An ongoing clinical trial designed to answer critical questions regarding treatment protocols for anti-NMDA receptor encephalitis, a relatively rare but often devastating condition, is continuing to expand trial sites and enroll participants, building excitement in the medical and patient communities. At Washington University School of Medicine in St. Louis, David Clifford, MD, the Melba and Forest Seay Professor of Clinical Neuropharmacology and chief of the Section of Neuroinfectious Diseases in the Department of Neurology, is the site principal investigator for the trial.
“We are delighted to have participated in developing this trial, the first randomized treatment trial for this important disease,” said Clifford. “We hope to understand if early aggressive intervention can improve the ultimate outcomes for these patients. This recently discovered disease has been introduced to many through ‘Brain on Fire,’ a book authored by Susannah Cahalan, a former WashU student, that was made into a movie. It is the most common form of autoimmune encephalitis, affecting both children and young adults.”
Anti-NMDA receptor encephalitis is an autoimmune, inflammatory disease caused by the body producing antibodies that attack N-methyl-D-aspartate receptors (NMDAR). NMDAR binds with glutamate — a primary neurotransmitter for passing along key signals in the human brain to regulate memory, mood, movement and other essential functions. NMDAR antibodies can cause NMDAR to drop to dangerous levels in individuals, resulting in a host of serious cognitive and physical symptoms.
While clinicians have become more adept in recent decades at quickly diagnosing and treating patients who present with the clinicals symptoms and classic biofluid markers of NMDAR encephalitis, the unfortunate reality is that treatment outcomes have not improved significantly. Many patients do respond to current treatment approaches in varying degrees, but the high rate of patients who relapse or suffer from long-term consequences points to the need for improvements in treatment options and protocols.
The Encephalitis Treatment with Inebilizumab for NMDAR and Guidance on Serum + CSF biomarkers to predict Health outcomes (ExTINGUISH) trial, led by Stacey Clardy, MD, PhD, of the University of Utah, began enrolling adult patients in 2022 and pediatric patients in 2024, with the goal of enrolling a total of 116 participants. This will allow for statistically significant analysis of the findings in this international, randomized, double-blinded, placebo-controlled clinical trial. The trial methodology was outlined in detail in a recent article published in Neurology Open Access.
The primary goal of the trial is to test the safety and efficacy of inebilizumab as a treatment for NMDAR encephalitis. Inebilizumab is a monoclonal antibody that is currently approved for treating neuromyelitis optica spectrum disorder (NMOSD), which, like NMDAR encephalitis, is an autoimmune disease. Inebilizumab is an effective treatment for NMOSD because it depletes B cells, a type of antibody-producing immune cell. In comparison with rituximab — the monoclonal antibody medication currently used as a treatment option for NMDAR encephalitis — inebilizumab has demonstrated a more comprehensive and sustained suppression of B-cell activity.
In addition to this primary goal, the scope and design of the clinical trial allows for secondary and tertiary outcomes that could have implications for how clinicians and researchers treat and study encephalitis in the future. The study uses an adapted version of the modified Rankin Scale in conjunction with building a robust biorepository of blood and cerebrospinal fluid to validate certain biomarkers as indicators of whether a patient has encephalitis and how severe it is. The trial also emphasizes “softer” measures for determining the severity of a patient’s condition, looking at quality-of-life outcomes for patients and caregivers in addition to clinical and cognitive outcomes.
The ExTINGUISH trial is supported by the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) and funded by the NIH via the National Institute of Neurological Disorders and Stroke (NINDS). This trial is also an international effort, as Clardy noted in a 2023 webinar for the Child Neurology Society, with sites across Europe as well as the U.S. and ongoing input and active participation by a host of international experts on NMDAR encephalitis, including Josep Dalmau, MD, PhD, who first identified the disease.
With the publication of the Neurology article, the investigators are expecting increased awareness about, and enrollments in, the trial. “We welcome early referrals of individuals with new diagnosis of NMDA Receptor encephalitis,” said Mengesha Teshome, MD, assistant professor of neurology in the Section of Neuroinfectious Diseases at WashU Medicine, who is coordinating the study along with Clifford.
Wong KH, Day GS, Torner JC, Cudkowicz M, Coffey CS, Cho HJS, Utz U, Clifford DB, Katz E, Ratchford J, Flavin S, Dialino-Felix A, Dill LM, Kamp C, Klawiter EC, Singleton JR, Fedler J, Klingner EA, Ecklund D, Klements D, Costigan M, Steinhart E, Pearson B, Desir C, Dalmau JO, Titulaer MJ, Clardy SL. A Phase-2B Double-Blind Randomized International Prospective Trial of Inebilizumab in NMDAR Encephalitis: The ExTINGUISH Trial. Neurology Open Access. 2025;1(2):e000007. doi:10.1212/WN9.0000000000000007