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The Future of Anti-NMDAR Encephalitis Treatment: Exploring the ExTINGUISH Clinical Trial

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April 10, 2024 | by Khashayar Eshaghi, PennNeuroKnow and IAES Collaboration

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The staff at IAES is proud to present to all of you another wonderful article/blog from the amazing team at PennNeuroKnow. Since 2019 IAES has been extremely lucky to be in partnership with the PennNeuroKnow(PNK) team to help us all better understand complex medical issues related to AE and neurology in general. The talented PNK team continues to keep us up-to-date and help clarify the complexities we face each day along our AE journey, and we are eternally grateful! You can find out much more about this stellar group at: https://pennneuroknow.com/

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Introduction

You may have heard of current clinical trials striving to uncover new treatments for autoimmune encephalitis (AE). An exciting trial to look out for is the ExTINGUISH Trial — a promising clinical study in this field.

The Extinguish trial is set to evaluate the use of a monoclonal antibody in the treatment of anti-NMDAR Encephalitis, which is a subtype of AE. Recent successes in employing monoclonal antibodies, notably in treating complex neurological conditions like Alzheimer’s disease1, emphasize the potential breakthrough that this trial could signify.

The main goal of the ExTINGUISH trial is to assess the effectiveness of a specific monoclonal antibody, known as inebilizumab, in treating anti-NMDAR encephalitis2. Monoclonal antibodies are routinely utilized in the treatment of AE. However, the goal of researchers is to continue to make this technology better and more effective for patients.

What is inebilizumab?

In patients with autoimmune encephalitis, the body’s immune system mistakenly attacks the brain, causing inflammation. Inflammation causes the immune system to produce a kind of protein called an antibody. Typically, these antibodies flag things like invading viruses or bacteria for the immune system to find and destroy. In AE, antibodies play a harmful role by mistakenly flagging brain cells. As the immune system attacks the brain, patients with AE develop a host of symptoms, like seizures, mood changes, altered mental status, and memory loss3.

In an attempt to alleviate the symptoms of AE, scientists have long been interested in designing a drug that would prevent the immune system from making harmful antibodies. Recent research suggests that the best approach might be to fight fire with fire: by engineering a monoclonal antibody that specifically targets the immune cells responsible for generating the harmful antibodies at the onset of AE4. A monoclonal antibody is a special kind of protein created in a lab that can target and attach to specific harmful substances or cells in the body, helping the immune system to identify and neutralize them (figure 1).

monoclonal antibodies - The Future of Anti-NMDAR Encephalitis Treatment: Exploring the ExTINGUISH Clinical Trial

Figure 1. Monoclonal antibodies serve to assist the immune system in neutralizing cells responsible for producing detrimental antibodies in AE.

 

A new monoclonal antibody called inebilizumab has shown promise as a potential treatment for a subtype of AE, called anti-NMDAR encephalitis5.

Inebilizumab was recently approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune disorder affecting the central nervous system.

The fact that this monoclonal antibody is proving effective for patients with another autoimmune neurological disorder suggests it could work for AE as well6.

How is inebilizumab different from current monoclonal antibody treatments for anti-NMDAR Encephalitis ?

Another monoclonal antibody called rituximab is already a secondary treatment option for anti-NMDAR encephalitis that is used when first-line therapies fail or produce an adequate response7. Rituximab works by targeting one group of immune cells making the harmful antibodies in AE, called B cells. While rituximab can help manage anti-NMDAR encephalitis for some patients by getting rid of B cells, it does not work for everyone7. This could be because B cells live for a short time, but produce other longer-lived versions of themselves, called plasma cells and plasmablasts.

Moreover, monoclonal antibodies work by recognizing a specific marker on the cells that they aim to neutralize. For instance, rituximab targets all cells that express a specific marker called CD20 on their surface. While rituximab removes the B cells that express CD20, it leaves the plasma cells and plasmablasts in the body because they often lack the CD20 surface marker. Therefore, these long-lasting immune cells can continue to produce the problematic antibodies that lead to anti-NMDAR encephalitis8.

This is where inebilizumab comes into play. Inebilizumab targets a different surface marker called CD19. This marker is not only expressed by B cells, but it is also present on the surface of their longer-lasting progeny, the plasma cells and plasmablasts. Therefore, by targeting all cells that express CD19 inebilizumab is capable of neutralizing the original B cells as well as the longer-lasting plasma cells and plasmablasts (figure 2)8.

Figure 2. Inebilizumab inhibits the production of plasma cells and plasmablasts that produce harmful antibodies against the brain.

By getting rid of more of the immune cells producing harmful antibodies against the brain, inebilizumab may be an even more effective treatment for anti-NMDA encephalitis than rituximab8,9.

The ongoing clinical trial

Clinical trials are scientific tests for new medications or treatments to determine if promising new treatments are more effective than what is currently on the market. In what are called placebo-controlled clinical trials, some participants get the new treatment, while others get a placebo. A placebo is a version of the treatment without the active ingredient of the medicine in it. This helps researchers compare how well the real treatment works by checking if there is a noticeable difference between those who get the medicine and those who get the placebo. It is a way to make sure the treatment is genuinely effective. Following the trial’s conclusion, should the new treatment prove effective, members of the placebo group will likewise be granted access to it.

The clinical trial for inebilizumab is called the ExTINGUISH Trial. The ExTINGUISH Trial aims to assess the effectiveness of inebilizumab compared to a placebo in treating moderate-to-severe NMDAR encephalitis alongside standard therapies. This trial involves 120 participants with moderate to severe anti-NMDAR encephalitis and evaluates patient outcomes using various measures that assess their daily functioning, brain abilities, quality of life, and predict how they may progress over a 16-week period. The study also aims to find biological markers that can be used to predict how well the treatment will work in future patients. Doctors and researchers will monitor levels of the anti-NMDAR antibodies responsible for the symptoms of AE as well as a measure of activation of the B cells that produce these harmful antibodies2,10. This will allow doctors to determine whether patients with certain levels of these substances in their body respond better or worse than others.

Ultimately, this trial aims to find more effective treatments for anti-NMDAR encephalitis, paving the way for improved care for individuals facing this condition. Looking ahead, these advancements in clinical trials offer hope for developing better treatments and understanding AE, potentially leading to breakthroughs in managing and preventing the disease in the future.

Additionally, while the current trial focuses on anti-NMDAR encephalitis, the insights gained from understanding the mechanisms of action and treatment response could potentially apply to other types of AE as well. While the immediate beneficiaries of this trial are individuals with anti-NMDAR encephalitis, the broader implications may extend to those with different forms of AE in the future, offering hope for improved treatment options and outcomes across various autoimmune encephalitis conditions.

References

  1. van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., Froelich, L., Katayama, S., Sabbagh, M., Vellas, B., Watson, D., Dhadda, S., Irizarry, M., Kramer, L. D., & Iwatsubo, T. (2023). Lecanemab in Early Alzheimer’s Disease. The New England journal of medicine, 388(1), 9–21. https://doi.org/10.1056/NEJMoa2212948
  2. Day, G., Titulaer, M., Wong, K.-H., Torner, J., Cudkowicz, M., Coffey, C., Lungu, C., Klawiter, E., Singleton, J. R., Mitchell, D., Fedler, J., Ecklund, D., Klements, D., Costigan, M., & Clardy, S. (2022). The extinguish trial: A phase-2b randomized placebo-controlled trial of inebilizumab in Anti-NMDA receptor encephalitis (P5-1.004). Neurology, 98(18_supplement). https://doi.org/10.1212/wnl.98.18_supplement.1651
  3. Hébert, J., Muccilli, A., Wennberg, R. A., & Tang-Wai, D. F. (2022). Autoimmune Encephalitis and Autoantibodies: A Review of Clinical Implications. The journal of applied laboratory medicine, 7(1), 81–98. https://doi.org/10.1093/jalm/jfab102
  4. Frampton J. E. (2020). Inebilizumab: First Approval. Drugs, 80(12), 1259–1264. https://doi.org/10.1007/s40265-020-01370-4
  5. Samanta D, Lui F. Anti-NMDAR Encephalitis. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551672/
  6. Nie, T., & Blair, H. A. (2022). Inebilizumab: A Review in Neuromyelitis Optica Spectrum Disorder. CNS drugs, 36(10), 1133–1141. https://doi.org/10.1007/s40263-022-00949-7
  7. Smets, I., & Titulaer, M. J. (2022). Antibody Therapies in Autoimmune Encephalitis. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 19(3), 823–831. https://doi.org/10.1007/s13311-021-01178-4
  8. Chen, D., Gallagher, S., Monson, N. L., Herbst, R., & Wang, Y. (2016). Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies. Journal of clinical medicine, 5(12), 107. https://doi.org/10.3390/jcm5120107
  9. Day, G. (2023). State of care for autoimmune encephalitis and the extinguish trial of inebilizumab. Neurology live. https://www.neurologylive.com/view/state-care-autoimmune-encephalitis-extinguish-trial-inebilizumab
  10. The extinguish trial of inebilizumab in NMDAR encephalitis (extinguish). Yale Medicine. (2024). https://www.yalemedicine.org/clinical-trials/the-extinguish-trial-of-inebilizumab-in-nmdar-encephalitis-extinguish

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