First-in-Human Study of CHF 6795, an Oral Selective P2X3 Antagonist for Refractory Chronic Cough

Abstract Rationale: P2X3 receptor activation on airway sensory nerves represents one mechanism leading to cough hypersensitivity (Spanevello et al. 2020). In this first-in-human study, we evaluated a novel oral, selective P2X3 antagonist, CHF6795. Methods: The primary objective of this randomized, double-blind, placebo-controlled study was to assess safety, tolerability and pharmacokinetics (PK) of single and multiple ascending doses, Part 1 and 2 respectively (Part 1: 40-1280 mg; Part 2: 40-320 mg BID for 14 days) of CHF6795 in healthy male subjects. Part 3 investigated the food and sex effect on PK following 320 mg single dose administration. Safety variables included Adverse Events (AEs)/Adverse Drug reactions (ADRs), vital signs, ECG parameters, taste disturbances and laboratory evaluations. Results: Seventy-five healthy male participants were randomized in Part 1, 44 in Part 2 and 16 male and female subjects in Part 3. CHF6795 was rapidly absorbed (between 1-3 h post-dose) and slowly eliminated (mean t1/2:15.6-18.4 h). Systemic exposure increased approximately dose-proportionally. High-fat breakfast slightly delayed and decreased absorption, without impacting bioavailability. Females had slightly higher plasma exposure than males. No deaths or Serious Adverse Events occurred in the study. The overall frequency of ADRs was 17.3% in Part 1 and 22.7% in Part 2. Vertigo was the most frequent ADR, occurring in the majority of participants at the highest dose in Part 1 and Part 2, leading to early discontinuation of the 320 mg BID dose on Day 4. There were no meaningful taste alterations in any study part. Vital signs and ECG parameters were unrevealing except for an increase from baseline in mean QTcF at the highest dose in Part 1 and Day 1 of Part 2 (largest mean change of 19.3 msec and 11.4 msec, respectively) with only 2 individual QTcF changes above 30 msec (31 and 42 msec) observed in Part 1 at the 1280 mg dose. In Part 2, on Day 14, mean QTcF changes were comparable to placebo for all administered active doses. Laboratory evaluation revealed mild increase in mean creatinine concentration in all study parts, not associated with increase in cystatin-C, therefore, excluding nephrotoxicity. Conclusions: CHF6795 was rapidly absorbed and slowly eliminated in healthy participants. Systemic exposure generally increased dose-proportionally. No relevant food or sex effects on PK were noted. CHF6795 was generally safe and well tolerated up to single doses of 880 mg and multiple doses of 160 mg BID for 14 days.