Effectiveness of fevipiprant in reducing exacerbations in patients with severe asthma (LUSTER-1 and LUSTER-2): two phase 3 randomised controlled trials

Background: Fevipiprant, an oral antagonist of the prostaglandin D₂ receptor 2, reduced sputum eosinophils and improved lung function in phase 2 trials of patients with asthma. We aimed to investigate whether fevipiprant reduces asthma exacerbations in patients with severe asthma. Methods: 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. Findings: 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. Interpretation: 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. Funding: Novartis.