The FDA Advisory Committee Voices Concerns over Gefapixant’s Efficacy for Chronic Cough

The recent meeting of the Pulmonary-Allergy Drugs Advisory Committee concluded with a vote of 12-1 against the approval of gefapixant for the treatment of chronic cough. This decision is based on the current evidence, which suggests that the small reductions in cough frequency observed during phase III trials do not provide a clinically meaningful benefit to patients. Chronic cough, defined as a persistent cough lasting more than 8 weeks, currently has no approved therapy. Despite the potential need for a new treatment option, the committee expressed reservations about the efficacy of gefapixant.

One of the main concerns voiced by the advisory committee was the modest effect demonstrated by gefapixant in reducing cough frequency. In the pivotal trials, twice-daily treatment with a 45-mg dose of gefapixant resulted in a 15-17% relative reduction in 24-hour cough frequency compared to placebo at weeks 12 and 24, which fell short of the expected 30% reduction. While there were some additional benefits reported in patient-reported outcomes (PROs), such as a higher proportion of patients experiencing a significant increase in the Leicester Cough Questionnaire total score, these improvements were minimal.

The FDA also raised concerns about the measurement system used to track patients’ coughs in the trials. In its 2022 complete response letter, the agency requested a recount of the coughing frequency using a different methodology. Furthermore, the FDA advised that the results were challenging to interpret due to various issues and uncertainties. Without clear evidence of a clinically meaningful benefit, the risks associated with the drug, even if mild, outweigh any potential benefits.

Additional concerns regarding gefapixant’s side effects were also discussed during the advisory committee meeting. The studies showed that 65% of patients receiving the drug experienced taste disturbances, leading to treatment discontinuation in 14% of cases. This common side effect may have also potentially unblinded study participants, impacting the reliability of the trial results.

Chronic cough affects a significant proportion of adults, estimated to be between 5% and 10%. When the cough persists despite treatment for underlying conditions such as chronic obstructive pulmonary disease (COPD) or asthma, it is classified as refractory. In cases where no underlying medical condition explains the cough, it is considered unexplained. Currently, there are several off-label products used for the treatment of chronic cough, including neuroleptics, opioids, and local anesthetics. However, their use is limited due to potential risks and a lack of strong evidence supporting their efficacy.

The Search for Effective Treatment

The potential approval of a new drug for chronic cough has significant implications for patients who suffer from this condition. Given the lack of approved therapies and the widespread nature of chronic cough, any approved drug would likely be widely used and require long-term treatment. However, the efficacy of gefapixant remains uncertain.

Research suggests that the purinergic P2X3 receptor may play a role in cough sensitivity, and gefapixant is designed to decrease the receptor’s sensitivity to stimuli, ultimately suppressing coughs. While this mechanism of action appears promising, the advisory committee’s reservations about gefapixant’s efficacy cast doubt on its potential as a viable treatment option for chronic cough.

In light of the latest FDA advisory committee meeting, it is evident that gefapixant faces significant challenges in securing approval for the treatment of chronic cough. The committee’s concerns regarding its modest effect, measurement system, and side effects have raised doubts about the drug’s efficacy and safety. With no approved therapies currently available for chronic cough, patients and healthcare providers continue to search for effective treatment options.


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