First-in-class P2X3 receptor antagonist shows promise for chronic cough treatment

 

In two phase 3 studies, the P2X3 receptor antagonist gefapixant not only reduced the frequency of cough in patients with refractory or unexplained cough but also increased their quality of life [1].

COUGH-1 and COUGH-2 are 2 randomised, placebo-controlled, double-blind studies in parallel design, testing the efficacy of gefapixant in adults without substantial abnormalities in their chest x-ray, suffering ≥1 years from refractory or unexplained chronic cough. The 2 studies included just over 2,000 patients for treatment with gefapixant 45 mg twice daily, or 15 mg twice daily, or placebo over 12 (COUGH-1) and 24 (COUGH-2) weeks.

Primary endpoints were objectively measured 24-h cough frequency as well as safety and tolerability. Secondary endpoints included awake cough frequency and a quality of life assessment of chronic cough evaluated by the Leicester Cough Questionnaire. As may be expected with this diagnosis, the study population was mainly female (74% COUGH-1, 75% COUGH-2) and Caucasian (78% COUGH-1, 80% COUGH-2). Mean values for the duration of chronic cough ranged from 10.7 to 11.9 years in the different groups, mean frequency of 24-h cough frequency from 27.0-37.9 and 26.8-27.4 in COUGH-1 and COUGH-2, respectively.

Although the placebo response was greater than expected, results for the primary endpoint of 24-h coughs per hour was significantly reduced by gefapixant versus placebo in both studies but only at the higher dosage of 45 mg twice daily: COUGH-1 -18.45 (P=0.041) and COUGH-2 -14.64 (P=0.031). “Statistically significant reductions in awake cough frequency with 45 mg of gefapixant in COUGH-2 support our primary analysis,” said Prof. Lorcan McGarvey (Queen’s University Belfast, UK). “A similar trend was observed for COUGH-1, but it just failed to meet statistical significance.” Gefapixant 45 mg also reached significance for cough-related quality of life in COUGH-2 (odds ratio vs placebo 1.41; P=0.042).

Adverse events and discontinuations were dose related, occurring most frequently in the 45 mg groups. Discontinuations of treatment occurred in 15% and 20% in COUGH-1 and COUGH-2, respectively, and were mainly related to taste disturbances. Serious adverse event happened in 2.9% and 3.2% of patients, respectively.

“These findings are notable as COUGH-1 and COUGH-2 are the first successful companion phase 3 trials of patients with refractory or unexplained chronic cough, and they provide evidence to support gefapixant as a potential novel treatment option for these patients with unmet needs,“ concluded Prof. McGarvey.

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   1. McGarvey L, et al. Two Phase 3 Randomized Clinical Trials of Gefapixant, a P2X3 Receptor Antagonist, in Refractory or Unexplained Chronic Cough (COUGH-1 and COUGH-2). LBA 3800, ERS International Virtual Congress 2020, 7-9 Sept.

Posted on 29 October 202023 February 2021