317 Characterization of pharmacokinetics, pharmacodynamics, tolerability and clinical activity in phase I studies of the novel allosteric tyrosine kinase 2 (TYK2) inhibitor NDI-034858

Tyrosine kinase 2 (TYK2) is an obligate mediator of signaling via IL-23, IL-12 and the type I interferon receptors, and is a validated therapeutic target in psoriasis and psoriatic arthritis. NDI-034858 is a novel, oral, allosteric, investigational TYK2 inhibitor with high selectivity for TYK2 over JAK1, JAK2, and JAK3 kinases. NDI-034858 was studied in multiple placebo-controlled Phase I studies. These included two trials in healthy volunteers receiving single ascending doses (six dose groups, N = 5-6 per group; versus placebo, N = 12) and multiple ascending doses (four dose groups, N = 6 per group; versus two placebo groups, N = 4 per group) for 2 weeks. NDI-034858 was also studied in patients with moderate to severe psoriasis treated daily for 4 weeks (three dose groups, N = 21 total; versus placebo, N = 5). Across the studies, the pharmacokinetic parameters of NDI-034858 were calculated. Pharmacodynamic effect was tested in a cytokine-induced ex vivo assay using whole blood samples, which demonstrated that exposure to NDI-034858 correlated with activity. No serious adverse events or deaths were observed in the studies, and treatment emergent adverse events were as expected for inhibition of TYK2. Exploratory efficacy endpoint analysis in patients with moderate to severe psoriasis using the Psoriasis Area and Severity Index (PASI) score suggested improvement in the disease. These data support further development of NDI-034858. Phase 2b trials in psoriasis and psoriatic arthritis are ongoing.