Proof of Pharmacology, Safety, and Pharmacokinetics of the Novel TRPA1 Antagonist BI 1839100: A Randomized, Placebo-Controlled, Parallel Group, First-In-Human Study in Healthy Male Participants.

BI 1839100 is a selective antagonist of transient receptor potential ankyrin 1 (TRPA1). Topically applied TRPA1-agonistic allyl isothiocyanate (AITC), inducing non-invasively measurable increased dermal blood flow (DBF), is known as a skin challenge model to assess TRPA1-target engagement and pharmacodynamic (PD) activity of TRPA1 inhibitors. This study aims to support the pharmacological rationale of BI 1839100 based on preclinical evidence and to test its safety, pharmacokinetic (PK) profile, and PD effects using an AITC skin challenge in a phase I first-in-human clinical study. In vitro and in vivo experiments were conducted in human TRPA1-overexpressing human embryonal kidney (HEK)293 cells and mice, respectively. Exposure to BI 1839100 and AITC demonstrated a BI 1839100 exposure-related reduction of AITC-induced Ca(2+) increase in HEK293 cells and skin edema in mice. Healthy male participants, aged 18-45 years, were randomized within 10 cohorts in the single-ascending dose part (n = 80) and two cohorts in the PD part (n = 32). All received single doses of BI 1839100/placebo followed by safety and PK measurements. In the PD part, participants underwent an AITC skin challenge twice; at baseline and at time to peak drug concentration after BI 1839100/placebo administration. No significant imbalance in occurrence of adverse events was detected between single doses of BI 1839100 up to 300 mg and placebo, and PK profiles were dose-proportional in the 40-300 mg range. BI 1839100 demonstrated a dose-dependent inhibitory effect on DBF after the AITC skin challenge, indicating TRPA1-targeted pharmacological activity and potentiating BI 1839100 for further clinical development for a broad range of TRPA1 antagonistic applications.