A drug Merck is developing for chronic cough failed to win over a panel of advisors to the Food and Drug Administration on Friday, making approval unlikely.
The FDA’s Pulmonary-allergy Drugs Advisory Committee (PADAC) voted on whether the evidence demonstrates that the drug — gefapixant — provides a clinically meaningful benefit to adult patients with refractory or unexplained chronic cough, given its small reduction in cough frequency and results from patient-reported outcomes.
The committee’s final vote — 12 to 1 against — was largely due to the clinical benefit shown versus placebo, which analysts described as marginal. Unsurprisingly, Merck took issue with the clear majority of downvotes.
“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,” Merck’s Joerg Koglin, SVP, global clinical development, noted in a statement.
Chronic cough is defined as a cough lasting longer than eight weeks without a positive diagnosis. Refractory chronic cough (RCC) is a condition where a patient has a positive diagnosis for conditions that could cause chronic cough — such as upper airway cough syndrome (UACS), gastroesophageal reflux disease (GERD) or asthma — and whose cough doesn’t resolve via treatment.
Merck is developing gefapixant, a P2X3 inhibitor, for the treatment of RCC or unexplained chronic cough (UCC) in adults. Neither RCC nor UCC currently has an approved therapy.
The FDA, for its part, held that the numerical reduction in cough frequency in patients was small — on the order of 14 % to 18% versus a placebo arm. The agency questioned whether that reduction is clinically meaningful and the PADAC agreed.
The sole “yes” vote came from the patient advocate. As their rationale, committee members emphasized the slim effectiveness of the drug over placebo as well as disagreement between primary (cough reduction) and secondary (patient-reported outcomes) endpoints.
Subjects in the placebo cohort also had a reduction in frequency, either reflecting that UCC and RCC resolve on their own over time or the trial induced a placebo effect. Merck countered that such an effect is a known factor in cough trials, given the nervous system’s involvement in cough, and that previous trials with codeine also showed a placebo effect.
However, “The marginal difference between the active and placebo arms, in addition to the pronounced cough reduction overall, was damning in the eyes of the committee despite the low safety risks associated with gefapixant,” Leerink analyst Daina Graybosch summed up in a Friday investor note.
Then again, there was discussion that chronic cough — which occurs in fits and episodes — is not well-captured by mean or median cough reductions. Measures of patient benefit must better reflect how a patient experiences the condition, committee members noted. In other words, different study design parameters and endpoints are needed to inform future chronic cough trials.
In addition, patients who received the drug experienced loss of taste, a well-known adverse effect related to P2X3 inhibitors.
While the FDA is not bound by its advisory committees’ guidance, it takes such advice into consideration. Gefapixant’s FDA decison date is set for December 27. The FDA declined to approve the drug last year.