Gate Neurosciences demonstrates zelquistinel preclinical efficacy and therapeutic potential in autism spectrum disorders in new peer-reviewed study

March 5, 2024

INDIANAPOLIS, March 5, 2024 – Gate Neurosciences, a clinical-stage biotechnology company using precision medicine approaches to develop next-generation neuroscience therapies, today announced the publication of its latest peer-reviewed research demonstrating the therapeutic potential of zelquistinel (GATE-251) to address symptoms of autism spectrum disorder (ASD). The paper, published in Neuropharmacology, showed the robust efficacy of zelquistinel in reducing social and behavioral symptoms of ASD in multiple mouse models, with the effects being more pronounced with longer treatment regimens at a lower dose level.

Zelquistinel, Gate Neurosciences’ lead program, is a third-generation, rapid-acting oral drug candidate in its portfolio of NMDAR positive allosteric modulators (NMDAR PAMs), which are designed to enhance synaptic function in patients with mood and cognitive disorders. Based on the role of disrupted synaptic plasticity and unbalanced excitation/inhibition in autism, and the well-established mechanism of zelquistinel of enhancing NMDAR-mediated plasticity, scientists from Gate and the Université de Tours, France, sought to evaluate zelquistinel’s efficacy in addressing symptoms commonly associated with ASD.

The study was conducted in three different mouse models of ASD: two models of ASD caused by genetic factors, Shank3 mutant and Fmr1 null mice; and one model for ASD caused by environmental factors, mice exposed in utero to valproic acid. Zelquistinel was tested in 30, 100, 300, and 1,000 μg/kg doses. In genetic mouse models, a single dose of zelquistinel led to the resolution of behavioral symptoms, which was sustained for at least 24 hours. Administering a 100 μg/kg dose of zelquistinel daily for 18 days fully resolved behavioral and social symptoms in nine days across all mouse models, and the effect was sustained for a longer period of time.

“It is now well-established that synaptic health and plasticity is closely tied to many diseases of the central nervous system,” said Mike McCully, CEO of Gate Neurosciences. “We believe that enhancing synaptic plasticity through NMDAR PAMs, such as zelquistinel, can rapidly and durably restore healthy brain function and relieve disease symptoms across mood, neuropsychiatric, neurodegenerative, and neurodevelopmental disorders like autism spectrum disorder. These are important findings for Gate, as we continue exploring our NMDAR PAM portfolio in diseases other than depression with synaptic dysfunction at their core.”

Additional findings from this study include:

- The effects of zelquistinel on social symptoms were still present two weeks after treatment withdrawal in the Fmr1 null mouse models receiving the 100 μg/kg dose for 18 days. This was not due to the prolonged drug exposure, as the level of zelquistinel in the brain fell below the limit of detection within two hours of administration. This may point to a strengthening of the underlying synaptic network well after the drug’s administration.

- Across all models, dosing repeatedly with zelquistinel did not lead to a desensitization of beneficial effects. Instead, the beneficial effect increased during the daily dosing regimen, suggesting a favorable safety and pharmacodynamic profile.

- Dose-dependent effects of zelquistinel, established in previous in-human clinical trials, were also seen in this study. Wild-type mice that were administered a high dose of zelquistinel (300 μg/kg) had deleterious effects. However, administering a lower dose of 100 μg/kg to wild-type mice provided beneficial effects.

- Comparing the effects of zelquistinel to d-cycloserine, another NMDAR modulator, showed that d-cycloserine was less efficient in addressing ASD-like symptoms of Shank3 mice.

The data presented in the paper provide insight into the potential of zelquistinel to treat additional disorders of synaptic dysfunction beyond depression. Currently, Gate is currently exploring the use of zelquistinel and apimostinel (second-generation NMDAR PAM) to treat major depressive disorder (MDD), as well as other psychiatric and neurodegenerative disorders, including schizophrenia and Alzheimer’s disease cognition.

A Phase 2 clinical trial of zelquistinel for MDD is slated to initiate later in 2024.

About Gate Neurosciences

Gate Neurosciences, headquartered in Indianapolis, is a precision medicine biotechnology company focused on advancing next-generation central nervous system (CNS) treatments that address the growing needs in mental health. The company is developing a portfolio of novel mechanisms of action that enhance synaptic function to address neuropsychiatric and neurocognitive diseases, including major depressive disorder. Using learnings from extensive clinical, preclinical and translational data, along with a better understanding of CNS development challenges, the company is advancing its clinical pipeline using evidence-driven, precision psychiatry approaches.

Corporate Contact:

Rob Houghtaling

Sr. Director, Corporate Development

Gate Neurosciences, Inc.

Media Contact:

Azeem Zeekrya