Daxdilimab in Moderate-to-Severe Discoid Lupus Erythematosus: Efficacy and Safety Results From a Phase 2, Randomized, Placebo-Controlled Trial

Introduction: Discoid lupus erythematosus (DLE) is the most prevalent form of chronic cutaneous lupus erythematosus (CCLE).1 Plasmacytoid dendritic cells (pDCs) are increased in the lesional skin of patients with CLE and are key mediators of disease immunopathogenesis through their association with type I interferon biology.2 Daxdilimab is a human IgG1 monoclonal antibody targeting immunoglobulin-like transcript 7 (ILT7), a cell-surface protein exclusively expressed on pDCs. Binding of daxdilimab to ILT7 results in targeted reduction in the number of pDCs in the tissue and blood.2 We report results from a phase 2 trial (NCT05591222) evaluating the efficacy and safety of two doses of daxdilimab in patients with DLE. Method: A multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled patients aged 18–75 years with chronic, moderate-to-severe, treatment-refractory DLE for ≥ 6 months with active disease at baseline (Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity [CLASI-A] ≥ 8) and without systemic features. Patients were randomized 1:1:1 to receive low dose (LD) daxdilimab, high dose (HD) daxdilimab, or placebo for 24 weeks, with dosing every 4 weeks from Day 1 through Week 20. The primary efficacy endpoint was mean change in CLASI-A score from baseline to Week 24. Secondary endpoints included the proportion of patients achieving ≥ 50% reduction in CLASI-A score (CLASI-50) and those achieving a score of 0/1 on the Cutaneous Lupus Activity Investigator's Global Assessment (CLA-IGA) scale (CLA-IGA 0/1) at Week 24. Safety was assessed up to Week 24. Primary endpoint was analyzed in the full analysis set using a mixed model for repeated measures. Results: Overall, 72 patients were randomized to LD daxdilimab (n=24), HD daxdilimab (n=23), or placebo (n=25). Baseline demographics and disease characteristics were generally comparable across treatment groups (mean±SD age, 48.8±12.0 years; 69.4% female). At baseline, the overall mean±SD CLASI‑A and CLA-IGA scores were 15.2±6.30 and 3.1±0.63, respectively. Both doses of daxdilimab met the primary and secondary endpoints. Significant reductions in CLASI‑A vs placebo were observed at Week 24, with treatment response evident as early as Week 4. At Week 24, the LS mean difference in change from baseline in CLASI-A vs placebo was –6.0 (90% confidence interval [CI]: –8.7, –3.2; P=0.0005) for LD and –5.7 (90% CI: –8.5, –2.9; P=0.0012) for HD. At Week 24, adjusted response rates (standard error [SE]) were significantly increased for CLASI-50 (Placebo: 23.7% [8.5]; LD: 61.7% [10.1], P = 0.0037; HD: 62.1% [10.3], P=0.0044) and CLA-IGA 0/1 (Placebo: 8.9% [5.6]; LD: 60.3% [11.0], P< 0.0001; HD: 51.6% [11.2], P=0.0007) compared with placebo. Daxdilimab was well tolerated with no serious adverse events or death reported. Treatment-related adverse events occurred in 58.3%, 56.5% and 60.0% of patients in the LD, HD, and placebo groups, respectively One patient in the HD group discontinued the study due to arthralgia. Conclusion: Daxdilimab demonstrated significant improvement in the primary endpoint of CLASI-A and consistent efficacy across secondary endpoints, with a favorable safety profile in patients with moderate-to-severe DLE. These findings support the role of pDCs in disease pathogenesis of DLE and the potential of targeting this pathway.