Gate Neurosciences, Inc.

INDIANAPOLIS--( BUSINESS WIRE )-- Gate Neurosciences , a synaptic health biotechnology company focused on advancing next-generation precision central nervous system (CNS) treatments, today announced new research presented at the recently concluded 2024 annual meeting of the American College of Neuropsychopharmacology (ACNP), held in Phoenix from December 8-11, 2024. “The synapse is a therapeutic target, and we are determined to communicate our novel findings on the unique pharmacology of modulating synapses. Our new research presented at ACNP this week can help to uncover the massive potential of molecules that address synaptic weakening underlying many CNS diseases,” stated Mike McCully, president and CEO of Gate Neurosciences. “Synaptic function-enhancing molecules like ketamine and our ‘stinel programs operate in a fundamentally different paradigm than traditional CNS drugs that require constant time on-target to work. Our new translational insights clearly highlight that dosing frequency influences the short and long-term effectiveness of these types of molecules and is a critical factor to their successful development.” The two ACNP presentations detailed new insights on the pharmacology of molecules that enhance synaptic function and neuroplasticity, including both ketamine and Gate’s lead program, zelquistinel (GATE-251), and highlighted Gate’s emerging translational work to optimize dosing dynamics. A hallmark of both ketamine and zelquistinel is that a single dose triggers rapid, long-lasting metaplasticity effects on synapses which persist well-beyond clearance from their target receptors — a phenomenon termed “event-driven pharmacology.” New preclinical data shared by Gate at the ACNP conference demonstrate that optimizing dose level and dose frequency using translational measures of synaptic strength and plasticity may be necessary to maximize therapeutic effects and avoid loss of efficacy. Zelquistinel is currently in Phase 2 development (VITALIZE Study) as a once-weekly oral treatment for depression and other diseases of synaptic dysfunction such as Alzheimer’s cognition and schizophrenia. ACNP Poster Presentation Details Title: Zelquistinel, a Novel NMDAR Modulator with Rapid-Acting & Sustained Effects: Optimizing Dose and Dose Interval Based on Translational Measures of Synaptic Plasticity Abstract Number: P208 Lead Author: Jeffrey Burgdorf, Ph.D. Summary: In vivo effects on NMDA receptor-mediated synaptic modulation, duration of plasticity and metaplasticity, and emotional learning were assessed following single, daily, and once-weekly dosing of zelquistinel in mice. Single doses of zelquistinel enhanced synaptic strength and learning, daily dosing actively suppressed this beneficial effect, and weekly dosing sustained or increased the beneficial effects. Title: More May Not Be Better: Ketamine Dosing Frequency Modulates Synaptic Strength, Metaplasticity and Emotional Learning Abstract Number: P215 Lead Author: John Donello, Ph.D. Summary: Single doses versus five daily doses of ketamine were compared in mice. Single doses of ketamine had electrophysiological and behavioral effects lasting for seven days, including enhanced in vivo synaptic strength, positively impacted metaplasticity, and enhanced emotional learning behavior. Five daily repeated doses of ketamine actively suppressed the beneficial effects of the drug. Full abstracts are published by ACNP and are available on the organization’s website . Other recent insights on the unique pharmacology of synaptic function-enhancing molecules shared by Gate Neurosciences and others include: the white paper, “Reshaping Neuropsychiatry,” 1 by Dr. Anantha Shekhar, co-founder of Gate Neurosciences; presentations at this year’s ASCP annual meeting 2 on emerging dosing concepts; and recent publications on zelquistinel’s mechanism of action, 3 preclinical data on ketamine metaplasticity, 4 and clinical data showing the loss of efficacy with daily ketamine dosing. 5 Shekhar, A. (2024, August 7). Reshaping neuropsychiatry. Drug Discovery World (DDW) . https://www.ddw-online.com/reshaping-neuropsychiatry-31040-202408/ Gate Neurosciences to share new data and research on its synaptic function molecules with multiple posters at 2024 ASCP meeting. (2024, May 15). Gate Neurosciences https://www.gateneuro.com/press-releases/gate-neurosciences-to-share-new-data-and-research-on-its-synaptic-function-molecules-with-multiple-posters-at-2024-ascp-meeting Zhang, X., Li, Y.-X., Berglund, N., Burgdorf, J. S., Donello, J. E., Moskal, J. R., & Stanton, P. K. (2024). Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-D-aspartate receptors Neuropharmacology , 259 , 110100. https://doi.org/10.1016/j.neuropharm.2024.110100 Brown, K. A., & Gould, T. D. (2024). Targeting metaplasticity mechanisms to promote sustained antidepressant actions. Molecular Psychiatry , 29 (4), 1114–1127. https://doi.org/10.1038/s41380-023-02397-1 Pattanaseri, K., Lortrakul, J., Jaisin, K., Srifuengfung, M., Sa-nguanpanich, N., Viravan, N., Pariwatcharakul, P., Makarasara, W., & Ratta-apha, W. (2024). A randomized controlled pilot study of daily intravenous ketamine over three days for treatment-resistant depression. BMC Psychiatry , 24 (1). https://doi.org/10.1186/s12888-024-05951-5 About Gate Neurosciences Gate Neurosciences is a synaptic health biotechnology company focused on advancing next-generation precision CNS treatments that address 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 (MDD). Using learnings from extensive clinical, preclinical, and translational data and a better understanding of CNS development challenges, the company is advancing its clinical pipeline using evidence-driven, precision psychiatry approaches.

INDIANAPOLIS--( BUSINESS WIRE )-- Gate Neurosciences , a synaptic health biotechnology company focused on advancing next-generation precision central nervous system (CNS) treatments, today announced the initiation of a Phase 2 clinical study with the University of Pittsburgh (Pitt) to assess the potential for extending the efficacy of apimostinel – a rapid-acting antidepressant drug candidate that enhances synaptic plasticity – in combination with Pitt’s digital therapeutic. The Phase 2 study ( Clinicaltrials.gov ID: NCT06400121 ) led by Dr. Rebecca Price Ph.D., the university’s associate professor of psychiatry, psychology and clinical and translational science, will assess the utility of combining Pitt’s Automated Self-Association Training (ASAT) tool in extending the duration of apimostinel’s single-dose antidepressant effects. ASAT is a digital neurocognitive training program that uses cognitive tasks to condition patients to associate thoughts about themselves with positive attributes. The combination of neurocognitive training in the presence of apimostinel is hypothesized to leverage a “primed window of brain plasticity” as a more targeted and efficient method to extend relief in depressed patients. “Our precision drug candidates work by rapidly enhancing synaptic function and neuroplasticity, which has broad potential across mental health and cognitive disorders,” said Mike McCully, president and CEO of Gate Neurosciences. “This Phase 2 study partnership with Pitt gives us an exciting opportunity to potentially extend apimostinel’s treatment benefit in depressed patients with the ASAT platform, a synergistic and innovative digital tool.” Dr. Price has previously conducted a similar randomized clinical trial ( 1 , 2 , 3 ) with the rapid antidepressant drug ketamine, plus ASAT training, in patients with treatment-resistant depression. Dr. Price found that one 40-minute ketamine infusion combined with four days of ASAT exercises had statistically significant extended effects on depression that endured for three months, whereas a typical efficacy response from a single ketamine infusion lasts for up to seven days. Gate’s drug candidates apimostinel and zelquistinel share ketamine’s convergent downstream mechanism of enhancing neuroplasticity via the NMDA receptor; however, both of Gate’s molecules have exhibited a superior safety profile versus ketamine with evidence of reduced dissociative or psychotomimetic side effects. “We are thrilled to partner with Gate to further explore ASAT’s efficacy with apimostinel and build on our previous success with extending ketamine’s benefit for depressed patients,” said Dr. Price. “ASAT was crafted to complement rapid-acting treatments for psychiatric disorders. It is designed to be as efficient as possible with short digital administrations and shows promise for extending single-dose outcomes by months.” Apimostinel is a second-generation, intravenous NMDA receptor PAM (positive allosteric modulator) being developed by Gate Neurosciences for acute psychiatric disorders. In a prior single-dose Phase 2 study, apimostinel demonstrated rapid and statistically significant 24-hour antidepressant effects that lasted up to seven days and was well-tolerated. Most recently, Gate’s Phase 1 biomarker study of apimostinel showed positive dose-dependent qEEG biomarkers of NMDAR target activation. About Gate Neurosciences Gate Neurosciences is a synaptic health biotechnology company focused on advancing next-generation precision CNS treatments that address 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 (MDD). Using learnings from extensive clinical, preclinical, and translational data and a better understanding of CNS development challenges, the company is advancing its clinical pipeline using evidence-driven, precision psychiatry approaches.

Two poster presentations will feature novel findings of preclinical metaplasticity research and updated data from the recent apimostinel Phase 1 qEEG biomarker study Company will host its 3rd annual R&D Day with investigators and key opinion leaders to share new insights ahead of an upcoming Phase 2 MDD study with zelquistinel INDIANAPOLIS--(BUSINESS WIRE)-- Gate Neurosciences, Inc., a clinical-stage biotechnology company using precision medicine to develop next-generation neuroscience therapies, today announced upcoming activities at the 2024 annual meeting of the American Society of Clinical Psychopharmacology (ASCP), being held in Miami Beach, FL, from May 28-31, 2024. The company will present new preclinical and clinical data supporting its NMDAR PAM portfolio and will share novel insights from internal research on the biological mechanisms of neuroplasticity and synaptic function. Specifically, Gate Neurosciences will highlight its cutting-edge research on how a single dose of neuroplasticity-enhancing drugs can trigger both rapid-onset (i.e. hours) and long-lasting therapeutic effects (i.e. weeks), a phenomenon termed ‘event-driven pharmacology’. Gate’s new preclinical and clinical insights have yielded critical findings on CNS-specific ‘event-driven pharmacology’ and the importance of dosing intervals to optimize plasticity treatments. The company plans to share these new insights at its 3rd annual R&D Day at the conference with leading members of the scientific community in attendance. The session will also include updates on an upcoming Phase 2 study with a once-weekly oral program, zelquistinel (GATE-251), for Major Depressive Disorder. Gate Neurosciences 3rd Annual R&D Day at ASCP 2024: Location: Loews Hotel Miami Beach, Florida Date: Tuesday, May 30, 2024 Time: 12:15 p.m. to 1:45 p.m. “Over the past few years, the Gate team has made considerable progress in understanding mechanisms that rapidly and durably enhance synaptic function for treating CNS diseases. Dosing these compounds the right way is critical to success,” stated Mike McCully, CEO of Gate Neurosciences. “We look forward to sharing our new data and insights with the psychiatry community at the ASCP conference and discussing updated plans for our Phase 2 study of once-weekly oral zelquistinel in depression.” Poster Presentation Details: Poster #T14 Title: Apimostinel, a Novel NMDAR Modulator with Rapid-Acting, Sustained Effects and Favorable Drug-Like properties: Preclinical Studies Abstract Number: T14 Presentation Session: Poster Session II, Salon 4 Presentation Date and Time: 12:30pm – 2:25pm, Thursday May 30th 2024 Lead Author: Jeffrey Burgdorf, PhD Poster #T14 details new preclinical data supporting apimostinel as an acute psychiatry drug candidate with lasting metaplasticity effects. Key takeaways include: Single dose of apimostinel acutely enhanced LTP with metaplasticity lasting 7 days, and produced robust antidepressant-like effects without ketamine-like side effects Apimostinel dose-dependently enhanced qEEG alpha in correlation with CSF exposure, as a biomarker of NMDA receptor target activation Repeat doses of apimostinel led to larger and longer-lasting metaplastic effects At the Society of Biological Psychiatry (SOBP) Annual Meeting earlier this month, Gate presented additional data on the specific NMDAR PAM mechanism of action of apimostinel. Poster #T21 Title: A Phase 1 Safety, Pharmacokinetics (PK) and Quantitative Electroencephalography (qEEG) Pharmacodynamics Study of Single and Multiple Ascending Doses of Intravenous Apimostinel Compared with Placebo in Healthy Volunteers Abstract Number: T21 Presentation Session: Poster Session II, Salon 4 Presentation Date and Time: 12:30pm – 2:25pm, Thursday May 30th 2024 Lead Author: Ronald M. Burch, MD PhD Poster #T21 is the first scientific presentation of findings from the apimostinel Phase 1 clinical trial assessing safety and qEEG biomarkers. Key takeaways include: Apimostinel was generally safe and well-tolerated following multiple doses from 1-25mg Apimostinel dose-dependently stimulated qEEG alpha power qEEG alpha power stimulation with apimostinel was consistent with CSF Cmax drug concentrations that maximally stimulate NMDA receptors in vitro qEEG alpha power stimulation with apimostinel was consistent with efficacious doses in a previous Phase 2a clinical MDD study Full abstracts will be published by ASCP following the conclusion of the 2024 Annual Meeting. 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.