EMD Serono, the healthcare business of Merck KGaA, Darmstadt, Germany, in the US and Canada, announced that the US FDA has granted Breakthrough Therapy Designation (BTD) to enpatoran, an oral selective inhibitor of toll-like receptors 7 and 8 (TLR7/8), for the treatment of lupus with active cutaneous manifestations. The designation covers both cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) presenting with active skin involvement — a population for which no targeted therapy is currently approved anywhere in the world.
BTD entitles the program to intensive FDA guidance, more frequent agency interactions, and eligibility for rolling and priority review, supporting a potentially compressed path to submission.
The designation was supported by data from the Phase II WILLOW study (NCT05162586), a global, multicenter, randomized, double-blind, placebo-controlled, dose-finding trial employing a basket design across two cohorts. Cohort A enrolled patients with CLE or SLE with active lupus rash and met its primary endpoint, demonstrating a statistically significant dose-response relationship in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) scores at Week 16 (p = 0.0002). At Week 24, up to 91.3% of patients receiving enpatoran achieved a CLASI-50 response (≥50% improvement from baseline) and up to 60.9% achieved a CLASI-70 response, compared with 38.5% and 11.5%, respectively, in the placebo group, according to data presented at LUPUS 2025. Cohort B, which enrolled patients with moderate-to-severe active SLE, did not meet its primary endpoint of dose-response relationship on British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate at Week 24; however, in the prespecified subgroup of patients with active cutaneous involvement at baseline (CLASI-A ≥8), BICLA response rates reached up to 58.6% versus 31.7% for placebo, with CLASI-70 responses of up to 60.5% versus 26.8% for placebo, as reported at EULAR 2025. Enpatoran was well-tolerated across both cohorts, with treatment-emergent adverse event rates ranging from 60.6% to 64.2% — comparable to placebo — and no new safety signals identified.
Enpatoran inhibits TLR7 and TLR8, innate immune receptors that recognize single-stranded RNA and drive downstream interferon and pro-inflammatory cytokine production implicated in lupus pathogenesis. In Cohort A, treatment produced a rapid reduction in interferon gene signature scores beginning at Week 2 that was sustained through Week 24, confirming pathway engagement. The oral route and upstream mechanism distinguish it from approved SLE biologics such as anifrolumab (Saphnelo), which targets the type I interferon receptor, and belimumab (Benlysta), which blocks B-lymphocyte stimulator.