FDA Rejects Drug for Chronic Cough

The FDA declined to approve oral gefapixant for treating chronic cough, Merck announced on Wednesday.

In its complete response letter, “the FDA concluded that Merck’s application did not meet substantial evidence of effectiveness” for the treatment of unexplained or refractory chronic cough, according to the drugmaker, but no safety concerns were cited.

No approved drug exists for treating chronic cough, and the agency’s decision represents the second rejection for the non-narcotic, selective P2X3 receptor antagonist for this indication. The move comes a little more than a month after the FDA’s Pulmonary-Allergy Drugs Advisory Committee recommended against approval in a near-unanimous vote.

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

In two phase III trials, twice-daily treatment with gefapixant at the 45-mg dose level resulted in a 15-17% relative reduction in 24-hour cough frequency over placebo at weeks 12 and 24, though the difference was significant in only one of the studies. Nearly two-thirds of patients receiving the drug experienced taste disturbances or loss of taste, a cause of early treatment discontinuation in 14%.

“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.”

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 therefore drugs targeting P2X3 would decrease sensitivity to stimuli and suppress coughs.

Another investigational agent in the class (BLU-5937; camlipixant) showed benefit for chronic cough in a phase II study and was associated with less taste disturbance as well. That drug is now being tested in the phase III CALM-1 and CALM-2 trials.

Any approved drug is expected to be widely prescribed, as chronic cough affects an estimated 5% to 10% of all adults, and these individuals would require long-term treatment. Currently, off-label products with questionable evidence and safety are often prescribed, including neuroleptics and opioids.

Defined as a cough that lasts for at least 8 weeks, it is considered refractory when not relieved by treatment for an existing condition that induces coughing — e.g., asthma or chronic obstructive pulmonary disease — or simply unexplained when no underlying medical condition is present.

Staff writer Elizabeth Short contributed to this report.