Energy Trial in Warm Autoimmune Hemolytic Anemia (wAIHA): Design of a Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Nipocalimab, an FcRn Blocker

Abstract

Background: Warm autoimmune hemolytic anemia (wAIHA) is a rare condition characterized by the premature destruction of red blood cells (RBCs) mainly in the presence of pathogenic immunoglobulin G (IgG) autoantibodies that preferentially bind to RBCs at 37°C, resulting in extravascular hemolysis of these RBCs in the spleen (or liver). Patients with wAIHA can experience acute or chronic worsening of anemia, increased risk of thromboembolic events, and premature death. Innovative targeted therapies that address the underlying pathogenesis of wAIHA are needed, as there is currently no approved treatment for this disease. Nipocalimab is a high affinity, fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the neonatal Fc receptor (FcRn) to lower circulating IgG levels, including pathogenic autoantibodies. Nipocalimab is being evaluated across multiple IgG-mediated diseases. A completed phase 2 study in patients with generalized myasthenia gravis demonstrated rapid, durable total serum IgG and pathogenic IgG autoantibody reductions and meaningful clinical response [Guptill J, et al. AAN 2021. Presentation 2157]. Aim: Describe the rationale and study design of ENERGY, an ongoing, adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study that will evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of nipocalimab compared with placebo in patients with wAIHA (NCT04119050). Methods: Subjects ≥18 years of age who have been diagnosed with primary or secondary wAIHA and are currently receiving treatment for wAIHA or have previously received treatment for wAIHA will be included in the study. Subjects with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Stable doses of corticosteroids or immunosuppressants will be allowed. Approximately 111 patients will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, patients may enter an open-label extension period to receive nipocalimab for 144 weeks with a follow-up period of 6 weeks after last assessment. Results: ENERGY will include approximately 160 sites across 19 countries, including Brazil, Canada, China, Czech, Egypt, France, Germany, Greece, Hungary, Japan, Israel, Malaysia, Netherlands, Italy, Poland, South Korea, Spain, the United Kingdom, and the United States. The primary endpoint is percentage of participants achieving durable response of improvement in hemoglobin (Hgb). The secondary endpoints include change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale, corticosteroid dose reduction from baseline, and normalization of hemolytic markers. Conclusion/Summary: The results of ENERGY have the potential to identify a novel treatment option to address the significant unmet needs of patients with wAIHA. Enrollment is ongoing in this clinical trial.