P143 Efficacy of the oral tyrosine kinase 2 (TYK2) inhibitor TAK-279 in two preclinical mouse models of colitis

Abstract

Abstract Background Tyrosine kinase 2 (TYK2), a member of the Janus kinase (JAK) family, is required for the downstream signalling of interleukin (IL) 12 and 23, and interferons (IFN) α/β, which are involved in the pathogenesis of several autoimmune diseases, including inflammatory bowel disease (IBD).1 JAK inhibitors are approved for treatment of IBD, but their dosing levels may be limited due to adverse effects related to JAK1–3 inhibition. TAK-279 is a highly-selective, oral, allosteric TYK2 inhibitor, which binds to the JAK homology 2 pseudokinase domain of TYK2, but not JAK1–3.1,2 This study assessed the efficacy of TAK-279 in two IL-23-dependent preclinical mouse models of colitis induced by (i) adoptive T-cell transfer (TCT) and (ii) anti-CD40 monoclonal antibody (α-CD40 mAb). Methods In the TCT colitis model, CD4+CD45RBhi T cells were transferred to severe combined immunodeficient mice at Day 0, and disease progression followed for 48 days. In the α-CD40 colitis model, T- and B-cell-deficient Rag2-/- mice were challenged with agonistic α-CD40 mAb at Day 0, and disease severity analyzed on Day 7. Mice were divided into four groups per model (n = 12–16 and n = 10 per group in the TCT and α-CD40 models, respectively) to receive vehicle (negative control) or TAK-279, orally, twice-daily, at doses intended to provide either 24hr IC90 (high dose) or IC50 (low dose) coverage, or once-weekly intraperitoneal α-IL-12/23 p40 mAb (positive control). At the end of the treatment period, colonic tissue was obtained; colon weight:length (CWL) ratio, total histology score (THS) and transcriptomic analysis were used to assess efficacy and mechanism of action. Statistical significance of differences between groups was determined using analysis of variance with Tukey’s post hoc test. Results In both models, TAK-279 was maximally efficacious at the IC90 dose; CWL ratio and THS were significantly reduced relative to vehicle and the response was comparable with α-IL-12/23 p40. IC50 dosing was not sufficient in the α-CD40 model and IC90 dosing was required for significant efficacy (Figure). Transcriptomic analysis showed TAK-279-dependent downregulation of genes associated with cytokine signalling, including those related to T-helper 17 cell phenotypes and the IFN α/β pathway. Conclusion TAK-279 was efficacious in two preclinical mouse models of colitis and induced relevant cytokine signalling changes; IC90 coverage provided maximal efficacy in both models. These results support the potential role of potent and selective TYK2 inhibition for the treatment of IBD, where TAK-279 is expected to achieve IC90 coverage in humans. 1. Leit S et al. J Med Chem 2023;66:10473–96. 2. Gangolli EA et al. STAT 2022;1:5.