Late Breaking Abstract - Phase 2a randomised, double-blind, placebo-controlled, crossover study of a novel P2X3 receptor antagonist S-600918 in patients with refractory chronic cough

Background: P2X3 receptors in airway vagal afferent nerves play an important role in cough reflex hypersensitivity. S-600918, an oral P2X3 receptor antagonist, has high selectivity for P2X3 homomer compared with P2X2/3 heteromer, which could reduce coughs with minimal taste-related side effects. Objectives: To evaluate the efficacy and safety of S-600918 in patients with refractory chronic cough. Methods: This was a randomised, double-blind, placebo-controlled, cross-over, multi-centre study involving refractory chronic cough patients in Japan. Patients were randomly assigned by 1:1 ratio to receive 150 mg S-600918 or matched placebo first, both orally q.d. in the morning for 2 weeks. After washout phase of 2 to 3 weeks, the patients underwent the alternative treatment arm. The primary endpoint was reduction rate in objective daytime cough count per hour from baseline, adjusted for placebo. Results: A total of 31 patients (mean age 50.0; SD 14.6) were enrolled. Daytime coughs were reduced by 31.6% (p=0.0546; 95%CI [-0.8, 53.6]) relative to placebo, while the 24-hour coughs, a secondary endpoint, was significantly reduced by 30.9% (p=0.0386). Overall incidence of treatment-emergent adverse events (AEs) was not significantly different between the two treatments. Specifically, taste change (1/31; 3.2%) and taste injury (1/31; 3.2%) were observed during S-600918 treatment. Conclusions: S-600918, P2X3 receptor-selective antagonist, showed a potential to reduce coughs for the first time with low incidence of taste disturbance after 2 weeks of administration, and thus is likely a promising therapeutic option of refractory chronic cough.