Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral TYK2 Inhibitor D-2570 in Healthy Subjects: A First-in-Human Phase I Study.

D-2570 selectively binds to the pseudokinase domain of tyrosine kinase 2, which mediates the downstream cytokine signaling pathways involved in immune regulation. The safety, tolerability, pharmacokinetics, and pharmacodynamics of D-2570 were evaluated in a randomized, double-blind, placebo-controlled phase I study conducted in healthy Chinese subjects. The study consisted of three parts: single ascending dose (D-2570: 3-48 mg once daily) study, multiple ascending dose (D-2570: 6-36 mg once daily for 10 days) study, and food effect (D-2570: 9 mg) study. D-2570 was rapidly absorbed, with peak plasma concentration at around 4 h and exposure increased sub-proportional across the dose groups. Following multiple dosing, mean terminal elimination half-lives at steady state ranged from 22.22 to 33.86 h, with modest area under curve accumulation (1.74- to 2.08-fold) showing no dose dependence. A high-fat meal increased area under the concentration time curve from time zero extrapolated to infinite time and maximum plasma concentration by 33% and 15% for the 9-mg dose, with no significant effect on median time to maximum concentration. The inhibitory effect of D-2570 on the release of interferon-gamma induced by interleukin-12/interleukin-18 increased dose-dependently in the range of 6-36 mg. No deaths or serious treatment-emergent adverse events occurred, and all the adverse events were Grade 1 or 2 in severity. D-2570 was well tolerated in healthy Chinese subjects, and its pharmacokinetic profile was characterized. These results provide the rationale for dose selection in future clinical trials and support advancing D-2570 as a potential treatment option for autoimmune diseases mediated by tyrosine kinase 2. Trial Registration: Chinadrugtrials.org.cn (CTR20222168).