A Double‐Blind, Randomized, Placebo‐Controlled, Phase 2 Trial of Obexelimab in Systemic Lupus Erythematosus with Exploration of Response Based on Gene Pathway Co‐Expression Patterns

Objective Obexelimab is an investigational, bifunctional, noncytolytic monoclonal antibody that binds CD19 and FcyRIIb to inhibit B cells, plasmablasts, and plasma cells. This trial evaluated the efficacy and safety of obexelimab in the treatment of patients with systemic lupus erythematosus (SLE). Methods During Screening, patients with active, non‐organ‐threatening SLE received corticosteroid injections to ameliorate symptoms while immunosuppressants were withdrawn (≤10 mg/day prednisone equivalent and ≤400 mg/day hydroxychloroquine allowed). Patients with improved disease activity were randomized 1:1 to obexelimab 5 mg/kg IV or placebo once every 2 weeks until Week 32 or loss of improvement (LOI). Results 104 patients were randomized. Analysis of the primary endpoint, proportion of patients reaching Week 32 without LOI, used an efficacy‐evaluable (EE) population defined as patients who completed the study or withdrew for flare or treatment‐related toxicity. This endpoint did not reach statistical significance: 21/50 (42.0%) obexelimab‐treated vs. 12/42 (28.6%) placebo‐treated patients (p=0.183). Time to LOI was increased in obexelimab‐treated vs. placebo‐treated patients in the EE (HR 0.53, p=0.025) and intention‐to‐treat (HR 0.59, p=0.062) populations. In obexelimab‐treated patients, B cells decreased approximately 50%, and trough concentration and inclusion in baseline gene expression clusters with high B cell pathway modules were associated with increased time to LOI. Obexelimab was associated with infusion reactions but was generally safe and well‐tolerated. Conclusion Although the primary endpoint was not reached, secondary analysis showed time to LOI was significantly increased in obexelimab‐treated patients, and analysis of patient subsets defined by gene expression patterns at baseline suggests a responding subpopulation. image