Sustained and Increasing Skin Clearance with Continuous Envudeucitinib in Moderate-to-Severe Plaque Psoriasis: Results from the ONWARD3 Long-Term Extension Study

Introduction and Objective: Envudeucitinib (ESK-001), an investigational highly selective oral next-generation TYK2 inhibitor demonstrated strong efficacy and safety through Week 24 in the pivotal Phase 3 ONWARD1 and ONWARD2 trials1. ONWARD3, an ongoing long-term extension (LTE), is evaluating efficacy and safety with continued treatment. Here, data from ONWARD3 based on 48 weeks of continuous envudeucitinib treatment are presented. Methods: Patients who completed Week 24 of ONWARD1 or ONWARD2 were eligible to enter ONWARD3 and receive open-label envudeucitinib 40 mg BID. Efficacy after 48 weeks of continuous envudeucitinib treatment was evaluated in ONWARD3, comprised of patients initially randomized to envudeucitinib in ONWARD1 or ONWARD2 who enrolled in ONWARD3. Endpoints included: ≥90% improvement in Psoriasis Area and Severity Index (PASI90), PASI100, static Physician’s Global Assessment (sPGA) 0/1 and 0, scalp-specific PGA (ssPGA) 0/1, ≥4-point improvement in worst pruritus Numeric Rating Scale (NRS) score, and Dermatology Life Quality Index (DLQI) 0/1, all assessed using non-responder imputation (NRI). Maintenance of response was assessed among patients who achieved each respective endpoint at Week 24 of ONWARD1 and ONWARD2, by evaluating proportions maintaining efficacy after 24 additional weeks. Safety through Week 48 was also evaluated. Results: Among 773 patients in ONWARD3, 75.4% and 53.7% of patients treated with envudeucitinib for 48 weeks achieved PASI90 and PASI100, respectively, with 75.2% and 54.5% achieving sPGA 0/1 and sPGA 0, and 82.0% achieving ssPGA 0/1. Responses extended beyond skin clearance with 78.3% of patients reporting a ≥4-point improvement in worst pruritus NRS score, and 72.2% reporting DLQI 0/1. Patients who switched from placebo (n=367) or apremilast (n=369) to envudeucitinib demonstrated robust increases across assessed endpoints. After 32 and 24 weeks of envudeucitinib treatment respectively, responses in these groups were generally consistent with those observed in patients continuously treated with envudeucitinib. Further, among responders after 24 weeks of envudeucitinib treatment in ONWARD1 and ONWARD2, between 80% and 90% of patients maintained their respective responses after an additional 24 weeks of treatment in ONWARD3. Among all patients enrolled in ONWARD3 (N=1509), safety remained consistent with previously reported findings (total exposure: 1041.8 patient-years), with no new signals or patterns identified. Overall, 69.9% of patients experienced ≥1 treatment-emergent adverse event (TEAE) and 3.3% experienced ≥1 serious adverse event. The majority of events were Grade 1 or 2 and resolved. The discontinuation rate remained low, with 3.9% of patients discontinuing due to TEAE. The most common TEAEs were nasopharyngitis (14.6%; EAIR 22.4/100PY), upper respiratory tract infection (12.0%; 17.9/100PY), influenza (4.6%; 6.6/100PY), urinary tract infection (4.0%; 5.8/100PY), and acne (2.7%; 3.9/100PY). No deaths, MACE events, tuberculosis reactivation, lymphomas, or clinically significant lab findings were observed. Conclusion: Continuous treatment with envudeucitinib for 48 weeks demonstrated high rates of skin clearance, itch improvement, and quality of life benefits, with the majority of Week 24 responders maintaining responses after 24 additional weeks of treatment. Safety findings were consistent with ONWARD1 and ONWARD2, and with observations from the Phase 2 program.