Merck & Co. is racing against the clock to launch the first medication for chronic coughing on the market. With the FDA expressing further reservations about the pharmaceutical company’s candidate, it seems that the route it has taken thus far will be even more fraught with delays.
The FDA has expressed concerns about Merck’s P2X3 receptor antagonist drug, gefapixant, in advance of an advisory committee hearing that is scheduled for tomorrow. The FDA’s investigation revealed minimal variation across treatment groups. Yesterday, the examination was made public in FDA briefing materials.
The FDA sent Merck a comprehensive response letter in the beginning of 2022 on the use of gefapixant as a therapy for people with refractory chronic cough or cough that cannot be understood. Resubmitting for approval, Merck has now provided fresh analyses that satisfy the agency’s need for further efficacious data.
This time, the New Jersey-based pharmaceutical company modified its cough counting method for monitoring effectiveness by utilizing inter-rater validity research and a verification analysis of the recording compression formula to recollect coughs in two critical studies.
The dosage of 45 mg of gefapixant twice a day, which Merck is requesting clearance for, demonstrated a little decrease in cough frequency based on the recount data. Due to the “small treatment effect” and limited expertise with the outcomes used in the setup, as stated in the documents released on November 15, the FDA is now unsure if the decrease is clinically relevant.
P030 and P027, both 52-week double-blind, placebo-controlled studies, were part of the gefapixant program in question. Cough frequency at 24 weeks was the main outcome in P030, whereas P027 assessed it at 12 weeks. It was computed by dividing the total number of cough episodes within a 24-hour period by the length of the recording. Whereas the p-value for P027 was 0.057—slightly beyond the limit for statistical significance—the statistical significance of cough frequency decrease in P030 was 0.03—safely lying within the 0.05 barrier.
The FDA observed that for the smaller trial P027, the recount caused the p-value change to be more than 0.05. The regulator also noted that from base to week 24 or week 12, the geometric average ratio decreased relative to placebo by -15% to -17%, which was the point estimate for lowering cough frequency in both studies. The agency claims that the reported result is significantly less than the 30% relative decrease that both studies were intended to achieve.
There are no treatments for chronic cough that have been authorized by the FDA yet, thus there is no regulatory yardstick for choosing endpoints or interpreting effectiveness data. This, along with Merck’s “complicated presentation of the data,” made it difficult for the FDA to interpret the outcomes in a clinical context, the agency said.
With that in mind, the agency did its own post hoc study of absolute cough frequency, which showed very little variations in median cough frequency across treatment groups. In light of this data and the fact that the placebo response rate was high, the FDA is skeptical that gefapixant actually helps patients.