Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial

doi:10.1016/S2213-2600(16)30179-5

The Lancet Respiratory Medicine

Volume 4, Issue 9, September 2016, Pages 699-707

https://doi.org/10.1016/S2213-2600(16)30179-5 Get rights and content

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

Novartis Pharmaceuticals, AirPROM project, and the UK National Institute for Health Research.

Introduction

Asthma is a chronic inflammatory airway disease that is characterised by heterogeneity in clinical phenotype and response to therapy.¹ Eosinophilic airway inflammation, mediated by type 2 immunity, is a common feature of asthma.¹ Treatment strategies that specifically target eosinophilic airway inflammation substantially reduce asthma exacerbations in patients with uncontrolled eosinophilic airway inflammation and, to a lesser extent, improve lung function and asthma control.2, 3, 4, 5, 6, 7

Increasing evidence shows that prostaglandin D₂ (PGD₂), which acts on the PGD₂ receptor 2 (DP₂ receptor; also known as CRTH2), might have an important role in mediating eosinophilic airway inflammation in asthma. The DP₂ receptor mediates the migration of T-helper-2 cells, delays their apoptosis, and stimulates them to produce the cytokines interleukin-4, interleukin-5, and interleukin-13.8, 9, 10 The DP₂ receptor also affects the migration of and cytokine release from type 2 innate lymphoid cells;¹¹ importantly, DP₂ is expressed by eosinophils and directly mediates their chemotaxis and degranulation.12, 13 The number of DP₂-positive cells in the bronchial submucosa increases with the severity of asthma.¹⁴ The DP₂ receptor is also expressed on airway epithelial cells and directly promotes their migration and differentiation.¹⁴ Therefore, the DP₂ receptor is a promising new drug target in the treatment of asthma. Fevipiprant (QAW039) is an orally administered, highly selective, and potent antagonist of the DP₂ receptor, but not of the more general homoeostatic PGD₂ receptor DP₁.

Research in context

Evidence before this study

We searched PubMed for reports published in English before Feb 1, 2016, on the use of prostaglandin D₂ receptor 2 (DP₂ receptor; also known as CRTH2) antagonists in asthma with the terms “DP₂”, “CRTH2”, “prostaglandin D₂”, and “asthma”. We also searched the reference lists of identified reports. The most relevant reports identified were of two randomised controlled trials of the compound OC000459, which was found to improve forced expiratory volume in 1 s (FEV₁) and asthma-related quality of life in steroid-naive patients. The compound BI671800 was assessed in two separate randomised controlled trials, one in steroid-naive adults with asthma, and one in patients receiving inhaled fluticasone. In both cases, 6 weeks of treatment resulted in modest but significant improvements in FEV₁ compared with placebo.

Added value of this study

To our knowledge, this is the first study to assess the effects of a DP₂ receptor antagonist in patients with moderate-to-severe asthma. We showed that fevipiprant reduces eosinophilic airway inflammation in this group of patients and is associated with improved lung function and asthma-related quality of life. Control of eosinophilic airway inflammation is an important goal of asthma treatment because it has been previously shown to reduce the frequency of asthma exacerbations.

Implications of all the available evidence

Fevipiprant is a potentially important drug because it is a well tolerated oral agent that leads to significant reductions in eosinophilic airway inflammation in patients with moderate-to-severe asthma who are already receiving high-dose inhaled or oral corticosteroids.

We tested the hypothesis that, in patients with sputum eosinophilia (eosinophil count ≥2%) and persistent, moderate-to-severe asthma, treatment with fevipiprant (225 mg twice per day orally) for 12 weeks, in addition to conventional treatment, reduces the eosinophil count in induced sputum compared with placebo.

Section snippets

Study design

We performed a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial at Glenfield Hospital (Leicester, UK). The study protocol was approved by the UK National Research Ethics Committee (Leicestershire, Northamptonshire, and Rutland; approval number 11/EM/0402) and the UK Medicines and Healthcare Products Regulatory Agency.

Participants

We recruited participants from a regional refractory asthma clinic providing tertiary care for a population of 4 million people. Suitable

Results

Between Feb 10, 2012, and Jan 30, 2013, we screened 117 patients, of whom 61 met the inclusion criteria and were randomly assigned to receive fevipiprant (n=30) or placebo (n=31; figure 2). Three patients in the fevipiprant group and four patients in the placebo group withdrew because of asthma exacerbations. One patient who was assigned to receive fevipiprant was incorrectly given placebo at the mid-treatment visit. One patient who was assigned to receive fevipiprant was incorrectly given

Discussion

Compared with placebo, fevipiprant significantly reduced eosinophilic inflammation in the sputum and bronchial submucosa in patients with persistent, moderate-to-severe asthma and sputum eosinophilia. Compared with placebo, fevipiprant significantly improved AQLQ(S) scores, post-bronchodilator FEV₁, and functional residual capacity in all patients, and ACQ-7 scores in the predefined subgroup of patients who had uncontrolled asthma at baseline. Exploratory analyses of bronchial biopsies

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^*: Contributed equally

^†: Co-senior authors

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ArticlesFevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design

Participants

Results

Discussion

Lancet

Lancet

Lancet Respir Med

J Allergy Clin Immunol

Blood

Chest

J Allergy Clin Immunol

Trends Mol Med

Pulm Pharmacol Ther

Asthma phenotypes: the evolution from clinical to molecular approaches

Nat Med

Mepolizumab and exacerbations of refractory eosinophilic asthma

N Engl J Med

Articles
Fevipiprant, a prostaglandin D₂ receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial