Arialys Therapeutics Publishes Preclinical Data in Nature Communications Supporting ART5803 as a First-in-Class Precision Therapeutic for Anti-NMDA Receptor Autoimmune Neuropsychiatric Disease

Arialys Therapeutics, a clinical-stage biotechnology company pioneering new precision medicines for autoimmune neuropsychiatric diseases, today announced the publication of preclinical data in Nature Communications demonstrating that its lead drug candidate, ART5803, effectively blocks the underlying disease mechanism in anti-NMDA receptor encephalitis (ANRE) and rapidly reverses behavioral symptoms in a non-human primate model. The findings support the continued clinical development of ART5803 as a first-in-class, targeted therapeutic. The company is currently completing Phase 1 safety studies for ART5803 and plans Phase 2 evaluation in anti-NMDA receptor encephalitis (ANRE) and autoimmune psychosis patients in the second half of 2025.

“This study underscores the promise of ART5803 to directly address neuropsychiatric disease caused by anti-NMDA receptor-targeting pathogenic antibodies,” said Peter Flynn, Ph.D. President and CEO of Arialys Therapeutics. “Despite our understanding of the disease mechanism and its severity, ANRE lacks an approved therapy. Further, there is a growing body of data identifying significant levels of anti-NMDA receptor autoantibodies in subpopulations of patients diagnosed with diseases that result in psychosis and dementia.”

“These data provide compelling evidence that ART5803 can directly block the pathogenic effect of autoantibodies that target the NMDA receptor, resulting in a rapid resolution of symptoms,” said Mitsuyuki (Mickey) Matsumoto, Ph.D., Chief Scientific Officer of Arialys Therapeutics and senior author of the paper. “Our detailed structural and functional analyses confirm that ART5803 precisely inhibits NMDA receptor internalization induced by the pathogenic autoantibodies, while preserving normal receptor function. In addition, our discovery of a potential molecular mimicry mechanism for anti-NMDA receptor autoantibody generation broadens the understanding of disease initiation and may inform future indication expansion for ART5803.”

Anti-NMDA receptor encephalitis (ANRE) is a rare, potentially lethal, poorly managed, and often misdiagnosed neurological disease. ANRE is caused by pathogenic autoantibodies that bind to and crosslink NMDA receptors in the brain, leading to receptor internalization and synaptic dysfunction. The result is a range of debilitating neuropsychiatric symptoms including psychiatric and behavioral alterations, cognitive decline, seizures, coma, and diminished autonomic function. A significant percentage of ANRE patients are pediatric, where NMDA receptor-specific autoantibodies can also result in neurological development deficits. There are no approved therapies for this disease, and current treatments rely on broadly immunosuppressive therapies, which are associated with delayed efficacy and significant side effects.

Recent findings have also identified anti-NMDA receptor autoantibodies in other neurological and psychiatric diseases such as schizophrenia, depression, bipolar disorder, and dementia. Arialys is planning clinical assessment of ART5803 in anti-NMDA receptor autoantibody-positive psychosis patients. The company is also currently testing patient samples using a proprietary high-throughput screen for autoantibodies to identify enriched disease indications and subpopulations for future clinical development.

ART5803 is a humanized, monovalent IgG1 antibody engineered to selectively bind the GluN1 subunit of the NMDA receptor without disrupting receptor function or causing internalization. In this study, ART5803 demonstrated the ability to potently block NMDA receptor internalization in cellular and neuronal models and reversed both molecular and behavioral hallmarks of disease in a novel marmoset model of ANRE. Notably, ART5803 exhibited rapid onset of action and was well tolerated in vivo. The publication also includes a detailed characterization of ART5803’s binding epitope, its mechanism of action, and population pharmacokinetic modeling supporting the feasibility of systemic administration in patients.

In addition to demonstrating the therapeutic potential of ART5803, the paper revealed a potential link between infections—specifically Toxoplasma gondii and certain bacterial pathogens—and the generation of pathogenic anti-NMDA receptor autoantibodies. Epitope mapping analysis identified regions of potential molecular mimicry between microbial proteins and the GluN1 subunit of the NMDA receptor, suggesting that infections could serve as environmental triggers for disease initiation. Notably, toxoplasmosis and bacterial infections are well-established risk factors for a range of neuropsychiatric conditions. These findings not only suggest a basis for disease pathogenesis but also support broader therapeutic opportunities for ART5803 across autoimmune neuropsychiatric disorders.

ART5803 is currently being evaluated in a Phase 1 clinical trial in healthy volunteers. In February 2025, Arialys announced completion of all single ascending dose (SAD) cohorts and initiation of multiple ascending dose (MAD) cohorts. The company expects to share initial clinical data in the second half of 2025 and initiate Phase 2 proof-of-concept studies.

The publication was completed in collaboration with researchers from Astellas Pharma Inc., University of California, Davis, Kitasato University School of Medicine, and Vanadro LLC.

About Arialys Therapeutics

Arialys was founded by investors Avalon Bioventures, Catalys Pacific and MPM to meaningfully expand the treatment possibilities for neuropsychiatric disorders driven by autoimmune disease. Using a combination of highly sensitive autoantibody detection, patient sampling and receptor structural biology, Arialys has developed a first-in-class precision therapy to specifically block pathogenic autoantibodies in the brain. Arialys is headquartered in La Jolla, California. For more information, visit www.arialysrx.com.

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