Janssen colleagues Umair Amin, MBBS (left), associate director of clinical research and maternal-fetal immunology, and Waheeda Sirah, clinical research director in the same division, discuss their company’s new therapy for HDFN. (Photo by Larry Luxner)

VALENCIA, Spain—For 35 years, Kenneth J. Moise Jr., MD, has built his career around hemolytic disease of the fetus and newborn (HDFN), formerly known as Rhesus disease.

HDFN due to anti-D antibodies—which occurs in the second or subsequent pregnancies of RhD-negative women when the biological father is RhD-positive—used to be far more common. But since 1967, the disease has been preventable by injecting the mother with anti-Rho(D) immune globulin, which neutralizes any RhD-positive antigens that may have entered her blood during pregnancy.

Even so, HFDN continues to persist, largely in underprivileged pockets of wealthy countries and across the developing world. If not treated in time, it can cause life-threatening anemia in the fetus or infant.

“We’re still doing the same thing we did when I started my career in 1988,” said Dr. Moise, a professor of women’s health and director of the Comprehensive Fetal Care Center at Dell Medical School of the University of Texas at Austin.

“Although Rh-immune globulin has had a major impact on this disease, it’s hurt us from a technical expertise point of view. You have to do 30-50 of these procedures to become proficient, and 10 a year to stay proficient. When I started, I was doing 3-4 a week, and now maybe 1 every 2-3 weeks.”

Kenneth J. Moise Jr., MD, is a professor of women’s health at Dell Medical School, a division of the University of Texas in Austin. He spoke about Janssen’s nipocalimab therapy for hemolytic disease of the fetus and newborn at the 20th World Congress in Fetal Medicine, held June 25-29, 2023, in Valencia, Spain. (Photo by Larry Luxner)

He added: “We know that even in experienced hands, mortality rates can be as high as 20% when attempting to do these procedures at under 22 weeks of gestation.”

But now, a new therapy is on the horizon—a potential breakthrough which Dr. Moise was closely involved with as the lead investigator.

Janssen, a division of Johnson & Johnson, recently unveiled the results of its proof-of-concept phase 2 open-label UNITY clinical trial of nipocalimab for 13 pregnant women at high risk of early-onset severe HDFN. The trial began in 2019 and is expected to conclude next year.

Dr. Moise, speaking on June 26, 2023, at the Fetal Medicine Foundation’s 20th World Congress in Valencia, Spain, announced that 92% of pregnancies treated with nipocalimab resulted in live births, with 54% delivering at or after 32 weeks without intrauterine transfusions.

Nipocalimab is a monoclonal antibody believed to selectively block FcRn to reduce levels of circulating immunoglobulin G (IgG) antibodies, including autoantibodies and alloantibodies that underlie multiple conditions.

Thousands Still Die From ‘Totally Treatable Disease’

The incidence of HDFN appears to vary depending on ethnicity. According to Dr. Moise, the disease affects 5% of Caucasian women, but less than 1% of Asian women. Curiously, one of the world’s highest rates is found in Spain’s Basque region, where 30% of women test RhD-positive.

“We actually think it started here, and as the Spaniards colonized the Americas and started mixing with other ethnicities, it spread,” said Dr. Moise, who helped Janssen design the trial and has supervised it from the beginning, in an onsite interview with Rare Disease Advisor.

“When a woman gets pregnant, the first thing we do is check her blood type. In a certain percentage of patients, they’re Rh-negative, so they’re at risk of developing problems in the event some of their baby’s blood gets into their bloodstream,” he said. “That shot we give is very effective in preventing problems. But sometimes the shot is forgotten, or we don’t give enough, and she develops antibodies. It doesn’t hurt the first baby, but it will hurt the second baby.”

Even though, as Dr. Moise said, “this is a totally treatable disease,” HDFN still causes about 50,000 deaths a year worldwide.

“In the US, about 1% of women, in general, have an antibody we should be concerned about,” he said. “Rh makes up about a third of that 1%, but there are no great numbers in the US right now. We don’t even have a national database to know how much is out there.”

Kattayoun Kordy, MD, is senior director of rare disease clinical development/immunology at Janssen. A pediatric gastroenterologist and clinical pharmacologist who’s traveled the world doing HIV clinical care in developing countries—ranging from Ecuador and Thailand to Malawi and South Africa—she said the paucity of clinical trials among pregnant women is mainly to blame for the lack of new approaches to treat HDFN over the years.

“The traditional therapy for this condition is really based on an invasive, surgical procedure called intrauterine transfusion,” Dr. Kordy explained. “It’s only provided with very special techniques at specialty care centers. It carries a risk to the fetus by possibly causing fetal loss, and maybe even premature birth. Currently, that has been the standard of care for many years now.”

Stopping the Transfer of Pathogenic Antibodies

Nipocalimab, on the other hand, prevents the placental transfer of pathogenic antibodies into the fetus.

“We do hope that, in the future, we’ll meet the unmet medical need of HDFN and go beyond just the high‑risk population,” she said, estimating that the disease affects roughly 80 of every 100,000 pregnancies in the United States. “There is still quite a lot of work to be done to really understand the true prevalence in this disease because we do believe it is currently underdiagnosed.”

Members of the Janssen team at the Fetal Medicine Foundation’s 20th World Congress in Valencia, Spain. At the center is Kattayoun Kordy, MD, the company’s senior director of rare disease clinical development/immunology. (Photo by Larry Luxner)

With encouraging results from its phase 2 trial, Janssen is now planning to launch a placebo-controlled, blinded, randomized phase 3 trial, dubbed AZALEA, later this year. Involving 120 patients, it will take place over 3 years in Europe, South America, and Australia, and will be the first for a disease that’s unique to pregnancy, he said. Janssen estimates that trial will end in 2029.

“The preclinical work for this was massive—all this work in primates, then a human phase 1 trial, then we had to design phase 2,” Dr. Moise said. “We picked women who had lost babies at under 24 weeks. That’s why it took us longer to recruit everybody. Plus, COVID hit us.”

To date, only 9 drugs have been approved specifically for pregnant women, and Janssen is the only pharmaceutical firm that’s developing a novel therapy for severe HDFN. In fact, some women will get pregnant specifically to be in this trial. Its primary endpoint will be the proportion of pregnancies that don’t result in fetal loss, intrauterine transfusion, hydrops fetalis, or neonatal death.

Dr. Moise, who has devoted the last 35 years to treating HDFN, said: “This is something I built my academic career around. It’s my swan song.” But he added that he welcomes any new potential therapy that could revolutionize the way physicians help women and their babies affected by this disease.

“I want to train another generation to do what I do,” he said. “It’s important that we leave a legacy.”