Background/Purpose: BMS-986195 is a potent, covalent, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases essential in antigen-dependent B-cell signaling and function. BTK also plays a critical signaling role downstream of low-affinity activating Fcγ receptors (FcγR) in monocytic cells, high-affinity immunoglobulin E receptors (FcεRI) in granulocytes, and the RANK receptor on osteoclasts. Pharmacologic inhibition of BTK, therefore, represents an intriguing approach for the treatment of autoimmune disorders such as RA and lupus. The present report details the cellular and in vivo pharmacology of BMS-986195.

Methods: The potency and selectivity of BMS-986195 were evaluated against a panel of 245 kinases. Cellular assays included antigen-dependent responses in B cells and immune complex-stimulated cytokine production in human peripheral blood mononuclear cells. BTK inactivation was determined using active-site probe-based measures of unmodified active sites, and these assays were used to determine the in vitro rate of inactivation in human whole blood, as well as the kinetics and dose relationships of in vivo inactivation of BTK in mice and cynomolgus monkeys after oral administration. The efficacy of BMS-986195 was evaluated in collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice, as well as against nephritis in NZB/W lupus-prone mice.

Results: BMS-986195 is a potent and highly selective inhibitor of BTK, which acts by covalently modifying an active-site cysteine residue. The compound 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 (3.5×10^-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 FcγR-dependent TNF-α 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.

Conclusion: The high selectivity, rapid rate of BTK inactivation and robust efficacy at low doses in preclinical models of RA and lupus support investigation of BMS-986195 in human autoimmune disorders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bms-986195-is-a-highly-selective-and-rapidly-acting-covalent-inhibitor-of-brutons-tyrosine-kinase-with-robust-efficacy-at-low-doses-in-preclinical-models-of-ra-and-lupus-nephritis/