Merck & Co (NYSE: MRK) today announced that the U.S. Food and Drug Administration (FDA) has accepted a new drug application (NDA) for gefapixant (MK-7264), an oral, selective P2X3 receptor antagonist for the treatment of adults with refractory chronic cough (RCC) or chronic cough of unknown cause (UCC). An RCC is a cough that persists despite proper treatment for the underlying disease, while a UCC is a cough whose root cause cannot be determined despite a thorough evaluation.
The NDA will be discussed at an upcoming advisory committee meeting, no date has yet been set. FDA has set the Prescription Drug User Fee Act (PDUFA) target date of December 21, 2021. Currently, there are no approved treatments for RCC and UCC. If approved, Gefapixant would be the first drug specifically designed to treat RCC and UCC.
"This application underscores our commitment to helping patients with refractory or unexplained chronic cough who currently have limited treatment options," said Roy Baynes, M.D., senior vice president, head of global clinical development and chief medical officer at Merck Research Laboratories. If approved by the FDA, Gefapixant will be the first drug specifically designed to assist these patients, and we look forward to attending the advisory committee meetings and reviewing our application with the FDA."
The Gefapixant NDA is based on the results of two critical phase III clinical trials (COUSE-1, COUSE-2). COUGH-1 and COUGH-2 are the first concurrent phase 3 trials ever conducted in adult patients with RCC and adults with UCC. Data from these two trials were presented at the online European Respiratory Society (ERS) International Congress in September 2020.
The results showed that the study met its primary endpoint: a statistically significant reduction in 24-hour COUGH frequency (measured objectively with 24-hour audio recordings) at week 12 (the Cay-1 study) and 24 (the Cay-2 study) was observed in the twice-daily 45mg gefapixant treatment group compared with the placebo group. Notably, in both studies, the twice-daily 15mg dose of gefapixant did not meet the primary efficacy end point.
The data were as follows: (1) In the CAF-1 study, at 12 weeks of treatment, the 24-hour COUGH frequency was significantly reduced by 18.45% in the twice-daily 45mg gefapixant group compared with the placebo group (95%CI:-32.92 to -0.86; P = 0.041); (2) In the CAF-2 study, at week 24, 45mg twice daily of gefapixant significantly reduced 24-hour COUGH frequency by 14.64% compared with placebo (95%CI:-26.07 to -1.43; P = 0.031). On average, patients who received 45mg of gefapixant twice daily had a 62 percent reduction in COUGH frequency on the Cugle-1 trial and a 63 percent reduction in COUGH frequency on the Cugle-2 trial compared with baseline.
Secondary endpoints supported the study's primary observation. Early morning COUGH frequency results, which are usually similar to 24-hour COUGH frequency results, were statistically significant in the twice-daily 45mg dose group in the Caught-2 study (estimated relative reduction 15.79%, 95%CI:-27.27 to -2.50; P =0.022), a significant trend was observed in the COUGH-1 study (an estimated relative reduction of 17.68%, 95%CI:-32.5 to 0.50; P = 0.056). At week 24, the twice-daily 45mg dose group showed a significant improvement in cough-related quality of life compared to the placebo group (HR=1.41, P =0.042). In the 45mg dose group, 77.1% of patients showed clinically significant improvements in cough-related quality of life (measured by LCQ).
In both studies, the safety and tolerability of gefapixant were consistent with those reported in previous studies. The incidence of serious adverse events was similar among all groups (< 4%). The 45mg group had a higher frequency of drug discontinuation due to adverse events and a higher incidence of taste-related adverse events. Most taste-related adverse events were mild to moderate.
It is estimated that between 5% and 10% of adults worldwide suffer from chronic cough. Some of these patients had refractory chronic cough (RCC) and chronic cough of unknown cause (UCC) and were more sensitive to triggers that would not normally cause a cough in healthy subjects. This includes everyday activities (such as talking and laughing), changes in temperature, and exposure to aerosols or food odors. To date, treatment options for these patients are extremely limited, and many patients often have not been in remission for years.
Given the large unmet need among these patients, the results of the COUSE-1 and COUSE-2 studies are very encouraging and suggest that gefapixant has the potential to provide a new treatment option for populations of patients struggling with the burden of this disease.
