FDA Panel Votes Against Gefapixant for Chronic Cough

The Food and Drug Administration’s (FDA) Pulmonary-Allergy Drugs Advisory Committee has voted against the approval of gefapixant for the treatment of refractory chronic cough (RCC) or unexplained chronic cough (UCC) in adults. The panel voted 12 to 1 that the evidence does not demonstrate a clinically meaningful benefit.

Gefapixant is an orally administered, selective P2X3 receptor antagonist. It is believed that excessive activation of P2X3 receptors is associated with neuronal hypersensitization in the airways and lungs leading to chronic cough.

The panel reviewed data from two pivotal phase 3 trials, COUGH-1 (ClinicalTrials.gov Identifier: NCT03449134) and COUGH-2 (ClinicalTrials.gov Identifier: NCT03449147), as well as two supplementary phase 3 trials. The supplementary trials were part of the New Drug Application resubmission and included patients with chronic cough and stress urinary incontinence (ClinicalTrials.gov Identifier: NCT04193176) and those with a recent diagnosis of chronic cough (ClinicalTrials.gov Identifier: NCT04193202).

Findings from the pivotal trials showed a small reduction in cough frequency with gefapixant compared with placebo (relative reduction in geometric mean ratio of 15-17%), with a median absolute reduction of 1 to 2 coughs per hour. 

“With a large placebo response and wide range of cough frequencies at baseline, we question if the small treatment difference in cough frequency is noticeable to patients,” the panel stated in the meeting brief. The committee also noted that since neither supplementary trial assessed cough frequency, results from those trials would not help in interpreting the clinical benefit of gefapixant.

To assess whether the treatment effect was clinically meaningful to patients, the panel looked at supportive evidence from patient-reported outcomes (PRO), including the Leicester Cough Questionnaire, the Cough Severity Diary, and the Cough Severity Visual Analog Scale. Results showed a small treatment effect across the PRO endpoints favoring gefapixant, though it could not be established whether this effect had an impact on clinical meaningfulness due to certain limitations.

Commenting on the vote, Dr Joerg Koglin, senior vice president, global clinical development, Merck Research Laboratories, said: “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 believes in the value gefapixant can provide to adults living with this condition and today’s discussion underscored the clear need for new treatments.”

Though not bound to the panel’s recommendations, the FDA does take them into account when deciding on approval. A regulatory decision is expected on December 27, 2023.