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Higher doses of the investigational oral drug gefapixant significantly decreased cough frequency compared to placebo in two highly anticipated phase III studies, but well over half of patients in both trials reported taste-related adverse events.

Results with the P2X3 receptor antagonist at 45 mg twice daily in the and trials, reported at the , showed 62% and 63% reductions from baseline in cough frequency.

COUGH-1, which followed 730 patients for 12 weeks, also yielded an 18.5% reduction in daily cough relative to placebo (95% CI -32.9% to -0.9%; P=0.041) in patients receiving the 45-mg twice daily dose. COUGH-2, which followed 1,314 patients for 24 weeks, saw a 14.64% reduction in daily cough frequency relative to placebo at this dosage (95% CI -26.1% to -1.4%; P=0.031), according to Lorcan McGarvey, MD, of Queens's University in Belfast, Northern Ireland.

A 15-mg dose twice daily, however, failed to demonstrate significantly greater efficacy than placebo.

Merck & Co.'s gefapixant is one of several P2X3 antagonists under development for the treatment of refractory or unexplained chronic cough, but it is the first to complete phase III trials.

"The rationale for treating chronic cough with a P2X3 receptor antagonist centers on the view that [adenosine triphosphate] contributes to cough hypersensitivity through activation of this receptor, which is expressed on the airway sensory nerves thought to be important in cough," McGarvey said.

Findings from a phase IIb trial involving 253 patients, reported last month in , showed significant reduction in cough frequency in patients treated with 50 mg of oral gefapixant twice daily for 12 weeks, compared to placebo. But roughly half (48%) of patients reported issues with taste distortion at this dosage.

This side effect was seen, too, in well over half of COUGH-1 and COUGH-2 participants (58% and 69%, respectively), compared to 10.7% and 19.5%, respectively, at the lower gefapixant dose and 3.3% and 8.3%, respectively, in the placebo groups.

Study withdrawal due to adverse events in COUGH-1 and COUGH-2 occurred in 15% and 20%, respectively, of patients in the high-dose groups, compared to 3% and 8%, respectively, with the lower dosage.

McGarvey noted that 5%-10% of adults globally suffer from chronic cough, and a subset of these patients have refractory or unexplained chronic cough and appear more sensitive to various triggers. These triggers can include talking, laughing, a change in air temperature or exposure to aerosols or food odors. No treatments are specifically approved for the condition.

Participants in the two trials were adults with a history of chronic cough lasting at least 1 year and no substantial abnormalities on chest radiology within the previous 5 years that could be contributing to cough.

All study participants also had (VAS) scores of 40 mm or greater at both screening and baseline visits.

The primary study endpoint was improvement in daily cough frequency measured using an ambulatory digital audio recording device. Secondary endpoints included awake coughs per hour and percentage of participants with a greater than 1.3 point increase from baseline in the Leicester Cough Questionnaire (LCQ) total score.

COUGH-1 had a 12-week treatment period and a 40-week extension, and COUGH-2 had a 24-week treatment period and a 28-week extension period.

Roughly three-fourths of the study participants in both trials were women and 80% were white. A total of 39% and 33%, respectively, in COUGH-1 and COUGH-2 were 65 or older.

In addition to meeting primary study endpoints, the 45-mg dosage met key secondary endpoints.

Improvements in awake cough frequency paralleled the 24-hour cough frequency outcome, and significantly more participants in the high-dose group demonstrated a clinically important improvement in cough-related quality of life at week 24, with an odds ratio of 1.41 (P=0.042) compared with placebo.

Also, 77.1% of the high-dose group experienced a clinically important level of improvement in their quality of life related to cough, as measured through the LCQ.

Merck hasn't said whether or when it plans to seek marketing approval. In , the company merely indicated that it "plans to share data from COUGH-1 and COUGH-2 with regulatory authorities worldwide."

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