SAT0226 A first-in-human, study of BMS-986165, a selective, potent, allosteric small molecule inhibitor of tyrosine kinase 2

Abstract

BackgroundTyrosine kinase 2 (Tyk2) is a member of the JAK family that phosphorylates STAT proteins downstream of the IL-12, IL-23 and the Type I interferon receptor. Tyk2 genetic variants have been linked to multiple autoimmune diseases,1 with a deactivating coding variant conferring significant protection against multiple immune-mediated disorders including systemic lupus erythematosus (SLE).2 Selective pharmacologic inhibition of Tyk2 has proven daunting, given the high degree of similarity among JAK catalytic domains. Using a novel approach, we have developed BMS-986165, a highly selective and potent small molecule inhibitor, which blocks receptor-mediated Tyk2 activation by stabilizing the regulatory pseudokinase domain of the protein. Lupus-like disease is strongly inhibited in NZB/W mice treated with BMS-986165. Together, these data establish Tyk2 as a highly promising therapeutic target for SLE.ObjectivesWe report the first evidence of safety, pharmacokinetics (PK), target engagement (TE), and pharmacodynamic activity (PD) of BMS-986165, a novel inhibitor of Tyk2.MethodsSafety, PK, TE, and PD were assessed in a randomized, double-blind, single and multiple ascending dose study of 108 (83 active: 25 placebo) healthy participants (NCT02534636). Target engagement was assessed by an ex vivo assay, IL-12 and IL-18 induced IFNγ production. Roferon-A was administered to assess in vivo pharmacodynamic effects of BMS-986165 on physiological manifestations of IFN exposure and on IFN-regulated gene (IRG) expression.ResultsBMS-986165 was safe and overall well-tolerated. There were no serious adverse events and the frequency of non-serious adverse events were similar in the active (75%) and placebo (76%) groups. The most frequently reported adverse events by preferred term were headache (23% active versus 28% placebo), nausea (12% active versus 8% placebo), rash (12% active versus 8% placebo), and upper respiratory tract infection (11% active versus 12% placebo).After oral administration, BMS-986165 was rapidly absorbed and exhibited an apparent elimination half-life of 8–15 hours. Modest accumulation (1.4x-1.9x) was observed after multiple dosing. BMS-986165 inhibited IL-12/IL-18-induced IFNγ production in ex vivo assays in a dose and concentration dependent manner. Following an in vivo challenge with a clinical dose of Interferon-alfa-2A, BMS-986165 demonstrated dose-dependent inhibition of lymphocyte count decreases and expression of 53 IRGs in blood (Figure 1).ConclusionsBMS-986165 is a safe and potent Tyk2 inhibitor with clear evidence of ex vivo and in vivo biologic activity in healthy participants, and the potential for once daily dosing. Overall, Inhibition of IL-12/23 and type I IFN pathways support further testing of BMS-986165 in diseases such as lupus and psoriasis. A Phase 2 study in patients with moderate-to-severe psoriasis is ongoing (NCT02931838).References Liang Y, Zhu Y, Xia Y, Peng H, Yang XK, et al. Therapeutic potential of tyrosine kinase 2 in autoimmunity. Expert Opin Ther Targets. 2014 May;18(5):...

Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases

“…Further research on TYK2 JH2 binders resulted in a clinical compound, BMS-986165, having a picomolar potency against TYK2 JH2 and efficacy in preclinical mouse models of SLE and IBD [145]. A phase I study with 108 participants found BMS-986165 to be safe and well-tolerated with no serious adverse events [146]. In a recently published phase II study of 267 patients with moderate to severe psoriasis BMS-986165 showed clinical efficacy at a daily dose of 3 mg and higher [147].…”

Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis

“…This is distinct from other tyrosine kinase inhibitors, such as Janus kinase (JAK) 1-3 inhibitors, which bind the adenosine triphosphate binding site in the kinase domain (competitive inhibition). 8,11 In cell-based assays, deucravacitinib showed approximately 100-to 200-fold greater selective inhibition for TYK2 than JAK1/JAK3, and was >3000-fold more selective for TYK2 than JAK2. 8,11 Deucravacitinib has been shown to inhibit type I IFN responses and IL-12 signaling in the blood of healthy volunteers at oral doses > _2 mg twice daily (BID).…”

“…8,11 In cell-based assays, deucravacitinib showed approximately 100-to 200-fold greater selective inhibition for TYK2 than JAK1/JAK3, and was >3000-fold more selective for TYK2 than JAK2. 8,11 Deucravacitinib has been shown to inhibit type I IFN responses and IL-12 signaling in the blood of healthy volunteers at oral doses > _2 mg twice daily (BID). 11 In psoriasis, inhibition of TYK2 by deucravacitinib is expected to downregulate the IL-23/T H 17 pathway and keratinocyte activation and to downregulate the type I IFN pathway.…”

“…8,11 Deucravacitinib has been shown to inhibit type I IFN responses and IL-12 signaling in the blood of healthy volunteers at oral doses > _2 mg twice daily (BID). 11 In psoriasis, inhibition of TYK2 by deucravacitinib is expected to downregulate the IL-23/T H 17 pathway and keratinocyte activation and to downregulate the type I IFN pathway. As such, the objectives of this study were to evaluate pharmacodynamic responses to treatment with deucravacitinib by investigating changes in IL-23/T H 17 and type I IFN pathway biomarkers through analyses of differentially expressed genes (DEGs) in lesional and nonlesional skin biopsy samples; and to assess the selectivity of deucravacitinib for TYK2 over JAK1-3 using laboratory parameters.…”

Reducing False Positives through the Application of Fluorescence Lifetime Technology: A Comparative Study Using TYK2 Kinase as a Model System

“…26,27 The limitation of configuring primary screening assays at a saturating concentration of substrate is the bias toward the identification of inhibitors with covalent, noncompetitive, or uncompetitive modes of action and the enrichment of subsequent hits with highly potent substrate-competitive molecules. Given that TYK2 is a well-validated and established drug discovery target with inhibitors in clinical trials 28,29 and that the primary aim of this study was to provide a comparison in the hit-finding performance of the three comparator detection technologies, the decision was taken to proceed with assays configured with saturating concentrations of ATP. By screening with saturating ATP, the proportion of false-positive hits identified increased, further showcasing the capacity of FLT to identify true active compounds relative to TR-FRET configurations and correct for those that are falsely positive.…”