Safety, pharmacokinetics and pharmacodynamics of ICP-332, an oral TYK2 inhibitor, in healthy participants: a randomized, double-blind, placebo-controlled phase I study

Abstract

ICP-332 is a novel, orally administered TYK2 inhibitor with high selectivity, intended for the treatment of immune inflammatory diseases such as atopic dermatitis, psoriatic arthritis, inflammatory bowel disease and lupus. This Phase I study assessed its safety, pharmacokinetics, pharmacodynamics, and food effect in Chinese healthy participants. This study was designed as a randomized, double-blind, placebo-controlled trial in healthy participants. It consisted of a single-ascending-dose (SAD) part with six cohorts (5, 15, 40, 80, 160, and 320 mg) and a multiple-ascending-dose (MAD) part with three cohorts (40, 80, and 160 mg administered once daily for 14 days). Food-effect evaluation was included at the 80 mg SAD level. In each cohort, eight participants were randomized (6:2) to receive either ICP-332 or placebo. Following oral administration, plasma samples were collected to determine ICP-332 concentrations, and safety tolerance was monitored and assessed throughout the study. This study enrolled 72 healthy participants, with 48 and 24 completing the SAD and MAD phases, respectively. After oral administration, ICP-332 showed rapid absorption, with median time to peak concentration ( T max ) of 0.5–2.0 h and mean elimination half-life ( t ½ ) of 2.692–7.275 h. Dose-proportional exposure was confirmed in both the SAD (5–320 mg) and MAD (40–160 mg) phases; area under the concentration–time curve ( AUC last ) ranged from 146.3 to 11,667.5 h·ng/mL in the SAD phase and from 1386.0 to 6513.5 h·ng/mL at steady state in the MAD phase. ICP-332 also induced rapid and dose-dependent suppression of TYK2 activity, as evidenced by dose-related reductions in high-sensitivity C-reactive protein and a trend toward decreased interferon gamma-induced protein 10 levels versus placebo. In terms of safety, treatment-emergent adverse events were all mild to moderate in severity, with no participant withdrawals. TEAE incidence was comparable to placebo in the SAD phase and slightly higher in the MAD phase. ICP-332 exhibited favorable safety, pharmacokinetics and pharmacodynamics profiles across the 5–320 mg dose range, with rapid absorption, dose-proportional exposure, and mild, reversible adverse events. A high-fat meal did not significantly affect its pharmacokinetics, pharmacodynamics or safety. These results support continued clinical development of ICP-332 as a promising treatment for autoimmune diseases. http://www.chinadrugtrials.org.cn/index.html CTR20211781.