Poster Presentation - SOMANZ ASM Society of Obstetric Medicine of Australia and New Zealand ASM 2023

Design of a phase 3 study of nipocalimab in pregnancies at risk for severe hemolytic disease of the fetus and newborn (#56)

Dick Oepkes 1 , Eleanor Tiblad 2 3 , Kenneth J Moise Jnr 4 5 , Enrico Lopriore 6 , EJT (Joanne) Verweij 1 , Prasheen Agarwal 7 , Rattandeep Batra 7 , Anna Beutler 7 , Yosuke Komatsu 7 , Edwin Lam 7 , Jocelyn H Leu 7 , Leona E Ling 7 , Robert M Nelson 7 , Victor Olusajo 7 , Claudia Russu 7 , Shumyla Saeed-Kawaja 7 , Lisa B Schwartz 7 , May Lee Tjoa 7 , Jannine Williams 7 , Xie L Xu 7 , Umair Amin 7 , Waheeda Sirah 7
  1. Department of Obstetrics, Department of Fetal Therapy, Leiden University Medical Centre, Leiden, The Netherlands
  2. Centre for Fetal Medicine, Karolinska University Hospital, Stockholm, Sweden
  3. Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
  4. Dell Medical School , University of Texas, Austin, Texas, United States
  5. Comprehensive Fetal Care Centre, Dell Children's Medical Centre, Austin, Texas, United States
  6. Department of Pediatrics, University of Leiden Medical Centre, Leiden, The Netherlands
  7. Spring House, Johnson & Johnson Pharmaceutical Companies, Pennsylvania, United States

Objective: Nipocalimab, a fully human, high affinity, neonatal Fc receptor (FcRn)-blocking monoclonal antibody, inhibits transplacental maternal immunoglobulin (IgG) and alloantibody transfer and lowers circulating maternal IgG alloantibody levels. The potential for nipocalimab safety and efficacy in the prevention of fetal anemia, intrauterine transfusions (IUT), and poor outcomes is supported by results from UNITY, an open-label, single-arm, phase 2 study (NCT03842189) conducted in alloimmunized, pregnant individuals at high risk of early-onset (<24 weeks gestational age [GA]) severe hemolytic disease of the fetus and newborn (HDFN).

 

Methods: The AZALEA study is a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial evaluating efficacy and safety of nipocalimab versus placebo in alloimmunized pregnant individuals at risk of severe HDFN (N≈120) with singleton pregnancies who have an obstetric history of fetal anemia or requiring ≥1 IUTs, or fetal loss or neonatal death due to HDFN. Participants must have alloantibody titers for RhD, Rhc, RhC, RhE (≥16) or Kell antigens (≥4) and an antigen-positive fetus in the current pregnancy. The study includes a screening period (8-16 weeks GA), double-blind treatment period (13-35 weeks GA), planned delivery at ~37 weeks GA, and postnatal follow‑up periods of 24 weeks for maternal participants and 104 weeks for neonates/infants. Maternal participants will be randomized 2:1 (nipocalimab:placebo) to receive weekly intravenous infusions. During the double-blind period, weekly monitoring by middle cerebral artery Doppler peak systolic velocity (MCA-PSV) for a value ≥1.5 multiples of the median (MoM) will inform the need for cordocentesis confirmation of fetal anemia and IUT. Subsequent IUTs will be determined by MCA-PSV ≥1.5 MoM and/or time interval since the first IUT timed empirically by the investigator.

 

Results: The primary endpoint is the proportion of pregnancies that do not result in fetal loss, IUT, hydrops fetalis, or neonatal death. 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 including exploratory endpoints are safety, patient- and caregiver-reported outcomes, pharmacokinetics, pharmacodynamics (e.g., FcRn placental receptor occupancy and IgG), nipocalimab immunogenicity.

 

Conclusion: AZALEA, the first placebo-controlled, randomized, global, multicenter, prospective clinical trial in severe HDFN, is designed to study the safety and efficacy of nipocalimab, a novel, noninvasive treatment to reduce the risk of fetal anemia in high-risk HDFN pregnancies.