Abstract

BackgroundThe prostaglandin D2 (PGD2) receptor 2 (DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the DP2 receptor that inhibits the binding of PGD2 and its metabolites.MethodsSPIRIT, 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.ResultsIn 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 FEV1 were observed for both doses of fevipiprant versus placebo; these were without multiplicity adjustment and should be interpreted with caution. SPIRIT was terminated early, on 16 December 2019, by the Sponsor.ConclusionsIn patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile.Trial registrationClinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517.

Highlights

  • The prostaglandin ­D2 ­(PGD2) receptor 2 (­DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers

  • The overall safety profile was comparable for patients who were newly recruited or rolled-over from previous Phase 3 studies and was comparable with that observed in previous Phase 2 and 3 trials of fevipiprant [9, 11, 12]

  • Previous studies with other D­ P2 receptor antagonists have reported safety findings not seen with fevipiprant [19], e.g. it has been reported that nasopharyngitis is a more common adverse event in patients treated with a ­DP2 receptor antagonist compared with placebo [15], this was not the case in the SPIRIT study

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Summary

Introduction

The prostaglandin ­D2 ­(PGD2) receptor 2 (­DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the ­DP2 receptor that inhibits the binding of ­PGD2 and its metabolites. The prostaglandin D­ 2 receptor 2 (­DP2 receptor) is expressed on a broad range of key inflammatory and structural cells involved in the pathogenesis of asthma. It is a chemokine receptor with a diverse range of ligands in addition to prostaglandin ­D2 ­(PGD2), including several ­PGD2‐derived metabolites [4]. Other Phase 2 studies showed that optimal dose response was achieved with fevipiprant 150 mg once daily [9] and that patients treated with fevipiprant 225 mg twice daily had a 3.5-times greater reduction in sputum eosinophils compared with placebo, a significant effect on blood eosinophil count was not demonstrated [10]

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