BMS-986195

Description: Branebrutinib (formerly BMS-986195) is a highly selective and rapidly acting covalent/irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK) with IC50 of< 1 nM and robust efficacy at low doses in preclinical models of RA (Rheumatoid Arthritis) and Lupus Nephritishighly. BMS-986195 acts by covalently modifying an active-site cysteine residue of BTK. It is more than 5000-fold selective for BTK over all kinases outside of the Tec family, and selectivity ranges from 9- to 1010-fold within the Tec family. BMS-986195 inactivated BTK in human whole blood with a rapid rate of inactivation (3.5x10-4 nM-1·min-1) and potently inhibited antigen-dependent interleukin-6 production, CD86 expression and proliferation in B cells (IC50 < 1 nM) without effect on antigen-independent measures in the same cells. A similar potency was measured against FcgammaR-dependent TNF-alpha production in human cells. In mice, a dose as low as 0.5 mg/kg, taken orally (PO) daily (QD), resulted in peak BTK inactivation of 98% after only the second dose. BTK was inactivated to similar levels in whole blood, lymph nodes and spleen in a dose-dependent manner. BMS-986195 demonstrated robust efficacy in murine models of RA including CIA and CAIA, protecting against clinically evident disease, histologic joint damage and bone mineral density loss. In both models, maximal efficacy was observed at doses <=0.5 mg/kg PO QD, which achieved >=95% inactivation of BTK in vivo. At similar doses, the compound was also highly protective against nephritis in the NZB/W mouse model of lupus. To investigate the dynamics of BTK inactivation and resynthesis of BTK, cynomolgus monkeys were given single or multiple doses of BMS-986195. 100% peak inactivation of BTK was obtained with a single administration of BMS-986195 at 0.5 mg/kg PO.

References: 2017 ACR/ARHP Annual Meeting, September 18, 2017.