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P2X3 Receptor Antagonist Shows Promise for Chronic Cough

An investigational drug that targets the purinergic receptor P2X3 significantly reduced cough frequency in people with refractory and unexplained chronic cough, according to results from a phase IIb trial.

In more than 250 participants treated for 12 weeks, those taking the highest dose (50 mg twice daily) of gefapixant experienced significant improvement in chronic cough, reducing their cough frequency by 37% compared with placebo (95% CI -55.3 to -14.9, P=0.0027), reported Jaclyn A. Smith, PhD, of the University of Manchester in England, and colleagues in Lancet Respiratory Medicine.

Smith told MedPage Today that the P2X3 receptor antagonist drug was originally studied as a pain reliever, and then as a bladder control drug. She explained that purinergic receptor P2X3 is an ATP-gated ion channel largely found on peripheral sensory nerves and expressed in fibers innervating the airways.

A small proof-of-concept study in patients with chronic cough refractory to other treatments showed 2 weeks of treatment with very high dose (600 mg twice daily) gefapixant reduced cough frequency by 75% versus placebo. But all of the study participants (n=24) experienced disturbances in taste on the high-dose treatment, and six patients withdrew from the trial due to the treatment-related adverse event (AE).

The current trial recruited adult patients with refractory chronic cough, or unexplained chronic cough, from 44 primary outpatient pulmonologist or allergist sites in the U.K. and U.S. All patients had chronic coughs lasting a year or longer (mean duration 14.5 years), without evidence of chest abnormality, and a score of 40 mm or more on a 100-mm cough severity visual analogue scale. Most of the recruited patients (70%) had no history of smoking.

The participants were randomly assigned to receive placebo or one of three doses (7.5 mg, 20 mg, or 50 mg) of oral gefapixant twice daily for 84 days and the primary endpoint was placebo-adjusted change from baseline in awake cough frequency after 12 weeks.

From Dec. 21, 2015, to July 26, 2016, 253 patients were randomly assigned to placebo (n=63), or gefapixant at 7.5 mg (n=64), 20 mg (n=63), or 50 mg (n=63) twice daily.

The participants were asked to keep a cough severity diary, including reporting on how many times they coughed per hour. Objective measurement was also done by fitting the participants with a device to record cough sounds over four 24-hour periods during the study. Cough severity was measured with the Leicester Cough Questionnaire during six office visits.

The authors reported that at baseline, the patients coughed about 28 times/hour on average. After 12 weeks of treatment, patients in the 50-mg group coughed around 11.3 times/hour.

Patients treated with the two lower doses of the drug experienced more profound cough reduction at 12 weeks than placebo-treated patients, but the difference was not statistically significant at 18.2 coughs/hour with placebo, 14.5 coughs/hour with 7.5 mg, and 12.0 coughs/hour with 20 mg.

The estimated percentage change relative to placebo was:

7.5 mg gefapixant: -22.0% (95% CI -41.8 to 4.6, P=0.097)

20 mg: -22.2% (95% CI -42.0 to 4.3, P=0.093)

50-mg: -37.0% (95% CI –53.3 to -14.9, P=0.0027)

Taste disturbance (dysgeusia) was the most common AE with the study drug, occurring in three (5%) placebo-treated patients, six (10%) patients in the 7.5-mg group, 21 (33%) in the 20-mg group, and 30 (48%) in the 50-mg group. A total of 16% of patients (10 patients total) in the 50-mg treatment group withdrew from the study because of dysgeusia.

Smith told MedPage Today that a phase III study which involves 45-mg and 15-mg doses of the drug is underway.

“The lower dose is still being looked at for good reason, I think,” she said. “There was a hint in this study that these lower doses might be effective, and they were certainly better tolerated in terms of the taste side effect.”

In an accompanying comment, Richard S. Irwin, MD, of the University of Massachusetts Medical School in Worcester, and colleagues, wrote that phase III trials should answer remaining questions about the efficacy of the drug, and whether its taste-related side effects will be tolerated at an effective dosage.

They noted that cough frequency remained below baseline for 2 weeks after the drug was stopped in the 50-mg group, and did not show evidence of a rebound effect.

“However, because the same finding was also seen with placebo, it is not clear if the lasting improvement was due to the study population,” they wrote. “We look forward to the phase 3 trials that are underway before we know the true degree of efficacy at a 50 mg dose of gefapixant in controlling unexplained chronic cough and whether the associated taste-related adverse events are tolerable.”


The study was funded by Afferent Pharmaceuticals/Merck. Several co-authors are company employees.

Smith disclosed relevant relationships with, and/or support from, Afferent Pharmaceuticals/Merck, Ario Pharma, GlaxoSmithKline, NeRRe Therapeutics, Menlo, Bellus, Bayer, Chiesi, Boehringer Ingelheim, Genentech, and NeoMed, as well as being named inventor on a patent owned by the Manchester University NHS Foundation Trust and licensed to Vitalograph. Co-authors disclosed multiple relevant relationships with industry.

Irwin disclosed no relevant relationships with industry. A co-author disclosed support from a U.S. Chronic Cough Expert Input Forum sponsored by Merck.