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

American Journal of Perinatology, vol. 42, pp. 842–853

Abstract

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.

Authors 15

1. E. J. T. Verweij Aachen Division of Fetal Therapy Department of Obstetrics, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Division of Fetal Therapy, Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands

2. Eleonor Tiblad

   Karolinska Institutet

   Affiliation as printed

   Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden

3. Enrico Lopriore Aachen Division of Neonatology Department of Pediatrics, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands

4. Dick Oepkes Aachen Division of Fetal Therapy Department of Obstetrics, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Division of Fetal Therapy, Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands

5. Prasheen Agarwal
   Affiliation as printed

   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

   Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, United States

6. Edwin Lam
   Affiliation as printed

   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

   Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, United States

7. Jocelyn H. Leu
   Affiliation as printed

   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

   Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, United States

8. Leona E. Ling
   Affiliation as printed

   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

9. Robert M. Nelson
   Affiliation as printed

   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

   Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, United States

10. Victor Olusajo
    Affiliation as printed

    Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

    Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, United States

11. Shumyla Saeed-Khawaja
    Affiliation as printed

    Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

12. May Lee Tjoa
    Affiliation as printed

    Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

13. Jie Zhou
    Affiliation as printed

    Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

14. Waheeda Sirah
    Affiliation as printed

    Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts

    Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, United States

15. Kenneth Joseph Moise

    Dell Children's Medical Center of Central Texas · The University of Texas at Austin

    Affiliation as printed

    Comprehensive Fetal Care Center at Dell Children's Medical Center, Austin, Texas

    Dell Medical School, The University of Texas at Austin, Austin, Texas

    Comprehensive Fetal Care Center at Dell Children's Medical Center, Austin, United States

    Dell Medical School, The University of Texas at Austin, Austin, United States