A Phase-2B Double-Blind Randomized International Prospective Trial of Inebilizumab in NMDAR Encephalitis: The ExTINGUISH Trial.

Abstract

Background and objectives: The lack of approved therapies for N-methyl-d-aspartate receptor (NMDAR) encephalitis has contributed to substantial variability in treatment. Inebilizumab is a humanized anti-CD19 monoclonal antibody that can be administered intravenously. Inebilizumab may be an efficacious treatment for patients with NMDAR encephalitis, with the potential to achieve early robust and sustained suppression CD19⁺ plasmablasts, some plasma cells, and NMDAR autoantibodies, with the potential to improve short-term and long-term outcomes in patients with NMDAR encephalitis.

Methods: The ExTINGUISH trial is a multisite, phase 2B, randomized, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of inebilizumab 300 mg for the acute treatment of participants with moderate-to-severe NMDAR encephalitis. ExTINGUISH will randomize 116 patients across the United States and Europe. Participants will receive standard first-line immunotherapies (intravenous steroids and intravenous immunoglobulins and/or plasma exchange) before randomization (1:1). In addition, cyclophosphamide rescue therapy will be offered to participants with persistent moderate-to-severe disease 6 weeks after randomization. Primary outcomes will be measured 16 weeks from randomization using the change in the adapted ExTINGUISH modified Rankin scale and accepted safety measures in 32 weeks. Secondary outcomes will be measured up to 96 weeks and include comprehensive neuropsychological tests, bedside cognitive screening tools, and quality-of-life/functional indices. Clinical data will be combined with blood and CSF biomarkers of immune activation to inform putative biologic contributors to outcomes (exploratory outcomes). Study operations are supported by the National Institute of Neurological Disorders and Stroke-supported Network for Excellence in Neuroscience Clinical Trial (NeuroNEXT) infrastructure.

Discussion: The ExTINGUISH trial will determine the safety and efficacy of inebilizumab as a treatment of NMDAR encephalitis while evaluating the utility of clinical, cognitive, and quality-of-life outcome measures and supporting standardized collection and measurement of biofluid biomarkers. These innovations will inform development of future treatments and trials for patients with NMDAR encephalitis and other types of autoimmune encephalitis. The ExTINGUISH trial opened to enrollment of adult patients (older than 18 years) in 2022 and pediatric patients (older than 12 years) in 2024; enrollment is ongoing.