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Background: Bruton's tyrosine kinase (BTK) is a promising biological target for rheumatoid arthritis treatment. This study examined safety, efficacy, and pharmacokinetics of BMS-986142, an oral, reversible BTK inhibitor. The aim was to compare the efficacy of BMS-986142 with placebo on a background of methotrexate in patients with moderate-to-severe rheumatoid arthritis and inadequate response to methotrexate. Methods: This phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study was conducted across 14 countries and 79 clinical sites. We recruited people aged 18 years or older with a documented diagnosis of rheumatoid arthritis at least 16 weeks before screening with an inadequate response to methotrexate with or without inadequate response to up to two tumour necrosis factor inhibitors. Participants were randomly assigned (1:1:1:1) to oral BMS-986142 (100 mg, 200 mg, or 350 mg) or placebo once daily for 12 weeks. Randomisation was done using an interactive voice response system and stratified by prior treatment status and geographical region. All participants, care providers, investigators, and outcome assessors were masked to treatment allocation. Co-primary endpoints were 20% and 70% improvement in American College of Rheumatology criteria (ACR20 and ACR70) at week 12. Primary endpoints were assessed in the efficacy analysis population (all randomised patients who received at least one dose of the study drug and did not discontinue the study). Safety endpoints were analysed in the as-treated analysis population, which included all patients who received at least one dose of the study drug (patients were grouped according to the treatment they actually received vs the treatment to which they were randomised). This trial was registered with ClinicalTrials.gov, number NCT02638948. Findings: Between Feb 24, 2016 and May 3, 2018, 248 patients were randomised (73 in the BMS-986142 100 mg group, 73 in the 200 mg group, 26 in the 350 mg group, and 75 in the placebo group; one post-randomisation exclusion); mean age was 56·7 years (SD 12·7); 214 (87%) of 247 were women, 33 (13%) were men, and 188 (76%) were White. Pre-specified interim analysis resulted in discontinuation of the 350 mg BMS-986142 dose due to elevated liver enzymes and absence of benefit versus placebo. Co-primary endpoints were not met. Response rates for ACR20 (placebo: 23 [31%] of 75; 100 mg: 26 [36%] of 73; 200 mg: 31 [42%] of 73) and ACR70 (placebo: three [4%] of 75; 100 mg: three [4%] of 73; 200 mg: seven [10%] of 73) were not significantly different to placebo; estimate of difference versus placebo for ACR20 was 4·9 (95% CI –10·2 to 20·1; p=0·52) for 100 mg and 11·8 (–3·6 to 27·2; p=0·14) for 200 mg, and for ACR70 the estimate of difference was 0·1 (–16·0 to 16·5; nominal p=1·00) for 100 mg and 5·6 (–10·5 to 21·9; nominal p=0·21) for 200 mg. Six patients experienced serious adverse events (four in the placebo group [mouth ulceration, open globe injury, rheumatoid arthritis flare, and endometrial adenocarcinoma] and two in the BMS-986142 100 mg group [angina pectoris and intestinal obstruction]); there were no deaths. Interpretation: Further investigation of BMS-986142 in people with rheumatoid arthritis is not warranted. An absence of clinical benefit in this study, together with other study results, highlights the need for additional research on the extent of BTK inhibition, treatment duration, and adequacy of drug distribution to inflammation sites, to understand the potential utility of BTK inhibition as a therapeutic strategy for rheumatoid arthritis. Funding: Bristol Myers Squibb.

Sphingosine‐1‐phosphate (S1P) binding to the S1P‐1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS‐986166, a prodrug of the active phosphorylated metabolite BMS‐986166‐P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS‐986166 versus placebo after single (0.75–5.0 mg) and repeated (0.25–1.5 mg/day) oral administration were assessed in healthy participants after a 1‐day lead‐in placebo period. A population model was developed to jointly describe BMS‐986166 and BMS‐986166‐P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS‐986166‐P concentrations and nadir of time‐matched (day –1) placebo‐corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5‐mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2‐bpm decrease in nDDHR over placebo.

[Image: see text] The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

Bruton’s tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjogren’s syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.