When a patient is admitted to the hospital with headaches, hallucinations, and memory loss, a doctor’s first instinct might be to diagnose him or her with a psychiatric disease such as schizophrenia or psychosis (1). But in some cases, the cause of the abnormal behaviors isn’t the brain; it’s the immune system.
One possible source of the disturbance is anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, a rare condition where immune cells attack a receptor on the surface of neurons. People with this disease can find themselves missing weeks of their memory and going through periods of mania or paranoia that lead to misdiagnosis, as writer Susannah Calahan described in her 2012 autobiography-turned-film "Brain on Fire".
“While there is a typical constellation of symptoms that we associate with the diagnosis, [patients] don't necessarily have all of those symptoms,” said Elizabeth Wilson, a pediatric neuroimmunologist at Cincinnati Children’s Hospital. “It certainly can be a bit of a gray area.”
Figuring out that the immune system is to blame is a slow process, and sometimes comes too late for patients who have already undergone brain damage. Even once a patient is diagnosed, treatments for anti-NMDA receptor encephalitis tend to be blunt and aimed at tamping down the whole immune system.
Researchers at Arialys Therapeutics think that there’s a better way to treat the condition. The biotech company is developing a new drug, so far dubbed ART5803, to treat anti-NMDA receptor encephalitis by precisely blocking the immune system’s interactions with neurons. If their drug succeeds in animal studies and makes its way into human trials, it could change the paradigm for how physicians treat not only anti-NMDA receptor encephalitis, but also a host of psychiatric diseases.
A misdirected immune attack
The immune system normally provides the body’s defenses by dispatching squadrons of cellular soldiers armed with molecular tools to ward off bacteria and other pathogens. But sometimes, immune cells get led astray by harmless molecules that trigger an outsized response. When those molecules are parts of a patient’s body, this can turn the immune system against the very organism it’s meant to protect.
In autoimmune encephalitis, the immune system attacks proteins found on normal neurons, which triggers immune cells to flood into the brain and lay siege to their supposed enemy. This causes inflammation in the brain that affects everything from memory to movement. While a person with encephalitis might first notice minor disturbances like headaches or muscle pain, over time, these symptoms can escalate, and the person can even end up in a coma.
If we had treatments that helped to improve longer term outcomes in these patients, it would be super beneficial.
- Elizabeth Wilson, Cincinnati Children’s Hospital
Anti-NMDA receptor encephalitis is one variety of autoimmune encephalitis. In this particular condition, autoantibodies specifically bind to the NMDA receptor found on neurons. This receptor detects signals from excitatory neurotransmitters, and when the antibodies bind to it, the receptor cannot function normally. While anti-NMDA receptor encephalitis is one of the most common types of autoimmune encephalitis, it is still relatively rare, affecting only one in 1.5 million people per year (2). It is more common among children than adults, and when it strikes early, it can lead to lasting cognitive delays.
To treat the condition, doctors typically prescribe systemic immunosuppressants such as steroids or intravenous immunoglobulin, which reduces the damage inflicted by autoantibodies, but also leaves the body defenseless against actual threats. “It's a very slow process, and patients still can be left with significant deficits,” Wilson said. “If we had treatments that helped to improve longer term outcomes in these patients, it would be super beneficial.”
For the team at Arialys Therapeutics, these pleas from doctors were a call to action to build something better. “The appealing thing was the unmet medical need, coupled with a really novel approach to treat it,” said Jay Lichter, Arialys Therapeutics’s president and CEO. Decades of research on the NMDA receptor meant that there were detailed diagrams of its structure and how it bound different molecules. “The mechanism was really quite straightforward,” Lichter said.
Arialys Therapeutics also benefitted from a bit of corporate serendipity that long preceded the company’s emergence. Around six years ago, a pharmaceutical company called Astellas Pharma had undergone an internal restructuring that brought together their neuroscience and immunology divisions. When the scientists on these teams started talking to each other, they realized that combining their expertise could enable them to tackle some big questions in the field of neuroinflammation, including encephalitis. ART5803 was the product of this interdisciplinary collaboration, and after Arialys Therapeutics launched in 2021, they acquired the molecule from Astellas Pharma in 2022 and started the race to the clinic.
Accelerating toward clinical trials
The molecule at the center of this project, ART5803, doesn’t look like a typical forked antibody. Instead, it is a one-armed antibody. This unique structure is crucial to ART5803’s mechanism of action: it binds to the NMDA receptor in a position close to the active site where the autoantibodies bind. Its single protruding arm juts out like a turnstile to keep autoantibodies from binding the NMDA receptor. “It’s a very intellectually satisfying mechanism,” Lichter said.
Even before Arialys Therapeutics bought the molecule, Astellas Pharma had already started testing it in marmosets, a type of monkey used as a primate model for nonclinical studies. They injected the marmosets with human autoantibodies that targeted the NMDA receptor, which quickly mimicked the symptoms of encephalitis in the monkeys: confusion, seizures, and behavioral changes. Then they injected ART5803 into the marmosets’ brains and within just one day, the marmosets made a noticeable recovery. Within two weeks, they were completely back to normal. The researchers presented these results at the American Academy of Neurology 2023 Annual Meeting.

After Arialys Therapeutics took over the development of ART5803, they repeated the experiments, but instead of injecting the drug directly into each marmoset’s brain, which would not be practical for delivering the drug to humans, they injected the drug into the marmoset’s body. Within one week, the marmosets’ behavioral and neurological symptoms improved significantly.
“It's an exciting idea and potential treatment model for these cases,” said Wilson, who is not involved in Arialys Therapeutics’s studies. “The idea of having a potential treatment that is focusing that much on one receptor is a very specific treatment for a specific disorder,” she said. “In general, the direction that medicine is going is more targeted treatment.”
With promising data from their animal model, Arialys Therapeutics is running toxicity studies and starting to plan for human studies. They had their first meeting with the Food and Drug Administration recently and plan to file for an Investigational New Drug in the summer of 2024. That will set them up to begin studying the drug in healthy volunteers in the fall and in encephalitis patients in 2025. “We're on a really accelerated path to get to the data,” Lichter said.
Even as the study picks up speed, Arialys Therapeutics scientists haven’t yet cleared all of their hurdles. Lichter noted that although most anti-NMDA receptor encephalitis patients are children, their initial studies will be limited to adults under the FDA’s orders. “As a pragmatic drug discovery person, I have to think about what the FDA is going to let me do,” he said. “At the end of the day, that's my audience.” He’s still optimistic that they will eventually be able to expand the indication and test the drug in the pediatric population.
New terrain for a new drug
Encephalitis isn’t the first time that the NMDA receptor has been in the spotlight. Drugs such as ketamine and PCP act by binding to the NMDA receptor. The receptor has also been implicated in many other brain diseases such as schizophrenia and dementia (3,4). In some cases, scientists have detected anti-NMDA receptor autoantibodies in these diseases, leading them to suspect that a subset of patients who are diagnosed with more common brain disorders may actually have autoimmune encephalitis (5,6). There have already been some prominent cases of this. In 2023, the Washington Post reported that a woman with schizophrenia who had been in a catatonic state for 20 years finally recovered after receiving drugs that suppressed her immune system (7).
Lichter thinks there may be many patients out in the world who have been diagnosed with psychiatric conditions such as schizophrenia, dementia, and bipolar disorder because their symptoms are psychiatric. But in reality, they may have an autoimmune encephalitis that has gone undiagnosed because they aren’t presenting the more advanced neurological symptoms that doctors expect to see. As a result, physicians may not order the lab test to measure autoantibodies, and even if they do, the milder symptoms that these patients display may be driven by lower levels of anti-NMDA receptor antibodies that the test might miss.

To be able to find these patients, the Arialys Therapeutics team developed a new test to measure the autoantibodies. Lichter said that the new test is 1,000 times more sensitive than the existing test available to clinicians. He expects the test to especially be an asset for Arialys Therapeutics as they enroll patients for future clinical trials. It will help them minimize the risk of testing the drug in a patient who wouldn’t respond because his or her condition isn’t driven by anti-NMDA receptor antibodies.
There’s a high demand for better tests among physicians who treat these patients, especially among cautious physicians considering prescribing Arialys Therapeutics’s future drug. “It would be really helpful to have the ability to identify the antibody earlier so that we would feel even more confident in using a medication like this where it's so targeted towards one specific antibody,” Wilson said.
Lichter plans to license the new test to a clinical lab so that doctors can use the test for their patients. His team is also building a biobank of samples from patients with a diverse set of diagnoses to figure out whether anti-NMDA receptor antibodies may play a previously undetected role in any of these conditions.
“The NMDA story … could be in a large number of common disorders,” Lichter said. “[ART5308] could become a very important product for a large swath of the population even though none of them are specific to one particular clinical characterization.”
References
- Titulauer, M. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12, 157-65 (2013).
- Dalmau, J. et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol 18, 1045-57 (2019).
- Coyle, J.T. NMDA receptor and schizophrenia: a brief history. Schizophr Bull 28, 920-6 (2012).
- Liu, J. et al. The Role of NMDA Receptors in Alzheimer’s Disease. Front Neurosci 13, 43 (2019).
- Tong, J. et al. Elevated serum anti-NMDA receptor antibody levels in first-episode patients with schizophrenia. Brain Behav Immun 81, 213-9 (2019).
- Doss, S. et al. High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types. Ann Clin Transl Neurol 1, 822-32 (2014).
- Sima, R. A catatonic woman awakened after 20 years. Her story may change psychiatry. Washington Post. 2023.