UNITY: Nipocalimab Improves Survival in Early-Onset Severe HDFN

Credit: University of Birmingham

Primary analysis of the Phase 2 UNITY trial supported the efficacy of nipocalimab therapy for pregnancies at an elevated risk for recurrent early-onset severe hemolytic disease of the fetus and newborn (HDFN).¹

Nipocalimab treatment in pregnancies at risk for HDFN led to a notably higher percentage of live births at or after 32 weeks gestation and delayed fetal anemia or intrauterine transfusions, as compared with the historical benchmark.

“For mothers with severe HDFN, the outcome not only of the condition but of the treatment can be devastating,” said Mark Kilby, DSc, MD, emeritus professor of fetal medicine at the University of Birmingham.² “This is why the search for therapies to reduce the consequences of the maternal immune response has been focused on this cohort of women.”

Occurring at 24 weeks gestation or earlier, early-onset severe HDFN has been correlated with significant fetal and neonatal morbidity and mortality.³ Standard of care for these high-risk pregnancies is monitoring for fetal anemia, followed by timely intrauterine transfusion to avoid fetal hydrops and pregnancy loss.

However, intrauterine transfusion complications can include fetal death, preterm prelabor rupture of membranes, and preterm birth, with early transfusions linked to a substantially high risk of perinatal loss.

Nipocalimab is an anti–neonatal Fc receptor (FcRn) blocker under development to inhibit transplacental IgG transfer and lower maternal IgG levels. In the open-label, single-group UNITY study, nipocalimab was evaluated for delaying or reducing the use of intrauterine transfusions in pregnancies with prior early-onset severe HDFN.

Analysis in UNITY was performed to assess intravenous nipocalimab treatment (30 or 45 mg per kg of body weight per week) administered from baseline at 14 weeks’ gestation until the planned last dose at 35 weeks’ gestation. Treatment was discounted per safety stopping rules or stopping criteria related to the initiation of intrauterine transfusion.

Study completion occurred at 24 weeks’ postpartum for maternal participants and at week 96 of life for infants. UNITY’s primary end point was live birth at 32 weeks’ gestation or later without intrauterine transfusions versus a historical benchmark.

Investigators set the value of 10% as a clinically meaningful difference from the historical data set in which none (0%) met the primary endpoint, according to published literature and unpolished data obtained with permission before the start of the study.

Between April 2019 and November 2022, 19 HDFN referral centers screened 23 women with singleton pregnancies. Of these women, 13 were enrolled in the study. At the time of the primary analysis, 11 maternal participants (85%) had completed all study visits and all 13 (100%) had completed the Week 4 postpartum visit.

Upon analysis, live birth at 32 weeks’ gestation or later, without an intrauterine transfusion, occurred in 7 of 13 study pregnancies (54%; 95% CI, 25–81). Meeting the primary efficacy endpoint, this rate was significantly higher than the 10% clinically meaningful difference from the historical benchmark (P <.001).

Among the 6 study pregnancies (46%) that did not meet the primary endpoint, fetal anemia leading to intrauterine transfusion was identified in 5 pregnancies at 24 week’s gestation or later. A single case of intrauterine transfusion was performed at 22 weeks but led to complications resulting in stillbirth. For the 7 pregnancies that met the primary endpoint, 6 (46%) received no antenatal or postnatal transfusions.

Treatment-related decreases in IgG levels and alloantibody titers were identified in maternal samples and cord blood blood. Nevertheless, safety findings showed nipocalimab remained well-tolerated in pregnant individuals and newborns, without unusual or serious infections.

UNITY’s positive results have led the US Food and Drug Administration (FDA) to grant Breakthrough Therapy Designation to nipocalimab. The pivotal Phase 3 AZALEA trial is enrolling pregnant individuals at risk for severe HDFN at any gestational age, with a history of the condition in a previous pregnancy.

“These are fantastic results. In this group of pregnant women with severe HDFN, the medical management with nipocalimab has significantly reduced the need for early-onset-in-utero fetal transfusion and improved the survival of these babies, reducing the risk of miscarriage and stillbirth,” Kilby added.²

Reference

1. _{EurekAlert! Birmingham host to investigational treatment trial which could improve outcomes of pregnancies affected by severe haemolytic disease. Published August 7, 2024, Accessed August 7, 2024. https://www.eurekalert.org/news-releases/1053600}
2. _{Moise KJ, Ling LE, Oepkes D, Tiblad E, Verweij EJT, et al. Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn. The New England Journal of Medicine. Published August 8, 2024. Accessed August 8, 2024.}
3. _{Lindenburg IT, van Kamp IL, van Zwet EW, Middeldorp JM, Klumper FJ, Oepkes D. Increased perinatal loss after intrauterine transfusion for alloimmune anaemia before 20 weeks of gestation. BJOG. 2013;120(7):847-852. doi:10.1111/1471-0528.12063}