Design of a Phase 3, Global, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study of Nipocalimab in Pregnancies at Risk for Severe Hemolytic Disease of the Fetus and Newborn

Abstract

Nipocalimab is a neonatal fragment crystallizable (Fc) receptor (FcRn)-blocking monoclonal antibody that inhibits placental immunoglobulin G (IgG) transfer and lowers circulating maternal IgG levels. In an open-label, single-arm, phase 2 study, nipocalimab demonstrated evidence of safety and efficacy that support further investigation in a pivotal phase 3 trial of recurrent hemolytic disease of the fetus and newborn (HDFN). The phase 3 AZALEA study aims to evaluate the efficacy and safety of nipocalimab in a larger population at risk for severe HDFN, defined as HDFN associated with poor fetal outcomes or neonatal death.AZALEA is a multicenter, randomized, placebo-controlled, double-blind, phase 3 study enrolling alloimmunized pregnant individuals (N ≈ 120) at risk for severe HDFN based on obstetric history. Participants are randomized 2:1 to receive intravenous 45 mg/kg nipocalimab or placebo weekly from 13-16 to 35 weeks gestational age (GA). During the double-blind treatment period, participants receive standard-of-care weekly monitoring for fetal anemia until planned delivery at 37 to 38 weeks of GA. Postnatal follow-up periods are 24 weeks for maternal participants and 104 weeks for neonates/infants.The primary endpoint is the proportion of pregnancies that do not result in intrauterine transfusion (IUT), hydrops fetalis, or fetal loss/neonatal death from all causes. Key secondary endpoints include the severity of HDFN as measured by a composite HDFN severity index, the earliest time to occurrence of IUT or hydrops fetalis, the modified neonatal mortality and morbidity index in liveborn neonates, and the number of IUTs received. Other endpoints are safety, patient- and caregiver-reported outcomes, pharmacokinetics, pharmacodynamics (e.g., IgG, FcRn receptor occupancy), and immunogenicity of nipocalimab.AZALEA, the first placebo-controlled, randomized, multicenter, prospective trial in severe HDFN, is designed to evaluate the safety and efficacy of nipocalimab, a potential preventive and noninvasive intervention, in at-risk HDFN pregnancies. · Severe HDFN leads to poor fetal/neonatal outcomes.. · IUTs are associated with complications and fetal loss.. · Nipocalimab blocks IgG recycling and placental transfer.. · Nipocalimab reduces fetal anemia and IUTs in early-onset severe HDFN.. · The phase 3 AZALEA study evaluates nipocalimab in severe HDFN..

Fig. 1

Nipocalimab mechanism of action. ( A ) Illustration of nipocalimab preventing IgG–FcRn interaction. IgG binds with moderate strength to FcRn at an endosomal pH of 6.0 but not at an extracellular pH of 7.4 (left). Nipocalimab binds strongly to FcRn under both conditions (pH 6.0 or 7.4), allowing rapid and complete blockade of FcRn. ( B ) Illustration of nipocalimab blocking transplacental IgG transfer and IgG recycling in maternal circulation. Placental IgG transfer (upper left panel) occurs when maternal IgG antibodies, including anti-erythrocyte IgG alloantibodies in EOS-HDFN, undergo pinocytotic uptake into syncytiotrophoblasts (the fetal–maternal barrier layer of the placenta), where they are bound to endosomal FcRn and undergo apical-to-basal transcytosis (transport and export) to enter the fetal vasculature. In maternal circulation, FcRn mediates IgG recycling in endothelial cells lining the maternal circulation (lower left panel), which functions to maintain high maternal serum IgG as well as anti-erythrocyte IgG alloantibodies available for placental transfer to the fetus. Nipocalimab is designed to block transplacental transfer of maternal IgG, including anti-erythrocyte alloantibodies (upper right panel), and to block FcRn-mediated IgG recycling to lower circulating maternal alloantibodies available for placental transfer (lower right panel). EOS-HDFN, early-onset severe hemolytic disease of the fetus and newborn; FcRn, neonatal Fc receptor; IgG, immunoglobulin G.

Fig. 2

AZALEA study design. ^a Treatment can start any day from Week 13 to 16. ^b R Day 1 (first dose of study intervention) can occur from GA Week 13 to 16. GA, gestational age; HDFN, hemolytic disease of the fetus and newborn; IV, intravenous; MCA-PSV, middle cerebral artery peak systolic velocity; QW, weekly; R, randomization.

Fig. 3

Multiple testing procedure. ^a One-sided level of significance. H, hypothesis; HDFN, hemolytic disease of the fetus and newborn; IA, interim analysis; IUT, intrauterine transfusion; PMA, postmenstrual age.