Highly selective, allosteric inhibition of TYK2 with oral ESK-001 in patients with moderate-to-severe plaque psoriasis: Results from STRIDE, a 12-week, randomized, double-blinded, placebo-controlled, dose-ranging phase 2 study.

Abstract

ESK-001, a novel allosteric, highly selective oral tyrosine kinase 2 inhibitor in development for treatment of immune-mediated disorders, was well-tolerated and achieved high levels of target inhibition in phase 1 studies with healthy volunteers. To assess clinical efficacy, safety, and pharmacokinetics of ESK-001 compared to placebo in patients with moderate-to-severe plaque psoriasis. STRIDE (NCT05600036, EudraCT Number 2022-002633-34) was a phase 2, double-blinded, 16-week study with patients randomized to 6 treatment groups for 12 weeks of placebo or ESK-001, ranging from 10 mg QD to 40 mg BID. ESK-001 demonstrated a dose-dependent improvement across all end points, with maximal efficacy observed in the highest dose arm (40 mg BID). At week 12, more patients achieved Psoriasis Area and Severity Index-75 in each ESK-001 dose arm compared to placebo: 64% in the 40 mg BID arm vs 0% with placebo (P < .0001). ESK-001 was well-tolerated, with no dose-limiting safety findings and a 2.6% rate of ESK-001 discontinuation due to adverse events. Small sample size per treatment group and 16-week study duration. ESK-001 demonstrated significant dose-dependent improvement in signs and symptoms of psoriasis while achieving continuous target inhibition at the highest dose in patients with psoriasis and was well-tolerated.