Understanding Precision Neuroscience As Treatment For Rare Autoantibody Disease
By Hong Sun, MD, Ph.D., senior director, global compound development team leader, neuroscience, Johnson & Johnson Innovative Medicine
Pursuing clinical research that can prompt earlier, accurate diagnosis and lead to novel targeted treatment options is critical to supporting people living with myasthenia gravis (MG). A rare autoimmune neuromuscular disease for which there is limited understanding of risk factors and no known cure, MG is not inherited or linked to any single gene and can affect anyone regardless of their racial or ethnic background. Currently, 700,000 people worldwide are estimated to live with the disorder. Symptoms are burdensome in everyday life but invisible to the unknowing eye — extreme fatigue, muscle weakness, vision impairment, trouble breathing, loss of motor control — and can easily be dismissed by others, leading people with MG to endure stigma and face misperceptions about being “lazy,” “unmotivated,” “depressed,” or that they’re exaggerating. What’s more, one of MG’s hallmarks, muscle weakness, is also associated with many other, more common brain disorders. Therefore, it’s not unusual for people with MG to receive one or more incorrect diagnoses in a frustrating process that can take several years to get right and then begin proper treatment.
Understanding The Current MG Treatment Landscape
Although we’ve known about MG for many years, treatments are largely limited to conventional non-specific broad immunosuppression (e.g., corticosteroids), immune modulation (e.g., IVIg infusions or plasma exchange), and surgery (e.g., thymectomy). These nonspecific treatments are limited by variable or slow onset of benefit, plus they can bring considerable adverse effects, including inhibiting the body’s ability to protect itself against infection or other illness. Furthermore, significant unmet medical need persists despite the availability of treatment options, as up to 20% of patients do not respond to treatment and are left with no viable therapeutic options. There is a need for more immune-selective treatments with better efficacy and tolerability for people living with generalized MG. Recently, more immune-selective therapies are being developed, including neonatal Fc receptor (FcRn) inhibitors.
At Johnson & Johnson, our dedicated research program is studying the application of precision neuroscience techniques in clinical trials for people living with generalized MG and other autoantibody diseases. Our approach focuses on FcRn, which promotes recycling of immunoglobulin-G (IgG) antibodies, maintaining circulating levels of IgG by preventing degradation. In people with MG, harmful IgG autoantibodies are formed and target the neuromuscular junction of skeletal muscles, resulting in symptoms including chronic muscle weakness and extreme fatigue. By using specific targeted FcRn receptor blockers, it is believed that we can inhibit FcRn-mediated recycling of IgG in people with MG, rapidly and sustainably lowering pathogenic IgG and alleviating MG symptoms. This approach would not affect other immunoglobulins like IgA, IgE, and IgM and T cell immunity, which are important to fight infections.
Advancing Novel Therapeutics For People Living With MG
For MG, biomarkers like acetylcholine receptor and muscle specific kinase antibodies can be used for diagnosis but may not predict treatment response1. At Johnson & Johnson, our program’s modeling and simulation work has shown a strong correlation between IgG lowering and clinical efficacy in generalized MG. IgG lowering is a biomarker for the FcRn class and by linking IgG reduction and clinical efficacy in generalized MG, this work provides foundational evidence to further explore the use of IgG as a potential biomarker for assessing the clinical efficacy of anti-FcRn antibody treatments in MG. Identifying and using novel biomarkers can reduce the size and increase the efficiency of clinical trials, ultimately improving the ability to bring more advanced treatments to patients earlier. In addition, continued research is critical to identify biomarkers that can aid in earlier and more accurate diagnosis, especially for seronegative MG patients, monitor and predict disease progression, gauge therapeutic benefit, and help guide choice of treatments.
These findings hold great promise for our ability to improve clinical trial efficiencies and develop precision therapeutics in neuroscience, reducing the trial participation and treatment burdens on people living with generalized MG by shortening the time to diagnosis and increasing the ability to monitor disease progression and therapeutic benefit. As our precision neuroscience capabilities continue to expand, we have the chance to make a difference in the lives of people worldwide who are coping with the disorder’s mysterious and invisible, yet debilitating, symptoms and often go for years without a correct diagnosis and path to meaningful treatment. We can continue to advance science by identifying biomarkers that help improve diagnostic accuracy, evaluate therapeutic benefit, and monitor disease progression. And, we hope to achieve earlier identification and diagnosis for patients, with an ultimate goal of reducing the treatment burden of this disease by developing highly immune-selective treatments that target the root cause of MG’s symptoms.
References:
- Kaminski HJ, Kusner LL, Wolfe GI, et al. Biomarker development for myasthenia gravis. Ann N Y Acad Sci. 2012;1275(1):101-106. doi:10.1111/j.1749-6632.2012.06787.x
About the Author:
Hong Sun, MD, Ph.D., is global compound development team leader, neuroscience at Johnson & Johnson Innovative Medicine. Dr. Sun is a neurologist and seasoned clinical researcher. She has been involved in development of several novel treatments for neurological diseases. Dr. Sun is very passionate in developing treatments to relieve burdens of CNS diseases, including neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease).