Achievement of Clinically Meaningful Treat-to-Target Thresholds with Envudeucitinib in Moderate-to-Severe Plaque Psoriasis: Results from ONWARD1 and ONWARD2

Background: Envudeucitinib (ESK-001), an investigational highly selective oral next-generation allosteric TYK2 inhibitor, was evaluated in patients with moderate-to-severe plaque psoriasis in the replicate Phase 3 ONWARD1 and ONWARD2 trials.1 This post-hoc analysis evaluated the achievement of clinically relevant treat-to-target thresholds2,3 for Psoriasis Area and Severity Index (PASI) and body surface area (BSA) in both studies. Methods: ONWARD1 and ONWARD2 randomized patients to envudeucitinib 40 mg BID (n=459/433), placebo (n=230/211, crossing over to envudeucitinib after Week 16), or apremilast 30 mg BID (n=223/215). Absolute PASI thresholds (0, ≤1, and ≤2,) and BSA (≤3%, ≤1%) were calculated post-hoc and assessed at Week 16 (vs placebo and apremilast) and Week 24 (vs apremilast) using non-responder imputation. Mean percent change from baseline in PASI was also summarized descriptively at Weeks 16 and 24 using modified baseline observation carried forward (mBOCF) imputation. Results: At Week 16, significantly more patients treated with envudeucitinib achieved clinically meaningful absolute PASI treatment targets than those receiving placebo or apremilast across both ONWARD1 and ONWARD2. At Week 16, absolute PASI thresholds with envudeucitinib vs placebo in ONWARD1 and ONWARD2 were, respectively: PASI=0, 29.4% vs 0.9% and 27.7% vs 0.9%; ≤1, 44.7% vs 3% and 40.9% vs 1.4%; and ≤2, 61.7% vs 7.4% and 55.9% vs 4.7%; (all p<0.0001), with envudeucitinib also significantly exceeding apremilast across all thresholds (PASI=0, 29.4% vs 4.0% and 27.7% vs 7.9%; ≤1, 44.7% vs 13% and 40.9% vs 14.0%; and ≤2, 61.7% vs 24.7% and 55.9% vs 22.8%; all p<0.0001). At Week 16, BSA ≤3% and ≤1% were achieved by 57.5% / 43.4% of patients treated with envudeucitinib in ONWARD1 and 54.0% / 41.3% in ONWARD2 vs 3.9% / 3.0% and 5.2% / 1.4% with placebo, and 26.0% / 15.7% and 22.3% / 13.5% with apremilast (p<0.0001). Responses deepened between Weeks 16 and 24 across all thresholds. At Week 24, 41.0%, 58.8%, and 68.8% of patients treated with envudeucitinib in ONWARD1, and 39.5%, 52.2%, and 64.7% in ONWARD2, respectively achieved PASI=0, ≤1, and ≤2, continuing to exceed apremilast (all p<0.0001); BSA ≤3% and ≤1% were achieved by 69.9% / 58.4% and 62.4% / 51.5% of patients treated with envudeucitinib vs 29.6% / 17.0% and 28.4% /18.6% with apremilast (p<0.0001), respectively. Rapid clinical improvement with envudeucitinib was observed as early as Week 2, with mean (SD) percent reductions from baseline in PASI of 29.2% (23.6) in ONWARD1 and 26.4% (24.7) in ONWARD2, increasing to 87.4% (24.6) and 86.1% (25.5), respectively, by Week 24. Conclusion: Treatment with envudeucitinib showed progressive achievement of increasingly stringent treat-to-target thresholds, with responses continuing to deepen from Week 16 through Week 24 across two independent Phase 3 studies, and improvements observed as early as Week 2. Overall findings were consistent with Week 52 results from the Phase 2 open-label extension.