BREAKING NEWS! First Clinical Trial for Anti-NMDA Receptor Encephalitis
Posted on December 01, 2021
In the spring of 2020, the Foundation expressed its strong support for the first-ever Clinical Trial for a promising new drug to treat anti-NMDA receptor encephalitis. Fast forward to the Fall of 2021, when we learned that the Trial was approved and will be funded by the National Institutes of Health (NIH).
The Trial is a Phase-2b, Double-Blind, Randomized Controlled Trial to Evaluate the Activity and Safety of Inebilizumab in Anti-NMDA Receptor Encephalitis and Assess Markers of Disease.
High-quality evidence is needed to inform the treatment of NMDAR encephalitis.
The ExTINGUISH Trial will prospectively study an optimized B-cell depletion therapy to promote better long-term outcomes in NMDAR encephalitis, to determine more meaningful cognitive endpoints, and to identify better biologic biomarkers to predict outcome.
Various off-label therapies have been proposed as “second-line” treatments in NMDAR encephalitis. The majority of second-line treatments target circulating B-cells with various degrees of blood brain penetrance and efficacy, and poor consensus on the timing, dose, and route of delivery of candidate agents. Inebilizumab is a promising therapeutic monoclonal antibody for the treatment of NMDAR encephalitis. This humanized monoclonal antibody against the B-cell surface antigen CD19 was recently shown to be safe and efficacious in the treatment of neuromyelitis optica spectrum disorder-another antibody-mediated disorder of the central nervous system. Compared to other off label B-cell depleting therapies, such as rituximab, inebilizumab not only depletes CD20+ B-cells, but also CD20- plasma blasts and plasma cells, resulting in robust and sustained suppression of B-cell expression.
The ExTINGUISH Trial will randomize 116 participants with moderate-to-severe NMDAR encephalitis to receive either inebilizumab or placebo in addition to first-line therapies. Patient outcomes will be ascertained at standard intervals using the modified Rankin scale and accepted safety measures, together with comprehensive validated neuropsychological tests, bedside cognitive screening tools, quality of life/functional indices, and outcome prediction measures. Clinical data will be combined with quantitative measures of NMDAR autoantibody titers and cytokines implicated in B-cell activation and antibody production within the intrathecal compartment to identify treatment responders, inform the biologic contributors to outcomes, and evaluate for biomarkers that may serve as early predictors of favorable outcomes in future clinical trials in NMDAR encephalitis.
N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis, with prevalence exceeding herpes encephalitis in industrialized nations. Typically, the disease affects patients aged 10-50 causing prominent psychiatric symptoms, altered consciousness, seizures, movement disorders and life-threatening dysautonomia. Intensive care, including cardiorespiratory support is required in 75% of cases. The diagnosis is confirmed by detection of IgG autoantibodies against central nervous system NMDAR in the cerebrospinal fluid.
Despite the severity of the illness, NMDAR encephalitis is most often a treatable neurological disease, with retrospective case series establishing the benefit of off-label intravenous steroids and immunoglobulins. These treatments are presumed to work through effects on IgG NMDAR autoantibody levels in the CSF, although prospective data informing predictors of treatment responses are limited. Even with prompt treatment, ~50% of patients remain disabled, requiring prolonged hospital admissions.
If you are interested in learning more about the study or to find out if you are eligible, please contact ExTINGUISH@hsc.utah.edu
You can also look up the study on clinicaltrials.govView Study
(ClinicalTrials.gov Identifier: NCT04372615). This study is sponsored by NINDS and Horizon Pharmaceuticals.
- University of Pennsylvania
- University of Cincinnati
- University of Virginia
- Massachusetts General Hospital
- University of Michigan
- Vanderbilt University
- University of Rochester
- University of Iowa
- University of Utah
- Yale University
- Mayo Clinic Jacksonville
- U.California Irvine
- Columbia University
- U.Texas Southwestern
- Barrow NI/St. Joseph’s
- Washington U. St Louis
- U. Alabama Birmingham
- U.California Davis
- Northwestern University
- Wake Forest
- Europe: Rotterdam and Barcelona
The Lead Investigators on the clinical trial are:
- Stacey L. Clardy MD PhD, University of Utah + Salt Lake City VA
- Maarten Titulaer MD PhD, Erasmus University Rotterdam, The Netherlands
- Gregory Day MD, Mayo Clinic Jacksonville, Florida
Contact information: ExTINGUISH@hsc.utah.edu