A Phase 2, Multicenter, Randomized, Double-blind Evaluation of the Efficacy and Safety of Oral GATE-251 or Placebo for the Reduction of Symptoms of Major Depressive Disorder in Adults

The goal of this clinical trial is to learn if GATE-251 works to treat depression in adults. It will also learn about the safety of GATE-251. The main questions it aims to answer are:
Does GATE-251 reduce depression scores in participants compared to participants who take a placebo (a look-alike tablet that contains no GATE-251)?
What medical problems are observed in participants who take GATE-251?
Participants will take one tablet of GATE-251 or placebo every week for 6 weeks. Participants will visit the clinic every week of the 6 week period to have the severity of their depression evaluated.

Start Date30 Sep 2024

Sponsor / Collaborator

Gate Neurosciences, Inc.Startup

NCT03726658 / CompletedPhase 1/2

A Two-Part, Double-Blind, Placebo-Controlled, Single- and Multiple-Dose (Part A) or Twice Daily Dose (Part B) Study of AGN-241751 in Adult Participants With Major Depressive Disorder

The purpose of this study is to evaluate the efficacy and safety of AGN-241751 in participants with Major Depressive Disorder

Start Date08 Nov 2018

Sponsor / Collaborator

Gate Neurosciences, Inc.Startup

NCT03586427 / CompletedPhase 2

A Double-Blind, Placebo-Controlled, Fixed-Dose Study of AGN-241751 in Adult Participants With Major Depressive Disorder

The purpose of this study is to evaluate the efficacy at 1 day post initial oral dose of AGN-241751 compared with placebo in participants with Major Depressive Disorder (MDD).

Start Date13 Jun 2018

Sponsor / Collaborator

Gate Neurosciences, Inc.Startup

100 Clinical Results associated with Zelquistinel

100 Translational Medicine associated with Zelquistinel

100 Patents (Medical) associated with Zelquistinel

Literatures (Medical) associated with Zelquistinel

01 Nov 2024·NEUROPHARMACOLOGY

Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-d-aspartate receptors

Article

Author: Berglund, Nils ; Zhang, Xiao-Lei ; Li, Yong-Xin ; Donello, John E ; Moskal, Joseph R ; Burgdorf, Jeffrey S ; Stanton, Patric K

Stinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca²⁺ intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca²⁺-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI.

01 May 2024·Neuropharmacology

The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism spectrum disorder

Article

Author: Jaccaz, Déborah ; Donello, John E ; Becker, Jérôme Aj ; Le Merrer, Julie ; Brugoux, Agathe ; Fonteneau, Mathieu ; Banerjee, Pradeep

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by deficient social communication and interaction together with restricted, stereotyped behaviors. Currently approved treatments relieve comorbidities rather than core symptoms. Since excitation/inhibition balance and synaptic plasticity are disrupted in ASD, molecules targeting excitatory synaptic transmission appear as highly promising candidates to treat this pathology. Among glutamatergic receptors, the NMDA receptor has received particular attention through the last decade to develop novel allosteric modulators. Here, we show that positive NMDA receptor modulation by zelquistinel, a spirocyclic β-lactam platform chemical, relieves core symptoms in two genetic and one environmental mouse models of ASD. A single oral dose of zelquistinel rescued, in a dose-response manner, social deficits and stereotypic behavior in Shank3^Δex13-16-/- mice while chronic intraperitoneal administration promoted a long-lasting relief of such autistic-like features in these mice. Subchronic oral mid-dose zelquistinel treatment demonstrated durable effects in Shank3^Δex13-16-/-, Fmr1^-/- and in utero valproate-exposed mice. Carry-over effects were best maintained in the Fmr1 null mouse model, with social parameters being still fully recovered two weeks after treatment withdrawal. Among recently developed NMDA receptor subunit modulators, zelquistinel displays a promising therapeutic potential to relieve core symptoms in ASD patients, with oral bioavailability and long-lasting effects boding well for clinical applications. Efficacy in three mouse models with different etiologies supports high translational value. Further, this compound represents an innovative pharmacological tool to investigate plasticity mechanisms underlying behavioral deficits in animal models of ASD.

12 Dec 2022·The international journal of neuropsychopharmacology

Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects

Article

Author: Stanton, Patric K ; Moskal, Joseph R ; Donello, John E ; Burgdorf, Jeffrey S ; Zhang, Xiao-Lei

Abstract:

Background:

The role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative and positive modulation of N-methyl-D-aspartate receptors (NMDAR) can produce rapid antidepressant effects. Here we report that zelquistinel, a novel NMDAR allosteric modulator, exhibits high oral bioavailability and dose-proportional exposures in plasma and the central nervous system and produces rapid and sustained antidepressant-like effects in rodents by enhancing activity-dependent, long-term synaptic plasticity.

Methods:

NMDAR-mediated functional activity was measured in cultured rat brain cortical neurons (calcium imaging), hNR2A or B subtype-expressing HEK cells, and synaptic plasticity in rat hippocampal and medial prefrontal cortex slices in vitro. Pharmacokinetics were evaluated in rats following oral administration. Antidepressant-like effects were assessed in the rat forced swim test and the chronic social deficit mouse model. Target engagement and the safety/tolerability profile was assessed using phencyclidine-induced hyperlocomotion and rotarod rodent models.

Results:

Following a single oral dose, zelquistinel (0.1–100 µg/kg) produced rapid and sustained antidepressant-like effects in the rodent depression models. Brain/ cerebrospinal fluid concentrations associated with zelquistinel antidepressant-like activity also increased NMDAR function and rapidly and persistently enhanced activity-dependent synaptic plasticity (long-term potentiation), suggesting that zelquistinel produces antidepressant-like effects by enhancing NMDAR function and synaptic plasticity. Furthermore, Zelquistinel inhibited phencyclidine (an NMDAR antagonist)-induced hyperlocomotion and did not impact rotarod performance.

Conclusions:

Zelquistinel produces rapid and sustained antidepressant effects by positively modulating the NMDARs, thereby enhancing long-term potentiation of synaptic transmission.

News (Medical) associated with Zelquistinel

15 May 2024

·www.biospace.com

Gate Neurosciences to Share New Data and Research Insights on its Synaptic Function Molecules with Multiple Posters at 2024 ASCP Annual Meeting

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.

Phase 1Phase 2ASCOClinical Result

24 Jan 2024

·www.biospace.com

Gate Neurosciences Announces Clinical Collaboration with Beacon Biosignals to Advance Precision EEG Biomarkers in Major Depressive Disorder

Collaboration entails the use of Beacon Biosignals’ FDA-cleared DreemTM 3S device in an upcoming Phase 2 clinical trial of Gate's lead oral program, zelquistinel, in Major Depressive Disorder INDIANAPOLIS--(BUSINESS WIRE)-- Gate Neurosciences, Inc., a clinical-stage biotechnology company using precision medicine approaches to develop next-generation neuroscience therapies, today announced a strategic collaboration with Beacon Biosignals to further advance the use of electroencephalogram (EEG) biomarkers across the company’s clinical pipeline in neuropsychiatry and cognition. Initially, this collaboration will entail the use of Beacon Biosignals’ FDA-cleared Dreem™ 3S headband device and neurobiomarker platform to conduct exploratory EEG and sleep analyses in depressed patients enrolled in Gate’s upcoming Phase 2 trial of zelquistinel, slated to initiate by mid-2024. Zelquistinel is a rapid-acting, once-weekly oral NMDA receptor positive modulator in development for treating major depressive disorder (MDD). “The Gate team is excited to partner with Beacon in pioneering a new era of precision psychiatry with innovative biomarker insights, approaches, and technology,” commented Mike McCully, CEO of Gate Neurosciences. “We will apply data and key learnings obtained from our combined experience in psychiatric clinical studies and EEG analyses to ultimately improve outcomes for patients across mental health, cognitive, and neurodevelopmental disorders.” The collaboration represents the next phase of precision psychiatry for Gate, building on its existing biomarker research including EEG data from prior zelquistinel clinical studies and translational EEG insights at the company’s recently expanded R&D operations in Evanston, Illinois. In November of 2023, the company announced positive results from a Phase 1 EEG biomarker study of apimostinel (second-generation injectable NMDA receptor modulator), which demonstrated a consistent, dose-dependent human EEG signature representing NMDAR target activation. In the upcoming zelquistinel Phase 2 depression study, Gate will use Beacon’s biomarker platform for deeper insights into patient diagnoses, treatment response, and target activation over six weeks of dosing. “In psychiatry, outcomes can vary widely within the same diagnosis; making it difficult for patients, families, and providers to determine the best treatment pathway for any individual,” said Jacob Donoghue, M.D., Ph.D., CEO of Beacon Biosignals. “Brain activity during sleep, as measured using Beacon’s at-home hardware and AI-powered software, will provide a level of precision understanding never before possible, empowering informed and accurate decisions for the treatment of conditions such as depression. We look forward to working with the team at Gate on the upcoming clinical trial for zelquistinel, and to making further progress on this cutting-edge research.” Beacon Biosignals’ analytics platform combines its large clinical EEG databases and proprietary machine-learning algorithms to identify neurobiomarkers that assist with patient stratification, assessing drug activity and therapeutic efficacy. A key component of this platform is the Dreem™ 3S EEG device, which is U.S. Food and Drug Administration cleared and clinically validated. The wearable device measures sleep architecture and EEG activity in patients with central nervous system disorders and is optimized for comfortable, longitudinal brain monitoring. The Dreem™ 3S data flows into Beacon Biosignals' analytics platform to provide validated neurophysiological endpoints for clinical trials. 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. About Beacon Biosignals Beacon's machine learning platform for EEG enables and accelerates new treatments that transform the lives of patients with neurological, psychiatric or sleep disorders. Through novel machine learning algorithms, large datasets, and advances in software engineering, Beacon Biosignals is changing the way patients are treated for disorders of the brain. For more information, visit . For careers, visit ; for partnership inquiries, visit . Follow us on Twitter (@Biosignals) or LinkedIn ( ).

Phase 2Phase 1

07 Nov 2023

·www.biospace.com

Gate Neurosciences Announces Positive Topline Human EEG Biomarker Results Demonstrating Dose-Dependent Target Activation in Phase 1 Study of Apimostinel

Demonstrated changes in qEEG biomarkers of target activation from baseline versus placebo, in response to single and multiple doses Dose-dependent qEEG effects were consistent with antidepressant efficacy observed in a prior Phase 2a depression study Well-tolerated with no psychotomimetic effects Results support upcoming Phase 2 study of zelquistinel, the company’s lead oral NMDA receptor modulator for major depressive disorder INDIANAPOLIS--(BUSINESS WIRE)-- Gate Neurosciences, Inc. a clinical-stage biotechnology company using precision medicine approaches to develop next-generation neuroscience therapies, today announced positive topline qEEG biomarker and safety results from its Phase 1 multiple ascending dose study of apimostinel in healthy volunteers. Results demonstrated a dose-dependent increase in qEEG pharmacodynamic biomarkers of NMDA receptor target activation from baseline, compared with subjects who received placebo. Maximal qEEG effects were observed at dose levels consistent with antidepressant efficacy observed in a prior Phase 2a proof of concept (POC) study of apimostinel, validating the biomarker for informing dose selection in future clinical efficacy studies across the class of molecules. Apimostinel was also generally well-tolerated with no ketamine-like dissociative side effects, highlighting its novel mechanistic approach of enhancing synaptic function. The positive human qEEG biomarker results with apimostinel are consistent with prior biomarker observations with zelquistinel, Gate’s lead program, which is currently being developed as a rapid-acting, once weekly, oral treatment for major depressive disorder (MDD). “We are very excited to see a consistent, objective biomarker of receptor activation across two independent clinical programs in both apimostinel and zelquistinel. These new positive qEEG results further advance our confidence in dose selection and our understanding of how this novel class of molecules achieves rapid and durable effects through event-driven pharmacology,” said Mike McCully, CEO of Gate Neurosciences. “We now have even more conviction in our upcoming Phase 2 depression study of zelquistinel, our lead rapid-acting oral program.” Summary of Apimostinel Phase 1 Safety and qEEG Topline Results: Safety & Tolerability Apimostinel was generally safe and well-tolerated across three ascending dose cohorts (1, 5, and 10 mg) receiving multiple doses and one single dose cohort (25 mg), in a total of 40 healthy volunteers. No observation of ketamine-like psychotomimetic or dissociative effects, consistent with safety from two prior clinical trials and reflective of apimostinel’s novel and differentiated NMDA receptor mechanism. qEEG Biomarker of Target Activation qEEG analysis showed a dose-dependent increase in pharmacodynamic biomarkers of NMDA receptor activation compared to placebo after IV administration, adjusted from baseline, at all evaluated timepoints. Maximal enhancement of qEEG signature was observed with apimostinel 10mg: qEEG dose response was consistent with drug CSF concentrations that maximally enhance the NMDA receptor in nonclinical studies. qEEG dose response was consistent with antidepressant efficacy observed in a prior POC clinical study, where a single 10mg IV dose of apimostinel demonstrated rapid, statistically significant antidepressant effects at 24 hours. Results validate similar qEEG biomarker observations with zelquistinel in prior clinical studies, confirming a class effect of these compounds, and inform dose selection in the next efficacy studies. Apimostinel is a rapid-acting injectable program behind the company’s lead oral small molecule zelquistinel, both of which are novel positive modulators of the NMDA receptor designed to enhance synaptic function in patients with mood and cognitive disorders. Gate plans to initiate a Phase 2 study of zelquistinel to confirm efficacy in MDD in Q1 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.

Clinical ResultPhase 1Phase 2

100 Deals associated with Zelquistinel

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 2	US	Gate Neurosciences, Inc.Startup	13 Jun 2018

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03726658 (CTgov)	Phase 1/2	Depressive Disorder, Major	226	AGN-241751 (AGN-241751 3mg Daily)	ncepqncqhf(yvtkunejgn) = rkdxywgmwt qyuzilxhki (fkjqxdduqq, qiokpjneri - ualivclqrd) View more	-	07 Jul 2023
				AGN-241751 (AGN-241751 10mg Daily)	ncepqncqhf(yvtkunejgn) = wojbtmccgl qyuzilxhki (fkjqxdduqq, bkijmzzwxe - mwltahizee) View more
NCT03586427 (CTgov)	Phase 2	Depressive Disorder, Major	251	AGN-241751 (AGN-241751 Dose 1)	evloepfzir(xlebqgxcyz) = jfmahrnxcj pxtuehbctp (foriozjnag, wwztndrahn - jjjcsldqaq) View more	-	02 Aug 2022
				AGN-241751 (AGN-241751 Dose 2)	evloepfzir(xlebqgxcyz) = vabkaqutdk pxtuehbctp (foriozjnag, npkvrumtnu - bytlsnbxed) View more

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