Nipocalimab delays, prevents transfusions for pregnancies at risk for hemolytic disease

Key takeaways:

• Among pregnant women who received nipocalimab infusions, 54% had live births without an intrauterine transfusion.
• Researchers did not observe increased risk for infection.

Nipocalimab resulted in more live births at 32 weeks’ gestation or later without fetal anemia or intrauterine transfusion for pregnancies at risk for early-onset severe hemolytic disease of the fetus and newborn, researchers reported.

Nipocalimab (Johnson & Johnson), a humanized monoclonal antibody and neonatal Fc receptor blocker, is under development for the treatment of multiple immunoglobulin G (IgG) autoantibody- or alloantibody-driven diseases. Early-onset severe hemolytic disease of the fetus and newborn, defined as occurring before 24 weeks’ gestation, is typically associated with substantial fetal and neonatal morbidity and mortality, Kenneth J. Moise Jr., MD, professor in the department of women’s health and co-director of the Comprehensive Fetal Care Center at Dell Medical School at the University of Texas, Austin, and colleagues wrote in The New England Journal of Medicine.

“The neonatal Fc receptor does two things,” Moise told Healio. “It maintains the amount of antibody in your bloodstream, particularly the amount of IgG. Second, it is the primary mechanism from which IgG crosses from the mother to the fetus. When this monoclonal antibody attaches to the receptor, it lowers the IgG in the mother’s bloodstream by about 85%. Then, it blocks the remaining IgG from crossing to the fetus via the placenta. Both of these actions are beneficial for this disease.”

Phase 2 efficacy data

Kenneth J. Moise Jr.

Moise and colleagues conducted an international, open-label, single-group phase 2 study with 13 women (mean age, 35.8 years) with 14 pregnancies at high risk for recurrent early-onset severe hemolytic disease of the fetus and newborn from eight national or regional referral centers in seven countries. Researchers evaluated IV nipocalimab 30 mg/kg or 45 mg/kg of body weight per week administered from 14 to 35 weeks’ gestation.

Primary outcome was live birth at 32 weeks’ gestation or later without intrauterine transfusions.

Overall, 92.3% of all pregnancies resulted in a live birth and 54% resulted in live births meeting the primary outcome, which was higher than the 10% clinically meaningful difference from the historical benchmark (P < .001). Of pregnancies meeting the primary outcome, five received nipocalimab 45 mg/kg of body weight. Median gestational age at delivery was 36 weeks and 4 days. Of the 92.3% of pregnancies resulting in live births, one newborn received one exchange transfusion and one simple transfusion while five received simple transfusions alone.

Forty-six percent of pregnancies did not receive any antenatal or neonatal transfusions. Six fetuses received intrauterine transfusions with five receiving transfusions at 24 weeks’ gestation or later and one receiving transfusion before fetal loss at 22 weeks and 5 days’ gestation.

“The endpoint proposed in the study was to get to 32 weeks’ gestation, have a live birth and not need a blood transfusion, and we reached that for over half the patients,” Moise said during an interview. “We expected almost all of these women to need a blood transfusion during their pregnancy due to their disease. All but one infant survived. For these women, most of whom had lost babies in previous pregnancies, they went home with a baby. That is an impressive study outcome.”

Researchers observed no cases of fetal hydrops and no unusual maternal or pediatric infections. In addition, researchers observed treatment-related decreases in alloantibody titers and IgG levels in maternal samples and cord blood.

“The [drug] efficacy was good and there were no major safety signals,” Moise told Healio. “One concern was when you lower the mother’s antibody level, it could potentially result in infection for the mother, as this drug is selective for all antibodies. We did not see any infections in the mothers. That was reassuring. Likewise, since we blocked the placenta [from receiving the mother’s antibodies], infants did well. They were, in fact, born with lower antibody levels, but none had overt infections other than the typical illnesses. There were no signals of increased infection risk due to low IgG levels, and levels rose over about 6 months as infants started making their own IgG.”

Larger study ongoing

A larger study, the phase 3 randomized AZALEA trial, is currently underway and will include about 120 women with a history of hemolytic disease of the fetus and newborn in a prior pregnancy as well as the presence of maternal alloantibody to RhD, Rhc, RhE or RhC antigen, with titers above the critical level. Researchers will randomly assign women 2:1 to nipocalimab once weekly infusion or saline placebo. All women will receive weekly ultrasounds and follow-up at experienced centers.

“We do not see a lot of trials done with pregnant women,” Moise told Healio. “This is not even to benefit the pregnant woman. This is a trial to benefit her unborn baby. This is a first of its kind, landmark trial with a unique approach. We hope to complete it in about 2 to 3 years.”

Reference:

• A study of nipocalimab in pregnancies at risk for severe hemolytic disease of the fetus and newborn (AZALEA). https://clinicaltrials.gov/study/NCT05912517. Accessed Sept. 24, 2024.

For more information:

Kenneth J. Moise Jr., MD, can be reached at kmoise@austin.utexas.edu.