Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough

Abstract

BackgroundThe purinoceptor subtype P2X3 has been shown to have significant involvement in the cough reflex; the heterotrimer version of the purinoceptor (P2X2/3) has been implicated in taste disturbance. The most advanced clinical candidate antagonist gefapixant has low selectivity among P2X3 receptors and induced taste disturbance, whereas newly developed sivopixant has high selectivity towards P2X3versus P2X2/3.MethodsIn a phase 2a, randomised, double-blind, placebo-controlled, crossover, multicentre study, adult patients with refractory or unexplained chronic cough received oral sivopixant 150 mg or placebo once daily for 2 weeks, followed by a 2–3-week washout period, and then crossed over to placebo or sivopixant for 2 weeks. Efficacy and safety of sivopixant were evaluated.ResultsOf 31 randomised patients, 15 in the sivopixant-first group and 15 in the placebo-first group completed the study. After 2 weeks’ treatment, the placebo-adjusted ratios of the average hourly number of coughs to baseline during daytime (primary endpoint) and over 24 h (secondary endpoint) were −31.6% (p=0.0546) and −30.9% (p=0.0386), respectively. Sivopixant also improved health-related quality of life. Treatment-related adverse events occurred in 12.9% and 3.2% of patients during sivopixant and placebo administration, respectively. Mild taste disturbance occurred in two patients (6.5%) during sivopixant administration.ConclusionsSivopixant reduced objective cough frequency and improved health-related quality of life, with a low incidence of taste disturbance, among patients with refractory or unexplained chronic cough.