Enpatoran shows encouraging signals in lupus, despite an unmet primary endpoint

Enpatoran, an inhibitor of toll-like receptors (TLR) 7 and 8, demonstrated potential clinical activity in patients with active systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE). While the study did not meet the primary endpoint defined as dose-response in the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) dose-response, observed BICLA rates and secondary outcomes indicate promise.

“TLR7 and 8 have emerged as important potential therapeutic targets for autoimmune diseases, including lupus,” Prof. Eric Morand (Monash University, Australia) informed [1]. Enpatoran is an oral small molecule that reversibly inhibits TLR7 and 8 activity, providing a rationale for its evaluation in SLE.

The phase 2 WILLOW study (NCT05162586) included participants with active SLE and CLE evaluated within 2 cohorts [1]. Cohort A focused on participants with active CLE and met its primary endpoint of a significant dose-response in CLE Disease Area and Severity Index-Activity (CLASI-A). The findings from cohort B, presented by Prof. Morand, evaluated the BICLA response at week 24 in participants with active SLE (BILAG 1A/2B) receiving standard-of-care treatment.

Out of 354 adults enrolled, the first 60 were randomised to placebo or enpatoran 100 mg twice daily. Subsequent participants were randomised to placebo or enpatoran 25 mg, 50 mg, or 100 mg twice daily.

Baseline characteristics were well-matched across groups. Over 90% of participants were women, the mean age was around 40 years, and about 80% had a high interferon gene signature and/or positive RNA autoantibodies. Around half were on corticosteroids >10 mg/day.

The study did not meet its primary endpoint of BICLA dose response at week 24. The response rates were 39.4% for placebo, 57.7% for the 25 mg group, 48.6% for the 50 mg group, and 49.1% for the 100 mg group (P>0.005 for all comparisons). Despite the absence of statistical significance, the results, particularly for the 25 mg arm, were viewed as clinically meaningful.

Several secondary endpoints showed statistically significant improvements, including BICLA response combined with clinically meaningful glucocorticosteroid reduction, as well as BICLA response in participants with active skin manifestations (CLASI-A ≥8), across all enpatoran doses compared with placebo. Prof. Morand also highlighted that suppression of the interferon gene signature was observed early and maintained throughout the study period.

Enpatoran was generally well tolerated, and the safety profile was aligned with previous findings. “These results support further investigation of enpatoran in patients with SLE,” Prof. Morand concluded.

1. Morand E, et Randomised, placebo-controlled phase II study of oral enpatoran, a first-in-class toll-like receptor 7/8 inhibitor, in systemic lupus erythematosus. LB0004, EULAR 2025, 11–14 June, Barcelona, Spain.

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Posted on 8 August 202525 August 2025