Merck's Gefapixant Shows Significant Cough Reduction in Phase 3 Trials for Refractory and Unexplained Chronic Cough, Despite High Rates of Taste-Related Discontinuations

Compiled by Keke

On September 8, at the European Respiratory Society (ERS) 2020 International Virtual Congress, MSD announced the results of two pivotal Phase 3 clinical trials (COUGH-1 and COUGH-2) evaluating gefapixant (MK-7264), an oral selective P2X3 receptor antagonist, for the treatment of adults with refractory or unexplained chronic cough: twice-daily oral administration of 45 mg gefapixant resulted in a statistically significant reduction in 24-hour cough frequency.

The COUGH-1 study demonstrated that at 12 weeks of treatment, patients receiving gefapixant experienced an 18.45% reduction in 24-hour cough frequency compared with placebo (95% CI [-32.92, -0.86]; p=0.041). The COUGH-2 study showed that at 24 weeks of treatment, patients receiving gefapixant had a 14.64% reduction in 24-hour cough frequency compared with placebo (95% CI [-26.07, -1.43]; p=0.031). However, in both studies, the group treated with oral gefapixant 15 mg twice daily failed to meet the primary efficacy endpoint; in COUGH-1, its performance was even worse than that of placebo. (See table below)

COUGH-1 and COUGH-2 are two international, randomized, double-blind, placebo-controlled Phase 3 clinical studies designed to evaluate the efficacy and safety of gefapixant in reducing cough frequency in adults with refractory or unexplained chronic cough. These trials represent the first Phase 3 studies conducted specifically in patients with refractory chronic cough. MSD stated that an estimated 5%–10% of adults worldwide suffer from chronic cough, a subset of which comprises refractory or unexplained cases. Patients with refractory chronic cough continue to experience persistent symptoms despite appropriate treatment. These patients either fail to respond to therapies targeting underlying conditions (such as asthma or gastroesophageal reflux disease), a condition referred to as refractory chronic cough (RCC), or have no identifiable underlying cause after thorough evaluation, known as unexplained chronic cough (UCC). Currently, there are no approved treatments for RCC or UCC.

These two studies enrolled a total of 2,044 participants [COUGH-1 (n=730) and COUGH-2 (n=1,314)], of whom 75% were female, with a mean age of 58 years and a mean cough duration of 11 years. Patients were randomized into three groups: gefapixant 45 mg twice daily, gefapixant 15 mg twice daily, or placebo. The primary endpoints were the 24-hour cough frequency at Week 12 and Week 24, respectively, measured as the number of coughs per hour using a 24-hour ambulatory digital audio recording device. Secondary endpoints included the hourly awake cough frequency and the percentage of participants achieving an increase in the Leicester Cough Questionnaire (LCQ) total score of more than 1.3 points from baseline. The COUGH-1 study consisted of a 12-week treatment period and a 40-week extension period, while COUGH-2 comprised a 24-week treatment period and a 28-week extension period. Key safety outcomes included the percentage of patients experiencing one or more adverse events (AEs) during treatment and follow-up, as well as the percentage of patients discontinuing treatment due to AEs.

Data show that twice-daily treatment with 45 mg gefapixant significantly reduced the 24-hour objective cough frequency in patients with refractory or unexplained chronic cough in both studies. On average, compared with baseline, cough frequency was reduced by 62% in patients receiving 45 mg gefapixant twice daily in the COUGH-1 study and by 63% in the COUGH-2 study.

Regarding secondary endpoints, in the COUGH-2 study, patients receiving gefapixant 45 mg twice daily achieved a statistically significant reduction in awake cough frequency (relative reduction of 15.79%; 95% CI [-27.27, -2.50]; p=0.022). Furthermore, there was a significant improvement in cough-related quality of life compared with the placebo group, with an odds ratio (OR) of 1.41 (p=0.042). In the COUGH-1 study, there was a trend toward significance (relative reduction of 17.68%; 95% CI [-32.57, 0.50]; p=0.056). In the 45 mg gefapixant treatment group, 77.1% of patients achieved a clinically important improvement in cough-related quality of life, as measured by the LCQ.

Furthermore, the safety and tolerability profile of gefapixant was consistent with previous reports. In the 45 mg dose group, 58.0% and 68.6% of patients experienced taste-related adverse events (AEs), respectively. Across both trials, serious adverse reactions were rare; however, there were indications that taste disturbances were intolerable for certain patients. The discontinuation rates due to AEs in the 45 mg dose group were 15% and 20% in the two trials, respectively, compared with 3% and 5% in the placebo groups.

Gefapixant is an investigational, oral, selective P2X3 receptor antagonist for the treatment of refractory or unexplained chronic cough. P2X3 receptors are one of the receptor types located on sensory nerve fibers (primarily C-fibers) in the airway epithelium. Chemical stimuli, including airway inflammation and mechanical stress/injury, can trigger their release from airway epithelial cells. The binding of extracellular adenosine triphosphate (ATP) to P2X3 receptors on airway C-fibers is also perceived as a signal of potential injury, generating action potentials that subsequently induce coughing. Blocking the binding of extracellular ATP to P2X3 receptors is believed to reduce the activation of sensory C-fibers and suppress cough. Furthermore, since P2X3 and P2X2/3 receptors are also present on taste buds, adverse events (AEs) are primarily related to taste disturbances; however, evidence suggests that molecular selectivity may influence the severity of these issues.

This summer, Bellus reported that the Phase 2 clinical trial of its P2X3 antagonist BLU-5937 failed to meet the primary endpoint. However, one of the molecular advantages of this investigational drug is its favorable tolerability profile. In the study, fewer than 10% of patients experienced taste disorders, and no participants withdrew due to this adverse effect. Taste disturbances have been more prevalent in clinical trials of other existing P2X3 antagonists. In addition to Merck’s gefapixant, a small trial of Bayer’s BAY 1902607 found that 61% of patients developed taste-related adverse reactions after treatment. If market competition intensifies, these tolerability issues could become a significant factor. Nevertheless, Merck has taken the first step toward success by being the first to demonstrate efficacy in the competitive landscape of P2X3 antagonist development, ahead of Bayer, Bellus, and Shionogi.

References:

1.Merck posts mixed phase 3 data on chronic cough drug gefapixant

2.Merck’s Gefapixant (45 mg Twice Daily) Significantly Decreased Cough Frequency Compared to Placebo at Week 12 and 24 in Patients with Refractory or Unexplained Chronic Cough