Safety, pharmacokinetics and pharmacodynamics of BI 705564, a highly selective, covalent inhibitor of Bruton's tyrosine kinase, in Phase I clinical trials in healthy volunteers

AIMS: To evaluate the safety, pharmacokinetics and pharmacodynamics of single‐ and multiple‐rising doses (MRDs) of BI 705564 and establish proof of mechanism. METHODS: BI 705564 was studied in 2 placebo‐controlled, Phase I clinical trials testing single‐rising doses (1–160 mg) and MRDs (1–80 mg) of BI 705564 over 14 days in healthy male volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A substudy was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. RESULTS: All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half‐life ranged from 10.1 to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single‐dose administration. Functional effects of BTK signalling were demonstrated by dose‐dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding‐related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54.2%) treated with BI 705564. CONCLUSION: BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B‐cell activation, and proof of mechanism through effects on allergic skin responses. Mild bleeding‐related adverse events were probably related to inhibition of platelet aggregation by BTK inhibition.