AB1289 STUDY DESIGN OF A PHASE 2/3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF NIPOCALIMAB, AN FcRn ANTAGONIST, IN WARM AUTOIMMUNE HEMOLYTIC ANEMIA (wAIHA)

Abstract

BackgroundWarm autoimmune hemolytic anemia (wAIHA) is characterized by the destruction of red blood cells (RBCs) by pathogenic autoantibodies which bind to RBCs and lead to their clearance in the spleen and liver. Patients with wAIHA can experience acute worsening of anemia, which can be a medical emergency, and have an increased risk of thromboembolic events and premature death. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity. FcRn, which is expressed in endothelial cells, is responsible for recycling IgG into the circulation and for the relatively long half-life of IgG antibodies compared to other Igs. It is expected that nipocalimab, by inhibiting IgG binding to FcRn, will prevent IgG recycling and lower pathogenic IgG autoantibodies that cause many autoimmune diseases including warm autoimmune hemolytic anemia (wAIHA).Nipocalimab has been studied in multiple phase 1 studies in healthy subjects and in a recently completed phase 2 study in subjects with Generalized Myasthenia Gravis (gMG). In the gMG phase 2 study, nipocalimab was well tolerated at doses from 5 mg/kg every 4 weeks to 60 mg/kg every 2 weeks. Treatment with nipocalimab was associated with rapid and durable total serum IgG and pathogenic IgG autoantibody reduction and meaningful clinical response. A statistically significant relationship between IgG autoantibody reduction and clinical benefit was observed. This study provided proof-of-concept evidence that lowering pathogenic IgG autoantibodies can ameliorate the autoimmune condition these antibodies cause.ObjectivesTo share the rationale and study design for an adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study in patients with wAIHA whose aim is to evaluate the efficacy, safety, tolerability, PK, and PD of nipocalimab compared with placebo1.MethodsMale or female patients ≥18 years of age who have been diagnosed with primary or secondary wAIHA and have not experienced a sufficient response or have not tolerated currently available treatments will be included in the study. Patients with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. 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.ResultsThe following endpoints will be analyzed:Primary endpoint:Percentage of participants achieving durable response of improvement in hemoglobin (Hgb).Main secondary endpoints:Change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale at the end of the double-blind period.Number of participants who attain normal lactate dehydrogenase, normal haptoglobin, and normal indirect bilirubin levels at a minimum of 3 consecutive visits after baseline.ConclusionA phase 2 study investigating nipocalimab in patients with gMG provided proof of concept for a phase 2/3 interventional study with nipocalimab in patients with wAIHA. This phase 2/3 study is currently enrolling in the USA and Europe.