consistently, in vitro experiments with TNF-α-stimulated primary F508del-CFTR osteoblasts demonstrated that correction of p.Phe508del-CFTR markedly decreased RANKL protein production, a major factor of bone resorption. These clinical and fundamental observations suggest that rescue of mutated CFTR protein improves bone remodeling and support the link between CFTR and bone cell physiology. These findings represent a step forward in the development of potential new therapies for CF-related bone disease.

Topics: Adult; Aminophenols; Bone Demineralization, Pathologic; Bone Density; Cells, Cultured; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Middle Aged; Mutation; Osteoblasts; Quinolones; Statistics as Topic

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Chromatography, High Pressure Liquid; Cystic Fibrosis; Humans; Limit of Detection; Quinolones; Sputum; Tandem Mass Spectrometry

Topics: Aminophenols; Aspergillosis, Allergic Bronchopulmonary; Chloride Channel Agonists; Comorbidity; Cystic Fibrosis; Humans; Pseudomonas Infections; Quinolones

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector.\ \ In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

Topics: Aminophenols; Antiporters; Canada; Cells, Cultured; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; France; Genes, Modifier; Genetic Association Studies; Humans; Lung; Male; Models, Genetic; Patient Acuity; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precision Medicine; Quinolones; Sulfate Transporters

Ivacaftor corrects the cystic fibrosis transmembrane conductance regulator (CFTR) gating defect associated with G551D mutation and is quickly becoming an important treatment in patients with cystic fibrosis (CF) due to this genetic mutation.. A single-center study was performed in CF patients receiving ivacaftor to evaluate the usefulness of high resolution computed tomography (HRCT) of the chest as a way to gauge response to ivacaftor therapy.. Ten patients with CF were enrolled for at least one year before and after starting ivacaftor. At time of enrollment, mean age was 20.9 ± 10.8 (range 10-44) years. There were significant improvements from baseline to 6 months in mean %FVC (93 ± 16 to 99 ± 16) and %FEV1 (79 ± 26 to 87 ± 28) but reverted to baseline at one year. Mean sweat chloride levels decreased significantly from baseline to one year. Mean weight and BMI improved at 6 months. Weight continued to improve with stabilization of BMI at one year. Chest HRCT showed significant improvement at one year in mean modified Brody scores for bronchiectasis, mucous plugging, airway wall thickness, and total Brody scores. Elevated bronchiectasis and airway wall thickness scores correlated significantly with lower %FEV1, while higher airway wall thickness and mucus plugging scores correlated with more pulmonary exacerbations requiring IV and oral antibiotics respectively.. Based on our findings, HRCT imaging is a useful tool in monitoring response to ivacaftor therapy that corrects the gating defect associated with the G551D-CFTR mutation.

Topics: Administration, Oral; Adolescent; Adult; Aminophenols; Child; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Molecular Targeted Therapy; Mutation; Prospective Studies; Quinolones; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Most patients with Cystic fibrosis (CF) have chronic sinus disease which may require multiple sinus surgeries and antibiotic courses. Ivacaftor can improve lung function, lower sweat chloride levels and improve weight by targeting the primary defect, a faulty gene and its protein product, cystic fibrosis transmembrane conductance regulator (CFTR) in patients with the G551D mutation. Its role in improving sinus disease has not been evaluated.. The objective of this study was to evaluate efficacy of ivacaftor in improving CF related sinus disease.. Observational study.. Twelve patients with cystic fibrosis and a G551D-CFTR mutation.. Twelve patients with a G551D-CFTR mutation were monitored for at least one year before and after starting ivacaftor.. Sinus disease progression was monitored by comparing computed tomography (CT) of sinuses before and at one year on therapy. Hospital admissions, pulmonary exacerbations, weight, BMI and lung function were also compared.. Median age was 17 years (range 10-44). Weight, BMI, FEV1 significantly increased and sweat chloride significantly decreased by six months on ivacaftor therapy. CT of the sinuses in all patients improved. Seven patients had severe sinus disease, improved to moderate in three and mild in remaining four. Four patients had moderate disease which improved to mild in all. One patient had normal sinus CT before and after the therapy.. Patients with CF and G551D mutation, within 6 months of starting ivacaftor had significant improvements in weight, BMI and mean % FEV1. Significant lessening of underlying sinus disease measured by CT scan was noted, suggesting a disease modifying effect.

Topics: Adolescent; Adult; Aminophenols; Child; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Male; Mutation; Paranasal Sinus Diseases; Quinolones; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

In patients with Cystic Fibrosis and a type III mutation, ivacaftor (Kalydeco(®), Vertex) can increase the opening time of the CFTR channel and improve chloride transport. Research showed significant improvement of lung function and increase in weight following ivacaftor use. However, ivacaftor showed to have adverse events on the sinonasal system as well, such as upper respiratory tract infections, nasal congestion and headaches. This case report showed a positive effect of ivacaftor on the sinonasal pathology in a 17 year old patient with CF. After 5 months of ivacaftor use, the CT-sinus showed complete resolution of the opacification of the paranasal sinuses and a decrease in symptoms of sinonasal disease. This positive effect of ivacaftor on sinonasal pathology seems promising, therefore more research is needed to evaluate the effect of ivacaftor on the upper airways in CF.

Topics: Adolescent; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Female; Forced Expiratory Volume; Genotype; Humans; Ion Transport; Mutation; Paranasal Sinus Diseases; Paranasal Sinuses; Quinolones; Tomography, X-Ray Computed

Chronic sinusitis is universal in cystic fibrosis (CF) and our current treatments are ineffective in reversing sinus disease. The objective of this work was to determine if increasing CF transmembrane conductance regulator (CFTR) activity by ivacaftor could treat CF sinus disease and assess its effect on primary sinus epithelial cultures.. Case report of 1 patient with long-standing chronic sinus disease and a new diagnosis of CF with a mild mutation (P205S) and a severe mutation (G551D). We discuss clinical changes in symptoms, radiographic findings, nasal potential difference testing, and nasal pH values before and after treatment with ivacaftor. We then developed primary sinonasal epithelial cell cultures from a biopsy of the patient to determine changes in airway surface liquid (ASL) pH and ASL viscosity after ivacaftor treatment.. Ivacaftor treatment reversed CT findings of CF sinus disease, increased nasal voltage and pH, and resolved sinus symptoms after 10 months of therapy. Ivacaftor significantly increased ASL pH and decreased ASL viscosity in primary airway cultures.. This report documents the reversal of CF sinus disease. Based on our in vivo and in vitro results, we speculate that ivacaftor may reverse CF sinusitis by increasing ASL pH and decreasing ASL viscosity. These studies suggest that CFTR modulation may be effective in treating CF and perhaps non-CF sinusitis.

Topics: Aminophenols; Anti-Inflammatory Agents; Cells, Cultured; Child; Chronic Disease; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Hydrogen-Ion Concentration; Ion Transport; Mutation; Quinolones; Respiratory Mucosa; Sinusitis; Treatment Outcome; Viscosity

Ivacaftor improves outcomes in cystic fibrosis (CF) patients with the G551D mutation; however, effects on respiratory microbiology are largely unknown. This study examines changes in CF respiratory pathogens with ivacaftor and correlates them with baseline characteristics and clinical response.. The G551D Observational Study enrolled a longitudinal observational cohort of US patients with CF aged 6 years and older with at least 1 copy of the G551D mutation. Results were linked with retrospective and prospective culture data in the US Cystic Fibrosis Foundation's National Patient Registry. Pseudomonas aeruginosa infection category in the year before and year after ivacaftor was compared and correlated with clinical findings.. Among 151 participants prescribed ivacaftor, 29% (26/89) who were culture positive for P. aeruginosa the year prior to ivacaftor use were culture negative the year following treatment; 88% (52/59) of those P. aeruginosa free remained uninfected. The odds of P. aeruginosa positivity in the year after ivacaftor compared with the year prior were reduced by 35% (odds ratio [OR], 0.65; P < .001). Ivacaftor was also associated with reduced odds of mucoid P. aeruginosa (OR, 0.77; P = .013) and Aspergillus (OR, 0.47; P = .039), but not Staphylococcus aureus or other common CF pathogens. Patients with intermittent culture positivity and higher forced expiratory volume in 1 second (FEV1) were most likely to turn culture negative. Reduction in P. aeruginosa was not associated with change in FEV1, body mass index, or hospitalizations.. Pseudomonas aeruginosa culture positivity was significantly reduced following ivacaftor treatment. Efficacious CFTR modulation may contribute to lower frequency of culture positivity for P. aeruginosa and other respiratory pathogens, particularly in patients with less established disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Substitution; Aminophenols; Aspergillus; Child; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Enzyme Activators; Female; Humans; Longitudinal Studies; Male; Middle Aged; Mutant Proteins; Mutation, Missense; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Staphylococcus aureus; Treatment Outcome; United States; Young Adult

Personalized drug therapy for cystic fibrosis (CF) is a long-term dream for CF patients, caregivers, physicians and researchers. After years of study, the fiction of personalized treatment has turned to hope. Basic information about CFTR mutations classes and new treatments is needed if we are to deal properly with the new CF era. The problems involved in this issue, however, should be evaluated with greater care and attention. VX-770 is a new drug available to treat CF patients with some class III CFTR mutations and other drugs are being studied regarding other classes. The scientific literature has constantly given information about each therapy, both in vitro and in vivo. The hope is increasing. Nevertheless the "scientific world" still lacks information about patients' reality and daily health related practical needs. Clinical trials have showed good evaluation of some drugs so far, but clinical response is a wide spectrum yet to be analyzed: CFTR mutations spectrum, costs related to the treatment with new drugs (for VX-770 therapy), variability of CF clinical expression, limitations to test in vitro drugs, absence of good clinical markers to evaluate drug response, absence of long-term studies and with patients below six years old, multidrug treatment used to improve the expression response, and finally, the most important problem, who will benefit from the new drugs therapy, are issues that constitute a barrier that should be overcome. Personalized drug therapy may not be a fiction anymore, but it is not yet a reality for all CF patients.

Topics: Aminophenols; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Precision Medicine; Quinolones

Ivacaftor is a novel oral pharmacologic agent that specifically targets the genetic defect of cystic fibrosis (CF) by augmenting chloride conductance through the CF transmembrane regulator (CFTR) protein. For individuals with CF and at least one copy of the G551D gating mutation, improvements in sweat chloride, nutritional parameters, lung function, respiratory symptoms, and exercise tolerance (i.e., 6-min walk distance) are attained within 2 weeks of initiating ivacaftor. However, there are no reports detailing the physiological and sensory implications of these improvements and their underlying mechanisms. We performed detailed cardiopulmonary exercise testing pre- and post-initiation of ivacaftor in a 27-year old male with CF (CFTR genotype F508del/G551D) and chronic airflow obstruction (FEV1/FVC=0.44). An improvement of FEV1 (by 16%) following ivacaftor was accompanied by clinically significant improvements in exercise capacity (by 14%) and exertional dyspnea (by up to 5 Borg scale units). These improvements were attributable, at least in part, to favorable alterations in the ventilatory response to exercise, including improvements in breathing patterns (e.g., increased tidal volume and reduced breathing frequency) and dynamic operating lung volumes (e.g., increased inspiratory reserve volume and inspiratory capacity) and decreases in dynamic mechanical ventilatory constraints.

Topics: Adult; Aminophenols; Cystic Fibrosis; Dyspnea; Exercise Tolerance; Humans; Male; Quinolones; Respiratory Function Tests; Respiratory Physiological Phenomena

Treatment efficacies of drugs depend on patient-specific pharmacokinetic and pharmacodynamic properties. Here, we developed an assay to measure functional levels of the CFTR potentiator VX-770 in human plasma and observed that VX-770 in plasma from different donors induced variable CFTR function in intestinal organoids. This assay can help to understand variability in treatment response to CFTR potentiators by functionally modeling individual pharmacokinetics.

Topics: Aminophenols; Antimutagenic Agents; Biological Assay; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Monitoring; Humans; Intestinal Mucosa; Intestines; Mutation; Organoids; Quinolones; Treatment Outcome

Topics: Aminophenols; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Molecular Targeted Therapy; Polymorphism, Single Nucleotide; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Financing, Organized; Foundations; Humans; Quinolones

Topics: Adult; Aminophenols; Antifungal Agents; Cystic Fibrosis; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Drug Antagonism; Enzyme Inhibitors; Humans; Itraconazole; Male; Mutation; Quinolones; Siblings

Treatment of liver disease, including hepatic steatosis, in patients with cystic fibrosis (CF) is limited. With the development of ivacaftor, which corrects the gating defect of the CF transmembrane regulator channel, there is a potential new therapy available for this subgroup of the CF patient population. We present an adolescent with CF who had significant improvement in hepatic steatosis with ivacaftor treatment while hypothesizing on a mechanism of why it occurred.

Topics: Adolescent; Aminophenols; Cystic Fibrosis; Fatty Liver; Female; Humans; Quinolones; Radiography

Ivacaftor is a novel CFTR potentiator that increases CFTR activity and improves clinical outcomes in cystic fibrosis (CF) patients with at least one copy of CFTR-G551D. Clinical trials have shown an improvement in lung function, weight and CF pulmonary exacerbation in adults with CFTR-G551D leading to the approval of ivacaftor as a novel CF therapy [1]. In vitro studies of ivacaftor have also shown significant improvements in CFTR chloride channel opening time in other non-G551D CFTR mutations suggesting that ivacaftor may be of benefit to patients with mutations other than gating mutations [2]. R117H-CFTR is a relatively common CFTR mutation that demonstrates an in-vitro response to ivacaftor [2,3]. A clinical trial has suggested that there may be a role for ivacaftor in older patients with R117H-CFTR although this trial did not include patients with very severe CF lung disease [4]. In 2014, ivacaftor was approved in the United States as a treatment for CF subjects aged greater than 6 years old with a copy of R117H-CFTR. We present a case demonstrating a substantial therapeutic effect of ivacaftor in a CF patient with genotype F508del/R117H and advanced lung disease.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Humans; Male; Middle Aged; Quinolones; Salvage Therapy

The underlying cause of cystic fibrosis (CF) is the loss of epithelial chloride and bicarbonate transport due to mutations in the CF transmembrane conductance regulator (CFTR) gene encoding the CFTR protein. Ivacaftor is a gene-specific CFTR potentiator that augments in vivo chloride transport in CFTR mutations affecting channel gating. Originally approved for the G511D CFTR mutation, ivacaftor is now approved for eight additional alleles exhibiting gating defects and has also been tested in R117H, a CFTR mutation with residual function that exhibits abnormal gating. P67L is a class 4 conductance (nongating) mutation exhibiting residual CFTR function. We report marked clinical improvement, normalization of spirometry, and dramatic reduction in radiographic structural airway changes after > 1 year of treatment with ivacaftor in a young adult with the compound heterozygous genotype P67L/F508del CFTR. The case suggests that ivacaftor may have a potential benefit for patients with CF with nongating mutations.

Topics: Adolescent; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Lung; Mutation; Quinolones; Radiography, Thoracic; Spirometry; Tomography, X-Ray Computed; Treatment Outcome

Topics: Aminophenols; Arkansas; Cystic Fibrosis; Health Services Accessibility; Humans; Medicaid; Patient Rights; Poverty; Quinolones; United States

Airway microbiota composition has been clearly correlated with many pulmonary diseases, and notably with cystic fibrosis (CF), an autosomal genetic disorder caused by mutation in the CF transmembrane conductance regulator (CFTR). Recently, a new molecule, ivacaftor, has been shown to re-establish the functionality of the G551D-mutated CFTR, allowing significant improvement in lung function.. The purpose of this study was to follow the evolution of the airway microbiota in CF patients treated with ivacaftor, using quantitative PCR and pyrosequencing of 16S rRNA amplicons, in order to identify quantitative and qualitative changes in bacterial communities. Three G551D children were followed up longitudinally over a mean period of more than one year covering several months before and after initiation of ivacaftor treatment.. 129 operational taxonomy units (OTUs), representing 64 genera, were identified. There was no significant difference in total bacterial load before and after treatment. Comparison of global community composition found no significant changes in microbiota. Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01) and that of Streptococcus 1 (S. mitis group) decreased (p<0.05), possibly in relation to the anti-Gram-positive properties of ivacaftor. The anaerobe Prevotella 2 correlated positively with the pulmonary function test FEV-1 (r=0.73, p<0.05). The study confirmed the presumed positive role of anaerobes in lung function.. Several airway microbiota components, notably anaerobes (obligate or facultative anaerobes), could be valuable biomarkers of lung function improvement under ivacaftor, and could shed light on the pathophysiology of lung disease in CF patients.

Topics: Adolescent; Amino Acid Substitution; Aminophenols; Anaerobiosis; Bacterial Typing Techniques; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Longitudinal Studies; Lung; Microbiota; Molecular Targeted Therapy; Mutation; Porphyromonas; Prevotella; Quinolones; Respiratory Function Tests; RNA, Ribosomal, 16S; Streptococcus; Treatment Outcome

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Peptide Fragments; Quinolones; Randomized Controlled Trials as Topic; Respiratory Function Tests

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Gene Deletion; Homozygote; Humans; Molecular Targeted Therapy; Quinolones

Chronic cystic fibrosis (CF) therapies have variable rates of prescribed use, and therapies are rarely prescribed to more than 80% of eligible patients. Ivacaftor was approved in the United States in January 2012 for patients ages 6 years and older with a G551D mutation in their CF gene.. To examine the rate of uptake and patterns of documented ivacaftor use among U.S. patients with CF during the first year after approval, to compare eligible patients with and without reported use, and to describe characteristics of early adopters of ivacaftor use.. A cross-sectional study of patients in the U.S. Cystic Fibrosis Foundation Patient Registry in 2012 with at least one encounter in which ivacaftor use was documented. Ivacaftor-eligible patients were defined as any individual 6 years of age or older with a G551D mutation. We performed bivariate and multivariate regression analyses, stratified by age group, to compare clinical and demographic characteristics of (1) eligible patients with and without documented ivacaftor use in 2012 and (2) early (February-June) versus late (July-December) adopters in 2012.. A total of 1,087 patients with CF with G551D mutations were in the U.S. Cystic Fibrosis Foundation Patient Registry in 2012. By June 2012, 64% of eligible patients had documented ivacaftor use, which increased to 81% by the end of 2012. Among eligible patients younger than 18 years of age, 85% were prescribed ivacaftor, with significantly lower odds among those with higher BMI percentile, fewer clinical encounters in 2011, and later age at diagnosis. Among eligible patients age 18 years or older, 79% were prescribed ivacaftor, with significantly lower odds in nonwhite patients and those with later age at diagnosis. Documented prescriptions of ivacaftor also varied by state of residence, with a range of 42-100% of eligible patients across states. The only association with early adoption of ivacaftor in 2012 was a decreased likelihood in adults with fewer than four encounters in 2011.. Uptake of ivacaftor use among eligible patients in the United States was rapid, with the majority of use initiated within 4 months of regulatory approval. Differences in ivacaftor prescriptions appear to be related to patient age, older age at diagnosis, and less frequent clinical encounters. Nutritional status also appears to play a role in children, and race seems to have an association in adults.

Topics: Adolescent; Adult; Aminophenols; Child; Cross-Sectional Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Logistic Models; Male; Multivariate Analysis; Mutation; Quinolones; Registries; United States; United States Food and Drug Administration; Young Adult

Previous studies of CF treatments have shown suboptimal adherence, though little has been reported regarding adherence patterns to ivacaftor. Electronic monitoring (EM) of adherence is considered a gold standard of measurement.. Adherence rates by EM were prospectively obtained and patterns over time were analyzed. EM-derived adherence rates were compared to pharmacy refill history and self-report.. 12 subjects (age 6-48 years; CFTR-G551D mutation) previously prescribed ivacaftor were monitored for a mean of 118 days. Overall adherence by EM was 61% (SD=28%) and decreased over time. Median duration between doses was 16.9 hours (IQR 13.9-24.1 hours) and increased over time. There was no correlation between EM-derived adherence and either refill history (84%, r=0.26, p=0.42) or self-report (100%, r=0.40, p=0.22).. Despite the promising nature of ivacaftor, our data suggest adherence rates are suboptimal and comparable to other prescribed CF therapies, and more commonly used assessments of adherence may be unreliable.

Topics: Adolescent; Adult; Aminophenols; Child; Clinical Pharmacy Information Systems; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Monitoring; Drug Prescriptions; Electronic Data Processing; Female; Humans; Male; Medication Adherence; Middle Aged; Prospective Studies; Quinolones; Young Adult

Topics: Adolescent; Aminophenols; Aminopyridines; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Quinolones; Randomized Controlled Trials as Topic

In clinical trials, patients with cystic fibrosis and a G551D mutation who received ivacaftor experienced improvements in pulmonary and nutritional outcomes. However, whether these improvements reflect a change in disease trajectory cannot be determined without longer-term analyses with an appropriate comparator population.. To examine, over a 3-year period, whether ivacaftor therapy affects pulmonary function and nutritional measures in patients with CF with a G551D mutation compared with patients with CF who are homozygous for the F508del mutation.. A propensity score was used to match patients with CF greater than or equal to 6 years of age who have a G551D mutation and received ivacaftor in clinical trials for up to 144 weeks with data from patients in the U.S. Cystic Fibrosis Foundation Patient Registry who are homozygous for the F508del mutation. Matching was based on variables including age, sex, weight for age, height for age, body mass index for age, % predicted FEV1, and chronic therapies (dornase alfa, inhaled antibiotics, inhaled and oral corticosteroids).. By calculating the annual estimated rate of decline in lung function for G551D patients receiving ivacaftor and comparing it with the rate of decline in lung function for matched F508del control patients, we show that the rate of lung function decline in G551D ivacaftor-treated patients was slower by nearly half. Moreover, treatment with ivacaftor is shown to improve body mass index and weight-for-age z scores for G551D patients over the 3-year analysis period.. These findings suggest that ivacaftor is a disease-modifying therapy for the treatment of cystic fibrosis.

Topics: Aminophenols; Body Mass Index; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Nutritional Status; Propensity Score; Quinolones; Registries; Respiratory Function Tests

Airways of patients with cystic fibrosis are deficient for nitric oxide. Low nitric oxide in cystic fibrosis has been shown to be associated with poor pulmonary function and risk of infection with certain pathogens. Treatment of cystic fibrosis patients with the cystic fibrosis transmembrane conductance regulator (CFTR)-targeting drug ivacaftor results in improved pulmonary function. The effect of ivacaftor on airway nitric oxide has not been assessed.. In this observational trial, fractional exhaled nitric oxide (FE(NO)) was measured before and 4 weeks after initiation of ivacaftor therapy, in patients with cystic fibrosis and a CFTR gating mutation. The effect of ivacaftor on FE(NO) was compared to treatment with inhaled dornase alfa or hypertonic saline for 4 weeks, respectively.. A total of 15 patients on ivacaftor therapy were studied. Pulmonary function improved significantly and mean (±SD) FE(NO) increased from 8.5±5.0 to 16.2±15.5 ppb. The effect was more pronounced in pediatric compared to adult patients. There was no linear correlation between changes in FE(NO), pulmonary function or sweat chloride concentration. Neither treatment with inhaled dornase alfa (n=15) or hypertonic saline (n=16) resulted in a change in FE(NO).. Therapy with ivacaftor results in an increase in nitric oxide formation in cystic fibrosis airways, while dornase alfa or hypertonic saline has no effect on airway nitric oxide. Some beneficial effects of CFTR targeting therapy in CF may result from improved airway nitric oxide production.

Topics: Adult; Aminophenols; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Exhalation; Female; Humans; Male; Mutation; Nitric Oxide; Quinolones; Young Adult

Topics: Adolescent; Adult; Aminophenols; Biomarkers; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Mutation; Quinolones; Treatment Outcome; Young Adult

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Biomarkers; Clostridioides difficile; Clostridium Infections; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Mutation; Quinolones; Spores, Bacterial; Treatment Outcome

Lower airway biomarkers of restored cystic fibrosis transmembrane conductance regulator (CFTR) function are limited. We hypothesized that fractional excretion of nitric oxide (FENO), typically low in CF patients, would demonstrate reproducibility during CFTR-independent therapies, and increase during CFTR-specific intervention (ivacaftor) in patients with CFTR gating mutations.. Repeated FENO and spirometry measurements in children with CF (Cohort 1; n=29) were performed during hospital admission for acute pulmonary exacerbations and routine outpatient care. FENO measurements before and after one month of ivacaftor treatment (150 mg every 12h) were completed in CF patients with CFTR gating mutations (Cohort 2; n=5).. Cohort 1: Mean forced expiratory volume in 1s (FEV1 % predicted) at enrollment was 72.3% (range 25%-102%). Mean FENO measurements varied minimally over the two inpatient and two outpatient measurements (9.8-10.9 ppb). There were no clear changes related to treatment of pulmonary exacerbations, gender, genotype or microbiology, and weak correlation with inhaled corticosteroid use (P<0.05). Between the two inpatient measurements, FEV1 % predicted increased by 7.3% (P<0.03) and FENO did not change. In Cohort 2, mean FENO increased from 6.6 ppb (SD=2.19) to 11.8 ppb (SD=4.97) during ivacaftor treatment. Mean sweat chloride dropped by 58 mM and mean FEV1 % predicted increased by 10.2%.. Repeated FENO measurements were stable in CF patients, whereas FENO increased in all patients with CFTR gating mutations treated with ivacaftor. Acute changes in FENO may serve as a biomarker of restored CFTR function in the CF lower airway during CFTR modulator treatment.

Topics: Adolescent; Aminophenols; Biomarkers; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Nitric Oxide; Quinolones; Young Adult

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Humans; Medication Adherence; Quinolones; Treatment Outcome

Cystic fibrosis (CF) conductance transmembrane regulator functions as a chloride (Cl-) channel in multiple organs, including the lungs. More than 1,800 disease-associated mutations have been identified, which can be divided into six classes. In patients with CF due to class III gating mutations, ivacaftor produces significant improvement in lung function, weight, reduction in sweat chloride level, and pulmonary exacerbations by enhancing the probability of chloride channel opening (gating). Although the benefit of ivacaftor in CF due to gating mutations is established, its potential role in patients with CF due to class IV conductance mutations is emerging. We report 6 months' prospective stability of lung function, improved BMI, reduced pulmonary exacerbations, and reduction in sweat chloride level in a patient with severe CF and the class IV R117H mutation. High-resolution CT scan also improved, thus highlighting the potential usefulness of ivacaftor in patients with severe CF due to class IV mutations.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Middle Aged; Mutation; Quinolones; Tomography, X-Ray Computed

There are nearly 2000 mutations in the CFTR gene associated with cystic fibrosis disease, and to date, the only approved drug, Kalydeco, has been effective in rescuing the functional expression of a small subset of these mutant proteins with defects in channel activation. However, there is currently an urgent need to assess other mutations for possible rescue by Kalydeco, and further, definition of the binding site of such modulators on CFTR would enhance our understanding of the mechanism of action of such therapeutics. Here, we describe a simple and rapid one-step PCR-based site-directed mutagenesis method to generate mutations in the CFTR gene. This method was used to generate CFTR mutants bearing deletions (p.Gln2_Trp846del, p.Ser700_Asp835del, p.Ile1234_Arg1239del) and truncation with polyhistidine tag insertion (p.Glu1172-3Gly-6-His*), which either recapitulate a disease phenotype or render tools for modulator binding site identification, with subsequent evaluation of drug responses using a high-throughput (384-well) membrane potential-sensitive fluorescence assay of CFTR channel activity within a 1 wk time frame. This proof-of-concept study shows that these methods enable rapid and quantitative comparison of multiple CFTR mutants to emerging drugs, facilitating future large-scale efforts to stratify mutants according to their "theratype" or most promising targeted therapy.

Topics: Aminophenols; Base Sequence; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Discovery; HEK293 Cells; High-Throughput Screening Assays; Humans; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Polymerase Chain Reaction; Quinolones; Sequence Alignment

Ivacaftor acts as a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) and increases the transepithelial chloride transport of CFTR in 9 of 10 known gating mutations causing cystic fibrosis. S549R is a rare gating mutation considered to be less sensitive to potentiators than all other gating mutations.. We report our first experience with ivacaftor in an 8-year-old boy with the rare S549R gating mutation. Besides subjective clinical improvements, the sweat chloride level and the lung clearance index decreased impressively within a few weeks of treatment while forced expiratory volume in the first second values remained in normal range.. We emphasize the value of measuring small airway function by lung clearance index as an outcome measure for new interventions targeting the correction of the CFTR defect at an age before traditional lung function parameters start to deteriorate.

Topics: Aminophenols; Breath Tests; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forced Expiratory Volume; Humans; Male; Mutation; Nitrogen; Quinolones; Treatment Outcome

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Biomedical Research; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Industry; Drug Therapy, Combination; Humans; Mutation; Quinolones

Topics: Adolescent; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Mutation; Precision Medicine; Quinolones

Topics: Acute Disease; Aminophenols; Aminopyridines; Benzodioxoles; Brain Ischemia; Cystic Fibrosis; Drug Combinations; Endovascular Procedures; Humans; Quinolones; Rectal Neoplasms; Stroke; Transanal Endoscopic Microsurgery

Current cystic fibrosis treatment is symptomatic and has greatly increased life expectancy over the last decades. However, mean age of death is still 29-years-old. Innovative therapeutic molecules aiming at restoring CFTR function are developed. Ivacaftor is the first medicine approved in 2012 for the 3% of patients worldwide carrying the rare CFTR mutation called G5510. Ivacafter is associated with a sustained improvement in respiratory function and a decreased frequency of pulmonary exacerbations. Other pharmacotherapies are being developed that aim at correcting other CFTR defects due to other CFTR mutations, especially the most frequent F508del mutation.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones; Therapies, Investigational

Topics: Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Male; Quinolones

Quinolinone-3-carboxamide 1, a novel CFTR potentiator, was discovered using high-throughput screening in NIH-3T3 cells expressing the F508del-CFTR mutation. Extensive medicinal chemistry and iterative structure-activity relationship (SAR) studies to evaluate potency, selectivity, and pharmacokinetic properties resulted in the identification of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.

Topics: Aminophenols; Animals; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dogs; Humans; Macaca fascicularis; Male; Mice; NIH 3T3 Cells; Quinolones; Rats, Sprague-Dawley; Structure-Activity Relationship

Ivacaftor (KALYDECO™, VX-770) is a CFTR potentiator that increased CFTR channel activity and improved lung function in patients age 6 years and older with CF who have the G551D-CFTR gating mutation. The aim of this in vitro study was to evaluate the effect of ivacaftor on mutant CFTR protein forms with defects in protein processing and/or channel function.. The effect of ivacaftor on CFTR function was tested in electrophysiological studies using a panel of Fischer rat thyroid (FRT) cells expressing 54 missense CFTR mutations that cause defects in the amount or function of CFTR at the cell surface.. Ivacaftor potentiated multiple mutant CFTR protein forms that produce functional CFTR at the cell surface. These included mutant CFTR forms with mild defects in CFTR processing or mild defects in CFTR channel conductance.. These in vitro data indicated that ivacaftor is a broad acting CFTR potentiator and could be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of ivacaftor.

Topics: Aminophenols; Animals; Cell Line; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; In Vitro Techniques; Ion Channel Gating; Mutation, Missense; Quinolones; Rats; Rats, Inbred F344; Thyroid Gland

New drugs are needed to enhance premature termination codon (PTC) suppression to treat the underlying cause of cystic fibrosis (CF) and other diseases caused by nonsense mutations. We tested new synthetic aminoglycoside derivatives expressly developed for PTC suppression in a series of complementary CF models. Using a dual-luciferase reporter system containing the four most prevalent CF transmembrane conductance regulator (CFTR) nonsense mutations (G542X, R553X, R1162X, and W1282X) within their local sequence contexts (the three codons on either side of the PTC), we found that NB124 promoted the most readthrough of G542X, R1162X, and W1282X PTCs. NB124 also restored full-length CFTR expression and chloride transport in Fischer rat thyroid cells stably transduced with a CFTR-G542XcDNA transgene, and was superior to gentamicin and other aminoglycosides tested. NB124 restored CFTR function to roughly 7% of wild-type activity in primary human bronchial epithelial (HBE) CF cells (G542X/delF508), a highly relevant preclinical model with endogenous CFTR expression. Efficacy was further enhanced by addition of the CFTR potentiator, ivacaftor (VX-770), to airway cells expressing CFTR PTCs. NB124 treatment rescued CFTR function in a CF mouse model expressing a human CFTR-G542X transgene; efficacy was superior to gentamicin and exhibited favorable pharmacokinetic properties, suggesting that in vitro results translated to clinical benefit in vivo. NB124 was also less cytotoxic than gentamicin in a tissue-based model for ototoxicity. These results provide evidence that NB124 and other synthetic aminoglycosides provide a 10-fold improvement in therapeutic index over gentamicin and other first-generation aminoglycosides, providing a promising treatment for a wide array of CFTR nonsense mutations.

Topics: Aminoglycosides; Aminophenols; Animals; Biological Transport; Cell Line; Chlorides; Codon, Nonsense; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Drug Synergism; Genes, Reporter; Humans; Luciferases; Mice; Mice, Inbred CFTR; Mice, Transgenic; Organ of Corti; Quinolones; Rats; Rats, Inbred F344; Time Factors; Transfection

Clinical trials have revealed that Ivacaftor significantly reduces sweat chloride in patients with cystic fibrosis who carry the G551D mutation. This finding has been incorporated into the commissioning guidelines in the UK with a sweat chloride reduction of 30% or below 60 mmol/L, specified as the main criteria for continued funding of Ivacaftor for individual patients. In a cohort of 24 adults who were prescribed Ivacaftor, there was no correlation between absolute or relative reductions in sweat chloride and improvements in lung function. This questions the validity of sweat chloride as a surrogate marker of clinical efficacy.

Topics: Aminophenols; Biomarkers; Body Height; Body Weight; Chlorides; Cohort Studies; Cystic Fibrosis; Forced Expiratory Flow Rates; Humans; Lung; Prospective Studies; Quinolones; Spirometry; Sweat

To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco) improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32-143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (-) ivacaftor, 3 only (+) ivacaftor and 3 (+/-) ivacaftor (1-5 tests per condition). The total number of gland measurements was 852 (-) ivacaftor and 906 (+) ivacaftor. A healthy control was tested 4 times (51 glands). For each gland we measured both CFTR-independent (M-sweat) and CFTR-dependent (C-sweat); C-sweat was stimulated with a β-adrenergic cocktail that elevated [cAMP]i while blocking muscarinic receptors. Absent ivacaftor, almost all CF glands produced M-sweat on all tests, but only 1/593 glands produced C-sweat (10 tests, 5 subjects). By contrast, 6/6 subjects (113/342 glands) produced C-sweat in the (+) ivacaftor condition, but with large inter-subject differences; 3-74% of glands responded with C/M sweat ratios 0.04%-2.57% of the average WT ratio of 0.265. Sweat volume losses cause proportionally larger underestimates of CFTR function at lower sweat rates. The losses were reduced by measuring C/M ratios in 12 glands from each subject that had the highest M-sweat rates. Remaining losses were estimated from single channel data and used to correct the C/M ratios, giving estimates of CFTR function (+) ivacaftor  = 1.6%-7.7% of the WT average. These estimates are in accord with single channel data and transcript analysis, and suggest that significant clinical benefit can be produced by low levels of CFTR function.

Topics: Amino Acid Substitution; Aminophenols; Case-Control Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Quinolones; Sweat; Sweat Glands

The development of ivacaftor represents a significant advance in therapeutics for patients with cystic fibrosis (CF) who carry the G551D mutation. Patients with an FEV1 < 40% predicted represent a considerable proportion of eligible patients but were excluded from phase 3 clinical trials, and the effectiveness of the drug in this population is, therefore, unknown.. Data were collected from adult CF centers in the United Kingdom and Ireland with patients enrolled in an ivacaftor compassionate use program (FEV1 < 40% or on lung transplant waiting list). Clinically recorded data were collated from patient records for 1 year prior and for a period of 90 to 270 days following ivacaftor commencement. Each patient was matched to two control subjects who would have met the requirements for the compassionate use program with the exception of genotype.. Twenty-one patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26.5% to 30.7% predicted (P = .01), representing a 16.7% relative improvement. Median weight improved from 49.8 to 51.6 kg (P = .006). Median inpatient IV antibiotic days declined from 23 to 0 d/y (P = .001) and median total IV treatment days decreased from 74 to 38 d/y (P = .002) following ivacaftor. Changes in pulmonary function and IV antibiotic requirements were significant compared with control subjects.. Ivacaftor was clinically effective in patients with CF who carry the G551D mutation and have severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.

Topics: Administration, Oral; Adult; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; DNA Mutational Analysis; Female; Follow-Up Studies; Forced Expiratory Volume; Genotype; Humans; Lung Diseases; Male; Mutation; Quinolones; Retrospective Studies; Severity of Illness Index; Young Adult

Topics: Aminophenols; Cystic Fibrosis; Drug Discovery; Drug Industry; Foundations; Humans; Quinolones; Research Support as Topic; United Kingdom; United States

Topics: Adult; Aminophenols; Cystic Fibrosis; Humans; Male; Quinolones; Respiratory System Agents; Tomography, X-Ray Computed

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Humans; Molecular Targeted Therapy; Mutation; Oxadiazoles; Quinolones

Cystic fibrosis (CF) is a life-shortening disease arising as a consequence of mutations within the CFTR gene. Novel therapeutics for CF are emerging that target CF transmembrane conductance regulator protein (CFTR) defects resulting from specific CFTR variants. Ivacaftor is a drug that potentiates CFTR gating function and is specifically indicated for CF patients with a particular CFTR variant, G551D-CFTR (rs75527207). Here, we provide therapeutic recommendations for ivacaftor based on preemptive CFTR genotype results.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Testing; Humans; Pharmacogenetics; Quinolones; Risk Assessment

The most common cystic fibrosis-associated mutation, the deletion of phenylalanine 508 (F508del), results in channels with poor membrane expression and impaired function. VX-770, a clinically approved drug for treatment of CF patients carrying the G551D mutation, and VX-809, a corrector shown in vitro to increase membrane expression of mutant channels, are currently undergoing clinical trials, but functional data at the molecular level is still lacking.. The effect of VX-770 and VX-809 on the multiple functional defects of F508del-CFTR was assessed via excised inside-out patch-clamp experiments.. VX-770 completely restores the low opening-rate of F508del-CFTR, with smaller open-time increase, in temperature-corrected and VX-809-treated channels. The shorter locked-open time of hydrolysis-deficient F508del-CFTR is also prolonged by VX-770. VX-809 does not improve channel function by itself as previously reported.. The results from these studies can be interpreted as an equilibrium shift toward the open-channel conformation of F508del-CFTR channels.

Topics: Adenosine Triphosphate; Aminophenols; Aminopyridines; Benzodioxoles; Carrier Proteins; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Patch-Clamp Techniques; Peptide Fragments; Quinolones

Topics: Aminophenols; Bronchiectasis; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Evidence-Based Medicine; Humans; Life Expectancy; Mutation; Oxidative Stress; Prevalence; Quinolones; Risk Assessment; Risk Factors; Smoking

Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel causes the genetic disease cystic fibrosis (CF). Towards the development of transformational drug therapies for CF, we investigated the channel function and action of CFTR potentiators on A561E, a CF mutation found frequently in Portugal. Like the most common CF mutation F508del, A561E causes a temperature-sensitive folding defect that prevents CFTR delivery to the cell membrane and is associated with severe disease.. Using baby hamster kidney cells expressing recombinant CFTR, we investigated CFTR expression by cell surface biotinylation, and function and pharmacology with the iodide efflux and patch-clamp techniques.. Low temperature incubation delivered a small proportion of A561E-CFTR protein to the cell surface. Like F508del-CFTR, low temperature-rescued A561E-CFTR exhibited a severe gating defect characterized by brief channel openings separated by prolonged channel closures. A561E-CFTR also exhibited thermoinstability, losing function more quickly than F508del-CFTR in cell-free membrane patches and intact cells. Using the iodide efflux assay, CFTR potentiators, including genistein and the clinically approved small-molecule ivacaftor, partially restored function to A561E-CFTR. Interestingly, ivacaftor restored wild-type levels of channel activity (as measured by open probability) to single A561E- and F508del-CFTR Cl(-) channels. However, it accentuated the thermoinstability of both mutants in cell-free membrane patches.. Like F508del-CFTR, A561E-CFTR perturbs protein processing, thermostability and channel gating. CFTR potentiators partially restore channel function to low temperature-rescued A561E-CFTR. Transformational drug therapy for A561E-CFTR is likely to require CFTR correctors, CFTR potentiators and special attention to thermostability.

Topics: Aminophenols; Animals; Biotinylation; Cell Line; Cricetinae; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genistein; Iodides; Ion Channel Gating; Mutation; Quinolones; Temperature

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.. To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.. We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.. Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.

Topics: Adolescent; Adult; Aminophenols; Biomarkers; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Follow-Up Studies; Forced Expiratory Volume; Genetic Markers; Hospitalization; Humans; Hydrogen-Ion Concentration; Intestine, Small; Lung; Male; Microbiota; Mucociliary Clearance; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Respiratory System Agents; Sputum; Sweat; Treatment Outcome; Young Adult

Studies have endeavored to reconcile whether dysfunction of neutrophils in people with cystic fibrosis (CF) is a result of the genetic defect or is secondary due to infection and inflammation. In this study, we illustrate that disrupted function of the CF transmembrane conductance regulator (CFTR), such as that which occurs in patients with ∆F508 and/or G551D mutations, correlates with impaired degranulation of antimicrobial proteins. We demonstrate that CF blood neutrophils release less secondary and tertiary granule components compared with control cells and that activation of the low-molecular-mass GTP-binding protein Rab27a, involved in the regulation of granule trafficking, is defective. The mechanism leading to impaired degranulation involves altered ion homeostasis caused by defective CFTR function with increased cytosolic levels of chloride and sodium, yet decreased magnesium measured in CF neutrophils. Decreased magnesium concentration in vivo and in vitro resulted in significantly decreased levels of GTP-bound Rab27a. Treatment of G551D patients with the ion channel potentiator ivacaftor resulted in normalized neutrophil cytosolic ion levels and activation of Rab27a, thereby leading to increased degranulation and bacterial killing. Our results confirm that intrinsic alterations of circulating neutrophils from patients with CF are corrected by ivacaftor, thus illustrating additional clinical benefits for CFTR modulator therapy.

Topics: Adult; Aminophenols; Cell Degranulation; Cells, Cultured; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Electrophoresis, Gel, Two-Dimensional; Female; Homeostasis; Humans; Immunoblotting; Magnesium; Male; Mutation; Neutrophils; Protein Transport; Proteome; Proteomics; Quinolones; rab GTP-Binding Proteins; rab27 GTP-Binding Proteins; Sodium; Tumor Necrosis Factor-alpha; Young Adult

Topics: Aminophenols; Aminopyridines; Base Sequence; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Quinolones; Sequence Deletion

Topics: Aminophenols; Cystic Fibrosis; Female; Humans; Intestine, Small; Lung; Male; Quinolones; Respiratory System Agents

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones

Topics: Adolescent; Age Factors; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Forced Expiratory Volume; Genetic Predisposition to Disease; Humans; Lung; Male; Mutation; Phenotype; Predictive Value of Tests; Quinolones; Recovery of Function; Respiratory System Agents; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Vital Capacity

Insights into the positive and negative effects of drugs to treat cystic fibrosis (CF) patients with a common mutation raise questions about how we discover and translate CF therapeutics (Veit et al. and Cholon et al., this issue).

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Mutation; Quinolones

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). Newly developed "correctors" such as lumacaftor (VX-809) that improve CFTR maturation and trafficking and "potentiators" such as ivacaftor (VX-770) that enhance channel activity may provide important advances in CF therapy. Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation (G551D) that affects only channel activity, a single compound is not sufficient to treat patients with the more common CFTR mutation, ΔF508. Thus, patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit. However, whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro, the impact of chronic therapy has not been established. In studies of human primary airway epithelial cells, we found that both acute and chronic treatment with VX-770 improved CFTR function in cells with the G551D mutation, consistent with clinical studies. In contrast, chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated CFTR correction in ΔF508 homozygous cultures. This result reflected the destabilization of corrected ΔF508 CFTR by VX-770, markedly increasing its turnover rate. Chronic VX-770 treatment also reduced mature wild-type CFTR levels and function. These findings demonstrate that chronic treatment with CFTR potentiators and correctors may have unexpected effects that cannot be predicted from short-term studies. Combining these drugs to maximize rescue of ΔF508 CFTR may require changes in dosing and/or development of new potentiator compounds that do not interfere with CFTR stability.

Topics: Aminophenols; Bronchi; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Epithelial Cells; Humans; Models, Molecular; Mutant Proteins; Protein Stability; Quinolones

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF.

Topics: Aminophenols; Bronchi; Cell Membrane; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Down-Regulation; Endocytosis; Epithelial Cells; Humans; Ion Channel Gating; Mutation; Quinolones; Suppression, Genetic; Time Factors

Topics: Acetates; Adult; Aminophenols; Androstadienes; Anti-Allergic Agents; Cyclopropanes; Cystic Fibrosis; Female; Fluticasone; Humans; Leukotriene Antagonists; Paranasal Sinus Diseases; Quinolines; Quinolones; Rhinitis, Allergic, Perennial; Sulfides; Treatment Outcome; Young Adult

The G551D cystic fibrosis transmembrane conductance regulator (CFTR) mutation is associated with severe disease in ∼5% of cystic fibrosis patients worldwide. This amino acid substitution in NBD1 results in a CFTR chloride channel characterized by a severe gating defect that can be at least partially overcome in vitro by exposure to a CFTR potentiator. In contrast, the more common ΔF508 mutation is associated with a severe protein trafficking defect, as well as impaired channel function. Recent clinical trials demonstrated a beneficial effect of the CFTR potentiator, Ivacaftor (VX-770), on lung function of patients bearing at least one copy of G551D CFTR, but no comparable effect on ΔF508 homozygotes. This difference in efficacy was not surprising in view of the established difference in the molecular phenotypes of the two mutant channels. Recently, however, it was shown that the structural defect introduced by the deletion of F508 is associated with the thermal instability of ΔF508 CFTR channel function in vitro. This additional mutant phenotype raised the possibility that the differences in the behavior of ΔF508 and G551D CFTR, as well as the disparate efficacy of Ivacaftor, might be a reflection of the differing thermal stabilities of the two channels at 37 °C. We compared the thermal stability of G551D and ΔF508 CFTR in Xenopus oocytes in the presence and absence of CTFR potentiators. G551D CFTR exhibited a thermal instability that was comparable to that of ΔF508 CFTR. G551D CFTR, however, was protected from thermal instability by CFTR potentiators, whereas ΔF508 CFTR was not. These results suggest that the efficacy of VX-770 in patients bearing the G551D mutation is due, at least in part, to the ability of the small molecule to protect the mutant channel from thermal instability at human body temperature.

Topics: Amino Acid Substitution; Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Mutagenesis, Site-Directed; Mutant Proteins; Oocytes; Protein Stability; Quinolones; Recombinant Proteins; Temperature; Xenopus laevis

Topics: Adult; Aminophenols; Cystic Fibrosis; Diabetes Mellitus; Humans; Hypoglycemic Agents; Male; Quinolones

Topics: Aminophenols; Bronchiectasis; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Monitoring; Female; Humans; Membrane Transport Modulators; Quinolones; Spirometry; Tomography, X-Ray Computed; Treatment Outcome

The purpose of this report was to evaluate the influence of 12 weeks of ivacaftor treatment on the aerobic function of 2 teenage patients with cystic fibrosis (CF; ΔF508/G551D) using a maximal cardiopulmonary exercise test.. One patient, with relatively mild disease, demonstrated no clinically meaningful changes in maximal oxygen uptake ((Equation is included in full-text article.)O2max). However, in the second case, with more established lung disease on imaging, (Equation is included in full-text article.)O2max improved by approximately 30%, an improvement out of proportion with early lung function changes. This improvement resulted from increased muscle oxygen delivery and extraction.. Cardiopulmonary exercise testing can monitor the extent and cause(s) of change following interventions such as ivacaftor, with the potential to identify functional changes independent from spirometry indices.. Cardiopulmonary exercise testing represents an important and comprehensive clinical assessment tool, and its use as an outcome measure in the functional assessment of patients with CF is encouraged.

Topics: Adolescent; Aminophenols; Body Weights and Measures; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Exercise Test; Female; Humans; Male; Quinolones; Respiratory Function Tests

Topics: Acetylcysteine; Administration, Oral; Aminophenols; Cell Membrane; Cystic Fibrosis; Deoxyribonuclease I; DNA; Female; History, 20th Century; Humans; Lung; Mutation; Pediatrics; Quality of Life; Quinolones; Recombinant Proteins

Topics: Aminophenols; Cystic Fibrosis; Drug Approval; Drug Design; Humans; Quinolones; United States

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Quinolones

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Clinical Trials, Phase III as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Forced Expiratory Volume; Humans; Mutation; Quinolones

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Mutation; Oxadiazoles; Quinolones

Stratified approaches to treating disease are very attractive, as efficacy is maximised by identifying responders using a companion diagnostic or by careful phenotyping. This approach will spare non-responders form potential side-effects. This has been pioneered in oncology where single genes or gene signatures indicate tumours that will respond to specific chemotherapies. Stratified approaches to the treatment of asthma with biological therapies are currently being extensively studied. In cystic fibrosis (CF), therapies have been developed that are targeted at specific functional classes of mutations. Ivacaftor, the first of such therapies, potentiates dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein Class III mutations and is now available in the USA and some European countries. Pivotal studies in patients with a G551D mutation, the most common Class III mutation, have demonstrated significant improvements in clinically important outcomes such as spirometry and exacerbations. Sweat chloride was significantly reduced demonstrating a functional effect on the dysfunctional CFTR protein produced by the G551D mutation. Symptom scores are also greatly improved to a level that indicates that this is a transformational treatment for many patients. This stratified approach to the development of therapies based on the functional class of the mutations in CF is likely to lead to new drugs or combinations that will correct the basic defect in many patients with CF.

Topics: Aminophenols; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Predisposition to Disease; Humans; Lung; Molecular Targeted Therapy; Mutation; Patient Selection; Phenotype; Precision Medicine; Pulmonary Medicine; Quinolones; Respiratory System Agents; Sweat; Treatment Outcome

Cystic fibrosis (CF) is a life-shortening disorder that affects over 30,000 people in the U.S. and 70,000 worldwide. CF is caused by mutations in the CFTR gene, which codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is a chloride and bicarbonate channel and regulates several ion transporters at the epithelial cell membrane, controlling hydration or ionic composition of epithelial secretions. Management of CF is currently supportive, but recent advances in drug development have focused on therapies that assist mutant CFTR function. In the current review, we summarize the development and clinical experience with VX-770 (ivacaftor), a small molecule that increases CFTR chloride conductance in vitro and in vivo, including wild-type and G551D CFTR. The G551D CFTR mutation is the third most common CF disease-causing mutation, in which the CFTR protein localizes to the epithelial cell membrane but has defective gating. With restoration of adequate CFTR function through pharmacotherapy, it is possible that the clinical course of patients with CF could be markedly improved, including longevity, quality of life and treatment burden.

Topics: Aminophenols; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Mutation; Quality of Life; Quinolones

Ivacaftor, a cystic fibrosis transmembrane regulator (CFTR) potentiator, decreased sweat chloride concentrations and improved clinical measures in cystic fibrosis (CF) patients with the G551D mutation.. Sweat chloride measurements at day 15 had an overall positive predictive value (PPV) of 86.3%, a negative predictive value (NPV) of 65.5%, sensitivity of 73.9%, and specificity of 80.9% for an FEV1 improvement of ≥5% from baseline at week 16. For ivacaftor patients the median FEV1 improvement was 16.7%; for placebo patients 0.4%. For patients aged 6-11 years who received ivacaftor and who had a sweat chloride decrease of ≥40 mmol/L from baseline at day 15, a median weight gain of 11.2% at week 16, compared to 6% for those with a smaller decrease was observed.. Changes in sweat chloride concentration at day 15 following treatment with ivacaftor may have sufficient predictive potential to identify individuals that show improvement in pulmonary function and weight gain after 16 weeks of treatment.

Topics: Administration, Oral; Adolescent; Aminophenols; Child; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Humans; Male; Mutation; Quinolones; Sensitivity and Specificity; Sweat; Weight Gain

Recently, ivacaftor, a CFTR-potentiator, has been shown to be effective and safe in patients with cystic fibrosis carrying a G551D mutation and moderately impaired lung function. The objective of this retrospective study was to assess efficacy and safety of ivacaftor in severely ill patients with at least one G551D mutation.. Data from 14 patients with a FEV1 <40% predicted who received ivacaftor on a "named patient program" base in Germany were analyzed.. One patient took ivacaftor at a lower than recommended dose due to abundant mucus and a feeling to "suffocate." No additional severe adverse events were reported. One further patient stopped ivacaftor due to lung transplantation, one due to perceived poor effectiveness, one due to pregnancy, and one stopped standard therapy. The remaining patients took ivacaftor regularly and did not change other therapies. FEV1 increased by more than 5 %predicted in 5 of the 14 patients from baseline (average FEV1 during the year prior to ivacaftor). On average, FEV1 increased significantly by 5.2±5.6%predicted (p<0.01). The relative improvement in FEV1 was 19.7±22.1%.. Ivacaftor was effective in many patients with poor lung function. The response was, however, variable. Although the drug appeared safe for most of these patients, increased bronchial secretions may warrant intensified physiotherapy and intravenous antibiotic treatment when ivacaftor is initiated.

Topics: Adult; Aminophenols; Anti-Bacterial Agents; Bronchi; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Male; Pregnancy; Pregnancy Complications; Quinolones; Retrospective Studies; Treatment Outcome; Young Adult

The improvement over the last two decades in the treatment of cystic fibrosis led to an increase in life expectancy approaching 40 years at birth. Logically, the population of adult patients has been increasing and is currently 50% of patients followed in France. These therapeutic advances have justified the establishment in 2003 of a generalized neonatal screening for cystic fibrosis. The latest data of this screening show an incidence of CF of 1/5359 live births, far below the incidence of 1/2500 which was widely accepted twenty years ago. The performance of this screening is currently based on the dosage of trypsin immuno reactive, followed in case of exceeding the threshold of a search of the 30 most common mutations, can detect around 96% of 150 to 200 CF cases every year. Therefore, the possibility of a false negative of the screening cannot be excluded and evocative symptoms of cystic fibrosis, even for children born after 2003, will lead to prescribe a sweat test. While treatments available so far goal consequences of cystic fibrosis, a new therapeutic class to correct the functional defect of the mutated protein, called CFTR modulators, is emerging. Ivacaftor, leader of this new class, belonging to the category of "CFTR potentiator" got its access on the market in September 2012 for patients carrying the G551D mutation. New other molecules, named "CFTR correctors" which can have synergistic effect with ivacaftor and concern patients carrying the most common mutation--DF 508--are under development.

Topics: Adult; Aminophenols; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; France; Humans; Infant, Newborn; Molecular Targeted Therapy; Neonatal Screening; Quinolones

Topics: Adolescent; Aminophenols; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Homozygote; Humans; Mutation; Quinolones; Sweat

The cystic fibrosis (CF) protein forms an anion channel in epithelial cells, and the absence or defective function of this channel results in the clinical manifestations of CF. CF is an autosomal recessive disorder, and its many disease-causing mutations divide into five or six classes. There are 10 known class 3 gating mutations, the most common of which is G551D. Ivacaftor is a drug that in vitro increases open time and transepithelial chloride transport in all 10 gating mutations, but it is approved for use only in patients with the G551D mutation. We report complete normalization of sweat chloride concentration and rapid clinical improvement over 6 weeks of treatment with ivacaftor in a patient with CF with the gating mutation S549N. The findings suggest that ivacaftor should be considered for use in patients with any of the known gating mutations.

Topics: Aminophenols; Child; Chlorides; Cystic Fibrosis; Female; Humans; Mutation; Quinolones; Sweat

Topics: Aminophenols; Cost Sharing; Cystic Fibrosis; Drug Costs; Drug Discovery; Drug Industry; Health Expenditures; Humans; Orphan Drug Production; Quinolones; Social Justice; United States

Topics: Aminophenols; Cystic Fibrosis; Fund Raising; Humans; Molecular Targeted Therapy; Patient Participation; Private Sector; Quinolones; Research Support as Topic; Translational Research, Biomedical

Cystic fibrosis is a serious genetic disease due to mutations in the gene encoding CFTR (Cystic FibrosisTransmembrane conductance Regulator), a protein involved in cellular transmembrane transport, particularly of chloride ions. Ivacaftor is described as a selective potentiator of CFTR protein. It is now licensed for the treatment of cystic fibrosis patients 6 years of age and older who carry the CFTR G551D mutation, which is the case for about 4% to 5% of cystic fibrosis patients. Two randomised placebo-controlled trials of ivacaftor have been carried out in this setting, in a total of 213 patients. The frequency of pulmonary exacerbations fell in one of the two trials during the first 48 weeks of treatment, but there was no impact on the number of hospitalisations or the use of intravenous antibiotics. In both trials, addition of ivacaftor improved FEV1 by an average of about 10% at week 24 and increased body weight by an average of about 2.5 kg after 1 year. Upper respiratory tract infections occurred in the ivacaftor groups during these trials, with more cases of bacterial contamination and, possibly, more pulmonary exacerbations in the longer term. Ivacaftorcarries a risk of numerous pharmacokinetic interactions that can require dose adjustment, particularly for patients with hepatic impairment and those receiving cytochrome P450 isozyme 3A inhibitors or inducers. Given the absence of data, ivacaftor should be avoided during pregnancy. In practice, in 2013, it is not possible to determine the harm-benefit balance of ivacaftor due to the high risk of drug interactions, as well as a possible increased risk of infections and liver toxicity.

Topics: Aminophenols; Body Weight; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Interactions; Forced Expiratory Volume; Humans; Quinolones; Randomized Controlled Trials as Topic; Uncertainty

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Quinolones

Topics: Aminophenols; Child; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Hand; Humans; Male; Quinolones; Skin Aging; Sweat; Water

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Costs; Humans; Mutation; Precision Medicine; Quinolones; Rare Diseases; Respiratory System Agents; United Kingdom

Topics: Aminophenols; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Humans; Infant; Infant, Newborn; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Quinolones; Respiratory System Agents

Cystic fibrosis (CF) is a life-shortening inherited disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR), which encodes for the CF transmembrane conductance regulator (CFTR) ion channel that regulates chloride and water transport across the surface of epithelial cells. Ivacaftor, a drug recently approved by the US Food and Drug Administration, represents the first mutation-specific therapy for CF. It is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV(1) and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV(1) and sweat chloride would facilitate development of new drugs that target the defective CFTR. Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV(1) (10%-12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV(1), nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV(1) was apparent. The lack of correlation of sweat chloride with improvement in FEV(1) speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points.

Topics: Aminophenols; Chlorides; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Forced Expiratory Volume; Humans; Outcome Assessment, Health Care; Quinolones; Sweat; Treatment Outcome

We report on an adult with cystic fibrosis (ΔF508/G551D) with severe lung disease (forced expiratory volume (FEV1) in one second 24% predicted) who was admitted for a pulmonary exacerbation. He was managed with maximal medical therapy, but did not have significant improvement until after he was started on ivacaftor on hospital day 15. He subsequently had significant improvement in lung function with normalization of hypercarbia, oxygen saturation on room air, and increase in FEV1 to 36% predicted. Prior to use of ivacaftor he was being assessed for a lung transplant. However, after ivacaftor therapy for 6 months, he is no longer considering this treatment modality due to his improvement of lung function and functional status.

Topics: Adult; Aminophenols; Cystic Fibrosis; Forced Expiratory Volume; Humans; Lung Diseases; Male; Quinolones; Severity of Illness Index

Topics: Aminophenols; Cystic Fibrosis; Forced Expiratory Volume; Humans; Mutation; Quinolones

Topics: Aminophenols; Clinical Trials, Phase III as Topic; Cystic Fibrosis; Humans; Molecular Targeted Therapy; Mutation; Oxadiazoles; Precision Medicine; Quinolones

The investigational CFTR potentiator ivacaftor (VX-770) increased CFTR channel activity and improved lung function in subjects with CF who have the G551D CFTR gating mutation. The aim of this in vitro study was to determine whether ivacaftor potentiates mutant CFTR with gating defects caused by other CFTR gating mutations.. The effects of ivacaftor on CFTR channel open probability and chloride transport were tested in electrophysiological studies using Fischer rat thyroid (FRT) cells expressing different CFTR gating mutations.. Ivacaftor potentiated multiple mutant CFTR forms with defects in CFTR channel gating. These included the G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D CFTR gating mutations.. These in vitro data suggest that ivacaftor has a similar effect on all CFTR forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have CFTR gating mutations beyond G551D.

Topics: Aminophenols; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; DNA; DNA Mutational Analysis; Ion Channel Gating; Ion Transport; Mutation; Prognosis; Quinolones; Rats; Rats, Inbred F344; Thyroid Gland

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Costs; Humans; Molecular Targeted Therapy; Mutation; Precision Medicine; Quinolones; Small Molecule Libraries; United States; United States Food and Drug Administration

Topics: Aminophenols; Cystic Fibrosis; Drug Approval; Fund Raising; Humans; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Industry; Humans; Mutation; Quinolones; Respiratory System Agents

Topics: Aged; Aged, 80 and over; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Middle Aged; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Humans; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Humans; Mutation; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Humans; Mutation; Quinolones; United States; United States Food and Drug Administration

Topics: Aminophenols; Cystic Fibrosis; Humans; Polymorphism, Genetic; Precision Medicine; Quinolones; United States

Topics: Adolescent; Adult; Aminophenols; Animals; Anti-Bacterial Agents; Child; Child, Preschool; Congresses as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Drugs, Investigational; Female; Genetic Therapy; Humans; Infant; Infant, Newborn; Male; Mice; Mice, Transgenic; Molecular Targeted Therapy; Mutation; Neonatal Screening; Oxadiazoles; Practice Guidelines as Topic; Prognosis; Quinolones; Respiratory Function Tests; Treatment Outcome; Young Adult

Topics: Aminophenols; Child, Preschool; Cystic Fibrosis; Female; Hispanic or Latino; Humans; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Discovery; Humans; Models, Molecular; Mutant Proteins; Mutation; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Discovery; Humans; Mutant Proteins; Orphan Drug Production; Quinolones

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that cause loss of function of the CFTR channel on the apical surface of epithelial cells. The major CF-causing mutation, F508del-CFTR, is misfolded, retained in the endoplasmic reticulum, and degraded. Small molecule corrector compounds have been identified using high throughput screens, which partially rescue the trafficking defect of F508del-CFTR, allowing a fraction of the mutant protein to escape endoplasmic reticulum retention and traffic to the plasma membrane, where it exhibits partial function as a cAMP-regulated chloride channel. A subset of such corrector compounds binds directly to the mutant protein, prompting the hypothesis that they rescue the biosynthetic defect by inducing improved protein conformation. We tested this hypothesis directly by evaluating the consequences of a corrector compound on the conformation of each nucleotide binding domain (NBD) in the context of the full-length mutant protein in limited proteolytic digest studies. Interestingly, we found that VRT-325 was capable of partially restoring compactness in NBD1. However, VRT-325 had no detectable effect on the conformation of the second half of the molecule. In comparison, ablation of the di-arginine sequence, R(553)XR(555) (F508del-KXK-CFTR), modified protease susceptibility of NBD1, NBD2, and the full-length protein. Singly, each intervention led to a partial correction of the processing defect. Together, these interventions restored processing of F508del-CFTR to near wild type. Importantly, however, a defect in NBD1 conformation persisted, as did a defect in channel activation after the combined interventions. Importantly, this defect in channel activation can be fully corrected by the addition of the potentiator, VX-770.

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Endoplasmic Reticulum; HEK293 Cells; Humans; Mutation; Piperazines; Protein Binding; Protein Folding; Protein Structure, Tertiary; Quinazolines; Quinolones

Topics: Aminophenols; Anti-Bacterial Agents; Anti-Inflammatory Agents; Clinical Trials, Phase III as Topic; Cloning, Molecular; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Industry; Humans; Pharmacogenetics; Quinolones

Topics: Aminophenols; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Approval; Drug Discovery; Humans; Mutation; Quinolones

Modulator compounds intended to overcome disease-causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) show significant promise in clinical testing for cystic fibrosis. However, the mechanism(s) of action underlying these compounds are not fully understood. Activation of CFTR ion transport requires PKA-regulated phosphorylation of the regulatory domain (R-D) and dimerization of the nucleotide binding domains. Using a newly developed assay, we evaluated nine compounds including both CFTR potentatiators and activators discovered via various high-throughput screening strategies to acutely augment CFTR activity. We found considerable differences in the effects on R-D phosphorylation. Some (including UC(CF)-152) stimulated robust phosphorylation, and others had little effect (e.g., VRT-532 and VX-770). We then compared CFTR activation by UC(CF)-152 and VRT-532 in Ussing chamber studies using two epithelial models, CFBE41o(-) and Fischer rat thyroid cells, expressing various CFTR forms. UC(CF)-152 activated wild-type-, G551D-, and rescued F508del-CFTR currents but did not potentiate cAMP-mediated CFTR activation. In contrast, VRT-532 moderately activated CFTR short-circuit current and strongly potentiated forskolin-mediated current. Combined with the result that UC(CF)-152, but not VRT-532 or VX-770, acts by increasing CFTR R-D phosphorylation, these findings indicate that potentiation of endogenous cAMP-mediated activation of mutant CFTR is not due to a pathway involving augmented R-D phosphorylation. This study presents an assay useful to distinguish preclinical compounds by a crucial mechanism underlying CFTR activation, delineates two types of compound able to acutely augment CFTR activity (e.g., activators and potentiators), and demonstrates that a number of different mechanisms can be successfully employed to activate mutant CFTR.

Topics: Aminophenols; Animals; Blotting, Western; Cell Line; Chlorocebus aethiops; Colforsin; Cresols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diffusion Chambers, Culture; Dimerization; Enzyme-Linked Immunosorbent Assay; Gene Expression; High-Throughput Screening Assays; Humans; Ion Channel Gating; Ion Transport; Lentivirus; Membrane Transport Modulators; Mice; Mutation; Phosphorylation; Protein Structure, Tertiary; Pyrazoles; Quinolones; Retroviridae; Transduction, Genetic

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Infant, Newborn; Mutation; Neonatal Screening; Quinolones

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or conductance mutations) or both. There are currently no approved therapies that target CFTR. Here we describe the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (P(o)) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl(-) secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by approximately 10-fold, to approximately 50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na(+) and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures. These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway.

Topics: Absorption; Amino Acid Substitution; Aminophenols; Animals; Bronchi; Cells, Cultured; Chlorides; Cilia; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Synergism; Epithelial Cells; Epithelial Sodium Channels; Humans; Ion Channel Gating; Mice; Mutation; NIH 3T3 Cells; Quinolines; Quinolones; Sodium