Birmingham host to investigational treatment trial which could improve outcomes of pregnancies affected by severe haemolytic disease

Pregnant mothers have taken part in a clinical study (the UNITY trial) in Birmingham, which has found that nipocalimab, an investigational, fully human, monoclonal antibody, has the potential to improve the survival rate of unborn babies with rare, early-onset fetal anaemia, as a result of haemolytic disease of the fetus and newborn (EOS-HDFN).

The study investigated pregnancies complicated by severe EOS-HDFN (RhD (D) or Kell (K) alloimmunized pregnant individuals with singleton pregnancies) and evaluated the effects of nipocalimab at weekly intervals from 14-35 weeks of pregnancy.

The University of Birmingham and Birmingham Women’s Children’s NHS Foundation Trust were a study site for a global, multicentre, open-label trial, in which nipocalimab was given for the treatment of pregnancies at high risk of severe EOS-HDFN, and evaluated safety, efficacy, and the maternal metabolism of the monoclonal antibody.

Nipocalimab is an investigational monoclonal antibody, purposefully designed to bind with high affinity to block the fetal/neonatal fragment crystallizable (Fc) receptor (FcRn) and reduce levels of circulating immunoglobulin G (IgG) antibodies, including alloantibodies and autoantibodies that underlie multiple conditions. Blockade of IgG binding to FcRn in the placenta is also believed to prevent transplacental transfer of maternal alloantibodies to the fetus.

Results from a Phase 2 clinical trial published in the New England Journal of Medicine, sponsored by Johnson and Johnson, have demonstrated the majority of pregnant patients with severe HDFN who received nipocalimab achieved a live birth at or after the gestational age of 32 weeks, without the need for an intrauterine transfusion (IUT) throughout their entire pregnancy.

The study demonstrated that 54% of pregnant women treated with nipocalimab gave birth at or after 32 weeks of pregnancy, without any IUTs, compared to 0% in their previous pregnancy. Overall, the perinatal survival was 92%, whereas historically only 10% of pregnancies affected by severe HDFN reach this benchmark. 

Of the 46% requiring IUT, the majority were after 24 weeks of pregnancy, and only a single case was performed at 22 weeks, which sadly was complicated by a miscarriage. Nipocalimab was well tolerated by pregnant individuals and newborn/infants with no unusual infections despite IgG lowering in pregnancy. Serious adverse events were generally consistent with pregnancy conditions, HDFN outcomes, and gestational age at birth.

The Birmingham site investigator, Mark Kilby, Emeritus Professor of Fetal Medicine at the University of Birmingham and Honorary Consultant of Fetal Medicine, Birmingham Women’s and Children’s NHS Foundation Trust said:

“For mothers with severe HDFN the outcome not only of the condition but of the treatment, can be devastating. This is why the search for therapies to reduce the consequences of the maternal immune response has been focused on this cohort of women. The clinical study has found that nipocalimab is well tolerated and greatly increases the chance of unborn babies surviving severe EOS-HDFN, requiring less in-utero transfusion therapy.”

The promising results of the UNITY study have prompted the U.S. Food and Drug Administration (FDA) to grant a Breakthrough Therapy Designation (BTD) for nipocalimab for the treatment of alloimmunized pregnant individuals with HDFN. The AZALEA Phase 3 pivotal trial is currently enrolling pregnant individuals who are at risk for severe HDFN at any gestational age, who have a history of severe HDFN in a prior pregnancy.

“Dream come true” as baby born during lockdown through trial

Rosemary and Darren from Ireland were expecting baby Nessa when they took part in the clinical trial. Rosemary had had a previous in-utero transfusion for HDFN, and the couple had a child following treatment. Sadly, the couple lost a second baby after another in-utero transfusion.

Rosemary had contacted her doctors at the Rotunda Hospital in Dublin about the trial as she had previously read about it and saw on Facebook that sites were opening to recruit patients. Rosemary was desperate to avoid another in-utero transfusion and was referred to the Fetal Medicine Centre at Birmingham Women's and Children's Hospital 8 weeks into her pregnancy. She had cell-free fetal DNA testing to confirm the baby was 'suspectable' to the antibodies she had produced. Rosemary then had maternal infusions of nipocalimab intravenously at weekly intervals from 14 to 35 weeks.

Baby Nessa was born at 36 weeks weighing 6 pounds and 13 ounces and without the need for any IUTs.

Rosemary said: “When we were accepted onto the trial, we were both relieved and excited. Following the loss of our little girl Liliana, we were advised not to have any further pregnancies and we were devastated. This trial gave us hope of having another baby.”

“We were pregnant during the Covid lockdowns and as I was commuting from Ireland to Birmingham, it was a big worry but throughout our involvement in the trial, we felt supported, informed, understood and safe. We are forever grateful, the level of professionalism, compassion and empathy shown towards us is something we will never forget.”

“Our two sons, Ollie and Joey now have a little sister, Nessa, who is a bubbly happy healthy 4-year-old, full of mischief, giggles, and fun. To think the trial has given us what we believed was impossible, is a dream come true. To hear the trial has also given others living healthy children is fantastic. In a situation where we, like so many others felt was hopeless, to now know there is a treatment is like a miracle.”

Haemolytic disease of the fetus and newborn

Haemolytic disease of the fetus newborn (HDFN), which is also sometimes referred to as Rhesus disease, is caused by a system of red blood cell antigens (most commonly of Rhesus D type) which raises the pathological antibody response in a pregnant person (red cell alloimmunization). These “pathological antibodies” or alloantibodies can cross the placenta to the fetus and destroy its red cells, leading to progressive fetal anaemia and – if untreated – death of the fetus.

Doctors use ultrasound-directed, invasive, in-utero blood transfusions to treat these seriously unwell unborn babies with a success and survival rate of 98%. However, in 5% of HDFN pregnancies, the mother may have very high levels of extremely potent alloantibodies. This can lead to the development of significant fetal anaemia before 24 weeks.

In these rare cases, in-utero transfusion is much more challenging due to the small size of fetal blood vessels and the immature fetal heart, which makes the unborn baby less able to cope with a blood transfusion. Because of this, the risk of significant complications leading to miscarriage is as high as 20% (1 in 5 pregnancies). 

Professor Kilby added: "These are fantastic results. In this group of pregnant women with severe HDFN, the medical management with nipocalimab has significantly reduced the need for early-onset in-utero fetal transfusion and improved the survival of these babies, reducing risks of miscarriage and stillbirth. Furthermore, and very importantly, nipocalimab seems to be well tolerated and safe for the mother and her unborn/newborn baby.”   

Professor Kilby concluded:  "This research is a huge step forward for mothers who experience severe HDFN, as well as their partners, extended families, and of course, their children. "