The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study

Abstract

We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a 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 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h−1) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The 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 patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0 mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients).ATP-evoked cough was significantly inhibited by gefapixant 100 mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway.

ERS guidelines on the diagnosis and treatment of chronic cough in adults and children

“…Cellular stress releasing ATP appears to be an important stimulus [36]. Afferent neuronal traffic is relayed via vagal axons to the brainstem via at least two different biochemical pathways [37]. Cortical influences modulate the reflex, with females having a greater area of the somatosensory cortex devoted to cough.…”

The Powerful Placebo Effect in Cough: Relevance to Treatment and Clinical Trials

“…Cough medicines have evolved over centuries to maximize the placebo effect by being formulated as sweet viscous syrups and this evolution is still in progress today as pharmaceutical companies utilize new flavors and sensations to increase the impact of their OTC cough medicines. There is an ongoing research effort to develop new antitussive medicines and most of these involve clinical trials on actives in tablet form [4,59]. However, if these new active agents are eventually used commercially for the treatment of cough, the efficacy of the cough medicine would be greatly enhanced by formulating the medicine as a sapid sweet syrup in order to utilize a large placebo effect of treatment in addition to any pharmacological effect of the medicine.…”

“…Codeine was once deemed a powerful antitussive for all types of cough because of its presumed depressant effect on cough control at the level of the brainstem but doubts have been raised on its efficacy and it is no longer considered a 'gold standard' antitussive [3]. Much progress is being made on the peripheral mechanism of cough at the level of sensory nerves in the airway but clinical trials on some of the best candidates for a new cough medicine are proving difficult because of side effects [4]. The placebo effect in cough therapy is both a gift and a problem to those working on treatments for cough.…”

Chronic cough: ATP, afferent pathways and hypersensitivity

“…A unique hypersensitivity to ATP seems unlikely, given that another recent observation of A.H. Morice and co-workers was that cough responses to inhaled ATP are no more exaggerated in refractory chronic cough than they are to other inhaled irritants [28]. Furthermore, ATP appears not to act as a general sensititiser of nerves, given that gefapixant's blockade of ATP/P2X failed to modify responses to citric acid and capsaicin in the current study [25].…”

“…Extrapolating from the guinea pig model, the mode of action of gefapixant in humans is assumed to be through action on ATP-mediated activation of afferent nerves in the airway. Until now this assumption has not been explored, but in the current issue of the European Respiratory Journal MORICE et al [25] address this deficiency in our knowledge. The authors report the results of a phase 2 randomised placebo-controlled study on the effects of gefapixant on tussive responses to inhaled capsaicin, citric acid, ATP and distilled water in 24 patients with chronic refractory cough and 12 healthy controls.…”