Nipocalimab is an investigational, fully human monoclonal antibody under development by Janssen. This drug is a neonatal Fc receptor (FcRn) inhibitor, designed as an aglycosylated IgG1 monoclonal antibody. The development of nipocalimab originated with Momenta Pharmaceuticals before its acquisition by Janssen Research & Development, a subsidiary of Johnson & Johnson.
Mechanism of Action
The neonatal Fc receptor (FcRn) extends the life of Immunoglobulin G (IgG), the most common antibody in the bloodstream. FcRn binds to IgG antibodies and diverts them from normal cellular degradation, returning them to circulation and prolonging their half-life. In many autoimmune disorders, the body produces pathogenic IgG autoantibodies that attack its own tissues, and the FcRn recycling pathway perpetuates their harmful presence.
Nipocalimab is engineered to interrupt this cycle by selectively binding to the FcRn. This action occupies the site that IgG antibodies would use, preventing the receptor from rescuing pathogenic IgG. Instead of being recycled, these disease-causing antibodies are sent for degradation and clearance from the body. This process leads to a rapid, dose-dependent reduction in circulating IgG, including the harmful autoantibodies, without appearing to impact other parts of the immune system.
Therapeutic Applications
By lowering pathogenic IgG levels, nipocalimab is a potential treatment for various diseases driven by these antibodies. One primary area of investigation is Generalized Myasthenia Gravis (gMG), a chronic autoimmune disorder where autoantibodies attack proteins at the neuromuscular junction. This attack leads to muscle weakness, and reducing these autoantibodies aims to improve neuromuscular function.
Another application is in Hemolytic Disease of the Fetus and Newborn (HDFN), where maternal IgG alloantibodies cross the placenta and attack the fetus’s red blood cells, causing severe anemia. Nipocalimab is being studied in pregnant individuals to reduce these maternal antibodies and protect the fetus. This represents a potential non-invasive intervention to prevent the serious consequences of HDFN.
Nipocalimab is also being investigated for other autoimmune conditions. In Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), IgG autoantibodies are thought to damage the myelin sheath of peripheral nerves, causing progressive weakness and sensory loss. In Rheumatoid Arthritis, autoantibodies contribute to joint inflammation and damage. The drug is also being explored for Sjögren’s disease and other rare autoantibody-driven diseases.
Clinical Trial Insights
In the Phase 3 VIVACITY-MG3 trial for Generalized Myasthenia Gravis, nipocalimab met its primary endpoint. The treatment demonstrated a significant reduction in the Myasthenia Gravis-Activities of Daily Living (MG-ADL) score compared to placebo, indicating improved muscle weakness. These positive results supported regulatory submissions.
For Sjögren’s disease, the Phase 2 DAHLIAS study showed that nipocalimab led to significant improvements in disease activity, measured by the clinical EULAR Sjögren’s Syndrome Disease Activity Index (ClinESSDAI). The greatest improvements were seen in patients who had the highest levels of specific autoantibodies at the start of the study.
A Phase 3 trial is investigating nipocalimab for preventing HDFN. This is based on preclinical studies establishing that the drug can achieve a time- and dose-dependent reduction of IgG levels by more than 75 percent. These findings were consistent with observations in early-phase human trials.
Safety Profile
Based on data from studies such as the Phase 2 DAHLIAS trial for Sjögren’s disease, nipocalimab has been generally well-tolerated. During its clinical development, no major unexpected safety signals have been identified.
Across various trials, the most commonly reported adverse events have been infections and infestations. In the DAHLIAS study, these events were observed in a higher percentage of patients receiving nipocalimab compared to placebo. Other noted side effects include headache, fatigue, and injection site reactions. Safety monitoring also tracks changes in laboratory values, such as albumin levels.
Regulatory and Development Status
The U.S. Food and Drug Administration (FDA) has granted nipocalimab Fast Track designation for HDFN, gMG, and Sjögren’s syndrome. The drug also received Breakthrough Therapy designation from the FDA for HDFN and Sjögren’s disease. Both designations are intended to expedite the development and review of treatments for serious conditions.
Nipocalimab is in Phase 3 trials for HDFN, Sjögren’s syndrome, and Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT). For Generalized Myasthenia Gravis, Johnson & Johnson has submitted applications for approval in the United States. The FDA granted this application a Priority Review in late 2024.
In addition, nipocalimab is being studied in Phase 2 trials for other conditions like myositis and systemic lupus erythematosus. The European Medicines Agency (EMA) has also granted it Orphan Medicinal Product designation for HDFN.