PDF herunterladen
CC BY-NC-ND 4.0 · Am J Perinatol 2025; 42(07): 842-853
DOI: 10.1055/a-2404-8089
Original Article

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

Yosuke Komatsu
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
E.J.T. Joanne Verweij
2   Division of Fetal Therapy, Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands
,
Eleonor Tiblad
3   Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
,
Enrico Lopriore
4   Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
,
Dick Oepkes
2   Division of Fetal Therapy, Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands
,
Prasheen Agarwal
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Edwin Lam
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Jocelyn H. Leu
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Leona E. Ling
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Robert M. Nelson
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Victor Olusajo
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Shumyla Saeed-Khawaja
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
May Lee Tjoa
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Jie Zhou
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Umair Amin
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Waheeda Sirah
1   Janssen Pharmaceutical Companies of Johnson and Johnson, Cambridge, Massachusetts
,
Kenneth J. Moise 
5   Dell Medical School, The University of Texas at Austin, Austin, Texas
6   Comprehensive Fetal Care Center at Dell Children's Medical Center, Austin, Texas
› Institutsangaben Funding This study is sponsored by Janssen Research & Development, LLC. The medical writing support was funded by Janssen Global Services, LLC.
› Weitere Informationen
Auch verfügbar auf
   Lizenzen und Reprints

Abstract

Objective

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.

Study Design

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.

Results

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.

Conclusion

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.

Key Points

  • 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.

Keywords

neonatal Fc receptor blocker - nipocalimab - hemolytic disease of the fetus and newborn - HDFN - intrauterine transfusion - red blood cell alloimmunization - safety - efficacy - study design

Note

This study is registered with ClinicalTrials.gov Identifier: NCT05912517. EudraCT Number: 2021-002359-12. Available at: https://classic.clinicaltrials.gov/ct2/show/NCT05912517 . Date of registration: June 22, 2023.




Publikationsverlauf

Eingereicht: 10. Mai 2024

Angenommen: 22. August 2024

Accepted Manuscript online:
28. August 2024

Artikel online veröffentlicht:
17. September 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

Kommentar zu diesem Artikel:

Plain Language Summary of Publication: Design of the Phase 3 AZALEA Trial of Nipocalimab in Severe Hemolytic Disease of the Fetus and NewbornAm J Perinatol 2025; 42(07): 955-961
DOI: 10.1055/a-2529-4150