Late Breaking Abstract - The neurokinin-1 receptor antagonist orvepitant improves chronic cough symptoms: results from a Phase 2b trial

Background: No proven therapies exist for refractory chronic cough (CC). Neurokinin(NK)-1 antagonists may modulate the central neural hypersensitivity causing CC. The NK-1 antagonist orvepitant was assessed in CC in a Phase 2b dose-ranging study. Methods: A randomised, controlled, parallel group study recruited subjects with CC ≥1 yr and awake cough count >10/hr. Subjects took placebo (PBO) or one of 3 orvepitant doses (10, 20 or 30mg) once daily for 12-wks. Primary endpoint was awake cough frequency (CF) at Wk-12, using a VitaloJAK ambulatory cough monitor. Other efficacy measures were the patient recorded outcomes (PROs): Leicester Cough Questionnaire (LCQ), Cough Severity (CS) & Urge-to-Cough (UTC) VASs, and global ratings of change (GRoC). Results: 315 subjects were randomised and 275 were evaluable at Wk-12. Orvepitant 30mg resulted in clinically relevant and significant improvements in PROs in the full analysis set (FAS) at Wk 12: LCQ (PBO-corrected improvement 1.6, p=0.009), CS VAS (9.0mm, p=0.034) and UTC VAS (11.8mm, p=0.005). GRoC scores: for cough severity p=0.054, and frequency p=0.124. The CF endpoint was not significant in the FAS due to an exaggerated PBO response at Wk 12, most evident in the lower CF subjects. In a pre-defined sub-group of higher CF subjects (≥study median awake CF at baseline), a greater efficacy signal is evident with 30mg orvepitant in primary (geometric mean ratio vs PBO 0.71, p=0.066) and secondary efficacy endpoints (e.g. LCQ 1.9, p=0.041), with most being significant despite the study not being powered for sub-group analyses. Orvepitant was safe and well-tolerated. Conclusions: These data support orvepitant’s further evaluation in CC.