State of Care for Autoimmune Encephalitis and the ExTINGUISH Trial of Inebilizumab

Gregory Day, MD, MSc, MSCI, FAAN

A lack of approved therapies for N-methyl-D-aspartate receptor (NMDAR) encephalitis has led to substantial variability in how the condition is treated.¹ Inebilizumab (Uplizna, Horizon), a humanized anti-CD19 monoclonal antibody, may be a potentially efficacious treatment for NMDAR encephalitis, as the agent also has demonstrated early, robust, and sustained suppression of NMDAR autoantibodies, CD19+ plasmablasts and plasma cells that could lead to better longterm outcomes.

The ExTINGUISH trial (NCT04372615), a phase 2b randomized double-blind placebo-controlled study, evaluates the safety and efficacy of inebilizumab 300 mg for the acute treatment of moderate-to-severe NMDAR encephalitis.1 Participants (n = 120) will enroll from 20 sites in the United States and two sites in Europe (Barcelona, Spain; Rotterdam, The Netherlands). 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.

Recently, lead investigator Gregory Day, MD, MSc, MSCI, FAAN, a neurologist at Mayo Clinic in Jacksonville Florida, sat down in an interview with NeurologyLive®, to discuss more about the ExTINGUISH trial and the state of care for patients with autoimmune encephalitis. Day is a behavioral neurologist by training with an additional focus in patients with memory and thinking problems following autoimmune encephalitis or that present inflammatory causes of dementia and cognitive impairment. He also talked about the current treatment options that are available for patients as well as potential treatments that may be approved in the coming future.

NeurologyLive®: What is your assessment on the current state of care for autoimmune encephalitis?

We're talking about the ExTINGUISH trial, which is the first trial of its kind, arandomized placebo controlled trial of inebilizumab, an antiCD19 monoclonal antibody for patients with anti NMDA receptor encephalitis. We've known about antiNMDA receptor encephalitis for the last 15 years now and continuing to see more and more cases. But up until the launch of this trial, we haven't had any clinical trials that have been focused narrowly and specifically on patients with this disease. AntiNMDA receptor encephalitis is a devastating neurological illness. It's an inflammatory, auto antibody driven disease where the body produces antibodies, immune agents that are targeting NMDA receptors, that sit on the surface of neurons generally in the brain. It causes pretty rapid changes in behavior and thinking and motor function for our patients.

A typical patient is going to be on the younger side. More women are affected by this condition than men and often present psychiatric symptoms that can quickly degenerate into more complex neurologic dysfunction, encephalopathy, seizures, movement disorders, muscle spasms. Hence, these symptoms may cause patients to wind up in the hospital, especially if there's additional autonomic instability. Many patients require ICU admission for additional support. Perhaps, the great thing maybe, the best thing about this disease, is that because it is caused by antibodies, treating those antibodies can lead to an improvement in our patients. In addition, we think antibody treatment leads to pretty good outcomes over time in patients who get that diagnosis early and get the treatment they need.

What does the treatment toolbox look like for patients with autoimmune encephalitis?

The treatment up until now has essentially been governed by clinical consensus. Standard of care remains, and neurologists act how they normally would when we think that there's an autoimmune or inflammatory contributor to disease. Most patients receive first line therapy, which would be usually steroids, IV immunoglobulins, or sometimes steroids and IVIG, and sometimes will include plasmapheresis. In that first line approach, the goal is to reduce antibody production, and to limit the antibodies that are circulating. Some patients with this disease, particularly young women in childbearing age, are going to have a teratoma, a tumor, associated with this disease. If it's present then, it's most likely to be present in the ovaries. If we delve into that tumor, we see that teratomas have all kinds of cell types, but a key in patients with NMDA receptor encephalitis isthat teratoma has brain tissue in it. We think that's important in driving the response that leads to the breakdown of self tolerance to the spread and development of these auto antibodies that eventually end up in the brain causing their symptoms.

Screening for teratomas and other diseases associated with tumors is important. Removing those as early as is safe and practical is also important to treatment. With first line therapies, we see some patients respond. Now we see some patients actually improve and go back to normal which is great, but there's a big chunk of people who don't get there and need additional therapies as well. Over the last decade with increasing case series, high quality case series, informed by investigator intent and consensus,we've seen effective use of medications like rituximab. Rituximab, originally developed for treatment of lymphoma, targets lymphocytes, the CD20 marker on those lymphocytes, and is a monoclonal antibody that can be effective in treating patients with NMDA receptor encephalitis. Other drugs that have been used independent from rituximab include cyclophosphamide, which targets the immune system factors just a little bit more broadly. With the combination of tumor screening, tumor removal, including the first line therapy and second line therapy, we see that the vast majority of patients with this diagnosis improved to the point of discharge from hospital. Many returned to their prior living situation a smaller subset, continuing to have some pretty serious disability, and some are less than 10% dying as a consequence of the illness or complications thereof.

Current treatments that you are looking forward to in the next couple of months?

We're talking about standard of care, basically what we do now and what we have access to now. I painted a pretty rosy picture that sounds like patients are doing well with their care. Why would we need new therapies or new treatments? Well, the reality about the standard approach is that it is not standard. Different centers do different things. Some people advocate that we should be providing tons of treatment upfront, others say that we should be spacing it out using things more sparingly. They recognize that all our treatments can have side effects as well. The reality is that if we look at our experience with this disease, the literature, we're recognizing more and more cases earlier, and since 2013, when one of the key case series came out advocating for the use of rituximab, we're using rituximab a lot more frequently and a lot earlier in the disease course.

But even understanding all of that, we're not seeing improvements in outcomes from all our patients. We still have good outcomes in the majority of patients and that's something to be celebrated, but we're missing our opportunity for great outcomes. We have not moved the needle, even though we're using those agents that are available to us earlier in the disease process. What's coming next and what's forthcoming really leads into the need for this clinical trial. If we recognize that outcomes are good, we want to follow that by saying they're not great. We can do better; we should do better.

We definitely need drugs and agents that are FDA approved for this purpose to help advise and know when we should be starting therapy with true high quality evidence that comes from randomized controlled trials. Inebilizumab is the target agent in this clinical trial. It's supported by human evidence that comes from a treatment trial in NMO, neuromyelitis optica, and other antibody mediated diseases. In that case, targeting the aquaporin-4receptor and astrocytes. But NMO was effectively treated by an Inebilizumab in a placebo controlled trial and provides good quality evidence there. We think that using a CD19 targeting agent will allow for a broader spectrum of antibodies to be targeted. The CD20 cells that rituximab gets, those antibodies will be picked off as they also carry CD19. But the advantage of CD19 Is that plasma cells and particularly maybe long-lived plasma cells that may go on to contribute to some of the long lasting disability, they carry a CD19 marker. We're really hopeful that inebilizumab will reduce the level of those plasma cells and in doing so, will allow our patients to recover faster and more completely.

Hopefully patients will have just better long term outcomes, less chance of relapse, better chance of getting back to work to school to all the things that they value and that we want for our patients as providers and researchers. Until we have results from this trial, we're not likely to see any agents getting approved specifically for this disease. I think there is definitely room for further research and further studies and considering other immune suppressing agents as well and other combinations of those agents moving forward.

Transcript edited for clarity.

REFERENCES
1. Day G, Titulaer M, Wong KH, et al. The ExTINGUISH Trial: A Phase-2B Randomized Placebo-Controlled Trial of Inebilizumab in Anti-NMDA Receptor Encephalitis (P5-1.004). Neurology. Published May 2022, 98 (18 Supplement) 1651.