Leiomyomatosis peritonealis disseminata (LPD) is a rare condition characterized by multiple pelvic and abdominal nodules, which are composed of smooth-muscle cells. To date, no more than 200 cases have been reported. The diagnosis of LPD is difficult and there are no guidelines on the treatment of LPD. Currently, surgical excision is the mainstay. However, hormone blockade therapy can be an alternative choice.

CASE SUMMARY:

A 33-year-old female patient with abdominal discomfort and palpable abdominal masses was admitted to our hospital. She had undergone four surgeries related to uterine leiomyoma in the past 8 years. Computed tomography revealed multiple nodules scattered within the abdominal wall and peritoneal cavity. Her symptoms and the result of the core-needle biopsy were consistent with LPD. The patient refused surgery and was then treated with tamoxifen, ulipristal acetate (a selective progesterone receptor modulator), and goserelin acetate (a gonadotropin-releasing hormone agonist). Both tamoxifen and ulipristal acetate were not effective in controlling the disease progression. However, the patient achieved an excellent response when goserelin acetate was attempted with relieved syndromes and obvious shrinkage of nodules. The largest nodule showed a 25% decrease in the sum of the longest diameters from pretreatment to posttreatment. Up to now, 2 years have elapsed and the patient remains asymptomatic and there is no development of further nodules.

CONCLUSION:

Goserelin acetate is effective for the management of LPD. The long-term use of goserelin acetate is thought to be safe and effective. Hormone blockade therapy can replace repeated surgical excision in recurrent patients.

2017-03-01·Molecular psychiatry1区 · 医学

Ketamine: translating mechanistic discoveries into the next generation of glutamate modulators for mood disorders

1区 · 医学

Review

作者: Machado-Vieira, R ; Zarate, C A

A review.Over the last decade, numerous controlled studies have consistently described rapid, robust, and relatively sustained antidepressant response rates associated with single-dose ketamine infusions.Indeed, antidepressant response rates at 4, 24, and 72 h were 50%, 70%, and 35%, resp., in individuals with treatment-resistant depression (TRD) who received a single ketamine infusion.^1, ².Furthermore, a recent meta-anal. of seven trials (encompassing 147 ketamine-treated patients) found that a single ketamine infusion produced rapid, yet transient, antidepressant effects, with odds ratios for response and transient remission of symptoms at 24 h equaling 9.87 (4.37-22.29) and 14.47 (2.67-78.49), resp.³.It is important to note that, to date, no other treatment for depression has demonstrated comparable effects in terms of the magnitude of response to a single dose for TRD patients.Notably, ketamine has also been found to rapidly and robustly improve key dimensions such as anhedonia, fatigue, and suicidal thoughts in individuals with treatment-resistant major depressive disorder or bipolar depression.^4, ^5, ^6, ⁷.Given these extremely promising findings, the past decade has been marked by an explosion of research seeking to understand the neurobiol. underpinnings of rapid antidepressant response.^8, ^9, ^10, ¹¹.Ketamine use in clin. settings has seen even more rapid growth, despite the fact that ketamine's off-label clin. use in the community is still unregulated and not standardized.¹².Concomitantly, concerns surrounding chronic ketamine use and risk of neurotoxicity, cystitis, dissociative side effects, and abuse remain largely unresolved.To address such concerns, efforts are underway to bring ketamine to the market, standardize its use, and determine its real-world effectiveness (see, for instance, http://www.pcori.org/research-results/2016/electroconvulsive-therapy-vs.-ketamine-severe-resistant-depression).Here, we seek to summarize the ongoing evolution of theories regarding ketamine's mechanism of action; it is our hope that such information will be useful in determining which steps can best aid ongoing efforts to develop the next generation of antidepressant treatments that are safe, well-tolerated, and rapid-acting.The original hypothesis that N-methyl-D-aspartate (NMDA) antagonists had antidepressant effects-which was based on a series of elegant preclin. studies¹³-has been the prevailing theory to explain ketamine's antidepressant effects for the better part of almost three decades.Following a several years-long lull in the development of NMDA antagonists, the first report of ketamine's rapid antidepressant effects in a small group of depressed subjects appeared in 2000.¹⁴.Following a second years-long lull, in 2006, a hypothesis-driven study replicated the original findings of rapid onset of antidepressant effects in a larger sample of TRD patients who received a single ketamine infusion.The latter study led to an exponential surge in preclin. and clin. studies examining ketamine use in mood disorders.¹.At the cellular and mol. level, research has attempted to better characterize the neurobiol. processes implicated in ketamine's rapid antidepressant effects following the initial NMDA blockade.This research has led to important insights in addition to identifying alternate targets for drug discovery with the goal of maintaining ketamine's favorable therapeutic profile but eliminating areas of concern associated with its use, such as dissociative side effects and abuse potential.¹⁵.Some of the alternate theories currently being investigated to explain ketamine's actions are explored in greater detail below.The original preclin. evidence linking NMDA receptor antagonism and ketamine's rapid antidepressant effects led to a decade of preclin. and clin. trials with NMDA receptor antagonists.During this time, ketamine's antidepressant effects were consistently replicated in many pilot trials, and the onset and offset of antidepressant efficacy with a single administration became well characterized;¹ such studies also helped characterize the side effects associated with ketamine and the time frame in which these were likely to occur.In addition, other studies exploring ketamine enantiomers have shown exciting clin. results using different dosing routes and frequency.However, efforts to develop a 'better' or alternate version of ketamine were fraught with difficulties from the start.Several broad and subunit-selective NMDA antagonists that had been shelved after failing to demonstrate efficacy for other indications were reintroduced in the clinic as proof-of-concept agents for TRD.It is clear from these trials that some of these alternate ketamine NMDA receptor antagonists did indeed have some antidepressant properties.Nevertheless, none of them possessed all of ketamine's pos. traits, including: (1) rapid onset of antidepressant effects, (2) robustness of efficacy, (3) sustained efficacy with a single administration, and (4) efficacy in TRD.In addition, no other NMDA antagonists appeared to possess the richness of ketamine's therapeutic effects including its antisuicidal properties, its anti-anhedonic effects, and its therapeutic potential in other disorders such as post-traumatic stress disorder or obsessive compulsive disorder.Investigators wondered whether the modest efficacy seen with other NMDA receptor antagonists might be due to dose.That is, to produce few or no dissociative effects or elevations in blood pressure, doses of NMDA antagonists other than ketamine were purposely kept low and not increased, with the concomitant result that the drugs were better tolerated than ketamine but had limited efficacy.Whether these other drugs would have antidepressant effects and a side effect profile similar to ketamine's with higher doses remains unknown and, unfortunately, many of those experiments were not possible for a number of reasons.It should be noted that a number of NMDA receptor antagonists or glutamatergic NMDA receptor modulators are presently being studied that might conceivably yield promising results (for example, Rapastinel, CERC-301).¹.However, none of the other NMDA antagonists tested to date have shown the same rapid, robust, and sustained antidepressant effects as ketamine; in other words, they are simply not ketamine.Notably, convergent evidence from behavioral, cellular, and mol. ketamine studies supports the theory that enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity-with a concomitant increase in synaptic plasticity-is critical to ketamine's mechanism of action and may be the key to developing similarly rapid-acting antidepressants.Within the tripartite glutamate synapse,¹⁶ AMPA receptors work in tandem with NMDA receptors.Although early NMDA receptor blockade initially increases synaptic glutamate release, this effect leads to preferential activation of AMPA receptor activity in critical neuronal circuits, particularly the cortico-limbic-striatal circuits.AMPA receptor trafficking also plays a key role in activating plasticity signaling cascades; relatedly, the delivery of AMPA receptors to the stimulated synapse-particularly postsynaptic AMPA-is key to synaptic strength.¹⁷.This AMPA throughput model was first proposed almost a decade ago in a study demonstrating that pre-treatment with an AMPA receptor antagonist blocked ketamine's antidepressant-like effects and also upregulated hippocampal phosphorylated GluR1 AMPA receptors.¹⁸.This model posits that AMPA's restorative effects result from a rapid increase in glutamate levels and the associated AMPA receptor insertion.Building on this work, Duman and colleagues found that direct blockade of NMDA receptors on inhibitory gamma aminobutyric acid (GABA)-ergic neurons in the prefrontal cortex led to a series of other important changes before AMPA activation, resulting in disinhibition of pyramidal neurons; this, in turn, led to increased glutamate release and enhanced signaling via its AMPA receptors.¹⁹.Because AMPA appeared critical to ketamine's antidepressant effects, researchers reasoned that AMPA pos. modulators-also known as AMPAkines-could pos. influence mood.Previous studies evaluating AMPAkines in mood disorders achieved mixed results, potentially due to low bioavailability and toxicity profile.²⁰.To overcome the issue of low bioavailability, other AMPAkines were recently developed and tested in initial Phase 1 and 2 studies, particularly coluracetam (BCI-540)²¹ and ORG-26576.²².Both agents showed preliminary therapeutic effects in major depressive disorder when tested in small samples.^23, ²⁴.Addnl. targets for ketamine's mechanism of action are also being explored; some of these postulate enhanced AMPA throughput.For instance, Rapastinel (Glyx-13), an NMDA receptor modulator with glycine-like properties, appears to have rapid antidepressant efficacy in treatment-resistant depression and, in preclin. studies, has been shown to activate AMPA receptors.²⁵.4-Cl-KYN (AV-101), a glycine receptor antagonist, also requires AMPA/kainate receptor activation, as highlighted by the ability of pre-treatment with an AMPA receptor antagonist to abolish their antidepressant-like effects in animal models.²⁶.It should be noted that no evidence presently implicates AMPA receptor activation in conjunction with the NMDA receptor antagonist CERC-301 or the NMDA channel blocker AZD6765 (Lanicemine).²⁷.It should also be noted that there are other ways to achieve increased AMPA throughput, though these have not yet been clin. tested.In addition to the direct effects of AMPA throughput, activation of the AMPA receptor targeting at mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2), and brain-derived neurotrophic factor (BDNF) signaling pathways may also be relevant to the rapid antidepressant effects of ketamine and related mols. mTOR has multiple intracellular functions, including translation of proteins involved in synaptic plasticity and memory.Ketamine's ability to activate mTOR and multiple intracellular signaling cascades seems to be related to the increased AMPA receptor throughput and neuroproliferative effects in downstream targets regulated by ketamine.²⁸.In this context, activation of the mTOR signaling pathway via AMPA receptors was found to be linked to ketamine's rapid antidepressant-like effects and thought to rapidly reverse stress- and/or depression-mediated deficits.Supporting a key role for mTOR in the mol. effects of ketamine, another study found that a single subanesthetic dose of ketamine rapidly upregulated mTOR signaling and potentiation of synaptic transmission mediated by AMPA receptors;¹⁹ however, this finding has not always been replicated across studies.²⁹.With regard to the potential role of eEF2 and BDNF signaling in ketamine's rapid antidepressant effects, ketamine is known to increase BDNF signaling via post-synaptic AMPA receptor stimulation, permitting calcium influx and the resultant activity-dependent exocytosis of BDNF.It has also been hypothesized that ketamine suppresses eEF2 kinase activity that, in turn, reduces the suppression of protein translation, resulting in an upregulation of BDNF.³⁰.Alternately, these modulatory effects seem to underlie ketamine's blockade at resting NMDA receptors, which has been shown to affect specific downstream plasticity targets, particularly eEF2 inhibition.³⁰.Ketamine is also known to increase central and peripheral BDNF levels, which has been associated with changes in the number and function of synaptic connections in diverse preclin. studies.BDNF upregulation also induces acute changes in synaptic plasticity, mostly through increased surface expression of hippocampal AMPA receptors.^31, ³².These effects seem to be associated with the effects of AMPA activity on neuronal surface expression that consequently stimulate quick (30 min) eEF2- and BDNF-dependent potentiation.^30, ³¹.Glycogen synthase kinase 3 (GSK3) is another key target, and its inhibition has also been shown to be necessary for ketamine's rapid antidepressant-like effects mediated by AMPA receptors.²¹.One study found that mice expressing constitutively active GSK3 experienced no antidepressant-like effects in response to ketamine.³³.More recently, the same group demonstrated that administering an antidepressant dose of ketamine increased cell membrane AMPA GluR1 levels by inhibiting GSK3, suggesting that GSK3 inhibition makes a mechanistic contribution to ketamine's rapid antidepressant action based on the AMPA throughput model.³⁴.Furthermore, other glutamate receptors, monoamines, and G-protein-coupled receptors can also regulate AMPA receptors via protein phosphorylation and/or dephosphorylation mechanisms.²³.Building on this work, investigators began exploring those cellular and mol. ketamine targets that are largely NMDA receptor-independent.Interestingly, recent preclin. studies evaluating ketamine and its metabolites support mechanisms of action beyond simple NMDA antagonism to explain the rapid and sustained antidepressant effects of these mols., with a particular emphasis on enhanced AMPA to NMDA throughput (Figure 1).Of particular interest, a recent study found that ketamine metabolites activate AMPA receptors through an NMDA-independent mechanism at concentrations that equate to the Cmax of brain exposure after i.p. administration of antidepressant doses in mice.³⁵.Ketamine is rapidly broken down into diverse metabolites that include the hydroxyketamines (HKs), dehydronorketamine, and hydroxynorketamine (HNK) (Figure 2).Dehydronorketamine and HNK are downstream metabolites of ketamine and norketamine, resp.Norketamine's byproduct, (2R,6R)-HNK, is the major HNK metabolite found in the rodent brain as well as in human plasma after ketamine administration.It strongly activates hippocampal AMPA receptors and increases GluR1 chronically, but does not inhibit the NMDA receptor.^35, ³⁶ As with ketamine, pre-treatment with the AMPA receptor antagonist NBQX prevented the acute antidepressant effects of (2R,6R)-HNK injection.Furthermore, maintenance of (2R,6R)-HNK's ongoing antidepressant-like effects were prevented with NBQX.These preclin. findings suggest that synaptic AMPA activation and related increased synaptic activity play a key role in the sustained antidepressant effects associated with ketamine metabolites.³⁵.Intriguingly, these findings also echo and expand our decade-old original hypothesis,^18, ^37, ³⁸ which posited that increased glutamatergic throughput of AMPA receptors relative to NMDA receptors was key to explaining ketamine's rapid antidepressant effects; this model was recently expanded to explain the sustained antidepressant effects of ketamine's HNK metabolite ((2S,6S; 2R,6R)-HNK).³⁵.However, to date, no clin. study has evaluated the potential rapid and sustained antidepressant effects of this ketamine metabolite in depressed patients, or confirmed that AMPA throughput is critical to ketamine's acute and sustained antidepressant effects in humans.Such studies are planned.Finally, ketamine acts on several other targets beyond the glutamatergic system; these remain largely unexplored in the context of its rapid antidepressant effects.For instance, ketamine induces aminergic activation and inhibits reuptake, and also targets delta opioid and mu-receptor function.²³.Adipokines also appear to be affected by ketamine, which alters levels of leptin, resistin, and adiponectin; of the three, adiponectin levels were the strongest predictor of antidepressant response to ketamine,³⁹ supporting ketamine's putative role in reversing metabolic dysfunction during mood episodes.All of these mechanisms are worthy of further exploration and underscore the potential complexity of the different mechanisms implicated in ketamine's antidepressant effects.In conclusion, when it comes to elucidating ketamine's underlying mechanisms of action, several promising areas of further study emerge.Pharmacol. approaches that can bypass the initial neurobiol. changes associated with NMDA receptor antagonism and its related psychotomimetic effects, as well as reverse dysregulation of critical neural circuits and cellular signaling at these pathways/targets (for example, ketamine metabolites), may be a promising avenue.To synthesize much of the evidence reviewed above, recent studies have reinforced that AMPA receptor activation is important to ketamine's rapid and sustained therapeutic effects, specifically through glutamate release and the consequent stimulation of downstream pathways; these late-phase effects include a key role for ketamine's metabolites targeting at eEF2 and the BDNF pathway.This restorative effect results from elevated glutamate levels (glutamate surge-although not all investigations support the glutamate surge hypothesis) and increased AMPA receptor insertion (together with an increase in amines) as well as increased prefrontal cortex synaptogenesis and connectivity.These alternative mechanisms of action would be expected to trigger long-term changes in synaptic activation related to sustained antidepressant actions, but occur independently of the initial NMDA receptor blockade (Figure 1).Overall, NMDA receptor-independent mechanisms are comparatively underexplored but particularly appealing for the development of new agents capable of inducing sustained antidepressant effects; most importantly, this alternative path to discovery may include the development of an improved version of ketamine by exploring ketamine's metabolites, which are expected to bypass its dissociative adverse effects, as gleaned from studies with (2R,6R)-HNK.Given the complexity of the material reviewed above, we note that it is unlikely that a single mechanism could be responsible for ketamine's unique antidepressant effects.Ongoing studies examining the therapeutic profile of ketamine's metabolites and its downstream targets, as well as other ways of enhancing AMPA throughput mechanisms, should prove particularly insightful.Furthermore, the precise sequence of the cellular and mol. changes implicated in ketamine's mechanism of action remain to be identified.

CPT-Pharmacometrics & Systems Pharmacology

Concentration–QT modeling demonstrates that the selective mineralocorticoid receptor modulator, balcinrenone (AZD9977), does not prolong QT interval

Article

作者: Rekic, Dinko ; Dota, Corina ; Ebrahimi, Ahmad ; Sundell, Jesper ; Parkinson, Joanna ; Johansson, Susanne ; Melin, Johanna

Abstract:

Balcinrenone (AZD9977) is a selective mineralocorticoid receptor modulator in development in combination with dapagliflozin for treatment of heart failure with impaired kidney function and chronic kidney disease. A prespecified concentration–QT analysis was performed based on data from a phase I single ascending dose study prospectively designed as a thorough QT study substitute. Oral single doses of balcinrenone of 5–800 mg, plus fractionated doses of 800 and 1200 mg, were evaluated in 62 healthy male participants. Time‐matched 12‐lead digital electrocardiogram and plasma concentrations were measured pre‐dose and up to 48 h postdose in the participants. Analysis was performed using a linear mixed‐effect model, where baseline‐adjusted Fridericia‐corrected QT interval (ΔQTcF) was a dependent variable and time‐matched balcinrenone concentration an independent variable. The model fit was deemed adequate by evaluation of goodness‐of‐fit plots, and the slope of the concentration–ΔQTcF relationship was nonsignificant (−0.003 ms/μmol/L; 95% confidence interval [CI]: −0.181, 0.176). The high clinical exposure scenario was defined as the maximum concentration (2.156 μmol/L) following the highest expected therapeutic dose (40 mg once daily) under fed conditions and in presence of a strong cytochrome P450 3A4 inhibitor. Estimated baseline‐adjusted and placebo‐corrected QTcF interval (ΔΔQTcF) at this concentration was 0.35 ms (90% CI: −1.29, 2.00). Furthermore, the upper 90% ΔΔQTcF CI was estimated to be below the threshold of regulatory concern of 10 ms at all observed concentrations (up to 16.7 μmol/L). Hence, it can be concluded that balcinrenone does not induce QTcF prolongation at the high clinical exposure scenario.

项与 NMDA受体调节剂(元羿生物) 相关的新闻（医药）

2024-01-24

·BioSpace

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 ( ).

临床2期临床1期

2023-11-07

·BioSpace

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.

临床结果临床1期临床2期

2022-09-29

·BioSpace

Gate Neurosciences Publishes Data Highlighting Novel Mechanism of Lead Rapid-Acting Oral Antidepressant and Provides Business Update

Sept. 29, 2022 12:00 UTC New publication highlights novel and differentiated NMDA receptor mechanism, and rapid and long-lasting antidepressant activity with lead clinical program, Zelquistinel Supports further development of Zelquistinel in a Phase 2 confirmatory study in Major Depressive Disorder, with expected initiation in early 2023 Company highlights business update, recent and upcoming clinical milestones, and additions to advisory network, after emerging from stealth last month INDIANAPOLIS--(BUSINESS WIRE)-- Gate Neurosciences, Inc. today announced the results of research, published in the International Journal of Neuropsychopharmacology, supporting the mechanism of action and clinical foundation of Zelquistinel – the company’s lead oral program in Phase 2 development – as a rapid-acting, long-lasting and safe antidepressant. Publication highlights robust preclinical pro novel mechanism for lead Phase 2 clinical program, Zelquistinel The peer-reviewed manuscript spotlights Zelquistinel’s novel mechanism and pharmacology by which it elicits rapid and long-lasting antidepressant effects. Zelquistinel was shown to positively modulate NMDA receptors (NMDARs) and enhance synaptic plasticity in the hippocampus and medial prefrontal cortex. A single dose of the molecule demonstrated a dose-dependent antidepressant-like response within one hour of administration that was sustained for more than 7 days. The studies highlighted in the publication build upon a robust underlying translational data package and predictive dose model that is consistent across Gate’s class of NMDAR modulators. Zelquistinel’s potential as an oral pill was confirmed by its high bioavailability and brain exposure, and also shows 1000-fold greater potency and a longer plasma half-life compared to its precursor molecule Rapastinel (GLYX-13). In terms of safety, Zelquistinel lacked the sedative, ataxic, and motor impairment effects that are typically observed with NMDAR antagonists and notably, it reversed NMDAR antagonist side effects upon co-administration. These data highlight Zelquistinel’s novel, potent, and highly differentiated mechanism of action with potential for a significantly improved safety pro to other NMDAR-targeted antidepressants in development for depressive disorders. “Zelquistinel’s mechanism of action represents a novel pharmacological approach which may help address patient needs in the treatment of depression,” said Maurizio Fava M.D., Psychiatrist-in-Chief at Massachusetts General Hospital, and a key advisor to Gate Neurosciences. “The upcoming Phase 2 study seeks to navigate the known challenges of conducting trials in psychiatry to confirm efficacy in Major Depressive Disorder.” Business Update Since its inception in 2019, Gate Neurosciences has assembled and advanced a clinical-stage pipeline of next-generation central nervous system therapies, as previously highlighted when the company emerged from stealth-mode in August 2022. Alongside the previously detailed Zelquistinel, Apimostinel and Rapastinel programs acquired from AbbVie, the company has also acquired exclusive rights to preclinical mGlu2/3 receptor antagonists from Eli Lilly which it is currently developing for sleep disorders, and is advancing a preclinical-stage Insulin Growth Factor 2 Receptor (IGF2R) program for cognitive disorders in collaboration with Northwestern University. Recent Milestones Completed financings totaling $25M from life science-focused investors, including Innoviva, Luson Bioventures, Biocrossroads, and ThornApple Capital, among others. Appointed new Board of Directors member Sarah Schlesinger M.D., a leading clinical investigator and chair of the Institutional Review Board at Rockefeller University, and member of the Board of Directors of Innoviva, Inc. Successfully advanced Investigational New Drug (IND) Applications for lead clinical programs. Initiated a Phase 1b clinical study exploring human target engagement biomarkers with 2nd generation injectable NMDAR program Apimostinel, in development for acute severe depression. Established extensive scientific and clinical advisor network, including leading psychiatrists across top institutions in the US. Hosted an R&D Day event at the 2022 ASCP Annual Meeting: “Update on NMDAR Modulators for Depressive Disorders.” Published in several peer-reviewed journals highlighting novel NMDAR mechanism and antidepressant activity of lead programs. The full list of publication can be found at gateneuro.com/publications. Upcoming Milestones First patient dosed in a single- and repeat-dose Phase 1b safety and EEG (electroencephalography) target engagement biomarker study of Apimostinel in 40 healthy volunteers in Q4 2022 with topline readouts expected in Q1 2023. Initiation of a confirmatory Phase 2 study of Zelquistinel in subjects with major depressive disorder (MDD) in early 2023, with topline readout expected mid-2024. Advancement of Rapastinel (GLYX-13) into investigator-led studies in collaboration with multiple leading research hospitals, under the FDA’s Expanded Access Program, beginning in 2023. Key Additions to Advisory Network Gate Neurosciences has continued expanding its network of 20+ scientific and clinical advisors from top psychiatry institutions across the US, who are providing encouraging perspectives on the company’s NMDA receptor modulator portfolio. Recent key additions include Maurizio Fava, M.D., Psychiatrist-in-Chief at Massachusetts General Hospital, and Thomas Laughren, M.D., Former Director for the Division of Psychiatry Products at the FDA. NMDAR Modulator Portfolio: Data Highlights & Mechanistic Understanding The core scientific focus of Gate’s pipeline is addressing synaptic dysfunction, the hallmark disease biology of many cognitive and psychiatric disorders, by enhancing synaptic plasticity and normalizing brain signaling. NMDARs play an essential role in synaptic plasticity and are the targets of an emerging class of rapid-acting antidepressants. Considerable recent progress has been made, along with a suite of publications, clarifying the underlying mechanisms various NMDAR-targeted molecules. Gate Neurosciences’ lead programs are highly differentiated from other NMDAR-targeted antidepressants by acting through positive modulation instead of antagonism. Gate’s molecules positively modulate NMDAR activity on glutamatergic neurons to enhance synaptic plasticity and elicit antidepressant activity. In contrast, antagonists act through NMDARs located on GABA interneurons, causing a profound ‘burst’ of neurotransmitters and accompanying dissociative side effects, before indirectly stimulating downstream effects on synaptic plasticity. Gate’s novel approach represents a more direct mechanism for enhancing natural neuronal plasticity processes, with the potential for a significantly improved safety profile. Recent literature highlighting Gate’s novel mechanism can be found on its website. Key data highlights from the company’s lead NMDAR programs include: Zelquistinel: 3rd generation oral NMDAR modulator Development as a rapid, durable, and well-tolerated chronic oral therapy to address more than 17 million Americans with MDD Supported by a robust, de-risking translational data package across ~350 patients, including consistent target engagement and EEG biomarkers, safety, and clinical antidepressant efficacy A Phase 2a exploratory dose-finding study in MDD (n=251) showed that Zelquistinel 10mg delivered once-weekly was generally safe and well-tolerated, and demonstrated statistically significant differences from placebo on MADRS change from baseline at multiple timepoints over the study Apimostinel: 2nd generation IV NMDAR modulator Development as an acute injectable procedure for the rapid reduction of depressive symptoms in millions of Americans with acute depressive episodes Molecule is 1000-fold more potent than precursor compound Rapastinel, and is the most potent compound in Gate’s class of NMDAR modulators A Phase 2a proof-of-concept study in MDD (n=151) showed that a single dose of Apimostinel 10mg was generally safe and well-tolerated with no ketamine-like side effects, and demonstrated a 5.4-point difference from placebo on HDRS-17 change from baseline at 24-hours (p=0.0034) and a 74% response rate (p=0.0067), among the largest seen to-date within the class of rapid antidepressants Early Stage Research and Development Highlights Company continues to advance preclinical programs towards IND milestones in 2023 GATE-102: oral mGlu2/3 receptor antagonist for hypersomnia GATE-301: IGFBP2 mimetic for neurodegenerative and neurodevelopmental disorders GATE-252: 4th generation oral NMDAR modulator for cognitive disorders Company established cutting-edge research operations at Northwestern University’s Falk Center for Molecular Therapeutics led by Dr. Joseph Moskal Ph.D., the original inventor of Gate’s NMDAR platform Collaborating with leading research institutions with access to world-class laboratory facilities, equipment, and capabilities Advancing development of objective biomarkers for mood disorders, including novel methods to identify and predict patient responder subsets Advancing early research into growth-factor signaling and other novel drug targets of interest that enhance neuronal function and synaptic plasticity “We are excited about the momentum Gate Neurosciences has gathered heading into the remainder of the year, along with our upcoming clinical milestones for our lead programs,” said Mike McCully, President & CEO of Gate Neurosciences. “I believe our next-generation portfolio has true transformative potential for patients suffering from neuropsychiatric and cognitive disorders.” About Gate Neurosciences Gate Neurosciences is a precision medicine biotechnology company focused on advancing next-generation 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.

100 项与 NMDA受体调节剂(元羿生物) 相关的药物交易

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