ANA Investigates Therapeutic Advancements in Neuroimmunology

Abstract

Several immunosuppressive treatments have been approved by the US Food and Drug Administration (FDA) for multiple sclerosis and for neuromyelitis optica spectrum disorder (NMOSD). However, there are many neuroimmunological conditions that do not yet have licensed treatment options or widely established treatment algorithms. In the latest episode of the ANA Investigates podcast, Dr Jeffrey M. Gelfand, neuroimmunologist and Associate Professor of Neurology at University of California, San Francisco, discusses new licensed therapies for NMOSD, clinical strategies for off-label use of immunosuppressive therapies for a range of neuroinflammatory conditions, and some exciting emerging treatments in the field. NMOSD has become the model for development of novel therapeutics and clinical trial design in a rare neuroinflammatory disease. Three treatments for NMOSD licensed by the FDA in 2019 and 2020 target key aspects of the pathologic inflammatory response. In a phase 3 double-blind randomized trial, eculizumab, a humanized monoclonal antibody that inhibits C5, the terminal complement protein, led to lower risk of relapse compared to placebo. In a phase 3 randomized controlled trial, satralizumab, a humanized monoclonal antibody that targets interleukin-6 (IL-6), when added to other immunosuppressant treatment, exhibited a lower relapse risk compared to placebo. In a second phase 3 randomized trial, satralizumab monotherapy led to lower relapse rates compared to placebo. In a phase 2/3 randomized controlled trial, inebilizumab, a humanized monoclonal antibody against the B-cell and plasmablast surface antigen CD-19, led to lower relapse rates compared to placebo. There are several neuroinflammatory conditions that do not yet have licensed treatments, including autoimmune encephalitis, central nervous system vasculitis, neurosarcoidosis, and some neurologic manifestations of systemic autoimmune disease. For management of these conditions, clinicians typically turn to acute therapies like glucocorticoids, intravenous gamma globulin, and plasma exchange, and depending on the indication, may consider longer term therapies like purine and pyrimidine inhibitors, cyclophosphamide, B-cell–depleting therapies, IL-6 inhibitors, tumor necrosis factor inhibitors, and others. In the podcast, Dr Gelfand reviews these therapies in detail and discusses emerging data about novel therapeutic targets including checkpoint inhibitors. He also highlights two agents under investigation in autoimmune encephalitis: tocilizumab, another IL-6 inhibitor, and bortezomib, a proteosome inhibitor thought to target antibody-secreting plasma cells resistant to B-cell–depleting agents. Dr Gelfand’s message is hopeful: new immunemodulating therapies are improving prognosis and quality of life for patients with these rare conditions. Moreover, strategies used to advance treatments for NMOSD are likely to help inform clinical trial design and development of new treatments for other rare neuroinflammatory diseases.