U.S. FDA Accepts Merck’s New Drug Application for Gefapixant, an Oral Selective P2X3 Receptor Antagonist, for Refractory or Unexplained Chronic Cough

March 09, 2021 News /BioValleyBIOON/ -- Merck & Co. recently announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for the novel antitussive drug gefapixant (MK-7264), an oral, selective P2X3 receptor antagonist indicated for the treatment of adult patients with refractory chronic cough (RCC) or unexplained chronic cough (UCC). RCC is defined as a persistent cough despite appropriate treatment of the underlying condition, whereas UCC refers to a cough for which no underlying cause can be identified despite comprehensive evaluation.

This NDA will be discussed at the upcoming advisory committee meeting.MeetingAs discussed above, the date has not yet been determined.FDAThe target date under the Prescription Drug User Fee Act (PDUFA) has been set for December 21, 2021. Currently, there are no approved drugs for the treatment of RCC and UCC. If approved,Gefapixant will become the first drug specifically indicated for the treatment of RCC and UCC.

Roy Baynes, M.D., Senior Vice President of MSD Research Laboratories, Global Head of Clinical Development, and Chief Medical Officer, stated: “This submission underscores our commitment to helping patients with refractory or unexplained chronic cough who currently have limited treatment options. If approved by the FDA, gefapixant would be the first medication specifically designed to help these patients, and we look forward to participating in the Advisory Committee meeting and engaging with”FDA"Review our application together."

Chemical Structure of Gefapixant (Image source: medchemexpress.com)

Gefapixant NDA Based on2 Pivotal Phase IIIClinical TrialResults of (COUGH-1, COUGH-2). COUGH-1 and COUGH-2 were the first-ever parallel Phase 3 trials conducted in adult patients with RCC and adult patients with UCC. Data from these two trials were presented at the online European Respiratory Society (ERS) International Congress held in September 2020.

The results showed that the study met its primary endpoint: compared with the placebo group, the gefapixant 45 mg twice-daily treatment group demonstrated a statistically significant reduction in 24-hour cough frequency (objectively measured as hourly cough counts using 24-hour audio recording) at Week 12 (COUGH-1 study) and Week 24 (COUGH-2 study). Notably, the gefapixant 15 mg twice-daily treatment group did not meet the primary efficacy endpoint in either of the two studies.

Specific data were as follows: (1) In the COUGH-1 study, at Week 12 of treatment, the gefapixant 45 mg twice-daily group showed a statistically significant 18.45% reduction in 24-hour cough frequency compared with the placebo group (95% CI: -32.92 to -0.86; p=0.041); (2) In the COUGH-2 study, at Week 24 of treatment, the gefapixant 45 mg twice-daily group showed a statistically significant 14.64% reduction in 24-hour cough frequency compared with the placebo group (95% CI: -26.07 to -1.43; p=0.031). On average, patients receiving gefapixant 45 mg twice daily experienced a 62% reduction in cough frequency from baseline in the COUGH-1 trial and a 63% reduction from baseline in the COUGH-2 trial.

Secondary endpoints supported the primary findings of the study. Results for morning cough frequency were generally consistent with those for 24-hour cough frequency. In the COUGH-2 study, the 45 mg twice-daily dosage group achieved statistical significance (estimated relative reduction: 15.79%; 95% CI: -27.27 to -2.50; p=0.022), while in the COUGH-1 study, it showed a trend toward significance (estimated relative reduction: 17.68%; 95% CI: -32.5 to 0.50; p=0.056). At Week 24, the 45 mg twice-daily dosage group demonstrated significant improvement in cough-related quality of life compared with the placebo group (HR=1.41, p=0.042). Among patients in the 45 mg dosage group, 77.1% achieved a clinically meaningful improvement in cough-related quality of life, as measured by the Leicester Cough Questionnaire (LCQ).

In two studies, the safety and tolerability of gefapixant were consistent with those reported in previous studies. The incidence of serious adverse events was similar across groups (<4%). The 45 mg group had a higher frequency of discontinuation due to adverse events and a higher incidence of taste-related adverse events. Most taste-related adverse events were mild to moderate in severity.

Chronic Cough (Image source: quickanddirtytips.com）

It is estimated that 5%–10% of adults worldwide suffer from chronic cough. A subset of these patients have refractory chronic cough (RCC) or unexplained chronic cough (UCC), characterized by heightened sensitivity to various triggers that typically do not induce coughing in healthy individuals. These triggers include daily activities such as speaking and laughing, changes in air temperature, and exposure to aerosols or food odors. To date, therapeutic options for these patients remain extremely limited, with many failing to achieve relief over the course of several years.

Given the substantial unmet need in these patients, the results of the COUGH-1 and COUGH-2 studies are highly encouraging, indicating that gefapixant has the potential to provide a new therapeutic option for patients burdened by this condition. (Bioon.com)

Original Source: U.S.FDA Accepts Merck’s Gefapixant New Drug application for Review