FDA skeptical of Merck's gefapixant, even after cough recount

Merck & Co. is running out of time to get the first chronic cough medicine to market. Its path thus far has been wrought with delays and the future appears no different as the FDA expresses new doubts about the pharma’s candidate.

Ahead of an advisory committee panel to be held tomorrow, the FDA has raised questions about Merck’s gefapixant—a P2X3 receptor antagonist medicine—after the agency’s own analysis found little difference between treatment groups. The scrutiny was published in FDA briefing documents yesterday.

At the start of 2022, Merck received a complete response letter from the FDA for gefapixant as a treatment for adults with refractory chronic cough or unexplained cough. Merck is now back with a resubmission for approval based on new analyses that fulfill the agency’s request for more efficacy information.

This time around, the New Jersey-based pharma changed up its cough counting system used to track efficacy, recounting coughs in two pivotal trials using a recording compression algorithm validation study and an inter-rater reliability study.

Based on the recount results, 45 mg of gefapixant twice daily—the dosage Merck is seeking approval for—showed a small reduction in cough frequency. The FDA is currently questioning if that reduction is clinically meaningful, citing the “small treatment effect” and “limited experience with the endpoints used in this program,” in the Nov. 15 documents.

The gefapixant program at question included two 52-week, double-blind and placebo-controlled trials, dubbed P030 and P027. The primary endpoint in P030 was cough frequency at 24 weeks, while P027 evaluated the measure at 12 weeks. Cough frequency was calculated as the number of cough events over 24 hours divided by total duration of the recording. Statistical significance of cough frequency reduction was 0.03 in P030, resting safely in the threshold of 0.05 for statistical significance, while the p-value for P027 was 0.057—slightly outside the boundary for statistical significance.    

The FDA noted that the recount shifted the p-value to be greater than 0.05 for the smaller trial P027. The agency also acknowledged that the point estimate for reducing cough frequency was similar in both trials, a relative reduction in the geometric mean ratio of -15% to -17% compared to placebo from baseline to week 24 or week 12. The observed effect is considerably smaller than the 30% relative reduction that both trials were designed to reach, according to the agency.

Of interest is also an observed side effect of gefapixant. While the drug has a generally safe profile, the FDA pointed to a disturbance in or loss of taste that occurred in up to 65% of subjects receiving 45 mg and prompted discontinuation of treatment for 14% of patients.

There currently aren’t any FDA-approved therapies for chronic cough, meaning the indication lacks regulatory precedent, particularly when considering endpoint selection and interpretation of efficacy data. This, paired with Merck’s “complicated presentation of the data,” made it challenging for the FDA to assess the clinical meaning of the results, according to the agency.

Because it was difficult for the FDA to evaluate efficacy, the FDA conducted its own post hoc analysis of absolute cough frequency, which revealed only small differences between treatment groups for median cough frequency. Based on that finding and a high placebo response rate, the FDA questions if gefapixant results in an obvious benefit for patients.

The agency is urging the upcoming advisory committee panelists to gauge the clinical meaningfulness of the cough frequency results when they gather tomorrow.

While Merck’s chronic cough journey has been riddled with hangups, other chronic cough competitors have emerged from the woodwork, such as GSK. The Big Pharma paid out $2 billion to buy biotech Bellus Health this spring and secure a late-phase rival to gefapixant.

Bellus’ lead candidate is camlipixant, a molecule with the same mechanism of action as gefapixant. Camlipixant is currently being studied in a pair of phase 3 clinical trials, putting it on track to deliver data in the second half of 2024 and 2025. GSK has said it expects to win FDA approval for camlipixant and launch the drug in 2026.