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While nipocalimab is under consideration as the first marketed drug for HDFN, clinicians consider the importance of awareness and dedicated research into the rare disease.
Hemolytic disease of the fetus and newborn (HDFN) occurs when a pregnant person forms alloantibodies against the developing fetus during pregnancy. These circulating alloantibodies, which are the mother's immune reaction to the developing fetus, can cross the placenta through the fetal neonatal receptor (FcRn), causing harm to the fetus's red blood cells. This can result in anemia and, in severe cases, fetal death, which can occur in up to a quarter of cases of severe HDFN.
The condition is rare, affecting up to 80 of 100,000 pregnancies in the US, and severe HDFN is considered ultra-rare. There are currently no US Food and Drug Administration (FDA)-approved safe and effective therapies for HDFN, but a new drug, nipocalimab, is being studied in clinical trials for its potential to treat HDFN.1
In an interview with HCPLive, Katie Abouzahr, MD, Vice President and Autoantibody Portfolio Development Leader at Janssen Research & Development, discussed the lack of therapeutic options for this condition, and the results of a recent phase 2 study evaluating nipocalimab in pregnant patients at high risk of developing severe HDFN.
The rarity of the condition makes it difficult to conduct studies in this area and, historically, companies have been hesitant to conduct studies during pregnancy. Despite the critical importance of clinical research in advancing maternal-fetal health, only around 1% of clinical trials include the term “pregnancy” in their titles.
Rare diseases, such as HDFN, pose unique challenges to research, including enrolling enough patients into a clinical trial and ensuring a timely diagnosis and access to treatment. However, the severity of the disease and the unmet need for effective therapies drive the development of new and innovative treatments.
Given the significant impact of severe HDFN, Abouzahr and her team believe that it is a long-neglected area for bringing novel therapeutics forward. While there have been advances in other facets of maternal-fetal medicine and prenatal and neonatal care, there are currently no approved safe and effective therapies for HDFN. This underscores the critical need for continued research and development in this area.
In more severe cases, HDFN can result in fetal death. In addition to the disease itself, current treatment options for severe HDFN may necessitate repeated intrauterine transfusions. This procedure involves passing a needle through the mother's stomach and directly transfusing blood into the fetal circulation.
“It is invasive, requires access to specialist care, and is technically complex,” Abouzahr explained. “Even in the best hands, it carries an increased risk of fetal morbidity, mortality, and premature birth. After delivery, neonates retain maternal alloantibodies for several weeks, putting them at risk of severe morbidity such as jaundice, anemia, and other life-threatening complications.”
The impact of HDFN on patients and their families is significant and underscores the need for continued research and development in this area. Nipocalimab may be a viable candidate to kickstart the pipeline.
Nipocalimab is an anti-FcRn therapy that binds and blocks the fetal neonatal receptor with high affinity. By doing so, it reduces circulating autoantibodies, which could theoretically prevent the passage of harmful alloantibodies from the mother to the fetus in cases of HDFN.
Janssen is currently studying nipocalimab for the treatment of HDFN, reflecting the significant impact of the disease on patients and families. Results of the phase 2 UNITY trial, recently announced by Janssen via press release,2 reported positive topline results that demonstrated that the majority of available nipocalimab-treated pregnancies met the primary endpoint, meaning they achieved a live birth at or after gestational age of 32 weeks without requiring an intrauterine transfusion (IUT) throughout their pregnancy.
The phase 2 global, multicenter, open-label, non-blinded clinical trial investigated the safety and efficacy of nipocalimab for the treatment of alloimmunized pregnant adults at high risk for severe HDFN. The trial enrolled 14 participants to receive intravenous infusions of the drug and adverse events were monitored for up to 24 weeks post-delivery for parents and up to 96 weeks post-birth for children.
In addition to meeting its primary endpoint, nipocalimab demonstrated a safety profile that supports further development in the treatment of HDFN during the 20-week treatment period.
Based on the results of the trial, Abouzahr believes the drug has the potential to become a best-in-class treatment option for patients in need of a safe, effective, and targeted therapy.
“In drug development, it's crucial to anticipate and plan for potential challenges and opportunities,” Abouzahr stated. “We are very excited about the potential of nipocalimab to bring relief to patients suffering from these devastating diseases. Moving forward, we are eager to plan and execute the next phase of our program to continue developing this therapy for patients with HDFN.”
The pathway approach utilized by Janssen involves identifying a specific mechanism or target that can treat multiple diseases. In the case of the anti-FcRn, nipocalimab, it binds to the Fc neonatal receptor and prevents the recycling of pathogenic immunoglobulin G (IgG) antibodies, including autoantibodies, and the parsing of alloantibodies in pregnancy.
This approach may be used to treat a variety of autoantibody-driven diseases categorized into 3 segments: maternal fetal (HDFN), rare autoantibody diseases (warm autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, idiopathic inflammatory myopathies, and bullous pemphigoid), and prevalent rheumatic diseases (rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome).
The drug, which is currently being studied as a potential treatment option for myasthenia gravis, has the potential to be a safe, effective, and approved targeted therapy for patients with unmet needs.
“[Nipocalimab creates] a perfect kind of balance because it allows the immune system to still produce immunoglobulins, still function, but lowers the level of the autoantibodies,” Sindhu Ramchandren, MD, Director of Clinical Development and Clinical Leader, Neuroscience, Janssen, said to HCPLive in a previous interview.3 “We have the proof of concept with our phase 2 trial in myasthenia gravis where we were able to show that treatment with nipocalimab resulted in a significant reduction in the immunoglobulin autoantibody levels. And this also translated to improved symptoms of their activities of daily living.”
Utilizing the pathway approach with nipocalimab allows researchers to address these needs more efficiently and effectively than developing multiple therapeutics and enables them to reach patients with life-threatening or debilitating conditions sooner, ultimately improving their lives.
“In the case of maternal fetal and rare auto antibody diseases, there are few, if any, approved therapies,” Abouzahr explained. “In the case of HDFN, there are no non-invasive approved treatment approaches. In the prevalent rheumatology space, some approved therapies are not effective for all patients.”
For patients living with rare diseases, like HDFN, this approach may lead to the discovery of new treatment options. However, it's crucial to design programs that meet their needs, incorporating the patient voice and what they're looking for in a therapy. This involves speaking to patients and patient advocacy groups to understand what will make a difference to them and incorporating their input into clinical program development.
“Although each individual rare disease affects fewer people, the overall number of individuals living with rare diseases is significant, estimated at around 300 million worldwide,” Abouzahr stressed. “However, the nature of rare diseases makes it challenging to study, enroll patients in clinical programs, and raise awareness of the disease.”