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.

Abstract

Toll-like receptor (TLR)7 and TLR8 are nucleic-acid sensors involved in lupus pathogenesis. We aimed to investigate the efficacy and safety of enpatoran, an oral small-molecule TLR7/8 inhibitor, in participants with active skin manifestations of cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). WILLOW is a phase 2, randomised, double-blind, placebo-controlled, basket, dose-finding study conducted across 132 centres in 22 countries, enrolling patients into two cohorts (A and B) with different eligibility criteria. In Cohort A of the trial, we enrolled participants aged 18-75 years who had CLE only or SLE with mild or no extra-mucocutaneous disease activity (British Isles Lupus Assessment Group [BILAG]-2004 scores 1B, C, or D), and a Cutaneous Lupus Disease Area and Severity Index-activity (CLASI-A) score of 8 or higher. Participants were randomised (1:1:1:1) to receive placebo or enpatoran at a dose of 25 mg, 50 mg, or 100 mg twice per day for 24 weeks, in combination with standard of care. The primary objective was to evaluate the dose-response relationship of enpatoran in reducing disease activity, based on the percentage change from baseline in CLASI-A total score at week 16, analysed with a multiple comparison procedure-modelling approach. Efficacy analyses were done in the full analysis set of all randomly allocated participants. Safety was assessed in all patients who received at least one dose of study treatment. There was no involvement of people with lived experience of CLE or SLE in study design. This trial is registered with ClinicalTrials.gov (NCT05162586; completed); results from Cohort B will be reported separately. Between May 4, 2022, and Feb 6, 2024, 463 patients were screened for eligibility across cohorts A and B; 102 participants were randomly assigned within Cohort A and received treatment (safety population). Two participants (n=1 each from the enpatoran 25 mg and 50 mg groups) were randomly allocated to Cohort A but were subsequently found to have had BILAG scores ≥1A and 2B at screening and were therefore deemed ineligible and excluded; thus 100 participants were analysed for efficacy (placebo group n=26; enpatoran 25 mg group n=23; enpatoran 50 mg group n=25; enpatoran 100 mg group n=26). Participants in the full analysis set had a median age of 47 years (IQR 36-55); 77 (77%) were female, 23 (23%) were male, and 48 (48%) were White. At week 16, enpatoran had a significant, dose-dependent effect on CLASI-A score, with adjusted mean changes from baseline of -64 percentage points (95% CI -70 to -58) in the enpatoran 25 mg group, -68 percentage points (-75 to -61) in the enpatoran 50 mg group, and -72 percentage points (-80 to -64) in the enpatoran 100 mg group, versus -44 percentage points (-55 to -33) in the placebo group (p=0·0002 for dose-response relationship). The most common treatment-emergent adverse event was upper respiratory tract infection, which occurred in two (8%) of 24 patients in the enpatoran 25 mg group, four (15%) of 26 in the enpatoran 50 mg group, five (19%) of 26 in the enpatoran 100 mg group, and two (8%) of 26 in the placebo group. Overall, one (4%) participant in the placebo group, one (4%) in the enpatoran 100 mg group, and two (8%) in the enpatoran 25 mg group had serious adverse events; none were reported with enpatoran 50 mg. Enpatoran showed a significant and dose-dependent effect on disease activity in participants with active cutaneous manifestations of CLE or SLE, and was well tolerated. Merck Healthcare KGaA, Darmstadt, Germany.