BMS-986142

BMS-986142 (BMS 986142) is a potent, selective and reversible BTK inhibitor with IC50 of 0.5 nM; displays 20-60-fold selectivity over Tec family kinases, >10,000-fold selectivity over JAK2; potently inhibits signaling and functional end points, including calcium flux (IC50=9 nM), production of cytokines, proliferation, and surface expression of CD86 (IC50=3-4 nM); potently inhibits BCR-stimulated expression of CD69 on B cells in human whole blood with IC50 of 90 nM; exhibits excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile.Rheumatoid Arthritis Phase 2 Clinical(In Vitro):BMS-986142 potently inhibits human recombinant BTK with an IC50 of 0.5 nM in enzymatic assays. Against a panel of 384 kinases, BMS-986142 is highly selective, with only five other kinases (Tec, ITK, BLK, Txk, BMX) inhibited with 10,000 nM for both). When Ramos B cells are treated with anti-IgM to activate BCR, BMS-986142 inhibits BTK-dependent calcium flux with an IC50 of 9 nM.\n(In Vivo):BMS-986142 at 4, 10, and 30 mg/kg results in dose-dependent reductions of 26%, 43%, and 79% in clinically evident disease, respectively, at the end of the study. Interestingly, 4 mg/kg BMS-986142 provides an additive benefit in clinical scores (54% inhibition) when co-administered with MTX versus 19% inhibition with MTX alone. Co-administration of BMS-986142 at 4 mg/kg with MTX result in a 53% reduction in inflammation and bone resorption compared with 24% and 10%, respectively, with either drug alone. Furthermore, serum anti-collagen II IgG titers are significantly inhibited with 10 and 30 mg/kg BMS-986142. BMS-986142 also produces dose-dependent reductions in clinical scores when administration is delayed until the collagen booster on day 21. BMS-986142 doses of 2, 4, and 25 mg/kg in this therapeutic dosing regimen result in clinical score reductions of 17%, 37%, and 67%, respectively, at the end of the study.