Monoclonal Antibody Improves Pregnancy Outcomes in Cases of Early-Onset HDFN

Treatment with the neonatal Fc receptor-blocker nipocalimab may help to significantly delay or even prevent fetal anemia in pregnancies at high risk for severe hemolytic disease of the fetus and newborn (HDFN), according to the results of a phase II study published in the New England Journal of Medicine. The treatment was also associated with a significant decrease in the need for intrauterine transfusion.

Resulting from maternal-fetal blood-group mismatch that causes fetal red cell destruction — and anemia — HDFN can cause a range of serious complications and even fetal mortality when severe. Intrauterine transfusion is often used in the most severe cases of fetal anemia. However, intrauterine transfusion is associated with its own set of risks, including preterm birth, prelabor rupture of maternal membranes, and fetal loss.

In the small study of 13 pregnancies at high risk for recurrent early-onset severe HDFN, treatment with nipocalimab resulted in seven live births at 32 weeks gestation or later without intrauterine transfusion, a rate which is significantly greater than the 10% clinically meaningful difference from historical rates.

“In quantitative comparisons, outcomes in nipocalimab-treated pregnancies appeared to be substantially better than those of the most recent qualifying pregnancies or those reported in publications regarding the current management of early-onset HDFN,” the researchers wrote.

Maternal alloantibodies decreased during treatment by 4-32 times baseline levels. Sixty percent of neonates had IgG levels of less than 200 mg/dL at birth, following nipocalimab treatment received up to 35 weeks gestation.

Nipocalimab is a monoclonal antibody that blocks neonatal Fc receptor from binding with the mother’s immunoglobulin G (IgG) antibodies.

“The favorable outcomes that we observed with nipocalimab therapy are probably due to its FcRn binding affinity, which is more than 1,000 times that of IVIG and thus potentially affords greater inhibition of transplacental alloantibody transfer and lowering of the maternal alloantibody titer,” they noted. IVIG is sometimes used in cases of early-onset HDFN, though intrauterine transfusion is more common.

Five women (68%) experienced severe adverse events. Six women experienced severe adverse events of grade 3 or greater. Serious adverse events occurred in five neonates; four had severe adverse events.

Study participants were aged 18 years or older, carrying a single fetus and had a previous pregnancy, during which the fetus developed severe fetal anemia or a previous stillbirth with fetal and placental features associated with HDFN. They also had to have critical alloantibody titers for anti-D or anti-K. Lastly, they had to have a cell-free DNA level indicative of a D- or K-positive fetus. Most of the women (11) had anti-D alloantibodies, while two had anti-K.

Fetal anemia was monitored weekly using Doppler ultrasonography of the middle cerebral artery (MCA). Confirmed fetal anemia (defined as MCA peak systolic velocity of at east 1.5 multiples of the median) prompted intrauterine transfusion.

The pregnancies were enrolled at 14 weeks gestation. The women received weekly infusions of nipocalimab at dose of 30 mg/kg of baseline maternal body weight, which was later amended to 45 mg/kg of baseline body weight, and lastly to 45 mg/kg of current weight.

Delivery was planned for 37 weeks gestation. Between 48 and 72 hours prior to delivery, women who completed nipocalimab treatment were given a single bolus of IVIG (500 mg/kg). Neonates were also given IVIG at birth if their IgG level was below pre-specified threshold.