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 (SRDs/MRDs) of BI 705564 and establish proof of mechanism (PoM). METHODS BI 705564 was studied in two placebo-controlled, Phase I clinical trials testing SRDs (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in male healthy 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 sub-study 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 hours 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%) treated with BI 705564. CONCLUSION BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and PoM through effects on allergic skin responses. Mild bleeding-related adverse events were likely related to inhibition of platelet aggregation by BTK inhibition.