BDNF x M1 receptor

ANAVEX®3-71 treatment prevents cognitive impairment, reduces amyloid, and neuroinflammation even after a long drug washout ANAVEX®3-71 halts neurodegeneration and prevents cognitive decline in a transgenic Alzheimer’s disease model Confirmation of Anavex’s upstream SIGMAR1 oral small molecule drug platform in Alzheimer’s disease Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders, including Alzheimer's disease, Parkinson's disease, Rett syndrome, and other central nervous system (CNS) diseases, today reported a new peer-reviewed publication in the journal Neurobiology of Aging, titled “Early treatment with an M1 and sigma-1 receptor agonist prevents cognitive decline in a transgenic rat model displaying Alzheimer-like amyloid pathology”, featuring the orally available small molecule ANAVEX®3-71 (AF710B).1 This study ascertains potential disease-modifying properties of ANAVEX®3-71 (AF710B) on Alzheimer’s disease (AD) pathology and could be a drug candidate for a once daily oral preventive strategy. ANAVEX®3-71 activates the sigma-1 receptor (SIGMAR1) and the M1 muscarinic receptor (M1R). Data suggests that activation of SIGMAR1 results in the restoration of homeostatic function within the body and is pivotal to restoring neural cell balance and promoting neuroplasticity.2 Previous studies of ANAVEX®3-71 have demonstrated its potential to treat Alzheimer’s disease (AD)-like pathology at advanced stages of disease in animal models.3,4 ANAVEX®3-71, an orally available small molecule, has already successfully completed a Phase 1 human clinical trial demonstrating good safety and tolerability signals at all doses studied.5 In this publication, transgenic rats that develop AD-like symptoms as they age were treated with ANAVEX®3-71 for 7-months before they developed amyloid plaques, followed by a 4-week washout period. Preventative treatment with ANAVEX®3-71 reduced levels of insoluble and soluble amyloid-beta as well as plaque deposition in the aging cortex and hippocampus, areas heavily impacted by AD. Notably, the reduction in amyloid pathology was accompanied by a reduction in inflammatory glial activity which is connected to the disease cascade in AD and other dementias. ANAVEX®3-71 treatment downregulated the proinflammatory IL-1β and IL-6 cytokines, which are known to be associated with AD. Additionally, ANAVEX®3-71 treatment boosted brain derived neurotrophic factor (BDNF) which reinforces the evidence that ANAVEX®3-71 protects neurons. Importantly, these beneficial effects were sustained after a month-long drug washout. This differentiates ANAVEX®3-71 from other therapeutic approaches and suggests long-lasting, disease-modifying effects on AD pathology. This long-lasting effect was also observed in previous animal studies of ANAVEX®3-71 at advanced stages of the disease. The publication is consistent with previous scientific findings, including with the more advanced drug candidate ANAVEX®2-73 (blarcamesine), which successfully completed a Phase 2b/3 study in early Alzheimer’s disease, that SIGMAR1 activation acts upstream of multiple contributors to AD and other dementias including but not limited to mitochondrial dysfunction6, oxidative stress7, impaired autophagy8 and that amyloid pathology can be reduced by M1R stimulation9. The authors of the paper (Neurobiology of Aging 132 (2023) 220–232) from the Laboratory of Professor Cuello, MD at McGill University concluded: “This involved study could be considered as proof of principle for preventive therapies in Alzheimer’s disease and illustrates that this category of compounds, or similar effective agents, could be considered as candidates for preventive strategies to slow down the early amyloid pathology in Alzheimer’s disease, a condition that is increasingly diagnosed at preclinical stages.” “This publication is a confirmation of the scientific depth of Anavex’s upstream SIGMAR1 platform, which gives hope to the Alzheimer’s disease community, especially for the patients, families and caregivers who fight everyday against this devastating disease for a potential disease-modifying drug candidate with a once daily oral preventive strategy. We also look forward to presenting in an upcoming major publication the complete dataset of the Phase 2b/3 Alzheimer’s disease trial of ANAVEX®2-73 (blarcamesine), a potential next-generation precision medicine convenient once daily oral Alzheimer’s disease treatment,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. "We are also on track within our neurodevelopmental precision medicine Rett syndrome program to release top-line data of ANAVEX®2-73-RS-003 Phase 2/3 EXCELLENCE pediatric clinical trial in the current quarter of 2023.” Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of novel therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders, including Alzheimer's disease, Parkinson's disease, Rett syndrome, and other central nervous system (CNS) diseases, pain, and various types of cancer. Anavex's lead drug candidate, ANAVEX®2-73 (blarcamesine), has successfully completed a Phase 2a and a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study in Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer's disease. ANAVEX®2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson's Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 for the treatment of Parkinson's disease. ANAVEX®3-71, which targets sigma-1 and M1 muscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at www.anavex.com. You can also connect with the Company on Twitter, Facebook, Instagram, and LinkedIn. 1 Orciani C, Do Carmo S, Foret MK, et al. Early treatment with an M1 and sigma-1 receptor agonist prevents cognitive decline in a transgenic rat model displaying Alzheimer-like amyloid pathology [published online ahead of print, 2023 Sep 26]. Neurobiol Aging. 2023;132:220-232. doi:10.1016/j.neurobiolaging.2023.09.010 2 Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as Therapeutic Targets. 3 Fisher A, Bezprozvanny I, Wu L, et al. AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s Disease. Neurodegener Dis. 2016;16(1-2):95-110. doi:10.1159/000440864 4 Hall H, Iulita MF, Gubert P, et al. AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer's disease. Alzheimers Dement. 2018;14(6):811-823. doi:10.1016/j.jalz.2017.11.009 5 Fadiran EO, Hammond E, Tran J, et al. Concentration-QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease. Clin Pharmacol Drug Dev. 2023;12(9):888-901. doi:10.1002/cpdd.1303 6 Lahmy, V., Long, R., Morin, D., Villard, V., Maurice, T., 2014. Mitochondrial protection by the mixed muscarinic/sigma1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer’s disease model. Front. Cell. Neurosci. 8, 463. https://doi.org/10.3389/fncel.2014.00463 7 Arimon, M., Takeda, S., Post, K.L., Svirsky, S., Hyman, B.T., Berezovska, O., 2015. Oxidative stress and lipid peroxidation are upstream of amyloid pathology. Neurobiol. Dis. 84, 109–119. https://doi.org/10.1016/j.nbd.2015.06.013 8 Christ MG, Clement AM, Behl C. The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy. Trends Neurosci. 2020;43(2):79-81. doi:10.1016/j.tins.2019.12.002 9 Zhao LX, Chen MW, Qian Y, Yang QH, Ge YH, Chen HZ, Qiu Y. M1 Muscarinic Receptor Activation Rescues β-Amyloid-Induced Cognitive Impairment through AMPA Receptor GluA1 Subunit. Neuroscience. 2019 Jun 1;408:239-247. doi: 10.1016/j.neuroscience.2019.04.007. Epub 2019 Apr 11. PMID: 30981860 The content above comes from the network. if any infringement, please contact us to modify.

神经精神障碍是由神经和精神功能紊乱引发的一系列疾病，它们不仅对患者产生严重影响，而且给全球公共卫生事业带来了前所未有的压力。作为全球十大残疾和死亡原因之一，神经精神障碍有着巨大的医疗需求。 在这种形势下，我们迫切需要发现更为有效的治疗方法以应对神经精神障碍。值得高兴的是，目前已有多种前景广阔的治疗方法进入研发后期阶段，为患有抑郁症、精神分裂症和强迫症的数百万患者带来了新的希望。在今天的内容中，药明康德内容团队将结合公开资料深入剖析10种即将接受监管审查、具有巨大潜力的神经精神疾病药物，详细分析它们的作用机制、临床试验成果，以及它们可能为患者的日常生活带来的改变。 药物名称：Zuranolone 研发机构：Sage Therapeutics和渤健（Biogen） 适应症：MDD Zuranolone（SAGE-217/BIIB125）是一种每日一次、为期两周的口服疗法，用于治疗MDD和PPD。它是一种GABAA受体阳性别构调节剂。γ-氨基丁酸系统是大脑和中枢神经系统（CNS）的主要抑制性信号通路，对调节CNS功能有重要作用。Zuranolone靶向的是负责情绪、唤醒、行为和认知等功能的大脑网络。 Zuranolone已被FDA批准用于治疗PPD成人患者，但其针对MDD的适应症仍处于3期临床研究阶段。此前公布的临床试验结果显示，在第15天时，通过17项汉密尔顿抑郁量表（HAMD-17）评估，与安慰剂相比，zuranolone使MDD患者抑郁症状获得统计显著且具有临床意义的减轻（p=0.0141）。试验过程中观察到zuranolone快速起效，并表现出与既往临床研究一致的安全性特征。不仅如此，zuranolone的疗效具有持续性，有潜力作为根据需要才服用的抑郁症药物。 美国FDA要求Sage Therapeutics和渤健在MDD领域对zuranolone的治疗效果开展进一步的研究。Sage公司的首席执行官Barry Greene先生表示，两家公司正在思考监管机构的反馈，并评估下一步行动。如果最终获得批准，zuranolone将是MDD领域首款14天起效的治疗方法，目前的大多数疗法需要6-8周才能起效。 药物名称：Lumateperone 研发机构：Intra-Cellular Therapies 适应症：MDD Lumateperone（商品名：Caplyta）是一种口服、每日一次的非典型抗精神病药，已获批用于治疗成人1型或2型双相情感障碍（双相抑郁）相关的精神分裂症和抑郁发作，作为单药治疗和锂剂或丙戊酸盐的辅助治疗。虽然Caplyta的作用机制尚不清楚，但其疗效可通过中枢5-羟色胺受体2A（5-HT2A）的拮抗活性和中枢多巴胺D2受体的突触后拮抗活性联合介导。 今年3月，Intra-Cellular Therapies公司报告了其3期403试验的积极结果，显示该药物减轻了具有混合特征的MDD与双相抑郁症患者的临床症状。该公司表示，这些结果进一步增强了其对该药物治疗MDD的信心，并计划在2024年寻求监管批准。 药物名称：ALTO-100 研发机构：Alto Neuroscience 适应症：MDD ALTO-100是由Alto Neuroscience利用其人工智能生物标志物平台所开发的一款口服药物，其靶点为脑源性神经营养因子（BDNF），可恢复患者的神经可塑性，使大脑能够灵活适应新信息。值得一提的是，Alto Neuroscience的精准精神病学平台通过分析脑电活动、行为表现、可穿戴设备数据、遗传学和其他因素来检测大脑生物标志物，以便为每个患者匹配合适的药物。 此前公布的2期临床试验数据显示，ALTO-100治疗让带有生物标志物的MDD患者（n=59）在MADRS抑郁量表评分上出现15.5分的下降，此数值在不带有生物标志物的患者（n=64）身上仅为10.6分（p=0.001，d=0.6）。此外，有61%带有生物标志物的患者对该疗法产生临床应答（定义为具≥50%抑郁症状的下降），而仅有33%无生物标志物的患者显示临床应答（p=0.004）。 Alto Neuroscience在今年1月获得2500万美元股权投资，这使得其全部B轮融资金额达到约6000万美元，以及公司自2019年成立以来募集的权益资本达1亿美元。该公司表示，所获得的资金将会用于支持公司四项临床2期试验的进行。这些试验包含4项创新药物候选，涵盖3项不同中枢神经系统适应症。 药物名称：KarXT 研发机构：Karuna Therapeutics 适应症：精神分裂症 KarXT是一款口服非靶向多巴胺能与5-羟色胺能路径、并具双重机制的新式药物。KarXT由xanomeline和trospium chloride两种有效成分构成，旨在激活大脑中的毒蕈碱型乙酰胆碱受体的同时，减少对外周毒蕈碱型乙酰胆碱受体的作用。通过刺激毒蕈碱受体M1和M4，受体激动剂xanomeline可缓解负面症状，如冷漠、社会驱动力减少、提高认知能力，并对改善其它精神症状，如幻觉和妄想很有帮助。而季铵盐化合物trospium chloride为毒蕈碱受体拮抗剂，可抑制xanomeline于外周神经中的副作用。 在3期试验中，精神分裂症患者在接受治疗5周的KarXT治疗后，其阳性和阴性症状量表（PANSS）总分与安慰剂组患者相比，表现出具有统计学意义和临床意义的改善。KarXT组患者的PANSS降低20.6分，比安慰剂组多减少8.4分（p<0.0001）。安全性方面，KarXT表现出良好的耐受性，不良事件特征与此前的临床试验结果一致。由于治疗相关不良事件导致的试验中止的患者比例在治疗组（6%）和安慰剂组（5%）中相似。 Karuna创始人兼首席运营官Andrew Miller博士表示，如果获得批准，KarXT将成为50多年来第一种治疗精神分裂症的新型药物。该公司计划在今年年中向美国FDA递交新药申请（NDA），如果成功，预计将于2024年下半年推向市场。 此外，KarXT针对与阿尔茨海默病相关的精神病症状的临床试验也正处于3期研究阶段。 药物名称：Emraclidine 研发机构：Cerevel Therapeutics 适应症：精神分裂症 Cerevel Therapeutics开发的emraclidine是一款毒蕈碱乙酰胆碱受体M4的选择性正变构调节剂（PAM），这种作用机制使得该药物可以最大限度地减少与泛毒蕈碱激动剂相关的副作用。在动物模型研究中，emraclidine显示出高度的脑渗透性，并且在PET研究中表现出较好的靶点作用情况。目前这款药物正处于2期临床研究阶段。 在一项1b期研究中，使用emraclidine治疗六周时，患者的PANSS总分在统计学和临床意义上均有所改善。与安慰剂相比，emraclidine的总体耐受性良好。 药物名称：Pimavanserin 研发机构：Acadia Pharmaceuticals 适应症：精神分裂症 Pimavanserin是一款选择性血清素受体反向激动剂（SSIA），能够选择性地靶向5-HT2A受体，降低它的基础活性。在人体中，5-HT2A受体的活跃程度与幻觉相关。当它受到迷幻药物或其他激动剂的刺激后，中枢神经系统就会由于兴奋产生迷幻现象。而pimavanserin结合5-HT2A受体后能减弱它的活性，从而减少中枢神经系统的兴奋程度，降低出现幻觉或妄想的风险。 Pimavanserin在2016年获得FDA的批准，用于治疗与帕金森病有关的幻觉和妄想。FDA曾授予pimavanserin突破性疗法认定，用于治疗痴呆症相关精神病患者。Pimavanserin针对精神分裂症的阴性症状的适应症目前正处于3期临床研究中，此前公布的2期试验结果表明，当与现有抗精神病药物联合用药治疗精神分裂症患者时，该药物显著改善了患者在NSA-16量表上的表现。 Acadia公司预计将在2024年获得3期ADVANCE 2研究的顶线结果，有专家认为，KarXT有望被批准用于精神分裂症的整体治疗——如果这一预言成真，pimavanserin将成为首款获批用于治疗精神分裂症阴性症状的药物。 药物名称：AXS-05 研发机构：Axsome Therapeutics 适应症：阿尔茨海默病激越症状 AXS-05是一种新型口服在研N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，具有多种作用机制，用于治疗MDD和其他CNS疾病。AXS-05包含两种有效成分：右美沙芬和安非他酮。右美沙芬是一种非竞争性NMDA受体拮抗剂，安非他酮则用于增加右美沙芬的生物利用度，它也是一种去甲肾上腺素和多巴胺再摄取抑制剂。 AXS-05此前曾获得FDA突破性疗法认定，用于治疗MDD和阿尔茨海默病激越症状。它在2022年8月被FDA批准用于治疗MDD成人患者，成为了60多年来，首款具有新作用机制的抑郁症口服疗法。 AXS-05治疗阿尔茨海默病激越症状的研究已迈入3期临床试验阶段。试验结果表明，与安慰剂相较，AXS-05可造成阿尔茨海默病患者激越症状复发风险下降3.6倍（HR：0.275，p=0.014），同时显著降低患者的激越症状复发率。 基于这些结果，以及在2/3期ADVANCE-1研究中观察到的积极临床数据，Axsome公司表示将与美国FDA会面，讨论下一步的发展。 药物名称：NRX-101 研发机构：NRx Pharmaceuticals 适应症：双相抑郁症 NRX-101是第一种针对严重双相抑郁症和急性自杀意念/行为的在研药物，上述病症目前只能通过电休克疗法治疗。NRX-101由一种固定剂量的D-环丝氨酸和鲁拉西酮组成，靶向大脑的NMDA受体。NRX-101目前正处于3期临床研究中，今年1月，NRx公司宣布已经确定了第一个试验地点，预计在今年年初完成给第一批具有自杀意念的患者给药。 此外，围绕NRX-101还有一项2b/3期试验正在进行中，旨在治疗那些对于出现耐药性的自杀性双相抑郁症患者，该试验的数据预计在今年第四季度公布。 药物名称：Troriluzole 研发机构：Biohaven 适应症：强迫症 根据美国国家心理健康研究所的数据，强迫性障碍（强迫症）是一种以无法控制、反复出现的想法和行为为特征的慢性疾病。仅在美国，2022年有大约1.2%的成年人遭受到强迫症的困扰。 Troriluzole是一种新型的谷氨酸盐调节剂。谷氨酸盐是人体神经系统中重要的兴奋性神经递质之一，troriluzole的主要作用机制是减少神经突触间的谷氨酸盐。该候选药可通过提高位于神经胶质细胞的兴奋性氨基酸转运体的表达及功能，来增加谷氨酸盐再摄取，从而达到减少突触间的谷氨酸水平的目的。 Troriluzole正在被开发用于治疗强迫症和脊髓小脑共济失调，在开放标签和安慰剂对照临床试验中，最新的临床数据支持了troriluzole在强迫症治疗中的应用。Biohaven公司表示，预计今年年底将完成troriluzole治疗强迫症的3期研究的受试者招募。 药物名称：Fasedienol 研发机构：VistaGen Therapeutics 适应症：社交焦虑症 根据美国焦虑和抑郁协会的数据，仅在美国，社交焦虑症影响了大约1500万成年人，VistaGen开发的一款药物fasedienol将有望为上述人群提供帮助。Fasedienol是一种快速起效的在研鼻喷雾剂，具新颖的作用机制，可调节恐惧和焦虑的嗅觉-杏仁核神经回路，减弱交感神经自主神经系统的张力，目前正在3期临床试验中进行测试。 不久前，VistaGen公布了其临床3期PALISADE-2试验的积极结果，与安慰剂相比，试验组患者在公开演讲挑战中表现出平均主观痛苦单位量表（SUDS）评分显著快速下降——SUDS是一种经过验证的工具，用于测量痛苦、焦虑、愤怒和其他类似负面情绪的强度。试验中fasedienol鼻喷剂耐受性良好，未发现重度或严重不良事件，所观察到的治疗伴发不良事件均为轻度或中度。 总体来看，神经精神疾病治疗的潜力巨大。许多创新疗法正在研发中，它们有望改变全球数百万患者的生活质量。无论是基于全新作用机制的新药分子，还是被发现具有新适应症的现有化合物分子，当前的研发进展都非常令人期待。当然，该领域仍面临许多挑战，但是，到目前为止，已经取得的进展足以让我们对未来持乐观态度。随着我们对大脑的复杂机制及神经精神疾病的根本原因逐步加深了解，我们有理由期待一个遍布有效治疗方法的未来，使每一位患者都能从中受益。 大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料：[1] The Neuropsychiatric Pipeline: 10 Late-Stage Therapies to Watch，Retrieved August 20, 2023, from https://www.biospace.com/article/the-neuropsychiatric-pipeline-10-late-stage-therapies-to-watch-/ 内容来源于网络，如有侵权，请联系删除。