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 postdosing. 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 1 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. Conclusion Rapid and high occupancy of BTK and the lack of notable safety findings support further clinical development of branebrutinib.