Janssen’s Phase II study of nipocalimab for generalized myasthenia gravis (gMG) shows that serum IgG levels can be used as a supportive biomarker to manage this disease.
Janssen is progressing in managing the generalized myasthenia gravis (gMG) disease. (Michael Vi/Shutterstock)
Data from Janssen’s Phase II study of nipocalimab for generalized myasthenia gravis (gMG) shows that serum IgG levels can be used as a supportive biomarker to help manage this disease. Consequently, rather than waiting months to determine whether a therapy for this rare, hard-to-treat neuromuscular disorder is effective, physicians can use the biomarker in conjunction with the clinical examination to make that determination within a few weeks.
Sindhu Ramchandren, M.D., director of clinical development and clinical leader, neuroscience at Janssen, presented that finding at the American Academy of Neurology (AAN) meeting in early April.
What Did Ramchandren Said About the Relation Between IgG and Generalized Myasthenia Gravis?
Speaking to BioSpace just before her presentation, Ramchandren explained, “A healthy immune system makes IgG, which fight infections. Our blood vessels have the neonatal Fc receptor (FcRn), which helps regulate IgG levels in the blood. The FcRn receptors bind and recycle the IgG to prevent it from being broken down by the body’s enzymes. In a healthy system, this is good.”
In generalized myasthenia gravis and other autoimmune diseases, however, that process becomes a weapon – the body produces pathogenic IgG autoantibodies that turn against the body’s own cells. In gMG, these IgG autoantibodies target the neuromuscular junction – specifically, acetylcholine receptors (AChR), muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4). Initially, this results in a weakness in the muscles controlling the eyes and eyelids, known as ocular myasthenia gravis (ocular MG). As the condition progresses to become gMG, that weakness expands to affect the muscles of the head, neck, core, limbs and respiratory system.
Janssen is developing nipocalimab to treat gMG. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 anti-FcRn monoclonal antibody. “It binds the FcRn receptors and prevents IgG autoantibodies from binding,” Ramchandren said, which lowers total IgG and IgG pathogenic antibodies. Therefore, this mechanism of action may be helpful in autoimmune diseases like gMG.
The abstract presented at AAN correlated improvements in MG-ADL score with nipocalimab’s ability to reduce levels of total IgG and also lower levels of acetylcholine-receptor (AChR)- and Muscle-Specific-Tyrosine-Kinase (MuSK)- IgG autoantibodies in serum. Of the 54 patients who were randomized to one of the four nipocalimab dosing arms, 94% were seropositive for anti-AChR, and 6% for anti-MuSK. The number of MuSK autoantibody positive patients was too small to draw conclusions; total IgG and AChR IgG autoantibodies were reduced and correlated with improvements in the MG-ADL score.
Despite available standard-of-care therapies in generalized myasthenia gravis, there is still a significant unmet need for patients. “Current treatments have significant side effects, and between 20 and 25% of patients don’t respond to them at all,” Ramchandren said.
Nipocalimab aims to help fill that unmet need. “In the Phase II study of patients with gMG, we noted that nipocalimab achieved rapid, dose-dependent lowering of serum IgG including all IgG subclasses, and a reduction of the pathogenic IgG autoantibody levels.” It delivered rapid improvement for patients and deep and sustained effects.
This correlated to improvement in the disease course, as shown by improvements in the Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores. “Our study suggested the percentage reduction in IgG can be a supportive biomarker in the general management of gMG patients,” Ramchandren concluded. “If similar results are seen in Phase III trials, patients and their physicians will be able to assess how well they are doing by evaluating changes in their IgG levels.”
There appear to be no other known biomarkers to gauge the effectiveness of treatment for generalized myasthenia gravis. “Typically…physicians use clinical exams to determine improvements in disease manifestation, medication side effects, quality of life and other factors,” she explained. The problem is that “the current standard-of-care takes months to years to show any treatment effect.” Using IgG levels as a supportive biomarker, however, “you may potentially show a treatment has efficacy in about two weeks.”
The Vivacity PIII trial is recruiting globally, with the intent of enrolling 180 participants. This randomized, double-blind trial will compare the safety and efficacy of nipocalimab to placebo in participants with gMG. Patients will be dosed every two weeks for up to 24 weeks. Those completing the study may continue in an open-label extension with the possibility of monthly dosing.
“A pediatric study for gMG is planned to start soon,” she added. That study will evaluate the effect of nipocalimab on total serum IgG levels in participants between 2 and 18 years of age who have generalized myasthenia gravis and who do not respond to standard-of-care therapy. The children and adolescents in this study will receive nipocalimab intravenously every two weeks for 24 weeks.
“This is a really exciting time for neuro-immunology research,” Ramchandren said, as new, more efficacious therapies with fewer side effects are developed. “When we began investigating this molecule, we were excited about the mechanism of action, the possible potency and the targeted nature of nipocalimab. It has the potential to be a treatment for multiple autoimmune diseases.”
