Merck Receives Complete Response Letter for Cough Drug Gefapixant

The FDA has issued a complete response letter (CRL) for Merck’s new drug application (NDA) for gefapixant, a non-narcotic, oral treatment for refractory chronic cough (RCC) or unexplained chronic cough (UCC) in adults.

This is the second time the FDA has issued a complete response letter for Merck’s application for gefapixant. Merck had originally submitted the application for the cough indications in early 2021 based on results from the COUGH-1 and COUGH-2 clinical trials. In these phase 3 studies, adult patients treated with gefapixant 45 mg twice daily demonstrated a statistically significant reduction in 24-hour cough frequency compared with placebo at 12 weeks and at 24 weeks. The gefapixant 15 mg twice daily treatment arms did not meet the primary efficacy endpoint in either phase 3 study. These results were published in The Lancet in March 2022.

In January 2022, however, the FDA issued its first CRL and asked for additional information related to the measurement of efficacy. At the time, Merck officials said the agency’s questions were primarily related to the cough counting system used in generating the phase 3 data.

In the current action, the regulatory agency indicated the application did not provide evidence of effectiveness. The CRL was not related to the safety of gefapixant. Merck officials in a press release said they are reviewing the FDA’s feedback to determine next steps.

In July 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of gefapixant to treat refractory or unexplained chronic cough. The European Commission is now reviewing the application for marketing authorization in the European Union (EU). A final decision is expected later this year.

Chronic cough is defined as a cough lasting longer than eight weeks. In adults with RCC, the cough persists despite appropriate treatment of underlying conditions such as asthma or gastroesophageal reflux disease, and UCC is a cough where the underlying cause cannot be identified despite a thorough evaluation.

Gefapixant is a selective P2X3 receptor antagonist. P2X3 receptors are one of the receptor types found on sensory nerve fibers in the airway lining. It thought that gefapixant works by reducing sensory nerve activation and, subsequently, cough. In 2022, Japan and Switzerland approved gefapixant 45 mg; it is marketed with the brand name of Lyfnua.