Safety, Pharmacokinetics and Pharmacodynamics of Branebrutinib (BMS-986195), a Covalent, Irreversible Inhibitor of Bruton's Tyrosine Kinase: Randomised Phase I, Placebo-Controlled Trial in Healthy Participants.

AIMS: Branebrutinib (BMS-986195) is a potent, highly selective, oral, small-molecule, covalent inhibitor of Bruton's tyrosine kinase (BTK). This study evaluated safety, pharmacokinetics and pharmacodynamics of branebrutinib in healthy participants. METHODS: This double-blind, placebo-controlled, single- and multiple-ascending dose (SAD; MAD) Phase I study (NCT02705989) enrolled participants into 3 parts: SAD, MAD and JMAD (MAD in first-generation Japanese participants). In each part, participants were randomised 3:1 to receive branebrutinib (SAD: 0.3-30 mg; [J]MAD: 0.3-10 mg) or placebo. Participants in the MAD parts received branebrutinib daily for 14 days and were followed for 14 days post-dosing. Safety was assessed by monitoring, laboratory and physical examinations, vital signs and recording adverse events (AEs). Pharmacodynamics were assessed with a mass spectrometry assay that measured drug-occupied and free BTK. RESULTS: The SAD, MAD and JMAD parts of the study included 40, 32 and 24 participants. Branebrutinib was well tolerated and AEs were mild/moderate, except for one serious AE that led to discontinuation. Branebrutinib was rapidly absorbed, with maximum plasma concentration occurring within 1 hour and a half-life of 1.2-1.7 hours, dropping to undetectable levels within 24 hours. BTK occupancy was rapid, with 100% occupancy reached after a single 10-mg dose. BTK occupancy decayed predictably over time (mean half-life in MAD panels:115-154 hours), such that pharmacodynamic effects were maintained after branebrutinib plasma levels fell below the lower limit of quantification. CONCLUSIONS: Rapid and high occupancy of BTK and the lack of notable safety findings support further clinical development of branebrutinib.