25-OR: ADA Presidents' Select Abstract: Preclinical Evaluation of TYK2 Inhibitors in Type 1 Diabetes

Interferon-α (IFNα) plays a prominent role in type 1 diabetes (T1D) pathogenesis and mediates its effects through the IFN receptor (IFNAR) and the protein tyrosine kinases JAK1 and TYK2. Polymorphisms that decrease TYK2 activity are protective against T1D, and TYK2 inhibitors (TYKi) are being evaluated for therapeutic benefit in other autoimmune conditions. To test whether TYK2 inhibitors BMS-986202 and BMS-986165 have similar efficacy in diverse models of T1D, we evaluated their effect in vitro on human islets, EndoC-βH1 cells, and iPSC-derived islet-like aggregates and monitored diabetes incidence in RIP-LCMV and NOD mice following in vivo treatment with BMS-986202. TYK2i prevented IFNα-mediated upregulation of CXCL10, MX1, and HLA-ABC in human islets, iPSCs, and EndoC-βH1 and decreased IFNα-mediated STAT1/2 phosphorylation and apoptosis in human islets. Importantly, BMS-986202 reduced diabetes incidence in RIP-LCMV mice by 80% (n=18 vehicle/18 TYK2i; p