The Effect of Gefapixant, a P2X3 antagonist, on Cough Reflex Sensitivity: A randomised placebo-controlled study
IntroductionÂ We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.
MethodsÂ In this Phase 2, double-blind, 2-period study, chronic cough subjects (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100â€…mg or placebo in crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin, and distilled water were performed 1, 3 and 5â€…h after dosing. Mean concentrations evoking â‰¥2 (C2) and â‰¥5 (C5) coughs post doseÂ versusÂ baseline were co-primary endpoints. Objective cough frequency (coughsÂ·hrâˆ’1) over 24â€…h, and Cough Severity Visual Analogue Scale (VAS) were assessed in CC. Adverse events (AE) were monitored.
ResultsÂ 24â€…CC and 12â€…HV were randomised (mean age 61 and 38â€…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 gefapixantÂ versusÂ 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 18.0â€…mm lower for gefapixantÂ versusÂ placebo in CC subjects. Dysgeusia was the most frequent AE (75% HV and 67% CC).
ConclusionsÂ ATP-evoked cough was significantly inhibited by gefapixant 100â€…mg demonstrating peripheral target engagement. Cough count and severity were reduced in CC. Distilled water may also evoke cough through a purinergic pathway.
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Conflict of interest: Dr. Morice reports personal fees from Afferent, grants and personal fees from Merck, during the conduct of the study.
Conflict of interest: Dr. Kitt reports other from Merck/Afferent, during the conduct of the study; other from Merck/Afferent, outside the submitted work.
Conflict of interest: Dr. Ford has nothing to disclose.
Conflict of interest: Dr. Tershakovec reports personal fees and other from Merck, during the conduct of the study.
Conflict of interest: Dr. Wu reports that she was an employee of Merck Sharp & Dohme, Corp, during the conduct of the study.
Conflict of interest: Dr. Brindle has nothing to disclose.
Conflict of interest: Dr. Thompson has nothing to disclose.
Conflict of interest: Ms. Thackray-Nocera has nothing to disclose.
Conflict of interest: Dr. Wright has nothing to disclose.
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