Design of a Phase 3, Multicenter, Randomized, Open-Label Study of Nipocalimab or IVIG in Pregnancies at Risk for Fetal and Neonatal Alloimmune Thrombocytopenia (FREESIA-3)

Background: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare, life-threatening condition with fetuses at risk of intracranial hemorrhage. Maternal immunoglobulin (IgG) alloantibodies against fetal human platelet antigens (HPAs) cross the placenta, and bind to fetal platelets, leading to platelet destruction and thrombocytopenia. Currently, there is no routine prenatal screening for HPA alloimmunization. Intravenous immunoglobulin (IVIG) is well-described as standard-of-care treatment for FNAIT in most countries. Nipocalimab is a fully human, IgG1, high-affinity, effectorless, neonatal Fc receptor (FcRn)–blocking monoclonal antibody that inhibits transplacental IgG transfer and lowers circulating maternal IgG levels. Nipocalimab showed proof-of concept efficacy in preventing or delaying fetal anemia with an acceptable safety profile in an open-label phase 2 study of hemolytic disease of the fetus and newborn (ClinicalTrials identifier: NCT03842189). Identified nipocalimab risks include hypogammaglobulinemia and infection. This suggests that nipocalimab has potential to treat other IgG alloantibody-mediated perinatal diseases (eg, FNAIT). The open-label FREESIA-3 study aims to evaluate the efficacy and safety of nipocalimab with a contemporaneous reference arm of IVIG with/without prednisone in pregnancies at risk for FNAIT (ClinicalTrials.gov identifier: NCT06533098).

Design: FREESIA-3 is an open-label, multicenter, randomized, phase 3 study enrolling the most common subtypes, HPA-1a and/or HPA-5b, alloimmunized maternal participants with an HPA-1a or HPA-5b–positive fetus and a prior FNAIT-affected pregnancy without ICH or severe bleeding in the fetus or newborn (standard-risk). There are 2 cohorts (anti-HPA-1a, anti-HPA-5b). Participants from each cohort will be randomized (4:1) to weekly intravenous nipocalimab or IVIG with/without prednisone as per Lakkaraja et al (Am J Obstet Gynecol. 2016;215(4):471.e1-9.) at 13-16 weeks gestation. The IVIG reference arm establishes standard of care for maternal participants at risk of FNAIT. During the treatment period, maternal participants will receive every-2-week ultrasound monitoring for fetal bleeding and fetal growth and development. At birth and prior to hospital discharge, neonates will undergo cranial ultrasound to scan for perinatal/neonatal ICH, assess platelet count, and, per protocol, receive platelet transfusion. Postnatal follow‑up periods are 24 weeks for maternal participants and 104 weeks for neonates/infants.

Endpoints: The primary endpoint is a composite of fetal/neonatal death or adjudicated severe bleeding (including ICH) in utero to the first week post-birth, or platelet count at birth <30×10⁹/L. Secondary endpoints include neonatal platelet count at birth, adverse outcome of death of a fetus/neonate, neonate requiring platelet transfusion, adjudicated fetal and neonatal bleeding to the first week post-birth, and neonate requiring IVIG or platelet transfusions for treatment of thrombocytopenia. Additional endpoints consist of safety, patient- and caregiver-reported outcomes, pharmacokinetics, pharmacodynamics, and immunogenicity of nipocalimab.

Conclusion: The open-label FREESIA-3 trial will assess the efficacy and safety of nipocalimab in at-risk FNAIT pregnancies.