Background The small molecule BI 705564 is a highly selective, covalent and potent inhibitor (B cell CD69 activation IC50=2.2 nM) of the Brutons tyrosine kinase (BTK). BTK plays a critical role in the differentiation and function of B cells and myeloid cell lineages and may play a major role in autoimmune diseases. Blocking the BTK pathways may be a promising new treatment of autoimmune diseases like SLE.

Methods BI 705564 has been studied in 43 male healthy volunteers (HV) in a single-blinded, partially randomized, placebo-controlled trial testing single rising doses from 10 to 160 mg. In a double-blinded, randomized, placebo-controlled study BI 705564 was administered to 50 male HV at doses from 10 to 80 mg once daily for 14 days. Blood samples were analyzed for BI 705564 plasma concentrations, BTK target occupancy (TO) and CD69 expression in B cells stimulated ex-vivo with anti-IgD.

Results All doses of BI 705564 were well-tolerated in both studies. There were no serious adverse events (AEs) and reported AEs were mainly of mild intensity and not dose-limiting. There was no difference in the total number of subjects with AEs (combined data from both trials) between BI 705564 [28/75 (37.3%)] and placebo [8/18 (44.4%)] and no dose-relationship of AEs. The most frequently reported AE was headache (BI 705564: 8.0% vs placebo: 5.6%, combined data). There was no difference in the occurrence of infections (BI 705564: 6.5% vs placebo: 11.1%) or gastrointestinal disorders (BI 705564: 13.3% vs. placebo 11.1%) in both studies (combined data). There were no relevant drug-related changes in vital signs, ECGs and standard safety laboratory tests. Analysis of BI 705564 plasma exposures showed a terminal half-life between 5.7 and 14.2 hour with no relevant accumulation after multiple dosing. Doses of 20 mg and above resulted in an average TO 85% which is expected to result in clinical efficacy based on preclinical studies. After a single dose administration, TO was maintained for at least 48 hour consistent with the mechanism of a covalent irreversible inhibitor. Functional effects on BTK signalling were demonstrated by dose-dependent inhibition up to 100% of CD69 expression on anti-IgD stimulated B cells.

Conclusions BI 705564 was well-tolerated in healthy subjects after single and multiple doses. The favorable clinical safety profile and the high potential based on pre-clinical studies and effects on CD69 support further investigation of BI 705564 in patients with autoimmune diseases like SLE.

Funding Source(s): This study was funded by Boehringer Ingelheim.