Gefapixant reduces cough frequency in refractory, unexplained chronic cough

Treatment with gefapixant, a P2X3 receptor antagonist reduced cough frequency and cough-related quality of life in patients with refractory or unexplained chronic cough, according to results of two phase 3 trials.

“The rationale for treating chronic cough with a P2X3 receptor antagonist settles on the theory that [adenosine triphosphate] contributes to cough hypersensitivity through activation of this receptor, which is expressed in airway sensory nerves thought to be important in cough,” Lorcan McGarvey, MD, consultant respiratory physician and clinical professor in the School of Medicine at Queen’s University, Belfast, U.K., said during a presentation at the virtual European Respiratory Society International Congress.

Researchers conducted two phase 3, randomized, double-blind, placebo-controlled trials that included 2,044 adults with refractory or unexplained chronic cough. The COUGH-1 trial enrolled 730 patients (74% women; 78% white) and the COUGH-2 trial enrolled 1,314 patients (75% women; 80% white) to assess the safety and efficacy of gefapixant (Merck).

COUGH-1 and COUGH-2 are the first companion phase 3 trials ever conducted in patients with refractory chronic cough, according to a press release by Merck. Healio previously reported results of a phase 2b trial that demonstrated gefapixant reduced cough frequency in patients with chronic cough compared with placebo.

Patients in COUGH-1 and COUGH-2 had a diagnosis of refractory or unexplained chronic cough for at least 1 year and a baseline cough severity visual analog scale score of 40 mm or greater. In both COUGH-1 and COUGH-2, patients were randomly assigned to placebo, gefapixant 15 mg twice daily or gefapixant 45 mg twice daily.

Primary endpoints was 24-hour cough frequency at 12 weeks in COUGH-1 and at 24 weeks in COUGH-2. Secondary endpoints included awake cough frequency and Leicester Cough Questionnaire quality of life.

Patients assigned gefapixant 45 mg twice daily had a reduction in 24-hour cough frequency, with an 18.45% reduction relative to placebo at 12 weeks in COUGH-1 (P = .041) and a 14.64% reduction relative to placebo at 24 weeks in COUGH-2 (P = .031).

Gefapixant 15 mg twice daily did not meet the primary endpoint in either phase 3 trial.

The researchers also reported reduction in awake coughs per hour with gefapixant 45 mg (15.79% reduction relative to placebo in COUGH-2; P = .022; 17.68% reduction relative to placebo in COUGH-1; P = .056). Researchers observed clinically meaningful improvements in cough-related quality of life using the Leicester Cough Questionnaire at 24 weeks among patients assigned gefapixant 45 mg (OR = 1.41; 95% CI, 1.01-1.96; P = .042) compared with placebo. Seventy-seven percent of patients in assigned gefapixant 45 mg experienced a clinically important level of improvement in cough-related quality of life, according to the release.

The frequency of adverse events increased in a dose-related manner (COUGH-1: 75.3% with gefapixant 45 mg; 55.7% with 15 mg; COUGH-2: 87% with 45 mg; 78.7% with 15 mg). Adverse events and discontinuations in the 45 mg group were mainly due to taste disturbances. Overall discontinuations due to adverse events in COUGH-1 and COUGH-2 were 15% and 20%, respectively, with gefapixant 45 mg, 3% and 8%, respectively, with gefapixant 15 mg and 3% and 5%, respectively, with placebo.

“Gefapixant 45 mg twice daily significantly reduced cough frequency and improved cough-related quality of life,” McGarvey said. “COUGH-1 and COUGH-2 represent the first successful phase 3 clinical trials supporting gefapixant as a novel and effective treatment option for refractory and unexplained chronic cough.”