Abstract

Introduction We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.

Methods In this Phase 2, double-blind, 2-period study, chronic cough subjects (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin, and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking ≥2 (C2) and ≥5 (C5) coughs post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·hr−1) over 24 h, and Cough Severity Visual Analogue Scale (VAS) were assessed in CC. Adverse events (AE) were monitored.

Results 24 CC and 12 HV were randomised (mean age 61 and 38 years, respectively). Cough challenge threshold increased for ATP by 4.7-fold (C2, p=<0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). Distilled water C2 and C5 were increased significantly (p<0.001), by a factor of 1.4 and 1.3, respectively, in CC. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and least-squares (LS) mean Cough Severity VAS was 18.0 mm lower for gefapixant versus placebo in CC subjects. Dysgeusia was the most frequent AE (75% HV and 67% CC).

Conclusions ATP-evoked cough was significantly inhibited by gefapixant 100 mg demonstrating peripheral target engagement. Cough count and severity were reduced in CC. Distilled water may also evoke cough through a purinergic pathway.