FDA advisors told the agency that the current evidence does not support approval of gefapixant for chronic cough, a condition where no approved therapy exists.
On Friday, members of the Pulmonary-Allergy Drugs Advisory Committee voted 12-1 that the small reductions in cough frequency demonstrated in phase III trials of the P2X3 receptor antagonist do not amount to a clinically meaningful benefit for patients with refractory or unexplained chronic cough, defined as a cough persisting for more than 8 weeks.
The stage is now set for FDA to again reject Merck’s drug candidate. Beyond concerns about the drug’s modest effect, the agency in its 2022 complete response letter took issue with the measurement system used to track patients’ coughs in the two pivotal trials and requested that the coughing frequency be recounted using a different methodology.
In updated recount analyses presented on Friday, twice-daily treatment with a 45-mg dose of gefapixant resulted in a 15-17% relative reduction in 24-hour cough frequency over placebo at weeks 12 and 24 (the trials’ primary endpoints, with the difference significant in only one of them). The trials had been designed to show a 30% reduction.
Some further benefit was detected among patient-reported outcomes (PROs). In one of the trials, a significantly higher proportion of patients had a 1.3-point or greater increase on the Leicester Cough Questionnaire total score from baseline to 24 weeks (OR 1.4, 95% CI 1.0-2.0), but this represented just 3.3% more patients versus placebo.
“There are numerous issues and uncertainties that make it challenging to interpret the results and difficult to definitively conclude that the results are clinically meaningful, particularly when patients experienced similar improvements whether they received placebo or gefapixant,” said Stacy Chin, MD, of FDA’s Division of Pulmonology, Allergy, and Critical Care. “If there is not a clinically meaningful benefit, the product only confers risks, no matter how mild those risks might be.”
As previously detailed, studies showed that 65% of patients receiving gefapixant experienced taste disturbances, a cause of early treatment discontinuation in 14%. The common side effect may have potentially unblinded study participants as well.
Chronic cough affects an estimated 5% to 10% of all adults. It is considered refractory when not relieved by treatment for an existing condition that causes coughing — such as chronic obstructive pulmonary disease (COPD) or asthma — or simply unexplained when no underlying medical condition is present.
A host of products are used off-label for the condition (neuroleptics, opioids, local anesthetics), but they can carry risks and the evidence supporting their use is limited. It’s expected that any approved drug for the condition would be widely used and require long-term treatment.
While the cause of chronic condition is not fully clear, it’s hypothesized that the purinergic P2X3 receptor acts as one of many cough receptors and that gefapixant would decrease sensitivity to stimuli, thereby suppressing coughs.
While the FDA is not required to follow the recommendations of its advisory committees, it typically does.