RANDOMIZED, PLACEBO-CONTROLLED PHASE II STUDY OF ENPATORAN, A SMALL MOLECULE TOLL-LIKE RECEPTOR 7/8 INHIBITOR, IN CUTANEOUS LUPUS ERYTHEMATOSUS: RESULTS FROM COHORT A

O010 / #827 Topic: AS07 - Cutaneous Lupus Late-Breaking Abstract ABSTRACT CONCURRENT SESSION 01: FINDINGS FROM LUPUS CLINICAL TRIALS 22-05-2025 1:40 PM - 2:40 PM Background/Purpose No treatment is approved for cutaneous lupus erythematosus (CLE), which may occur in the presence or absence of systemic lupus erythematosus (SLE). Enpatoran is an oral small molecule toll-like receptor 7/8 inhibitor, with potential to modulate processes central to CLE and SLE pathophysiology. WILLOW ( NCT05162586 ) is a Phase II randomized double-blind placebo-controlled dose-finding parallel adaptive study in adults with SLE or CLE receiving standard of care to evaluate the efficacy and safety of enpatoran. WILLOW Cohort A enrolled patients with CLE or SLE who had active lupus rash. Methods Patients with Cutaneous Lupus Disease Area and Severity Index-Activity (CLASI-A) score ≥ 8 CLE were enrolled; they had CLE only, or SLE with mild or no extramucocutaneous disease activity [British Isles Lupus Assessment Group 2004 < 1B, C, D]). Patients were randomized 1:1:1:1 to 1 of 3 doses of enpatoran or placebo for 24 weeks, with an additional 2-week safety follow-up for patients not choosing to enter the long-term extension. The primary objective was to evaluate the dose-response relationship of enpatoran in reducing disease activity, based on change from baseline in CLASI-A score at Week 16. Secondary endpoints included change from baseline in Physician’s Global Assessment at Weeks 16 and 24, clinically meaningful corticosteroid (CS) reduction, and occurrence of Cutaneous Lupus Activity-Investigator Global Assessment 0 or 1 at Week 16 and Week 24. Exploratory endpoints included CLASI-A improvement ≥ 50%/70% (CLASI-50/70). Treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of special interest and laboratory parameters were collected from Day 1 to the end of safety follow-up. Results 102 patients were randomized, and 100 patients were included for efficacy evaluation (placebo n = 26; enpatoran low dose n = 23; mid dose n = 25; high dose n = 26). 77.0% of patients were female, and 58.0% had CLE only. At baseline, 59.0% of patients were receiving systemic CS, 38.0% immunosuppressants and 76.0% antimalarials; 71% had moderate-to-severe disease (CLASI-A ≥ 10). The primary outcome was achieved. At Week 16, a significant dose response for enpatoran in reducing CLASI-A from baseline was detected (p = 0.0002) (Table 1). Table 1 Dose-response relationship of enpatoran in reducing disease activity based on change from baseline in CLASI-A score at Week 16 (FAS; N = 100) Furthermore, up to 91.3% of patients receiving enpatoran achieved CLASI-50, and up to 60.9% achieved CLASI-70 at Week 16, compared with 38.5% and 11.5% of patients, respectively, receiving placebo. Enpatoran was well tolerated across all study doses. High-dose enpatoran was associated with a higher rate of TEAEs (Table 2) than lower doses or placebo; the most frequently reported TEAEs were infections and infestations. Table 2 Treatment-emergent adverse events (SAS; N = 102) Conclusions Enpatoran demonstrated a significant dose response in change from baseline in CLASI-A compared with placebo at Week 16 in patients with CLE or SLE and was well tolerated. Acknowledgments: The authors wish to thank Dominika Weinelt for their support with the study conduct and analysis. Medical writing support was provided by Nicole Jones on behalf of Amica Scientific, Macclesfield, UK, and sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany.

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