Enpatoran, an oral Toll-like receptor 7/8 inhibitor, significantly reduced skin disease activity in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) with active cutaneous manifestations, according to findings from the WILLOW phase 2 trial published in The Lancet Rheumatology.
Enpatoran is an oral, first-in-class small molecule that selectively inhibits TLR7 and TLR8, receptors involved in innate immune signalling and lupus pathogenesis. Preclinical and early clinical studies have shown that enpatoran reduces inflammatory mediators such as interleukin-6 and interferon-α. In lupus mouse models, it improved survival, kidney damage, autoantibody levels, and the interferon gene signature. It also reduced autoantibodies against DNA-containing antigens, including anti-double-stranded DNA antibodies. Preclinical evidence has additionally suggested that TLR7/8 signalling may contribute to glucocorticoid resistance, although the clinical relevance of this finding remains to be established.
WILLOW was a phase 2, randomised, double-blind, placebo-controlled, basket, dose-finding trial conducted at 132 centres across 22 countries. Adults aged 18–75 years with CLE alone or SLE with mild or no extra-mucocutaneous disease activity were enrolled. Participants had British Isles Lupus Assessment Group (BILAG)-2004 scores of B, C, or D and a Cutaneous Lupus Disease Area and Severity Index-activity (CLASI-A) score of at least 8. Participants were randomly assigned to placebo or enpatoran 25 mg, 50 mg, or 100 mg twice daily for 24 weeks, in addition to standard of care. The primary endpoint was the percentage change from baseline in CLASI-A total score at week 16.
Enpatoran produced a significant dose-dependent reduction in CLASI-A scores at week 16. Adjusted mean changes from baseline were −64 percentage points with 25 mg, −68 percentage points with 50 mg, and −72 percentage points with 100 mg, compared with −44 percentage points with placebo. The dose-response relationship was statistically significant (p=0·0002).
Enpatoran was generally well tolerated. Upper respiratory tract infection was the most common treatment-emergent adverse event, occurring in 8%, 15%, 19%, and 8% of participants in the 25 mg, 50 mg, 100 mg, and placebo groups, respectively. Serious adverse events occurred in 8% of participants receiving 25 mg, 4% receiving 100 mg, 4% receiving placebo, and none receiving 50 mg.
The findings are clinically relevant because cutaneous manifestations are common in lupus and can substantially affect quality of life. The results provide clinical support for targeting TLR7/8-mediated innate immune signalling as a potential treatment strategy for active cutaneous lupus.
As a phase 2 study, the findings require confirmation in larger and longer-term trials to establish the durability of response and long-term safety and to determine whether TLR7/8 inhibition benefits other manifestations of SLE. Overall, WILLOW supports further investigation of enpatoran as a potential oral targeted therapy for active cutaneous lupus.
References
- Morand EF, Werth VP, Wenzel J, Furie R, Dall’Era M, Sanchez-Guerrero J, et al. Efficacy and safety of enpatoran, a Toll-like receptor 7/8 inhibitor, in patients with skin manifestations of cutaneous lupus erythematosus or systemic lupus erythematosus: findings from Cohort A of a multicentre, international, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Rheumatol. 2026 Jul;8(7):e513-e527.
- Witte T, Fernandez-Ruiz R, Abramova N, Weinelt D, Moreau F, Klopp-Schulze L, et al. Enpatoran, a first-in-class, selective, orally administered toll-like receptor 7/8 inhibitor, in systemic and cutaneous lupus erythematosus: results from a randomised, placebo-controlled phase Ib study. Lupus Sci Med. 2025 Oct 23;12(2):e001705.