Benefit-risk profile of P2X3 receptor antagonists for treatment of chronic cough: Dose-response model-based network meta-analysis

Refractory or unexplained chronic cough disrupts quality of life and burdens healthcare systems around the world. The P2X3 receptor antagonist gefapixant is approved in many countries for its antitussive effects, but taste disturbances are a common adverse effect. Four newer, more selective P2X3 receptor antagonists have been developed to address this problem. How does the benefit-risk profile vary across the five available P2X3 receptor antagonists? A systematic review and network meta-analyses were conducted to evaluate the efficacy of P2X3 receptor antagonists, including gefapixant, sivopixant, eliapixant, camlipixant, and filapixant. Primary outcomes were a reduction rate in 24-hour cough frequency and incidence of taste disturbance. Dose-response curves, and median effective dose (ED50) were calculated. Effect size at ED50 was ranked according to SUCRA. The confidence was evaluated by CINeMA. Sixteen randomized controlled trials involving 4,904 participants were analyzed. The gefapixant regimen demonstrated an ED50 of 90.7 mg/day for cough frequency reduction. Gefapixant showed the highest antitussive effectiveness at ED50 (reduction rate in 24-h cough frequency, median 28.1%; 95% Credible Interval 21.0 to 35.6%; ranked 1/5; moderate certainty) but the highest prevalence of taste disturbance (absolute risk difference per 100 patients, median 38; 95%CrI 27 to 51; ranked 5/5; high certainty) and the highest prevalence of discontinuation. Camlipixant had a well-balanced profile (reduction rate in 24-h cough frequency, median 14.7%; 95%CrI 5.4 to 26.0%; ranked 3/5; low certainty; and taste disturbance, absolute risk difference per 100 patients, median 2; 95%CrI 1 to 6; ranked 2/5; low certainty). Placebo had a mean of 33.1% reduction in 24-h cough frequency. When used at safe doses, gefapixant had a favorable risk-benefit profile compared to the other four agents. Camlipixant showed initial promise, which may be further investigated by phase III trials currently underway. UMIN000050622