EFAVALEUKIN ALFA IN PATIENTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS OF A BAYESIAN ADAPTIVE, PHASE 2B, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED DOSE-RANGING STUDY

PV277 / #493 Poster Topic: AS24 - SLE-Treatment Background/Purpose SLE is a complex chronic autoimmune disease with diverse clinical manifestations. Impaired regulatory T cell (Treg) function is associated with SLE pathogenesis. Interleukin-2 (IL-2) is a key regulator of Treg homeostasis; decreased levels of circulating IL-2 are associated with aberrant Treg metabolism in SLE. Efavaleukin alfa, an IL-2 mutein Fc fusion protein with superior Treg selectivity, can preferentially expand Tregs in patients with SLE. This study ( NCT04680637 ) evaluated the safety and efficacy of efavaleukin alfa in patients with active SLE. Methods This was a Bayesian adaptive phase 2b, randomized, double-blind, placebo-controlled, multicenter, dose-ranging study in adult patients with active SLE with Hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) score ≥ 6, clinical hSLEDAI score ≥ 4 and inadequate response to standard-of-care (SOC) therapies. Patients were randomized to receive either placebo or efavaleukin alfa (low, medium, or high dose) every 2 weeks and continued SOC treatment for 52 weeks (Figure). The randomization ratio started as 1:1:1:1, then was adapted using Response Adaptive Randomization to allocate more patients to more efficacious doses and fewer patients to less efficacious doses, with a fixed 25% allocation to placebo based on the clinical efficacy at prespecified interim analyses (IAs).[1] Futility analyses were conducted using a Bayesian hierarchical model. The primary endpoint was the achievement of SLE Responder Index 4 (SRI-4) response at Week 52, defined as a ≥ 4-point reduction in hSLEDAI score, no new British Isles Lupus Assessment Group (BILAG) 2004 A and no > 1 new BILAG B scores, a < 0.3-point deterioration in Physician’s Global Assessment, and no use of more than protocol-permitted therapies. Patients were followed up for at least 6 weeks after the last dose for safety. An adjudication committee was utilized throughout the study to confirm eligibility, endpoints, and clinical outcomes. Figure. Clinical trial design utilizing response adaptive randomization Results A total of 168 participants (94.0% female; 56.0% White) from 13 countries across 4 continents were enrolled (mean [SD] age: 44.1 [11.8] years). The trial was discontinued due to meeting predefined futility criteria at its third IA. At the date of termination, 16, 17, and 14 patients in the low, medium, and high-dose efavaleukin alfa groups, respectively, and 15 patients in placebo had completed the Week 52 visit. Among these, a lower percentage of patients achieved an SRI-4 response at Week 52 in the 3 efavaleukin alfa groups (25-35.7%) compared to placebo (53.3%). All 168 patients who received at least 1 dose of study drug were included in the safety analysis (Table). Treatment-emergent adverse events (AEs) occurred in the efavaleukin alfa groups (82.9-100%) and placebo (70.7%). Incidences of serious AEs across efavaleukin alfa groups (5.1%-12.1%) were comparable with placebo (9.8%). The most frequent AEs (≥ 10.0%) in the overall efavaleukin alfa group were injection site erythema, injection site pruritus, injection site pain, injection site rash, injection site swelling, COVID-19, and headache. All injection site reactions were grade 1 or 2. No serious treatment-related AEs were observed. Table. Safety of efavaleukin alfa in patients with active SLE Conclusions The study was terminated as it met predefined futility criteria and not because of safety concerns. Treatment with efavaleukin alfa did not result in improvements of the efficacy endpoints over placebo in patients with active SLE. The safety profile observed in this study was consistent with the known profile of efavaleukin alfa. References: [1.] Garces S. Lupus Sci Med 2023;10:e000890.