Companies Provide Trial Updates on P2X3 Blockers for Chronic Cough

Executives from Merck, Bellus Health, Bayer, and Shionogi highlighted their P2X3 data for chronic cough.

Four pharmaceutical companies discussed updates to their investigational P2X3 antagonists, a new class of potential therapies aimed at refractory chronic cough, at this year's American Cough Conference.

Chronic cough affects an estimated 10% of the population, and about 50% of cases cannot be explained by other comorbidities after a thorough exam, such as asthma, gastroesophageal reflux disease, or asthma. There are no FDA-approved treatments for this condition.

P2X3 is an adenosine triphosphate–gated ion channel found on peripheral sensory nerves and expressed in airway fibers, which become hypersensitive. Candidates to inhibit P2X3 are gefapixant (Merck), BLU-5937 (Bellus Health), eliapixant (Bayer), and sivopixant(Shionogi).


Of the 4, gefapixant is furthest along; earlier this year, the FDA accepted Merck’s new drug application for the oral drug, with a target decision date of December 21, 2021. The filing is based on data from 2 phase 3 trials, COUGH-1 and COUGH-2. At the meeting Saturday, Carmen La Rosa, MD, executive director, Clinical Research, Merck, discussed subgroup analyses from the trials as well as ongoing studies in women with chronic cough and stress urinary incontinence and recent-onset chronic cough.

The multinational, randomized, double-blind, placebo-controlled studies assessed a combined total of 2044 participants, with 750 in COUGH-1 and 1314 in COUGH-2. Results from the studies, in which primary efficacy outcome measures were 24-hour cough frequency at week 12 for COUGH-1 and 24-hour cough frequency at week 24 for COUGH-2, were released last year.

The mean duration of cough in both groups was about 11 years, and baseline cough frequency was 20 to 30 coughs per hour, depending on whether you looked at a 24-hour range or only the times when the patient was awake, La Rosa said.

Patients received gefapixant 45 mg twice daily, gefapixant 15 mg twice daily, or placebo. Only the higher dose was statistically significant in both studies. In COUGH-1, gefapixant 45 mg significantly reduced 24-hour cough frequency vs placebo at 12 weeks (–18.45%; 95% CI, –32.92% to –0.86%; P = .041). In COUGH-2, gefapixant showed a significant reduction at 24 weeks compared with placebo (–14.64%; 95% CI, –26.07% to –1.43%; P = .031).

La Rosa also highlighted a recently released pooled analysis of the 2 studies, which showed a reduction in objective cough frequency at week 12 for both 24-hour frequency and awake cough frequency, –18.6% and –17.4%, respectively.

Another pooled analysis showed efficacy across different subgroups, and patient-reported outcomes also were favorable toward gefapixant, she said. Adverse events were mainly taste related and were dose dependent; 25% to 28% of patients discontinued in COUGH-1 and COUGH-2 due to these effects.


Catherine M. Bonuccelli, chief medical officer of Bellus Health, discussed the company’s P2X3 antagonist BLU-5937, which is in phase 2 trials.

One analysis using data from the RELIEF study examined the burden of cough frequency in patients with higher or lower cough frequency and found that there was disease burden across frequency levels, although it was greater at the higher frequency levels.

The RELIEF study itself was a 2-arm dose-escalation study, with doses increasing every 4 days (25, 50, 100, and 200 mg); the results in the intent-to-treat population favored the drug in reductions of awake cough frequency but did not reach statistical significance. When examining results based on higher levels of cough frequency (20 or more and 32.4 or more coughs per hour), statistical significance was reached, the company said.

There were no study discontinuations due to alterations in taste. The study was terminated early due to the impact of COVID-19.

A second study, SOOTHE, is still in the recruitment phase; the phase 2b study is examining the effect of 3 doses: 12, 50, or 200 mg. Based on the results from RELIEF, the company said it is “enriching” the population based on awake cough frequency at baseline. To that end, the primary end point population comprises patients with at least 25 coughs per hour. An exploratory population of patients with 10 to 15 coughs per hour will receive a dose of 200 mg.


This compound from Bayer is in a phase 2b dose-finding study, according to Melanie Wosnitza, MD, MSc, a vice president at Bayer and head, Clinical Development Pulmonology. Patients will be randomized to 1 of 3 doses: 25, 75, or 150 mg, or placebo, for 12 weeks.

Cough frequency will be monitored by the VitaloJAK cough monitor.

In an earlier study, eliapixant was studied at higher doses along with a related antagonist, filapixant, but Bayer dropped development of filapixant due to its higher rate of taste issues. Although in the current study the dose of eliapixant is lower than the previous trial, Wosnitza said it is a new formulation.


Sivopixant, or S-600918, a selective agonist, recently completed a phase 2b trial in which patients received doses of 50, 150, or 300 mg in a double-blind, global, parallel assignment study across 133 sites with 406 patients, said Yuko Matsunaga, MD, medical director, Shionogi. Treatment duration was 28 days. The trial is still being analyzed and results are not yet available, she said.

An earlier phase 2a study, conducted in Japan, showed a 31.6% reduction in the objective frequency of daytime cough after 2 weeks and a 30.9% reduction in frequency of cough over 24 hours. Two of 31 patients on the drug had taste-related adverse events.