Gefapixant Made Modest Symptom Improvements in Patients With Chronic Cough, Review Says

Taking 45 mg of gefapixant orally twice daily led to modest improvements in cough severity, cough frequency, and cough-specific quality of life in patients with refractory or unexplained chronic cough, according to a review published in JAMA.

Despite chronic cough affecting 2% to 18% of adults globally, the researchers explained that there are currently no licensed treatments for either refractory or unexplained chronic cough. On the other hand, P2X3 antagonists, a new class of antitussives, have shown some promise in clinical trials of treating chronic cough.

One promising P2X3 antagonist is gefapixant, which met the primary end point of reducing 24-hour cough frequency compared with a placebo. As a result, gefapixant has been licensed in Japan and Switzerland and could become the first licensed treatment for refractory or unexplained chronic cough across multiple countries globally.

Despite being approved in an increasing number of countries, the researchers noted that no previous studies evaluated all randomized trial evidence of gefapixant, which could potentially help regulatory agencies, guideline developers, clinicians, payers, and patients. Consequently, they performed a systemic review and dose-response meta-analysis to evaluate the impact of gefapixant in patients with refractory or unexplained chronic cough.

To create their study population, 2 reviewers independently searched various databases, including MEDLINE and Embase, from November 2014 to July 2023 and screened for parallel and crossover randomized clinical trials (RCTs) that compared either gefapixant with placebo or 2 or more doses of gefapixant with or without placebo in patients with refractory or unexplained chronic cough.

Man coughing

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After initially screening 713 titles and abstracts and 100 full-text articles, the researchers narrowed it down to 9 published RCTs that included 2980 patients. They explained that the included patients had a mean age of 58.5 years, a median cough duration of 11.6 years, and a mean of 75.7% were female; these characteristics are typical of those with refractory or unexplained chronic coughs.

From the studies selected, 2 reviewers independently extracted data on cough frequency, cough severity, cough-specific quality of life, and adverse events. The researchers explained that they used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach to rate the certainty of whether the patients would perceive the effects as important and to determine if something was greater or smaller than the minimal important difference (MID); the MID is the “smallest change in an outcome that patients would perceive as important.”

They measured cough frequency using the VitaloJAK cough monitor (MID, 20%). Also, the researchers measured cough severity using the 100-mm visual analog scale (VAS), which considered a higher score as worse (MID, 30 mm). Lastly, they measured cough-specific quality of life with the Leicester Cough Questionnaire (LCQ), the score ranging from 3 (maximal impairment) to 21 (no impairment) (MID, 1.3 points).

Through analyzing these studies, the researchers found that, compared with a placebo, orally taking 45 mg twice daily of gefapixant had small effects on awake cough frequency (17.6% reduction; 95% CI, 10.6%-24.0%; moderate certainty), cough-specific quality of life (mean difference, 1.0 points; 95% CI, 0.7-1.4; moderate certainty), and cough frequency (mean difference, –6.2 mm; 95% CI, –4.1 to –8.4; high certainty). Also, compared with a placebo, they found that orally taking 45 mg twice daily of gefapixant most likely caused an important increase in treatment-related adverse events (32%; 95% CI, 13-64 more) and taste-related adverse events (32%; 95% CI, 22-46 more).

“Gefapixant may provide benefit to some patients with refractory or unexplained chronic cough, but the magnitude is likely small and the risk of adverse events, particularly taste-related, remains substantial,” the authors wrote.

The researchers also acknowledged their study’s limitations, one being that the dose range restricted the included studies. Because fewer trials examined doses beyond 60 mg twice daily, the study yielded less precise results at higher doses.

Despite its limitations, they explained that the review helped to show that gefapixant led to modest symptom improvements in patients with chronic cough. Consequently, the researchers noted that gefapixant, despite its limited effectiveness, may still be superior to other treatments as the current therapies for refractory or unexplained chronic cough “pose substantial harms and have only low-quality evidence to support their benefits.”

“If such is the case, gefapixant may provide an option for patients who have tried and failed all other therapies for identifiable causes,” the authors wrote. “The small benefits of gefapixant and limitations of existing therapies underscore the urgent need for research to identify interventions with greater impact.”

Reference

Kum E, Patel M, Diab N, et al. Efficacy and tolerability of gefapixant for treatment of refractory or unexplained chronic cough: a systematic review and dose-response meta-analysis. JAMA. 2023;330(14):1359–1369. doi:10.1001/jama.2023.18035