Gefapixant may reduce cough frequency in chronic cough

New data published in The Lancet Respiratory Medicine show that a 50 mg dose of the P2X3 receptor antagonist gefapixant significantly reduced cough frequency in patients with chronic cough when compared with placebo.

The randomized, double-blind, placebo-controlled phase 2b clinical trial included 253 adults aged 18 to 80 years who were recruited from 44 pulmonary and allergist sites in the United States and United Kingdom and were randomly assigned to gefapixant 7.5 mg, 20 mg, 50 mg twice daily or placebo for 12 weeks. To qualify for inclusion, patients had to have refractory or unexplained chronic cough lasting 1 year or longer, no radiographic chest abnormality and 40 mm or more on a 100 mm cough severity visual analogue scale at enrollment.

The patients’ mean age was 60.2 years, 76% were women, the mean duration of cough was 14.5 years and the majority were never-smokers. Awake objective cough frequency, as measured with a sound recording device during four 24-hour periods, served as the primary efficacy endpoint.

Improvement in cough frequency

At baseline, patients coughed an average of 27.6 times per hour in the placebo group, 27.4 times per hour in the gefapixant 7.5 mg group, 24.1 times per hour in the gefapixant 20 mg group and 28.8 times per hour in the gefapixant 50 mg group. After 12 weeks of treatment, cough frequency declined to 18.2 coughs per hour with placebo, 14.5 coughs per hour with gefapixant 7.5 mg, 12 coughs per hour with gefapixant 20 mg and 11.3 coughs per hour with gefapixant 50 mg. For the 50 mg dose, this translated to a significant 37% reduction in cough frequency (P = .0027) relative to placebo. However, the decreases of 22% and 22.2% with the 7.5 mg and 20 mg doses, respectively, did not reach statistical significance when compared with placebo.

Treatment with gefapixant 50 mg, as compared with placebo, was also associated with improvements in secondary outcomes, including the cough severity visual analogue scale, mean daily cough severity diary scores, Leicester Cough Questionnaire scores, and Patient Global Impression of Change and Clinician Global Impression scores.

Adverse events included taste-related issues. Specifically, dysgeusia, the most frequently reported adverse event, occurred in 5% of the placebo group, 10% of the gefapixant 7.5 mg group, 33% of the gefapixant 20 mg group and 48% of the gefapixant 50 mg group. Although 11.8% of patients assigned gefapixant 50 mg reported that these taste effects were extremely bothersome, an acceptability questionnaire indicated that they were no less likely to take any dose of gefapixant than placebo for at least a year.

Frostbite was the sole serious adverse event that occurred during the study and was thought not to be treatment-related.

“Many patients with a chronic cough are driven to seek treatment because of the significant negative impact it can have on their quality of life, but at the moment physicians are unable to help,” Jaclyn A. Smith, MB, ChB, FRCP, PhD, from the division of infection, immunity and respiratory medicine at University of Manchester in the United Kingdom, said in a press release. “Ours is the first study to report a treatment that is safe and effective over the longer term, and phase 3 trials are already underway with an even larger group of people and over a longer time frame.”

Potential pitfalls

The researchers highlighted the strong placebo effect observed in the study as an important limitation, noting that patients’ expectations may have been affected by positive results with gefapixant from previous studies and the high likelihood of being assigned to a treatment group.

In a linked comment, Richard S. Irwin, MD, Cynthia L. French, PhD, and J. Mark Madison, MD, all from the University of Massachusetts Medical School, noted that Smith and colleagues addressed this potential limitation by analyzing cough frequency relative to placebo and wrote that statistically significant improvement was observed with gefapixant 50 mg.

They also emphasized the importance of practicing “intervention fidelity” by following best clinical practice guidelines for diagnosis and treatment of chronic cough to avoid leaving cough due to treatable underlying causes undiagnosed.

“We look forward to the results of the phase 3 trials that are underway before we know the true degree of efficacy of the 50 mg dose of gefapixant in controlling unexplained chronic cough and whether the associated taste-related adverse events are tolerable. We hope that the trials clearly show that the participants truly have unexplained chronic cough to avoid the concerns that there is a breach in intervention fidelity in determining that the participants have the condition,” they wrote. – by Melissa Foster

Disclosures: This study was funded by Afferent Pharmaceuticals, which has been acquired by Merck &Co. Smith reports she has received grants and personal fees related to the submitted work from Afferent Pharmaceuticals/Merck & Co.; grants from Ario Pharma, Bayer, Bellus, GlaxoSmithKline, NeRRe Therapeutics and Menlo; personal fees from Ario Pharma, Bayer, Bellus, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Menlo, Neomed and NeRRe Therapeutics; nonfinancial support from Vitalograph; and is a named inventor on a patent, owned by Manchester University NHS Foundation Trust and licensed to Vitalograph Ltd., describing the detection of cough from sound recordings. Please see the study for all authors’ relevant financial disclosures. Madison reports receiving financial support for support for consultancy at a U.S. Chronic Cough Expert Input Forum sponsored by Merck & Co. Irwin and French report no relevant financial disclosures.