fevipiprant and Asthma

Accumulating evidence has shown that prostaglandin D2 (PGD2)-chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) pathway plays an important role in promoting eosinophilic airway inflammation in asthma. We aimed to assess the efficacy and safety of CRTH2 antagonist fevipiprant in patients with persistent asthma compared with placebo.. We identified eligible studies by searching PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. The study was registered as CRD 42020221714 ( http://www.crd.york.ac.uk/PROSPERO ). Ten randomized controlled trials with 7902 patients met our inclusion criteria. A statistically significant benefit of fevipiprant compared with placebo was shown in improving forced expiratory volume in 1 s (MD 0.05 L, 95% CI: 0.02 to 0.07; p < 0.0001), Asthma Control Questionnaire score (MD -0.10, 95% CI: -0.16 to -0.04; p = 0.001), and Asthma Quality of Life Questionnaire score (MD 0.08, 95% CI: 0.03 to 0.13; p = 0.003). Fevipiprant decreased number of patients with at least one asthma exacerbation requiring administration of systemic corticosteroids for 3 days or more (RR 0.86, 95% CI: 0.77 to 0.97; p = 0.01). Some benefits were a little more pronounced in the high eosinophil population (with an elevated blood eosinophil count or sputum eosinophil percentage) and in the 450 mg dose group. Fevipiprant was well tolerated with no safety issues compared with placebo. Fevipiprant could safely improve asthma outcomes compared to placebo. However, most of the differences didn't reach the minimal clinically important difference (MCID), thus the clinical benefits remained to be confirmed.

Topics: Anti-Asthmatic Agents; Asthma; Humans; Indoleacetic Acids; Pyridines; Quality of Life; Randomized Controlled Trials as Topic; Receptors, Immunologic; Receptors, Prostaglandin

Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.

Topics: Adult; Anti-Asthmatic Agents; Antibodies, Monoclonal, Humanized; Asthma; Biological Products; Biomarkers; Clinical Trials, Phase III as Topic; Cytokines; Eosinophils; Forecasting; Humans; Indoleacetic Acids; Interleukin-4; Interleukin-5; Omalizumab; Pyridines; Th2 Cells; Treatment Outcome

Asthma is common and in many, particularly those with more severe disease, there remains a substantial unmet need. Success with biologics targeting eosinophilic inflammation underscore the value of treating inflammation in asthma beyond corticosteroids. Fevipiprant (QAW039) is an oral treatment for asthma. It competitively and reversibly antagonises the prostaglandin D2 receptor 2 (DP2) expressed on inflammatory and structural cells. Areas covered: We reviewed fevipiprant's mode of action and efficacy against other current and emerging pharmacological interventions for moderate-to-severe asthma. We undertook a literature review using the PubMed/Medline database, the U.S. National Library of Medicine's Clinical Trials website and from manufacturers' press releases with the search terms: 'QAW039', 'Fevipiprant', 'CRTH2 antagonists', 'DP2', 'DP1', 'monoclonal antibody', 'eosinophil' with 'asthma' plus the names of individual drugs. Three Phase 2 trials have been conducted and three Phase 3 trials (NCT02563067, NCT03052517, NCT02555683) are in progress. To date Fevipiprant's greatest success has been in targeting severe eosinophilic asthma. Expert opinion: Fevipiprant presents the possibility of a new orally active therapy for asthma. If successful in phase 3 trials it will have an enormous impact on the treatment paradigm for asthma and will potentially widen access for pre-biologic treatment to a larger population.

Topics: Administration, Oral; Anti-Asthmatic Agents; Asthma; Eosinophils; Humans; Indoleacetic Acids; Inflammation; Pyridines; Severity of Illness Index

Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with asthma, particularly of late onset. Current treatment options for CRSwNP have limitations, and there is an unmet need for other safe and effective therapies.. The aim of the THUNDER study was to determine the efficacy and safety of the prostaglandin D. THUNDER was a phase 3b, randomized, multicenter, double-blind, placebo-controlled, parallel-group, 16-week study of fevipiprant 150 mg or 450 mg once daily versus placebo. All patients received intranasal mometasone furoate 200 μg daily.. Ninety-eight patients were randomly assigned to fevipiprant 150 mg (n = 32), fevipiprant 450 mg (n = 34), or placebo (n = 32). Mean (SE) change from baseline in nasal polyp score at week 16 was 0.20 (0.224) for fevipiprant 150 mg, -0.10 (0.216) for fevipiprant 450 mg, and 0.14 (0.233) for placebo. Mean treatment difference was 0.05 (95% confidence interval, -0.59, 0.70; adjusted P = .979) for fevipiprant 150 mg versus placebo and -0.25 (95% confidence interval, -0.88, 0.39; adjusted P = .656) for fevipiprant 450 mg versus placebo. There was no meaningful difference in the secondary end points for fevipiprant versus placebo.. THUNDER provided no evidence of a role for fevipiprant in the treatment of patients with CRSwNP and asthma; future studies may establish a role for other DP

Topics: Asthma; Chronic Disease; Double-Blind Method; Humans; Indoleacetic Acids; Mometasone Furoate; Nasal Polyps; Pyridines; Rhinitis; Sinusitis; Treatment Outcome

The prostaglandin D. SPIRIT, a 2-treatment period (52-week, double-blind and optional 104-week single-blind), randomised, placebo-controlled, multicentre, parallel-group study, assessed the long-term safety of fevipiprant (150 mg and 450 mg o.d.) added to standard of care in patients ≥ 12 years with uncontrolled asthma. Stratified block randomisation was used. Patients were randomised in an approximate ratio of 3:3:1 (fevipiprant 150 mg, fevipiprant 450 mg or placebo). Patients were either newly enrolled or had participated in a previous fevipiprant Phase 3 trial. Primary endpoints were: time-to-first treatment emergent adverse event (AE); serious AE; and AE leading to discontinuation from study treatment. Data from both treatment periods were combined for analyses. Data were collected during study site visits.. In total, 1093 patients were randomised to receive fevipiprant 150 mg, 1085 to fevipiprant 450 mg, and 360 to placebo. Overall, 1184 patients had ≥ 52 weeks' treatment, while 163 received ≥ 104 weeks' treatment. Both doses were well tolerated, with a safety profile similar to placebo both in new patients and in those enrolled from previous studies. In exploratory analyses, reduced rates of moderate-to-severe asthma exacerbations, increased time-to-first moderate-to-severe asthma exacerbation and improved FEV. In patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile.. Clinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517 .

Topics: Administration, Inhalation; Asthma; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Indoleacetic Acids; Male; Middle Aged; Pyridines; Time Factors; Treatment Outcome

Fevipiprant, an oral antagonist of the prostaglandin D. LUSTER-1 and LUSTER-2 were two phase 3 randomised, double-blind, placebo-controlled, parallel-group, replicate 52-week studies; LUSTER-1 took place at 174 clinical sites in 25 countries and LUSTER 2 took place at 169 clinical sites in 19 countries. Fevipiprant or placebo was added to Global Initiative for Asthma Steps 4 and 5 therapy in adolescents and adults with severe asthma. Patients aged 12 years or older with uncontrolled asthma on dual or triple asthma therapy were randomly assigned by use of interactive response technology to one of three treatment groups (once-daily fevipiprant 150 mg, fevipiprant 450 mg, or placebo) in a 1:1:1 ratio within each of the randomisation strata: peripheral blood eosinophil counts (<250 cells per μL or ≥250 cells per μL), patient age (<18 years or ≥18 years), and use or non-use of oral corticosteroids as part of their standard of care asthma therapy. The primary efficacy endpoint was the annualised rate of moderate to severe asthma exacerbations with 150 mg or 450 mg doses of fevipiprant once daily compared with placebo over 52 weeks, in patients with high blood eosinophil counts (≥250 cells per μL) and in the overall study population. All patients who underwent randomisation and received at least one dose of study medication were included in efficacy and safety analyses. These trials are registered with ClinicalTrials.gov, NCT02555683 (LUSTER-1) and NCT02563067 (LUSTER-2), and are complete and no longer recruiting.. Between Dec 11, 2015, and Oct 25, 2018, 894 patients were randomly assigned to fevipiprant 150 mg (n=301), fevipiprant 450 mg (n=295), or placebo (n=298) in LUSTER-1. Between Dec 3, 2015, and July 10, 2018, 877 patients were randomly assigned to fevipiprant 150 mg (n=296), fevipiprant 450 mg (n=294), or placebo (n=287) in LUSTER-2. In the high eosinophil population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 1·04 (95% CI 0·77-1·41) for fevipiprant 150 mg and 0·83 (0·61-1·14) for fevipiprant 450 mg, and in LUSTER-2 it was 0·69 (0·50-0·96) for fevipiprant 150 mg and 0·72 (0·52-1·01) for fevipiprant 450 mg. In the overall population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 0·96 (95% CI 0·75-1·22) for fevipiprant 150 mg and 0·78 (0·61-1·01) for fevipiprant 450 mg and in LUSTER-2 it was 0·82 (0·62-1·07) for fevipiprant 150 mg and 0·76 (0·58-1·00) for fevipiprant 450 mg. In the overall pooled population of both studies, serious adverse events occurred in 53 (9%) patients in the fevipiprant 150 mg group, 50 (9%) in the fevipiprant 450 mg group, and 50 (9%) in the placebo group. Adverse events leading to death occurred in two (<1%) patients in the fevipiprant 450 mg group and three (<1%) in the placebo group.. Although neither trial showed a statistically significant reduction in asthma exacerbations after adjusting for multiple testing, consistent and modest reductions in exacerbations rates were observed in both studies with the 450 mg dose of fevipiprant.. Novartis.

Topics: Anti-Asthmatic Agents; Asthma; Double-Blind Method; Eosinophils; Female; Hospitalization; Humans; Indoleacetic Acids; Leukocyte Count; Male; Middle Aged; Pyridines; Treatment Outcome

Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D

Topics: Airway Remodeling; Asthma; Cell Movement; Eosinophilia; Eosinophils; Humans; Indoleacetic Acids; Models, Biological; Muscle, Smooth; Myofibroblasts; Pyridines; Receptors, Immunologic; Receptors, Prostaglandin

Topics: Acetates; Adult; Airway Management; Anti-Asthmatic Agents; Asthma; Budesonide; Cyclopropanes; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Monitoring; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Indoleacetic Acids; Male; Middle Aged; Pyridines; Quinolines; Receptors, Immunologic; Receptors, Prostaglandin; Severity of Illness Index; Sulfides; Treatment Outcome

There is an unmet medical need for allergic asthma patients who are uncontrolled on conventional therapies. The aim of this study was to collect efficacy and safety data for QAW039, an oral chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist, for the treatment of asthma.. This was an exploratory phase II, double-blind, randomized, placebo-controlled multi-center study. Patients with mild-to-moderate uncontrolled allergic asthma (N = 170) were either without or weaned off inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) and randomized (1:1) to QAW039 (500 mg once daily) or to placebo for 28 days.. Overall, 157 patients completed the study. There were no significant differences between QAW039 and placebo for trough forced expiratory volume in 1 s (FEV1) or Asthma control questionnaire (ACQ) in the total population. Subgroup analyses demonstrated that patients with a FEV1 <70% of predicted at baseline treated with QAW039 had significant improvement compared with placebo in trough FEV1 (QAW039- Placebo [Δ] = 207 mL; 90% confidence interval [CI]: 96, 319; P = 0.002) and ACQ7 (Δ = -0.41; 90%CI: -0.69, -0.13; P = 0.009). QAW039 reached a mean maximum concentration (Cmax) of 3440 ng/mL on day 28 at a median Tmax of 1 h (range 0.5-4 h). Most adverse events (AEs) were mild/moderate and balanced between both groups, with no serious AEs.. In the general study population, no improvement in lung function was observed with QAW039. However, a subgroup analysis revealed that patients with greater severity of airflow limitation (FEV1 < 70%) had improved lung function and asthma control when treated with QAW039. QAW039 also demonstrated a favorable safety profile.. ClinicalTrials.govNCT01253603.

Topics: Administration, Oral; Adult; Anti-Asthmatic Agents; Asthma; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Indoleacetic Acids; Male; Middle Aged; Pyridines; Receptors, Immunologic; Receptors, Prostaglandin; Treatment Outcome

Eosinophilic airway inflammation is often present in asthma, and reduction of such inflammation results in improved clinical outcomes. We hypothesised that fevipiprant (QAW039), an antagonist of prostaglandin D2 receptor 2, might reduce eosinophilic airway inflammation in patients with moderate-to-severe eosinophilic asthma.. We performed a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial at Glenfield Hospital (Leicester, UK). We recruited patients with persistent, moderate-to-severe asthma and an elevated sputum eosinophil count (≥2%). After a 2-week single-blind placebo run-in period, patients were randomly assigned (1:1) by the trial pharmacist, using previously generated treatment allocation cards, to receive fevipiprant (225 mg twice per day orally) or placebo, stratified by the use of oral corticosteroid treatment and bronchoscopy. The 12-week treatment period was followed by a 6-week single-blind placebo washout period. The primary outcome was the change in sputum eosinophil percentage from baseline to 12 weeks after treatment, analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01545726, and with EudraCT, number 2011-004966-13.. Between Feb 10, 2012, and Jan 30, 2013, 61 patients were randomly assigned to receive fevipiprant (n=30) or placebo (n=31). Three patients in the fevipiprant group and four patients in the placebo group withdrew because of asthma exacerbations. Two patients in the fevipiprant group were incorrectly given placebo (one at the mid-treatment visit and one throughout the course of the study). They were both included in the fevipiprant group for the primary analysis, but the patient who was incorrectly given placebo throughout was included in the placebo group for the safety analyses. Between baseline and 12 weeks after treatment, sputum eosinophil percentage decreased from a geometric mean of 5·4% (95% CI 3·1-9·6) to 1·1% (0·7-1·9) in the fevipiprant group and from 4·6% (2·5-8·7) to 3·9% (CI 2·3-6·7) in the placebo group. Compared with baseline, mean sputum eosinophil percentage was reduced by 4·5 times in the fevipiprant group and by 1·3 times in the placebo group (difference between groups 3·5 times, 95% CI 1·7-7·0; p=0·0014). Fevipiprant had a favourable safety profile, with no deaths or serious adverse events reported. No patient withdrawals were judged by the investigator to be related to the study drug.. Fevipiprant reduces eosinophilic airway inflammation and is well tolerated in patients with persistent moderate-to-severe asthma and raised sputum eosinophil counts despite inhaled corticosteroid treatment.. Novartis Pharmaceuticals, AirPROM project, and the UK National Institute for Health Research.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Anti-Asthmatic Agents; Asthma; Bronchoscopy; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Eosinophils; Female; Humans; Indoleacetic Acids; Leukocyte Count; Male; Middle Aged; Pulmonary Eosinophilia; Pyridines; Receptors, Immunologic; Receptors, Prostaglandin; Sputum; Treatment Outcome

Topics: Asthma; Asthma, Aspirin-Induced; Chronic Disease; Female; Humans; Indoleacetic Acids; Nasal Polyps; Pregnancy; Preimplantation Diagnosis; Pyridines; Rhinitis

Prostaglandin D. Eosinophils and ILC2s were isolated from peripheral blood of atopic asthmatic patients. Eosinophil shape change, ILC2 migration and IL-5/IL-13 cytokine secretion were measured after stimulation with seven PGD. Selected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11β-PGF

Topics: Adolescent; Adult; Aged; Asthma; Cell Movement; Cell Shape; Cells, Cultured; Eosinophils; Female; Humans; Indoleacetic Acids; Interleukin-13; Interleukin-5; Lymphocytes; Male; Middle Aged; Prostaglandin Antagonists; Prostaglandin D2; Pyridines; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction; Young Adult

Topics: Asthma; Humans; Indoleacetic Acids; Prostaglandins; Pyridines

The objective of this analysis was to characterize the population pharmacokinetics (PK) of fevipiprant in asthma patients and to evaluate the effect of baseline covariates on the PK of fevipiprant.. PK data from 1281 healthy subjects or asthma patients were available after single or once daily dosing of fevipiprant. Population PK analysis was conducted to describe fevipiprant plasma concentration data using a non-linear mixed effect modeling approach.. Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. Exploration of fevipiprant PK in the population from the phase III studies revealed an over-dispersed and skewed distribution. This unusual distribution was described using Tukey’s g-and-h distribution (TGH) on the between-subject variability of apparent clearance (CL/F). The model identified a significant impact of disease status on CL/F, with the value in healthy subjects being 62% higher than that in asthma patients. Bodyweight, age and renal function showed statistically significant impact on fevipiprant clearance; however, compared with a typical asthma patient, the simulated difference in steady-state exposure was at most 16%.. Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. The TGH distribution was appropriate to describe the over-dispersed and skewed PK data as observed in the current studies. Asthma patients had approximately 37% higher exposure than healthy subjects did. Other covariates changed exposure by at most 16%.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Biological Variation, Population; Child; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Humans; Indoleacetic Acids; Male; Middle Aged; Models, Biological; Multicenter Studies as Topic; Pyridines; Randomized Controlled Trials as Topic; Receptors, Immunologic; Receptors, Prostaglandin; Young Adult

Prostaglandin 2 (PGD2) mediated signalling of Chemoattractant Receptorhomologous molecule expressed on Th2 cells (CRTh2) receptor has been implicated in the recruitment of inflammatory cells. This explains the design of highly selective compounds with innate abilities to antagonize PGD2-CRTh2 interactions and prevent pro-inflammatory allergies such as rhinitis and uncontrolled asthma. The development of PGD2-competitive CRTh2 binders; CAY10471 and Fevipiprant represent remarkable therapeutic progress even though they elicit disparate pharmacological propensities despite utilizing the same binding pocket.. In this study, we seek to pinpoint the underlying phenomenon associated with differential CRTh2 therapeutic inhibition by CAY10471 and Fevipiprant using membraneembedded molecular dynamics simulation. Findings revealed that the common carboxylate group of both compounds elicited strong attractive charges with active site Arg170 and Lys210. Interestingly, a distinctive feature was the steady occurrence of high-affinity salt-bridges and an Arg170-mediated pi-cation interaction with the tetrahydrocarbozole ring of CAY10471. Further investigations into the active site motions of both ligands revealed that CAY10471 was relatively more stable. Comparative binding analyses also revealed that CAY10471 exhibited higher ΔG, indicating the cruciality of the ring stabilization role mediated by Arg170. Moreover, conformational analyses revealed that the inhibitory activity of CAY10471 was more prominent on CRTh2 compared to Fevipiprant.. These findings could further advance the strategic design of novel CRTh2 binders in the treatment of diseases related to pro-inflammatory allergies.

Topics: Asthma; Carbazoles; High-Throughput Screening Assays; Humans; Indoleacetic Acids; Molecular Dynamics Simulation; Molecular Structure; Pyridines; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic; Sulfonamides; Treatment Outcome

Topics: Anti-Asthmatic Agents; Asthma; Humans; Indoleacetic Acids; Pyridines; Treatment Outcome

Topics: Administration, Oral; Anti-Asthmatic Agents; Asthma; Humans; Indoleacetic Acids; Pyridines