New investigational treatment may prevent severe disease in fetuses and newborns

A treatment given during pregnancy has the potential to prevent a rare but serious disease in fetuses and newborn babies caused by maternal antibodies. This is according to the phase 2 UNITY clinical trial involving researchers at Karolinska Institutet. The study is published in the prestigious New England Journal of Medicine. 

In some cases, pregnant women can produce immunoglobulin G (IgG) antibodies that attack the red blood cells of the fetus in the womb. This can cause a rare disease called haemolytic disease of the fetus and newborn (HDFN), which can lead to severe anaemia, severe jaundice in the newborn and, at worst, brain damage or death. 

The harmful IgG antibodies in the mother’s bloodstream are transported via the placenta to the fetuses bloodstream by a receptor called the neonatal fragment crystallizable receptor (FcRn).  

The investigational drug, nipocalimab, can block the receptors, preventing the transport of maternal antibodies to the fetus and can also reduce the levels of IgG in the mother’s bloodstream. 

Now a multinational study on a small number of high-risk pregnancies demonstrates that nipocalimab has the potential to prevent and mitigate the course of the disease without causing serious side effects in the mother or the fetus.  

Eleonor Tiblad, physician and researcher at the Department of Medicine, Solna, Karolinska Institutet has led the Swedish part of the study, with patients from Karolinska University Hospital – one of the few hospitals in Scandinavia treating severe HDFN. 

“This is a major step forward because until now, the treatment of severe HDFN has consisted of repeated intrauterine blood transfusions, IUTs, to the fetus during pregnancy – an invasive and risky procedure that can lead to fetal death,” she says. “Neonatal intensive care, exchange transfusion and repeated blood transfusions are often required after birth, so it is very valuable to have a drug that can prevent this.” 

A total of 13 pregnant women from eight medical centres around the world were included in the study. All had a history of very severe HDFN in previous pregnancies and were treated with nipocalimab from 14 to 35 weeks of pregnancy. The women and fetuses were closely monitored, and the children will be followed until the age of two. 

The drug was not associated with an increased risk of severe infections or immunological complications. In the 13 maternal participants treated with nipocalimab, six of the babies (46 percent) did not require blood transfusions during either the fetal or neonatal period. 

In cases where transfusions were required during pregnancy, the anaemia occurred several weeks later than expected, when IUTs can be performed with significantly lower risk. Seven of the fetuses (54 percent) passed the 32nd week of pregnancy without the need for an intrauterine blood transfusion. One fetus died as a result of complications from an IUT. 

“It is gratifying that 12 out of 13 babies survived, as the survival rate is only around 38 percent in comparable pregnancies,” says Eleonor Tiblad. “In addition, far fewer babies were born prematurely.” 

The Phase 2 UNITY study is sponsored by Johnson & Johnson. Eleonor Tiblad and several co-authors receive honoraria as members of advisory boards and publication steering committees for the company. 

Johnson & Johnson is currently conducting a larger randomised placebo-controlled Phase 3 trial in HDFN, and is also studying the treatment of another IgG-mediated maternal-fetal disease, fetal neonatal alloimmune thrombocytopenia (FNAIT). 

Publication: “Nipocalimab in Early-onset Severe Haemolytic Disease of the Fetus and Newborn”, Kenneth J. Moise Jr, Leona E. Ling, Dick Oepkes, Eleonor Tiblad, EJT (Joanne) Verweij, Enrico Lopriore, John Smoleniec, Ulrich J. Sachs, Gregor Bein, Mark D. Kilby, Russell S. Miller, Roland Devlieger, Francois Audibert, Stephen P. Emery, Kara Markham, Mary E. Norton, Olga Ocón-Hernández, Pranav Pandya, Leonardo Pereira, Robert M. Silver, Rory Windrim, James B. Streisand, Jocelyn H. Leu, Arpana Mirza, Valerie Smith, Lisa B. Schwartz, May Lee Tjoa, Shumyla Saeed-Khawaja, Yosuke Komatsu, James B. Bussel, for the UNITY Study Group. The New England Journal of Medicine (NEJM), online August 8, 2024, doi: xxxxx