vx-770 and Respiratory-Tract-Infections

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

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

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

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

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