First-in-human, phase I, randomized, safety, pharmacokinetic, food-effect and pharmacodynamic study of a tyrosine kinase 2/Janus kinase 1 inhibitor, SDC-1801

AIM: The purpose of this study is to evaluate safety, tolerability, pharmacokinetics (PK), food-effect (FE) and pharmacodynamics (PD) of an oral tyrosine kinase-2 (TYK2)/Janus kinase-1 (JAK1) inhibitor, SDC-1801, in healthy adult participants. METHODS: This first-in-human study randomized 95 male and female participants. Parts one and two were double-blind, placebo-controlled escalation designs, investigating single (5, 10, 30, 75, 150 mg) and multiple (30, 100, 75, 140 mg/day) doses of SDC-1801 or matching placebo. Part three evaluated the FE of 75 mg SDC-1801 in an open-label, crossover design. RESULTS: There were no deaths or treatment-related serious adverse events (AEs) following SDC-1801, up to 150 mg; no treatment-emergent AEs (TEAEs) were severe with non-related headache most frequently reported. PK showed low to moderate variability and no consistent dose-exposure relationship; Tmax occurred 3-5 h post-dose with a geometric mean (GM) t1/2 of 15.2-27.0 h. Bioavailability appeared solubility limited, with lower exposure from the higher strength capsule and modestly higher exposure in the fed state. No safety stopping criteria were met. PD assessments demonstrated anti-inflammatory activity, with IFN-gamma induced protein-10 (IP-10), high sensitivity C reactive protein (hsCRP), and signal transducer and activator of transcription (STAT3/5) phosphorylation reductions with increasing exposure giving greater inhibition. At the highest exposure, there was a clear reduction of IP-10 levels at pre-dose on day 9, which rebounded following drug withdrawal. CONCLUSIONS: SDC-1801 was well tolerated to 150 mg; all TEAEs were mild or moderate, with unrelated headache most frequently reported. The PK profile supports the potential for a once- or twice-daily regimen, with evidence of target engagement for both TYK2 and JAK1.