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Objectives There are no approved therapies for cutaneous manifestations of lupus, which occur in isolation (cutaneous lupus erythematosus [CLE]) or as a manifestation of systemic lupus erythematosus (SLE). Toll-like receptors (TLR)7/8 are key upstream drivers of type I interferon (IFN) pathway activation and myeloid- and B-cell activation. Enpatoran is a novel, first-in-class, oral TLR7/8 inhibitor. In a Phase 2, 24-week, randomised, double-blind, placebo-controlled, dose-finding basket study (WILLOW [ NCT05162586]), enpatoran provided clinically meaningful improvements in cutaneous and systemic lupus disease activity, including reductions in cutaneous and systemic manifestations and suppression of IFN gene signatures, and was well tolerated. Based on results from the WILLOW study, evaluation of enpatoran in participants with cutaneous manifestations of lupus with or without systemic disease is warranted.Methods In a phase 3, randomised, double-blind, placebo-controlled study (one of two replicate, parallel studies) the efficacy and safety of enpatoran will be investigated in adults with SLE or CLE, and cutaneous manifestations (CLASI-A >=8) of discoid lupus erythematosus, or subacute CLE (with/without systemic disease), or acute CLE (with systemic disease). Participants will be randomised 1:1 to placebo or 50 mg enpatoran BID for 24 weeks alongside standard of care (with corticosteroid taper from Weeks 2–12), followed by a 4-week safety follow-up ( figure 1). Randomisation will be stratified by factors including region, systemic disease severity (none/mild or moderate/severe [BILAG >=1A/2B]) and cutaneous disease severity (CLASI-A 8–9 or >=10).Results The primary objective will be to demonstrate the efficacy of enpatoran for reducing cutaneous disease activity by achieving CLASI-70 response at Week 24; secondary endpoints include BICLA response at Week 24 in the subpopulation of participants with moderate to severe SLE to assess efficacy across all affected organs, and safety/tolerability in the overall population ( figure 1).Abstract PO:11:286 Figure 1Phase 3 study design and primary/key secondary endpointsConclusions This novel phase 3 trial design aims to benefit a broader group of participants than conventional CLE or SLE trials, by evaluating enpatoran in participants with cutaneous manifestations of lupus with or without systemic disease. This approach has the potential to transform the lupus treatment paradigm for cutaneous manifestations of the disease, whilst also addressing underlying lupus pathophysiology upstream of IFN.