Pharmacology and safety of TAS5315, a Bruton tyrosine kinase inhibitor, in healthy volunteers: First-in-human, randomized, ascending-dose studies.

Objective: TAS5315 is a Bruton tyrosine kinase (Btk) inhibitor in development for autoimmune and allergic diseases, including rheumatoid arthritis (RA) and chronic spontaneous urticaria (CSU). Two clinical studies evaluated the pharmacology and safety of single and multiple oral doses of TAS5315.

Methods: Two phase 1 studies (single ascending-dose [SAD] and multiple ascending-dose [MAD]) assessed the pharmacokinetics (including effect of food), pharmacodynamics (Btk occupancy, inhibition of basophil activation) and safety of TAS5315 (up to 8 mg/day) in healthy males.

Results: TAS5315 showed linear pharmacokinetics over a 0.01-8 mg dose range; maximum plasma concentration and area under the plasma concentration-time curve were reduced by ~40% by food. TAS5315 had dose dependent effects on Btk and basophil activation. In the SAD study, doses ≥2 mg resulted in mean Btk occupancy of almost 100% at 2 and 6 h, and >80% at 24 h, post-administration. TAS5315 1-8 mg/day inhibited basophil activation (mean change from baseline -55% to -89%). TAS5315 was generally tolerable. Although it dose-dependently reduced platelet aggregation (over 2-8 mg in both studies) and prolonged bleeding time (1-8 mg in the MAD study), no relationship between these effects and clinical symptoms was observed. All adverse drug reactions were mild and resolved without treatment; no noteworthy safety concerns were observed in either study.

Conclusions: These data indicate TAS5315 has potential as a novel therapeutic for immunological diseases associated with aberrant Btk signalling, including RA and CSU. Further evaluation of TAS5315 is warranted.