Researchers Rule Out Gefapixant to Help Unexplained Chronic Cough

Developing a chronic cough can significantly affect quality of life, with little explanation for the cause. Researchers have found that a chronic cough affects 2% to 18% of individuals worldwide and 10% to 60% have refractory or an unexplained cough that does not respond to treatment.

Image credit: Art_Photo - stock.adobe.com

Treatment options are slim for individuals suffering from a chronic cough, and offered therapies have a dosing limit, adverse effects, long term use concerns, and poor response. Published in JAMA Network, researchers conducted a study on the use of a P2X3 antagonists, gefapixant, compared to placebo as an effective treatment for chronic cough. The results showed modest improvements but significant adverse events.

Clinical trials have been conducted with antitussives that contain P2X3 antagonists as a treatment option for chronic cough. The P2X3 antagonists bind to the P2X3 receptors to block the receptor and prevent adenosine triphosphate to open the channel. This leads to the reduction of the activation of c-fibers that spread to the brainstem and somatosensory cortex that control the cough.

Gefapixant is a P2X3 antagonist that was used in a phase 3 trial that reduced 24-hour cough frequency in comparison to the placebo, although the FDA has not yet approved its use.

In the study, the researchers conducted a systematic review and dose-response meta-analysis that differed from previous clinical trials to assess the effects of gefapixant for individuals suffering with a chronic cough.

The researchers used randomized clinical trials (RCTs) that compared the use of gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo in individuals 18 years or older who had a chronic cough lasting longer than 8 weeks. Paired reviewers screened 713 titles and abstracts and 100 full-text articles to find 11 RCTs to begin their crossover and parallel design.

The study notes that the 2 reviewers that independently extracted the data used the grading of recommendation, assesement, development, and evaluation (GRADE) method when ranking if the individuals would distinguish the effectiveness as important, greater than the minimal important difference (MID), or less than MID.

Prior to finding the 11 RCTs, the researchers used 9 of them in their primary analysis of 2980 individuals. The study notes that between the 9 trials, 4 had the crossover design and 5 had a parallel design. Each of the trials, except for 1, compared different doses of gefapixant with a placebo.

The 45 mg twice daily dose of gefapixant compared with the placebo resulted in improvements for the cough frequency, severity, and quality of life. However, the researchers reported that this dose increased treatment-related and taste-related adverse events. The patients considered this in greater importance than the reduction of cough frequency.

With an increased dose of 60 mg twice daily, gefapixant was reported to reduce the cough frequency more, but raise the adverse effects of treatment and taste. Due to the risks and adverse events, gefapixant was discontinued.

“Because reporting of average effects rests on an assumption that all patients experience similar benefit, the risk differences were modeled for achieving at least the MID for gefapixant at 45 mg twice daily. For awake cough frequency, compared with placebo, only 6.9% more patients receiving gefapixant would achieve a 20% change from baseline,” said the study authors.

Although gefapixant was ruled out as a safe treatment to relieve chronic cough, the placebo used in the study reported improvements in awake cough frequency by 54.8%. However, the study notes that future studies will need to be conducted to understand the use of the placebo.

Reference

Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough. JAMA Network. News release. September 11, 2023. Accessed September 12, 2023. https://jamanetwork.com/journals/jama/fullarticle/2809599?guestAccessKey=7eeca61f-6e63-404e-b54e-fb61b407ac11&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=091123.