The ExTINGUISH Trial of Inebilizumab in NMDAR Encephalitis (ExTINGUISH)

What is a Clinical Trial and How Does it Work?

Our friends at Roche/Genentech have created a great video that provides an overview explaining what you need to know about clinical trials in general. We highly suggest you view it.

The ExTINGUISH Trial

This is the first-ever Clinical Trial for a promising new drug, Inebilizumab, to treat anti-NMDA receptor encephalitis, and will be funded by the National Institutes of Health (NIH).

The trial started recruitment January 2022 and is still seeking participants. International Autoimmune Encephalitis Society is honored to be supporting the ExTINGUISH trial along with Autoimmune Encephalitis Alliance and The anti-NMDA Receptor Encephalitis Foundation.

Lead investigator Gregory Day, MD, MSc, MSCI, FAAN, a neurologist at Mayo Clinic in Jacksonville Florida, sat down in an interview with NeurologyLive® for World Encephalitis Day (2-22-23), to discuss more about the ExTINGUISH trial and the state of care for patients with autoimmune encephalitis.

*All participants will be given standard “first-line” immunotherapies before randomization. Then, cyclophosphamide IV rescue therapy will be given to patients 6 weeks after if they fail to respond to initial treatment.

Main Inclusion Criteria (in part)

Enrollment is limited to 116 newly diagnosed patients with a confirmed diagnosis of anti-NMDAR Encephalitis who are 18 years or older. Patients must have received at least 3 days of methylprednisolone 1000 mg IV or equivalent corticosteroid within 30 days prior to randomization (Day 1). In addition, patients must have received EITHER of the following treatments within 30 days before randomization.

IVIg, at a minimum dose of 2 g/kg
Plasma exchange or plasmapheresis, with a minimum of 5 treatments. NOTE: These treatments may be provided during the screening period, but must be completed prior to randomization.

mRS of ≥3 at the screening visit, indicating at least moderate disability. Ability and willingness to attend study visits and complete the study.

Detailed Description

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 age 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 the detection of IgG autoantibodies against central nervous system NMDAR in the cerebrospinal fluid.

Despite the severity of the illness, NMDAR encephalitis is 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. 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. High-quality evidence is needed to inform the treatment of NMDAR encephalitis.

Inebilizumab

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- plasmablasts and plasma cells, resulting in robust and sustained suppression of B-cell expression.

Clinical Trial Details

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 (primary outcomes at 16 weeks), 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.

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.

Why Get Involved?

You, or your loved one is currently experiencing a dramatic and horrifying illness that came on suddenly throwing them and your family into crisis. When identified early and with aggressive treatment cases can be reversed and best outcomes can be achieved. Participation in this trial will ensure that the patient receives best practice in first line treatment and an opportunity to receive Inebilizumab, which appears to provide a promising path to best outcomes over current off-label treatments. Treatments for anti-NMDAr are not FDA approved which results in insurance denials/treatment delays. Treatment delays, in turn prevent best outcomes. Your participation will exclude you from the possible denial of second line treatment and will lead to the end result of a safe and effective FDA approved treatment for anti-NMDAr encephalitis in the future.

You Are Not Alone

IAES was founded by patient advocates in recovery from autoimmune encephalitis and have taken this journey before you. We are the family you never knew you had and will guide and support you through your AE journey each step of the way. You will receive personal support via our support group on Facebook. There you will meet other patients and advocates who will help you understand the disease, provide you with the resources you need for any challenge you might face and offer insider insights that will help you become a strong, educated advocate. You are not alone.

Contacts

Patients and/or care partners with Anti-NMDAR Encephalitis who think they meet criteria to participate should have their physician/treating clinician contact The EXTINGUISH Trial e-mail