Session Type: ACR Late-breaking Abstract Session
Session Time: 9:00AM-11:00AM
Tyk2 mediates signaling downstream of the receptors for IL-12, IL-23 and Type I interferons, all key drivers of autoimmune disorders such as SLE. BMS-986165, an investigational agent entering Phase 2 studies for the treatment of multiple immune-mediated disorders, is a highly selective inhibitor of Tyk2-mediated signal transduction that acts by stabilizing the pseudokinase domain of the protein. The current report describes the preclinical pharmacology of BMS-986165, including mouse models of lupus and inflammatory bowel disease.
The affinity of BMS-986165 for the pseudokinase domain of Tyk2 was evaluated using recombinant protein, and functional assays used both cells isolated from peripheral human blood and whole blood from lupus patients. The efficacy in a mouse model of lupus nephritis employed NZB/W lupus-prone mice in which BMS-986165 was administered PO QD for 16 weeks. Body weight, proteinuria, anti-dsDNA titers, and gene expression (kidneys and blood) were measured, and kidneys were examined histologically for nephritis and immune complex deposition. In a model of inflammatory bowel disease, colitis was induced in SCID mice by an agonistic anti-CD40 Ab, and effect of BMS-986165 (administered PO QD) was evaluated against both the body weight loss and histologically evident colitis.
BMS-986165 potently binds to the Tyk2 pseudokinase domain (Ki = 0.02 nM), and is highly selective against a panel of 265 kinases and pseudokinases. The compound potently inhibited IL-23-, IL-12-, and Type I interferon-driven cellular signaling and transcriptional responses (IC50 range 2-14 nM). BMS-986165 was approximately 200-fold selective against JAK1/3-dependent signaling in IL-2-stimulated T cells and >3,000-fold selective over JAK2-dependent EPO-induced signaling in TF-1 cells. In human whole blood, BMS-986165 inhibited Tyk2-dependent IFNa-induced signaling with an IC50 of 13 nM. Addition of BMS-986165 to whole blood from lupus patients led to reduced expression of Type I IFN response genes, a response identical to that achieved with an anti-IFNAR Ab and superior to an anti-IFNa Ab. BMS-986165 treatment in NZB/W lupus-prone mice rapidly (24 hours) reduced the elevated expression of Type I interferon-dependent genes and dose-dependently protected from nephritis and other disease endpoints with chronic dosing, with efficacy correlating with inhibition of Type I interferon-dependent gene expression. Protection from nephritis at 10 mpk trended to be superior to a blocking anti-Type I IFN receptor antibody (anti-IFNAR). BMS-986165 was also highly efficacious in the anti-CD40-induced colitis model in SCID mice, providing protection against both weight loss (wasting) and histologically evident colitis, and was as effective as an anti-p40 antibody.
In summary, the potent and highly selective suppression by BMS-986165 of the IL-23/TH17 axis, IL-12-mediated TH1 functions, and Type I interferon-driven modulation of immune pathways results in robust efficacy in preclinical models of SLE and IBD. These results provided the rationale for progression into human trials, and the compound is entering Phase 2 studies for the treatment of multiple immune-mediated disorders.
Disclosure: K. Gillooly, Bristol-Myers Squibb, 3; Y. Zhang, Bristol-Myers Squibb, 3; X. Yang, Bristol-Myers Squibb, 3; A. Zupa-Fernandez, Bristol-Myers Squibb, 3; L. Cheng, Bristol-Myers Squibb, 3; J. Strnad, Bristol-Myers Squibb, 3; M. Cunningham, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; E. Heimrich, Bristol-Myers Squibb, 3; X. Zhou, Bristol-Myers Squibb, 3; J. Chen, Bristol-Myers Squibb, 3; C. Chaudhry, Bristol-Myers Squibb, 3; S. Li, Bristol-Myers Squibb, 3; K. McIntyre, Bristol-Myers Squibb, 3; J. Carman, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; R. Moslin, Bristol-Myers Squibb, 3; S. Wrobleski, Bristol-Myers Squibb, 3; D. Weinstein, Bristol-Myers Squibb, 3; J. Burke, Bristol-Myers Squibb, 3.
To cite this abstract in AMA style:Gillooly K, Zhang Y, Yang X, Zupa-Fernandez A, Cheng L, Strnad J, Cunningham M, Heimrich E, Zhou X, Chen J, Chaudhry C, Li S, McIntyre K, Carman J, Moslin R, Wrobleski S, Weinstein D, Burke J. BMS-986165 Is a Highly Potent and Selective Allosteric Inhibitor of Tyk2, Blocks IL-12, IL-23 and Type I Interferon Signaling and Provides for Robust Efficacy in Preclinical Models of Systemic Lupus Erythematosus and Inflammatory Bowel Disease [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/bms-986165-is-a-highly-potent-and-selective-allosteric-inhibitor-of-tyk2-blocks-il-12-il-23-and-type-i-interferon-signaling-and-provides-for-robust-efficacy-in-preclinical-models-of-systemic-lupus-e/. Accessed March 24, 2018.
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