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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.

"This agent likely does something, but at the end of the day I struggled with the small effect size relative to the placebo effect," said Scott Evans, MD, of the University of Texas MD Anderson Cancer Center in Houston.

"I don't think the level of evidence supports that the drug makes a significant difference," said Mark Courey, MD, of the Icahn School of Medicine at Mount Sinai in New York City, who also noted the potential for unintended consequences.

"I am concerned that if the drug is readily available it could lead to a delay in diagnosis of other things, other illnesses," said Courey. "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 patients for other diseases. That could be potentially harmful."

The stage is now set for FDA to Merck's drug candidate. Beyond concerns about gefapixant'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 a new analysis.

In updated data 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. In one of the trials, a significantly higher proportion of gefapixant-treated 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 gefapixant to be generally safe, but also that 65% of patients receiving the drug experienced taste disturbances or loss of taste, a cause of early treatment discontinuation in 14%. The common adverse event may have potentially unblinded study participants as well.

Patients likely knew they were having a side effect, commented Brian Garibaldi, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore.

"That makes it really hard to know exactly what's driving that small difference between the placebo group and the folks who got the drug," he said.

Members of the panel also questioned whether the most appropriate endpoints had been chosen to determine benefit.

"I am a pulmonary clinician, I see patients with chronic cough, I understand the need," said Evans. "But I do want to be careful and resist my own urge to think that something's better than nothing, because I think we are establishing precedents here. And if we adopt the wrong markers and outcomes, I think we actually may limit our ability to identify the best drug."

The sole vote in support of gefapixant came from the committee's patient representative, who felt the risks were low and said relief is desperately wanted by this patient population.

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 or asthma -- or simply unexplained when no underlying medical condition is present.

A host of products are used off-label to treat chronic cough (neuroleptics, opioids, local anesthetics), but they can carry risks and the evidence supporting their use is limited. It's expected that any approved drug would be widely used and require long-term treatment.

Like several of the panelists, Leonard Bacharier, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, described himself as voting no "despite my wish to have been more positive."

Bacharier also expressed sympathy for chronic cough patients, but maintained the importance of not providing "just hope," but rather "providing predictably effective pharmacologics that are likely to make meaningful differences."

While the cause of the 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.

Sally Hunsberger, PhD, of the National Institutes of Health in Rockville, Maryland, stressed the importance of further research: "I hope that this 'no' vote doesn't discourage the continued search for treatments for this population."

Gefapixant is not the only P2X3 receptor antagonist in the pipeline. Recent phase II data with another investigational agent in the class showed benefit for chronic cough, and with less taste disturbance.

The FDA is expected to make a decision on gefapixant by late December. While the agency is not required to follow the recommendations of its advisory committees, it typically does.

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