Merck's New Drug Application for Gefapixant Rejected by U.S. FDA Despite Positive Phase III Data

Compiled by Fan Dongdong

Recently, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Merck Sharp & Dohme AG regarding the New Drug Application (NDA) for gefapixant, intended for the treatment of refractory chronic cough or unexplained chronic cough. This indicates that the non-narcotic, orally administered selective P2X3 receptor antagonist has officially been rejected by the FDA.

Although MSD did not specify the details of the complete response letter, it claimed that the U.S. FDA's rejection of gefapixant was not related to the drug's safety risks. MSD stated that it is reviewing the contents of the response letter and plans to meet with the U.S. FDA to discuss the next steps. The U.S. FDA initially accepted the New Drug Application (NDA) for gefapixant on March 1, 2021, which was primarily based on the data from the COUGH-1 and COUGH-2 studies. These were also the first Phase III trials conducted in patients with refractory chronic cough (RCC).

A total of 2,044 patients received gefapixant in the trial and were randomly assigned to receive either 45 mg of gefapixant twice daily, 15 mg of gefapixant twice daily, or a placebo. The primary efficacy endpoints for the COUGH-1 and COUGH-2 trials were the 24-hour cough frequency at week 12 and week 24, respectively. The trial results showed that, compared with the placebo group, patients in the 45 mg twice-daily gefapixant treatment group experienced a statistically significant reduction in 24-hour cough frequency at week 12 (COUGH-1 study) and week 24 (COUGH-2 study).

Specifically, in the COUGH-1 study, at week 12 of treatment, the 24-hour cough frequency in the group treated with gefapixant at a dose of 45 mg twice daily was significantly reduced by 18.45% compared to the placebo group. In the COUGH-2 study, at week 24 of treatment, the 24-hour cough frequency in the group treated with gefapixant at a dose of 45 mg twice daily was significantly reduced by 14.64% compared to the placebo group. The trial conclusions indicated that in patients taking gefapixant at a dose of 45 mg twice daily, the cough frequency decreased by 62% from baseline in the COUGH-1 trial and by 63% from baseline in the COUGH-2 trial.

Despite the recent rejection by the U.S. FDA, Merck & Co., Inc. (MSD) stated that it would not abandon future development efforts for gefapixant. Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development at Merck Research Laboratories, as well as Chief Medical Officer, expressed that MSD remains committed to advancing the development of gefapixant for patients with refractory or unexplained chronic cough and will collaborate with the U.S. FDA to address the agency’s feedback. "MSD believes that the clinical need to help patients manage chronic cough remains unmet, as there are currently no treatments specifically targeting this condition in the U.S. market."

It is estimated that 5% to 10% of adults worldwide suffer from chronic cough. Some of these patients have refractory chronic cough or unexplained chronic cough, and are more sensitive to various triggers that normally do not cause coughing in healthy subjects. MSD's gefapixant is an investigational oral, selective P2X3 receptor antagonist that can be used to treat refractory or unexplained chronic cough. The P2X3 receptor is one of the types of receptors on sensory nerve fibers in the airway lining, and blocking the binding of extracellular ATP to the P2X3 receptor is believed to reduce the activation of sensory C fibers and coughing.

However, the safety of the drug has indeed raised some concerns. Since P2X3 and P2X2/3 receptors are also present on taste buds, the majority of patients in the trial experienced side effects related to taste. A small number of patients developed mild to moderate taste disturbances after receiving gefapixant treatment, but no patients withdrew from the trial due to this side effect. Notably, taste disturbances are also common in existing clinical trials of other P2X3 antagonists. In addition to MSD's gefapixant, a small trial of Bayer's BAY 1902607 found that up to 61% of patients experienced taste-related adverse reactions after treatment.

Despite the U.S. FDA's recent rejection of gefapixant, the drug was approved not long ago by Japan's Ministry of Health, Labour and Welfare and is being marketed under the brand name Lyfnua. The approved dosage is 45 mg for the treatment of adults with refractory chronic cough or unexplained chronic cough.

Reference Source: Merck Remains Committed to Chronic Cough Drug Following FDA Rejection