UPDATE: FDA AdComm shoots down Merck's chronic cough med in 12-1 vote

An FDA advisory committee has voted against approving Merck & Co.’s gefapixant, a P2X3 receptor antagonist medicine designed to treat adults with chronic cough—a decision the Big Pharma disagrees with.

The 12-1 vote is meant to help guide the FDA in its approval decision, which is set to be made by Dec. 27. There currently aren’t any FDA-approved therapies for chronic cough, meaning the indication lacks regulatory precedent.

Merck—which already received a complete response letter from the FDA for gefapixant as a treatment for adults with refractory chronic cough or unexplained cough in 2022—returned with a resubmission for approval based on new analyses that fulfilled the agency’s request for more efficacy information. The reworked submission caused a significant delay for the Big Pharma, which had originally hoped to have the FDA’s blessing for gefapixant in 2021.

Now, the chances of an approval may be even slimmer.

While the New Jersey-based pharma changed up the cough-counting system used to track efficacy, the FDA said it still found it difficult to evaluate clinical meaningfulness. This prompted the agency to conduct its own post hoc analysis, which revealed only small differences between treatment groups for median cough frequency. Based on that finding and a high placebo response rate, the FDA questioned whether the reduction was clinically meaningful, citing the “small treatment effect” and “limited experience with the endpoints used in this program.”

The FDA’s concerns were echoed by many of the advisory panelists.

“I don’t think the level of evidence supports that the drug makes a significant difference. It’s unfortunate,” said Mark Courey, M.D., vice chair of quality for otolaryngology and head and neck surgery and the director of laryngology at the Grabscheid Voice and Swallowing Center at Mount Sinai in New York. “I am concerned that if the drug is readily available, it could lead to a delay in diagnosis of other illnesses because cough—while it can be very debilitating—is a symptom, not a disease in and of itself. And so, I think this would delay the evaluation of the patients for other diseases that could be potentially harmful.”

“My heart goes out to this patient population, who remain hopeful for a therapy that would make a difference,” said Leonard Bacharier, M.D., chief of pediatric allergy and immunology at Monroe Carell Jr. Children’s Hospital at Vanderbilt. “But I am just concerned that we don’t want to be providing just hope—we want to be providing predictably effective pharmacologics that are likely to make meaningful differences.”

The program in question included two 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. Statistical significance of cough frequency reduction was 0.03 in P030, resting safely within the threshold of 0.05 for statistical significance, while the p-value for P027 was 0.057—slightly outside the boundary for statistical significance.   

Multiple panelists voiced concerns that the proper endpoints may not have been chosen, as reduction of coughing fits was not measured. Merck representatives responded by noting that there is no agreed-upon clinical definition for a cough cluster.

“We don’t have a good precedent for endpoints, and we’re hearing loud and clear that the endpoints do need to be reconsidered,” said Paula Carvalho, M.D., professor of medicine at the University of Washington and academic section chief at the Boise VA Medical Center.

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

Any improvement is meaningful to someone with a severe chronic cough, panelist Jennifer Schwartzott, who has a chronic cough herself, pointed out. Schwartzott was the sole panelist to vote in favor of gefapixant.     

“If the patient takes the medication and it works for them, that’s wonderful. If they take the medication and it doesn’t work, they can just stop it,” Schwartzott said. “If they take the medication and get those adverse events, they could decide whether or not it’s worth it to them.”

The patient representative did acknowledge that she was “greatly on the fence” about her decision.

“Of course, we want better results,” Schwartzott said. “We want something that lasts longer. We want something that totally stops it. But this is a start.”

Several chronic cough patients spoke at the meeting about the embarrassment, inconvenience, pain and endless testing associated with the condition, emphasizing the importance that a medicine could have on improving their quality of life.

“We disagree with the committee’s assessment based on the strong, comprehensive gefapixant data showing a meaningful clinical benefit for adults with refractory or unexplained chronic cough,” said Joerg Koglin, M.D., Ph.D., senior vice president of global clinical development at Merck Research Laboratories, said in a Nov. 17 release. “Merck believes in the value gefapixant can provide to adults living with this condition and today’s discussion underscored the clear need for new treatments.”

While Merck’s chronic cough journey hangs in the balance, other competitors—such as GSK—continue to plug away at the indication. This spring, GSK paid out $2 billion to buy biotech Bellus Health this spring and secure a late-phase rival to gefapixant. Dubbed camlipixant, the molecule has the same mechanism of action as gefapixant and 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.  

Editor's note: This article was updated at 9:50 a.m. ET Nov. 20 to include a statement from Merck & Co.