Zasocitinib (TAK-279), a Selective, Oral TYK2 Inhibitor, Reduces Body Surface Area Involvement in a Phase 2b Trial in Moderate-to-Severe Plaque Psoriasis

Background: Zasocitinib (TAK-279) is an oral, allosteric, and highly selective inhibitor of tyrosine kinase 2 (TYK2). TYK2 mediates signaling from cytokines involved in the pathogenesis of psoriasis and other immune-mediated inflammatory diseases. In a phase 2b trial in patients with moderate-to-severe plaque psoriasis (NCT04999839), zasocitinib was well tolerated and demonstrated safety and efficacy, with a greater proportion of patients achieving skin clearance at doses ≥5 mg compared with placebo, with the two highest doses (15mg and 30mg) showing the strongest responses at Week 12. This analysis further evaluated the efficacy of the 15mg and 30mg doses of zasocitinib using body surface area (BSA) involvement. Methods: In this randomized, multicenter, double-blind, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were randomized 1:1:1:1:1 to receive oral zasocitinib (2, 5, 15 or 30mg) or placebo, once daily for 12 weeks. BSA outcome measures assessed at Week 12 were mean change in BSA from baseline, mean percentage change in BSA from baseline and the proportion of patients achieving a BSA threshold of ≤1% by visit. Mean change in BSA from baseline was prespecified. Results: Baseline mean (standard deviation [SD]) percentage BSA was generally consistent across the zasocitinib 15mg (n=53; 18.3 [10.3]), zasocitinib 30mg (n=52; 22.2 [14.3]) and placebo (n=52; 21.3 [13.6]) groups. Mean percentage BSA decreased as early as Week 2 and continued to decrease through to Week 12 in the zasocitinib groups, whereas scores slightly decreased in the placebo group. At Week 12, mean(SD) percentage BSA was 4.4 (5.3) (least-squares [LS] mean change: −14.7; LS mean percentage change: −72.9%) in the 15mg group, 6.5 (12.5) (LS mean change: −15.7; LS mean percentage change: −73.1%) in the 30mg group and 18.2 (13.6) (LS mean change: −4.0; LS mean percentage change: −19.3%) in the placebo group (p<0.001 for both doses versus placebo). From Week 8 onwards, higher proportions of patients achieved a BSA threshold of ≤1% in the zasocitinib 15mg and 30mg groups than in the placebo group (35.8% and 44.2% versus 0% at Week 12, respectively). Conclusion: Patients with moderate-to-severe plaque psoriasis who received the two highest doses of zasocitinib (15mg and 30mg) in the phase 2b trial achieved greater reductions in BSA than those who received placebo over 12 weeks. Further investigation of the efficacy and safety of zasocitinib in phase 3 studies in psoriasis is ongoing (NCT06088043; NCT06108544).

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