Safety and efficacy of P2X3 antagonist BAY 1902607 in refractory chronic cough

Background: ATP activates purinergic P2X receptors and is considered an important mediator in refractory chronic cough (RCC). We report a Phase 2a trial of BAY 1902607, a P2X3 receptor antagonist with high selectivity, in RCC. Methods: This double-blind, placebo-controlled, randomized study included a two-way crossover of oral BAY 1902607 (20, 80, 150, or 250 mg BID, 4 days each) and placebo BID in adult non-smokers with RCC lasting for ≥1 year (NCT03535168). The primary endpoints were VitaloJak-monitored 24-hour cough frequency and frequency/severity of AEs; other endpoints included cough severity measured by VAS at baseline and in each dosing period. Results: 23 patients were randomized (female, n=18 [78%]; Caucasian, n=22 [96%]; median [range] age: 60 [43–77] years; never-smokers, n=14 [61%]). BAY 1902607 doses ≥80 mg significantly decreased geometric mean 24-hour cough counts per hour vs placebo after 4 days of treatment: 80 mg, 17% (p=0.015); 150 mg, 28% (p<0.001); and 250 mg, 37% (p<0.001). Taste-related AEs occurred in 4%, 13%, 43%, and 57% of patients with BAY 1902607 20, 80, 150, and 250 mg, respectively, and in 12% with placebo. Taste-related AEs were mild-to-moderate in severity. BAY 1902607 improved cough severity at doses ≥80 mg; point estimates (90% CI) for VAS score change vs placebo: 80 mg, -8.1 (−14.3 to −1.9, p=0.017); 150 mg, −14.3 (−20.7 to −8.0, p<0.001); and 250 mg, −20.8 (−27.0 to −14.7, p<0.001) mm. Conclusions: BAY 1902607 significantly reduced 24-hour cough frequency and severity at doses ≥80 mg. Despite high P2X3 receptor selectivity of BAY 1902607, dose-related AEs of taste disturbance were observed in many patients.