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

Last Updated: 11/22/2024

SUMMARY

  • Nipocalimab is a fully human, effectorless immunoglobulin G1 (IgG1) anti-neonatal fragment crystallizable receptor (FcRn) monoclonal antibody that binds with high affinity to the IgG binding site on FcRn. Nipocalimab is an investigational agent being studied for the treatment of alloimmunized pregnant patients at risk for severe hemolytic disease of the fetus and newborn (HDFN).1-3
  • An ongoing phase 3, randomized, placebo-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
    • Serious adverse events (SAEs) were reported among 38% (5/13) of maternal patients and 42% (5/12) of neonates and infants.1

BACKGROUND

  • HDFN is an immune-mediated disorder affecting red blood cells (RBCs), wherein maternal antibodies attack fetal or newborn RBCs.7,8 HDFN develops when the fetus inherits antigen positivity from the father and the mother is antigen negative.9As 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.10 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.7,11,12
  • No cure exists for HDFN. Antenatal treatment primarily involves IUT (often serial) which is an invasive procedure with maternal and fetal risks.11
  • 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.13

CLINICAL DATA

Phase 3 Study: AZALEA

An ongoing phase 3, randomized, placebo-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 placebo 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.14
    • If an IUT is necessary, nipocalimab or placebo 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.

Eligibility Criteria for Study Participation in the AZALEA Study3,4
Select Inclusion Criteria
Select Exclusion Criteria
  • Pregnant patients aged 18-45 years with singleton pregnancies and an estimated GA of 130/7-166/7 weeks at randomization
  • History of severe HDFN in a prior pregnancy defined as one or more of the following:
    • Documented fetal anemia with hemoglobin level <0.84 MoM or received ≥1 IUT as a result of HDFN
    • Fetal loss or neonatal death due to HDFN, with maternal alloantibody titers ≥16 for RhD, Rhc, RhE, RhC antigens or ≥4 for Kell antigen and evidence of an antigen-positive fetus
  • Presence of maternal alloantibody titers ≥16 for RhD, Rhc, RhE, or RhC antigens and ≥4 for Kell antigen and an antigen-positive fetus during the current pregnancy
  • Cell-free-fetal-DNA consistent with an antigen-positive fetus
  • Screening laboratory results within the normal range for GA of pregnancy as follows:
    • Albumin ≥26 g/L
    • Alanine aminotransferase ≤2x ULN
    • Aspartate aminotransferase ≤2x ULN
    • Creatinine ≤70.7 μmol/L
    • IgG ≥6 g/L
  • Evidence of fetal anemia by ultrasound or repeated MCA-PSV with a value ≥1.5 MoM prior to randomization
  • History of severe preeclampsia prior to GA week 34 or severe fetal growth restriction in a previous pregnancy
  • Current uncontrolled hypertension
  • History of myocardial infarction, unstable ischemic heart disease, stroke, severe and/or uncontrolled hepatic, gastrointestinal, renal, pulmonary, cardiovascular, psychiatric, neurologic, musculoskeletal disorder, or hypertension, and/or other medical or uncontrolled autoimmune disorder(s)
  • History of receiving anti-FcRn therapies or receiving rituximab or eculizumab in the last 6 months
  • Currently receiving systemic corticosteroids or other immunosuppressants for disorders unrelated to pregnancy
  • Received or planning to receive plasmapheresis, immunoadsorption therapy, IVIG, or any IgG Fc-related protein therapeutics during the current pregnancy
  • Has a severe infection (including opportunistic infections), chronic infection, or requiring chronic treatment with anti-infectives
  • Confirmed or suspected clinical immunodeficiency syndrome, or a family history of congenital/hereditary immunodeficiency (unless ruled out in the patient)
  • Abnormal hematologic lab values at screening:
    • Hemoglobin <80 g/L
    • White blood cells <3.0 GI/L
    • Neutrophils <1.5 GI/L
    • Platelets <100 GI/L
Abbreviations: DNA, deoxyribonucleic acid; Fc, fragment crystallizable; FcRn, neonatal fragment crystallizable receptor; GA, gestational age; HDFN, hemolytic disease of the fetus and newborn; IgG, immunoglobulin G; IUT, intrauterine transfusion; IVIG, intravenous immunoglobulin; MCA-PSV, middle cerebral artery peak systolic velocity; MoM, multiples of the median; Rh, rhesus; ULN, upper limit of normal.
  • The primary endpoint will be:
    • 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 [defined as GA at birth plus chronologic age in weeks]), whichever is later.3,14
  • Key secondary endpoints will include3:
    • Number of participants 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 postmenstrual age (PMA) or at discharge (if <38 weeks is PMA)
    • Number of IUTs received during pregnancy
  • Safety endpoints will include3,14:
    • Maternal/fetal safety outcomes: Maternal death, adverse events (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 conducted a phase 2, open-label, single-group, international study to evaluate the efficacy and safety of nipocalimab in delaying or reducing the use of IUTs in pregnant patients with previous earlyonset severe HDFN.

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.
  • The primary analysis was conducted when the last maternal patient and infant pair reached postpartum week 4. For study design/methods, see Figure: UNITY Study Design.

UNITY Study Design1,4,15,16

A screenshot of a computer Description automatically generated

Abbreviations: IgG, immunoglobulin G; IUT, intrauterine transfusion; IV, intravenous; IVIG, intravenous immunoglobulin G; wks, weeks.
a30 mg/kg per baseline body weight followed by a switch to 45 mg/kg of baseline body weight (i.e., in those treated during a per-protocol dose increase).
b45 mg/kg of current body weight as assessed by measurement every 2 weeks.
cMaternal IVIG (500 mg/kg) 48 to 72 hours before delivery if low IgG.
dNeonatal IVIG (500 mg/kg) within 48 hours of birth if low IgG/infection risk.


Eligibility Criteria for Study Participation in the Phase 2 UNITY Study1,15
Select Inclusion Criteria
Select Exclusion Criteria
  • Age ≥18 years
  • Singleton pregnancy with estimated GA of 8-141/7 weeks15
  • Previous qualifying pregnancy with ≥1 of the following at ≤24 weeks GA:
    • Severe fetal anemia (hemoglobin <0.55 MoM for GA)
    • Fetal hydrops (ascites) with MCA-PSV MoM ≥1.5
    • Stillbirth with fetal or placental pathology indicative of HDFN
  • Maternal alloantibody titers for anti-D ≥32 or anti-Kell ≥4
  • Cell-free fetal DNA level which was consistent with D-positive or K-positive fetus
  • Currently pregnant with multiples (twins or more)
  • Preeclampsia in current pregnancy/history of preeclampsia in previous pregnancy
  • Gestational hypertension in current pregnancy
  • Current unstable hypertension
  • History of severe or recurrent pyelonephritis or ≥4 lower UTIs in the past year or previous pregnancy
  • History of genital herpes infection
  • Active infection at screening/baseline with Coxsackie, syphilis, cytomegalovirus, toxoplasmosis, herpes simplex 1 or 2, or tuberculosis
  • Requires treatment with corticosteroids or immunosuppression for disorders unrelated to pregnancy (low-potency topical corticosteroids or intra-articular corticosteroids permitted)
  • Currently receiving antibody-based drug or an Fc-fusion protein drug
  • Received plasmapheresis and/or IVIG during current pregnancy for HDFN
  • Has received or is expected to receive any live virus or bacterial vaccine within 12 weeks prior to screening or has a known need to receive a live vaccine while receiving nipocalimab, or within 12 weeks after the last administration of nipocalimab in the study or has received BCG vaccine within 1 year prior to the first administration of nipocalimab
Abbreviations: BCG, Bacille Calmett-Guérin; DNA, deoxyribonucleic acid; GA, gestational age; HDFN, hemolytic disease of the fetus and newborn; IVIG, intravenous immunoglobulin; MCA-PSV, middle cerebral artery peak systolic velocity; MoM, multiples of the median; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; UTI, urinary tract infection.
  • 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.1,16

Results

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.
    • 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).
    • 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.
  • For additional details, see Table: Antenatal and Postnatal Endpoint Results in the Most Recent Qualifying Pregnancy and the Study Pregnancy.

Antenatal and Postnatal Endpoint Results in the Most Recent Qualifying Pregnancy and the Study Pregnancy1
Endpoints
Most Recent Qualifying Pregnancy (N=13)
Study Pregnancy (N=13)
Primary efficacy endpoint
   Live birth at ≥32 wk of gestation
   without IUT, n (%)
0
7 (54)
Antenatal outcomes
   Live birth, n (%)a
5 (38)
12 (92)
      Median GA at delivery (IQR)
33 wk 0 days
(32 wk 0 days-35 wk 0 days)
36 wk 5 days
(36 wk 0 days-37 wk 1 day)
      Median IUTs per patient (IQR)
5 (5-5)
0 (0-3)
   ≥1 IUT, n (%)
11 (85)
6 (46)
      Median GA at first IUT (IQR)
20 wk 4 days
(18 wk 2 days-22 wk 1 day)
27 wk 1 day
(24 wk 1 day-29 wk 4 days)
   Median GA at delivery (IQR)
23 wk 6 days
(21 wk 0 days-32 wk 0 days)
36 wk 4 days
(35 wk 6 days-37 wk 1 day)
   Fetal hydrops, n (%)a
7 (54)
0
Postnatal outcomes in neonates and infants
   Phototherapy in neonates,
   n/N (%)
4/5 (80)
11/12 (92)
   Exchange transfusion in
   neonates, n/N (%)
0/5
1/12 (8)
   Simple erythrocyte transfusion in
   neonates and infants, n/N (%)
4/5 (80)
6/12 (50)
Abbreviations: GA, gestational age; IQR, interquartile range; IUT, intrauterine transfusion; wk, week.
aFetal loss (stillbirth) and fetal hydrops related to HDFN in the qualifying pregnancy were options for inclusion.

Clinical Outcomes of the Qualifying and On-Study Pregnancies5

Abbreviations: BLW, baseline weight; IUT, intrauterine transfusion; IVIG, intravenous immunoglobulin G; TAW, time-adjusted weight.

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.
  • Despite the supplementation of maternal IVIG before delivery and after nipocalimab treatment was completed to 35 weeks’ gestation, 6 of 10 neonates (60%) had IgG levels <200 mg/dL at birth.
  • In six pregnancies, cord blood alloantibody titers at delivery (measured 2-3 weeks after nipocalimab treatment) were low and below maternal levels.
  • 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 six pregnancies which discontinued treatment 2-3 weeks before delivery.
Safety
  • Of the 13 maternal patients, SAEs and severe AEs (grade ≥3) were reported in 5 (38%) and 6 (46%) patients, respectively.
  • Of the 12 neonates and infants, SAEs and severe AEs were reported in 5 (42%) and 4 (33%) patients, respectively. For details, see table: Safety Analyses According to Nipocalimab Dose Group.

Safety Analyses According to Nipocalimab Dose Group1
Event
30 mg/kg of Baseline Weight
30 and 45 mg/kg of Baseline Weighta
45 mg/kg of Baseline Weight
45 mg/kg of Current Weight
Total
Maternal participants, n
3
2
4
4
13
SAE or severe AE, n (%)
2 (67)
0
2 (50)
2 (50)
6 (46)
   Any pregnancy,
   puerperium, or perinatal
   condition
1 (33)
0
1 (25)
1 (25)
3 (23)
   Fetal death
0
0
0
1 (25)
1 (8)
   Retained placenta or
   membranes
0
0
0
1 (25)b
1 (8)
   Premature separation of
   placenta
0
0
1 (25)
0
1 (8)
   Fetal growth restriction
1 (33)
0
0
0
1 (8)
   Subchorionic hematoma
1 (33)
0
0
0
1 (8)
   Fetal heart rate
   deceleration abnormality
1 (33)
0
0
0
1 (8)
   Abdominal pain
0
0
1 (25)c
0
1 (8)
   Fetal anemia
1 (33)
0
1 (25)c
1 (25)
3 (23)
AESI, n (%)
1 (33)
1 (50)
1 (25)
2 (50)
5 (38)
   Any infection leading to
   treatment with oral or
   IV anti-infective
   agent
1 (33)
1 (50)
1 (25)
2 (50)
5 (38)
UTI
1 (33)
1 (50)
0
0
2 (15)
Bacteriuria
0
0
0
1 (25)
1 (8)
Mastitis
0
0
1 (25)
0
1 (8)
   Streptococcal UTI
0
0
0
1 (25)
1 (8)
Hypoalbuminemiad
0
0
0
0
0
Infants, n
3
2
4
3
12
SAE or severe AE, n (%)
3 (100)
2 (100)
2 (50)
1 (33)
8 (67)
Neonatal respiratory
   distress syndrome
1 (33)b
0
0
1 (33)
2 (17)
Jaundice,
   hyperbilirubinemia, or
   neonatal
   hyperbilirubinemia
2 (67)
1 (50)
1 (25)
1 (33)c
5 (42)
   Anemia or neonatal
   anemia
1 (33)c
2 (100)e
1 (25)c
1 (33)
5 (42)
   Upper respiratory tract
   infection
0
0
0
1 (33)b,f
1 (8)
   Blood IgG decreased
0
0
1 (25)c
0
1 (8)
AESI, n (%)
1 (33)
2 (100)
0
1 (33)
4 (33)
Infection resulting in
   treatment with oral or
   IV anti-infective agent
1 (33)
1 (50)
0
0
2 (17)
      Oral candida infection
0
0
0
1 (33)
1 (8)
      Ear infectiong
0
1 (50)
0
0
1 (8)
      Otorrheag
0
1 (50)
0
0
1 (8)
   IgG decreasedh
1 (33)
2 (100)
0
0
3 (25)
Abbreviations: AE, adverse event; AESI, adverse event of special interest; IgG, immunoglobulin G; IV, intravenous; SAE, serious adverse event; UTI, urinary tract infection.
aParticipants 4 and 5 initially received 30 mg/kg of baseline weight, and the dose was escalated to 45 mg/kg of baseline weight later in gestation in accordance with a protocol amendment.
bThe event was classified only as a SAE.
cThe event was classified only as a severe AE of grade ≥3.
dHypoalbuminemia was defined as an albumin level below 20 g/L.
eOne participant only had a SAE, and one participant only had a severe AE.
f This event of upper respiratory infection was a grade 2 AE and thus was not assessed as severe. However, the event was considered to be serious because the infant was hospitalized in accordance with the mother’s request. No pharmacologic intervention was administered.
gA decrease in the IgG level (defined below) and infections (AESI) developed in the infant, but the infectionsoccurred more than 1 year after the IgG level decreased.
hA decreased IgG level as an AESI was defined as a level <200 mg/dL at weeks 24 to 47 of age or as a level <300 mg/dL at weeks 48 to 96 of age.
  • 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
  • IgG levels at delivery were below the lower limit of normal in 9/10 neonates. IVIG 500 mg/kg (0-4 days) was administered after birth per protocol to 5/6 neonates with IgG <200 mg/dL.5
  • At 4 and 24 weeks of age, total IgG levels in neonates/infants remained near or just below the lower limit of normal and followed physiological nadir.5

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, and DERWENT® (and/or other resources, including internal/external databases) was conducted on 23 September 2024.

 

References

Show
1 Moise KJ Jr, Ling LE, Oepkes D, et al. Nipocalimab in early-onset severe hemolytic disease of the fetus and newborn. N Engl J Med. 2024;391(6):526-537.  
2 Ling LE, Hillson JL, Tiessen RG, et al. M281, an anti‐FcRn antibody: pharmacodynamics, pharmacokinetics, and safety across the full range of IgG reduction in a first‐in‐human study. Clin Pharmacol Ther. 2019;105(4):1031-1039.  
3 Komatsu Y, Verweij EJTJ, Tiblad E, et al. 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. [published online ahead of print September 17, 2024]. Am J Perinatol. doi:10.1055/a-2404-8089.  
4 Janssen Research & Development, LLC. A study of nipocalimab in pregnancies at risk for severe hemolytic disease of the fetus and newborn (HDFN) (AZALEA). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2024 October 07]. Available from: https://www.clinicaltrials.gov/study/NCT05912517 NLM Identifier: NCT05912517.  
5 Moise Jr KJ, Ling LE, Oepkes D, et al. Safety and efficacy of nipocalimab in pregnant individuals at high risk for early-onset severe hemolytic disease of the fetus and newborn: results from the phase 2 UNITY study. Oral Presentation presented at: 20th World Congress in Fetal Medicine; June 25-29, 2023; Valencia, Spain.  
6 Janssen Research & Development, LLC. A study to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics of M281 administered to pregnant women at high risk for early onset severe hemolytic disease of the fetus and newborn (HDFN). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2024 August 27]. Available from: https://www.clinicaltrials.gov/study/NCT03842189 NLM Identifier: NCT03842189.  
7 Ree IMC, Smits-Wintjens VEHJ, vander Bom JG, et al. Neonatal management and outcome in alloimmune hemolytic disease. Expert Rev Hematol. 2017;10(7):607-616.  
8 Basu S, Kaur R, Kaur G. Hemolytic disease of the fetus and newborn: current trends and perspectives. Asian J Transfus Sci. 2011;5(1):3-7.  
9 Pegoraro V, Urbinati D, Visser GHA, et al. Hemolytic disease of the fetus and newborn due to Rh(D) incompatibility: A preventable disease that still produces significant morbidity and mortality in children. PLoS ONE. 2020;15(7):e0235807.  
10 Delaney M, Matthews D. Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn. Hematology Am Soc Hematol Educ Program. 2015;2015(1):146-151.  
11 de Winter DP, Kaminski A, Tjoa M, et al. Hemolytic disease of the fetus and newborn: systematic literature review of the antenatal landscape. BMC Pregnancy Childbirth. 2023;23(1):12.  
12 de Haas M, Thurik FF, Koelewijn JM, et al. Haemolytic disease of the fetus and newborn. Vox Sang. 2015;109(2):99-113.  
13 Oepkes D, Moise Jr KJ, Lopriore E, et al. Safety, efficacy, and outcomes of current standard of care in pregnant individuals and their offspring at high risk of early-onset severe hemolytic disease of the fetus and newborn: results from the prospective observational Clarity study. Oral Presentation presented at: 20th World Congress in Fetal Medicine; June 25-29, 2023; Valencia, Spain.  
14 Oepkes D, Tiblad E, Moise Jr KJ, et al. Design of a phase 3 study of nipocalimab in pregnancies at risk for severe hemolytic disease of the fetus and newborn (HDFN). Poster presented at: 20th World Congress in Fetal Medicine; June 25-29, 2023; Valencia, Spain.  
15 Moise KJ Jr, Ling LE, Oepkes D, et al. Supplement to: Nipocalimab in early-onset severe hemolytic disease of the fetus and newborn. N Engl J Med. 2024;391(6):526-537.  
16 Moise KJ Jr, Ling LE, Oepkes D, et al. Protocol for: Nipocalimab in early-onset severe hemolytic disease of the fetus and newborn. N Engl J Med. 2024;391(6):526-537.