Nipocalimab - Clinical Studies in Hemolytic Disease of the Fetus and Newborn (HDFN)

SUMMARY

• The company cannot recommend any unapproved practices, procedures, or usage of nipocalimab.
• Nipocalimab is a fully human, aglycosylated, effectorless immunoglobulin G1 (IgG1) monoclonal antibody that binds with high affinity to the IgG-binding site on the neonatal fragment crystallizable receptor (FcRn) and is being studied for the treatment of hemolytic disease of the fetus and newborn (HDFN).^1-3
• An ongoing phase 3, randomized, placebo (PBO)-controlled, double-blind, multicenter study (AZALEA; NCT05912517) is evaluating the efficacy and safety of nipocalimab in pregnant patients at risk for severe HDFN.^3,4
• In a phase 2, open-label study (UNITY; NCT03842189), 54% (7/13) of patients with a history of early-onset severe HDFN had live births at ≥32 weeks gestational age (GA) without an intrauterine transfusion (IUT).^1,5,6
  • Nipocalimab was maintained at a pharmacologically active maternal concentration (>10 μg/mL) during weekly dosing, whereas its concentration in fetal cordocenteses samples, cord blood, colostrum, and breast milk remained low (≤10 μg/mL) across samples.⁷
  • Infant IgG levels were low at birth (cord blood median, 175 mg/dL; range, 92-941 mg/dL), reached a nadir by 24 weeks, and returned to the normal range (with 1 exception) between 16 and 96 weeks.⁷
  • Serious adverse events (SAEs) were reported among 38% (5/13) of maternal patients and 42% (5/12) of neonates and infants.¹
  • Infectious adverse events (AEs) in infants were predominantly mild to moderate and typical of early childhood, and most infants (6/7) achieved protective vaccine antibody titers (diphtheria and tetanus) by 96 weeks.⁷

BACKGROUND

• HDFN is an immune-mediated disorder affecting red blood cells (RBCs), wherein maternal antibodies attack fetal or newborn RBCs.^8,9 HDFN develops when the fetus inherits antigen positivity from the father and the mother is antigen negative.¹⁰As infant RBCs are attacked and broken down, infants develop hemolytic anemia. When left untreated, progressive fetal anemia leads to hydrops fetalis, a condition of widespread effusions that leads to high-output cardiac failure and ultimately fetal death.¹¹ The breakdown of heme leads to bilirubin, which is removed by the placenta in utero but accumulates in newborns and can cause hyperbilirubinemia with serious complications, including kernicterus, a severe cerebral condition.^8,12,13
• No cure exists for HDFN. Antenatal treatment primarily involves IUT (often serial) which is an invasive procedure with maternal and fetal risks.¹²
• An ongoing, prospective, global, observational, multicenter study aims to characterize the current standard of care (SOC), clinical course, and outcomes for pregnant patients and their offspring at high risk for early-onset HDFN. Interim results of 15 pregnant patients with 14 live births showed 2/15 (13%) pregnant patients achieved the primary outcome of a live birth at a GA of ≥32 weeks without an IUT. Overall, 5/7 (71%) pregnant patients who received intravenous immunoglobulin (IVIG) required ≥1 IUT which is similar to pregnant patients who did not receive IVIG (13/15; 86%). Additionally, 3/6 (50%) neonates who received IVIG required ≥1 simple transfusion which is similar to neonates who did not receive IVIG (8/14; 57%). All neonates/infants required hospitalization related with early-onset HDFN, and 13/14 (93%) required neonatal intensive care unit (NICU) hospitalization.¹⁴

CLINICAL DATA

Phase 3 Study: AZALEA

An ongoing phase 3, randomized, PBO-controlled, double-blind, multicenter study (AZALEA) is evaluating the efficacy and safety of nipocalimab in alloimmunized pregnant patients at risk for severe HDFN.³

Study Design/Methods

• The study aims to enroll 120 alloimmunized pregnant patients with singleton pregnancies at risk for severe HDFN.³
• The study will include a screening period (8-16 weeks GA), randomization (13-16 weeks GA), a double-blind treatment period (13-35 weeks GA), planned delivery at 37 - 38 weeks GA, and postnatal follow-up periods of 24 weeks for maternal patients and 104 weeks for neonates/infants.
• At 13-16 weeks of GA, patients will be randomized 2:1 to receive intravenous (IV) infusions of nipocalimab 45 mg/kg IV or PBO IV every week from randomization through GA week 35.
• During the double-blind treatment period, the need for cordocentesis, confirmation of fetal anemia, and the need for IUT will be assessed based on weekly fetal monitoring of middle cerebral artery peak systolic velocity (MCA-PSV) for a value of ≥1.5 multiples of the median (MoM).
  • Subsequent IUTs will be determined by MCA-PSV for a value of ≥1.5 MoM and/or time interval since first IUT and per investigator’s discretion.
  • The assessment parameters for fetal status will include trends of alloantibody titers, fetal well-being through ultrasound, and hematologic values obtained at the previous IUT.¹⁵
  • If an IUT is necessary, nipocalimab or PBO will be continued until all fetal blood is replaced by donor blood and laboratory tests confirm the absence of fetal RBCs.³
• For key select inclusion and exclusion criteria, see Table: Eligibility Criteria for Study Participation in the AZALEA Study.

• The primary endpoint will be^3,15:
  • The proportion of pregnancies that do not result in fetal loss (due to any reason), IUT, hydrops fetalis, or neonatal death (due to any reason), through the neonatal period (4 weeks of age or 41 weeks of postmenstrual age [PMA; defined as GA at birth plus chronologic age in weeks]), whichever is later
• Key secondary endpoints will include³:
  • Number of patients with HDFN by severity (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 through 38 weeks PMA or at discharge (if <38 weeks is PMA)
  • Number of IUTs received during pregnancy
• Safety endpoints will include^3,15:
  • Maternal/fetal safety outcomes: Maternal death, AEs, SAEs, adverse events of special interest (AESIs; infections requiring oral/IV anti-infective agents, maternal hypoalbuminemia with albumin <20 g/L), AEs leading to discontinuation, infections, serious infections, infusion reactions, hypersensitivity reactions, pregnancy complications, and IUT-related complications.
  • Pregnancy outcomes: Proportion of pregnancies with cesarean delivery, cesarean delivery due to IUT complications, preterm birth, fetal growth restriction, and preeclampsia.
  • Neonate/infant safety and development outcomes: Proportion of liveborn neonates/infants who died, proportion of liveborn neonates/infants with AEs, SAEs, infections, and serious infections, AESIs (infections requiring oral/IV anti-infective agents and infant IgG decreased with IgG <3.0 g/L at or after week 52), proportion of liveborn neonates/infants receiving IVIG for non-HDFN indications, proportion of liveborn neonates/infants with abnormal hearing, Bayley Scales of Infant and Toddler Development at weeks 52 and 104 in infants.
• Patient- or caregiver-reported outcomes will also be evaluated.³

Phase 2 Study: UNITY

Moise Jr et al (2024)¹ and de Winter et al (2026)⁷ reported results from a phase 2, open-label, single-group, multicenter study evaluating the efficacy and safety of nipocalimab in delaying or reducing the need for IUT in pregnant patients with previous early-onset severe HDFN. Maternal, fetal, and infant nipocalimab pharmacokinetics, IgG levels, and infant immunity were also reported.

Study Design/Methodology

• The study included a screening period between 8-14 weeks GA, followed by a treatment period where patients received once weekly IV infusions of nipocalimab from weeks 14-35.¹
• The primary analysis was conducted when the last maternal patient and infant pair reached postpartum week 4. Extended infant follow‑up for pharmacokinetics, immunoglobulin levels, infections, and vaccine responses continued through 96 weeks after birth.⁷ For study design/methods, see Figure: UNITY Study Design.

• For key select inclusion and exclusion criteria, see Table: Eligibility Criteria for Study Participation in the Phase 2 UNITY Study.

• The primary outcomes were the proportion of patients with a live birth at ≥32 weeks GA without an IUT and the incidence and severity of AEs, SAEs, and AESIs.^1,17

Results

Maternal/Fetal Outcomes

Baseline Patient Characteristics

• A total of 23 female patients were screened of which 13 were enrolled into the study.¹
• At the time of the primary analysis (cutoff date of November 1, 2022), 11 maternal patients completed all study visits, and all 13 patients had completed the week 4 postpartum visit.¹
  • The mean age among the maternal patients was 35.8±4.8 years.
  • The median time between study pregnancy and last qualifying pregnancy and last HDFN-affected pregnancy was 3.9 (0.3-10.9) years and 1.3 (0.1-7.5) years, respectively.
  • Of the 13 maternal patients, 11 (85%) patients had anti-D alloantibodies and 2 (15%) had anti-K alloantibodies.
  • The median GA at initiation of nipocalimab treatment was 14 weeks and 1 day.

Efficacy

• Live birth at ≥32 weeks GA without an IUT occurred in 54% (7/13) of patients (95% confidence interval [CI], 25-81) which was significantly higher compared to the 10% clinically meaningful difference from the historical benchmark (P<0.001).¹
  • Of these patients, 6 maternal-infant pairs did not receive antenatal or postnatal transfusions (1 neonate received a single simple transfusion).
  • Five (71%) of 7 patients who met the primary endpoint had received 45 mg/kg of baseline or current weight.
• Of the 6 patients who did not achieve the primary endpoint, 5 reported fetal anemia requiring IUT.¹
• For additional details, see Table: Antenatal Endpoint Results in the Most Recent Qualifying Pregnancy and the Study Pregnancy.

Pharmacokinetics

• Fetal exposure during maternal treatment:
  • Fetal cordocentesis samples collected at the first IUT were available for 4 patients.⁷
  • In all cases, maternal dosing occurred within 1 week prior to the first IUT, with the maternal serum concentration immediately beforehand of IUT ranging from 110 μg/mL to 572 μg/mL.⁷
  • Nipocalimab was detected in 1 of these 4 samples at a concentration of 0.04 μg/mL at gestational week 31.⁷
    • Maternal serum concentration at the time of cordocentesis was 522 µg/mL.¹⁸
• Colostrum and breast milk:
  • All 12 maternal patients were sampled for colostrum between 0 and 3 days after birth and/or for breast milk between 6 and 8 days after birth.⁷
  • Nipocalimab was detected in colostrum or breast milk only in patients who discontinued treatment less than 3 weeks before delivery (n=5), whereas no nipocalimab was detected when treatment was discontinued more than 7 weeks before delivery (n=7).⁷
  • Overall, 9 of 12 infants were breastfed, and nipocalimab was detected in 57% of colostrum samples (4/7) and 22% of breast milk samples (2/9).⁷
    • Of the 4 colostrum samples with detectable nipocalimab, 3 had concentrations <4 μg/mL (ie, below the 10 μg/mL pharmacologically active threshold) and 1 had a concentration of 68.4 μg/mL.
    • All nipocalimab-detectable breast milk samples (n=2) had nipocalimab concentrations <4 μg/mL, with none exceeding the threshold.
  • In 4 maternal patients with both colostrum and breast milk samples available⁷:
    • Two patients had a low drug concentration in colostrum (1.35 and 3.66 μg/mL), with an undetectable level (<0.01 μg/mL, ie, below the lower limit of quantification [LLOQ]) in breast milk.
    • One patient had an undetectable drug concentration in colostrum (<LLOQ) but a low concentration in breast milk (1.27 μg/mL).
    • One patient had a high drug concentration in colostrum (68.4 μg/mL) at 2 days after delivery and a low concentration in breast milk (0.58 μg/mL) at 8 days after delivery; the maternal serum nipocalimab concentration was 1100 μg/mL at delivery after dosing on the day of delivery.
  • At week 4 after birth, none of the 5 breastfed infants had a detectable serum nipocalimab concentration, including infants exposed to the highest colostrum nipocalimab concentration.⁷

Pharmacodynamics

• At 18 weeks' gestation, maternal IgG levels reduced by 85% from baseline, returning to normal by postpartum week 4 in patients who received IVIG and by postpartum week 24 in those who did not.¹
• During treatment, maternal alloantibody titers reduced by 4 to 32 times from baseline. By postpartum week 4, titers returned to near baseline or higher in 6 patients who did not receive an IUT and in patients with titer levels available at week 4.¹
• In 6 pregnancies, cord blood alloantibody titers at delivery (measured 2-3 weeks after nipocalimab treatment) were low and below maternal levels.¹
• In 3 pregnancies where treatment was discontinued more than 7 weeks before delivery, titers in both cord and maternal blood were higher compared to the 6 pregnancies which discontinued treatment 2-3 weeks before delivery.¹

Safety

• Of the 13 maternal patients, SAEs and severe AEs (grade ≥3) were reported in 5 (38%) and 6 (46%) patients, respectively.¹
• For details, see Table: Maternal Safety Analyses According to Nipocalimab Dose Group.

• In patients receiving nipocalimab, mild infusion reactions were reported in 1% (3/234) of infusions.¹
  • Temporary interruption of infusion was required in 1 case due to peripheral arm swelling and paresthesia.⁵

Neonatal/Infant Outcomes

Baseline Patient Characteristics

• Of the 13 study pregnancies, 12 resulted in live-born infants, and 1 pregnancy ended in fetal loss due to complications related to IUT.^1,7
  • Among the live-born infants, 4 (33.3%) were female.⁷
  • The median GA at birth was 36 weeks 5 days (range, 29 weeks 2 days to 37 weeks 3 days).^1,7
• GA categories at birth included the following⁷:
  • Very preterm (28 to <32 weeks): 1 infant (8.3%)
  • Preterm (32 to <37 weeks): 5 infants (41.7%)
  • Early term (37 to <38 weeks): 6 infants (50.0%)
• The median birth weight was 2825 g (range, 860-4000 g).⁷

Pharmacokinetics

• Cord blood at birth was available for 10 of the 12 infants. In the 3 infants delivered more than 7 weeks after the last nipocalimab dose, the nipocalimab concentration was undetectable in both maternal and cord blood at delivery.⁷
• Among 8 infants delivered less than 3 weeks after the last maternal dose, nipocalimab remained undetectable in cord blood for 7 infants despite measurable maternal serum concentrations at birth in all except 1 case (range, 0.02-100 μg/mL).⁷
• One infant delivered 8 days after the last maternal dose (30-45 mg/kg group) had a detectable cord blood concentration (0.7 μg/mL); the maternal serum concentration was 100 μg/mL at delivery.⁷
• Nipocalimab was undetectable in the 8 infants with available samples at postnatal week 4.⁷

Pharmacodynamics

• Cord blood IgG concentration at birth:
  • Cord blood IgG concentration at birth was available for 10 of the 12 live births.⁷
  • Despite maternal IVIG supplementation before delivery as well as completion of nipocalimab treatment at 35 weeks of gestation, 6 of 10 neonates (60%) had IgG levels <200 mg/dL at birth.¹
  • Cord blood IgG concentration was higher in infants delivered more than 7 weeks after the last maternal dose (>400 mg/dL) and lower in infants delivered within 3 weeks after the last dose (<400 mg/dL).⁷
• Serum IgG concentration over time:
  • Across all infants, the serum IgG concentration reached a physiologic nadir between weeks 4 and 24 after birth, with a median value of 305 mg/dL at week 4 and 273 mg/dL at week 24, followed by a subsequent increase.⁷
  • Infants with low IgG at birth who received IVIG showed an increase into the normal range for IgG at weeks 1 and/or 4, followed by a nadir at around week 24, whereas infants with low IgG at birth who did not receive IVIG demonstrated subnormal nadirs at 4 weeks with normalization by week 16.⁷
  • By week 24, the total serum IgG concentration was above the lower limit of normal in 8/9 infants; by weeks 48 or 96, the IgG level was within the age‑appropriate normal range in 6/7 infants.⁷

Safety

• Of the 12 neonates and infants, SAEs and severe AEs were reported in 5 (42%) and 4 (33%) patients, respectively.¹ For details, see Table: Infant Safety Analyses According to Nipocalimab Dose Group.

• IgG levels at delivery were below the lower limit of normal in 9 of 10 neonates. Per protocol, IVIG 500 mg/kg (administered at 0-4 days of age) was given to 5 of 6 neonates with IgG <200 mg/dL.⁵
• At 4 and 24 weeks of age, evaluable total IgG levels in neonates/infants remained near or just below the lower limit of normal and followed the physiological nadir.⁵

Immune Safety

• Infant Immune Safety Outcomes
  • During the first 24 weeks after birth, 6 infants experienced 8 infections, most of which were mild or moderate; 1 infant had a severe respiratory syncytial virus (RSV) infection requiring hospitalization.
  • After 24 weeks, infections were reported in 4 infants when the IgG concentration was within or near the normal range; all were mild or moderate in severity.
  • For details, see Table: Infant Infectious Adverse Events.

• Infant vaccination exposure and postvaccination IgG response during
  follow-up:
  • Routine vaccinations were administered per local guidelines, with diphtheria, tetanus, and pneumococcal vaccines given to 11 infants (92%) and rotavirus vaccine (live-attenuated) to 6 infants (50%) between birth and 93 weeks.⁷
  • Antidiphtheria and tetanus IgG responses were assessed in 7 infants, with 6 infants achieving protective titers by or before the 96-week visit.⁷
  • One infant had protective tetanus titers but subthreshold diphtheria titers approximately 20 months after the last vaccination.⁷

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 11 February 2026.