The study will evaluate the efficacy, safety, and tolerability of 450 milligrams (mg) of Rapastinel, compared to 10 mg of Vortixetine and placebo in participants with major depressive disorder (MDD).

开始日期2019-07-01

申办/合作机构

Naurex, Inc.

NCT03814733 / Completed临床1期

A Phase 1, Randomized, Double-blind, Double-dummy, Placebo-controlled, 5-period, Crossover Study Assessing the Effects of Rapastinel Compared to Alprazolam, Ketamine, and Placebo on Simulated Driving Performance in Normal Healthy Participants

Based on the pharmacological class of rapastinel, this study will be conducted to evaluate the participant's driving performance after single IV doses of rapastinel as compared with single oral doses of alprazolam, a benzodiazepine that demonstrates driving impairment, and placebo in healthy participants.

开始日期2018-11-05

申办/合作机构

Naurex, Inc.

NCT03799900 / Completed临床1期

A Two-part, Single-dose, Randomized, Double-blind, Placebo and Active-Controlled Crossover Study to Evaluate the Abuse Potential of Rapastinel in Healthy, Non-dependent, Adult Recreational Polydrug Users

Based on the pharmacological class of rapastinel, this study will be conducted to evaluate the abuse potential of single doses of rapastinel as compared with ketamine, a NMDAR antagonist that is a Schedule III dissociative anesthetic, and placebo in recreational polydrug users.

开始日期2018-11-01

申办/合作机构

Naurex, Inc.

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项与 Naurex, Inc. 相关的文献（医药）

2017-05-01·Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology1区 · 医学

GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine

1区 · 医学

Article

作者: Lopresto, Dora ; Aghajanian, George ; Bang, Eunyoung ; Taylor, Jane ; Liu, Rong-Jian ; Kato, Taro ; Hare, Brendan ; Burgdorf, Jeffery ; Moskal, Joseph ; Duman, Catharine ; Duman, Ronald S

GLYX-13 is a putative NMDA receptor modulator with glycine-site partial agonist properties that produces rapid antidepressant effects, but without the psychotomimetic side effects of ketamine. Studies were conducted to examine the molecular, cellular, and behavioral actions of GLYX-13 to further characterize the mechanisms underlying the antidepressant actions of this agent. The results demonstrate that a single dose of GLYX-13 rapidly activates the mTORC1 pathway in the prefrontal cortex (PFC), and that infusion of the selective mTORC1 inhibitor rapamycin into the medial PFC (mPFC) blocks the antidepressant behavioral actions of GLYX-13, indicating a requirement for mTORC1 similar to ketamine. The results also demonstrate that GLYX-13 rapidly increases the number and function of spine synapses in the apical dendritic tuft of layer V pyramidal neurons in the mPFC. Notably, GLYX-13 significantly increased the synaptic responses to hypocretin, a measure of thalamocortical synapses, compared with its effects on 5-HT responses, a measure of cortical-cortical responses mediated by the 5-HT_2A receptor. Behavioral studies further demonstrate that GLYX-13 does not influence 5-HT₂ receptor induced head twitch response or impulsivity in a serial reaction time task (SRTT), whereas ketamine increased responses in both tests. In contrast, both GLYX-13 and ketamine increased attention in the SRTT task, which is linked to hypocretin-thalamocortical responses. The differences in the 5-HT₂ receptor synaptic and behavioral responses may be related to the lack of psychotomimetic side effects of GLYX-13 compared with ketamine, whereas regulation of the hypocretin responses may contribute to the therapeutic benefits of both rapid acting antidepressants.

2015-11-01·Behavioural brain research3区 · 心理学

Rapastinel (GLYX-13) has therapeutic potential for the treatment of post-traumatic stress disorder: Characterization of a NMDA receptor-mediated metaplasticity process in the medial prefrontal cortex of rats

3区 · 心理学

Article

作者: Burch, Ronald M ; Kroes, Roger A ; Burgdorf, Jeffrey ; Gross, Amanda L ; Moskal, Joseph R ; Schmidt, Mary ; Stanton, Patric K ; Disterhoft, John F ; Zhang, Xiao-lei ; Weiss, Craig

Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Contextual fear extinction (CFE) in rodents has been well characterized and used extensively as a model to study the neurobiological mechanisms of post-traumatic stress disorder (PTSD). Since CFE is NMDA receptor modulated and neural circuitry in the medial prefrontal cortex (MPFC) regulates both depression and PTSD, studies were undertaken to examine the effects of rapastinel for its therapeutic potential in PTSD and to use rapastinel as a tool to study its underlying glutamatergic mechanisms. A 21-day chronic mild unpredictable stress (CUS) rat model was used to model depression and PTSD. The effects of CUS alone compared to No CUS controls, and the effects of rapastinel (3 mg/kg IV) on CUS-treated animals were examined. The effect of rapastinel was first assessed using CUS-treated rats in three depression models, Porsolt, sucrose preference, and novelty-induced hypophagia tests, and found to produce a complete reversal of the depressive-like state in each model. Rapastinel was then assessed in a MPFC-dependent positive emotional learning paradigm and in CFE and again a reversal of the impairments induced by CUS treatment was observed. Both synaptic plasticity and metaplasticity, as measured by the induction of long-term potentiation in rat MPFC slice preparations, was found to be markedly impaired in CUS-treated animals. This impairment was reversed when CUS-treated rats were administered rapastinel and tested 24 h later. Transcriptomic analysis of MPFC mRNA expression in CUS-treated rats corroborated the link between rapastinel's behavioral effects and synaptic plasticity. A marked enrichment in both the LTP and LTD connectomes in rapastinel-treated CUS rats was observed compared to CUS-treated controls. The effects of rapastinel on depression models, PEL, and most importantly on CFE demonstrate the therapeutic potential of rapastinel for the treatment of PTSD. Moreover, rapastinel appears to elicit its therapeutic effects through a NMDA receptor-mediated, LTP-like, metaplasticity process in the MPFC.

2015-11-01·Neuroscience3区 · 医学

The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus

3区 · 医学

Article

作者: Burgdorf, J ; Gross, A ; Weiss, C ; Zhang, X-L ; Boikess, S R ; Stanton, P K ; Rex, C S ; Burch, R M ; Khan, M A ; Disterhoft, J F ; Moskal, J R ; Kroes, R A

Rapastinel (GLYX-13) is an N-methyl-d-aspartate receptor (NMDAR) modulator that has characteristics of a glycine site partial agonist. Rapastinel is a robust cognitive enhancer and facilitates hippocampal long-term potentiation (LTP) of synaptic transmission in slices. In human clinical trials, rapastinel has been shown to produce marked antidepressant properties that last for at least one week following a single dose. The long-lasting antidepressant effect of a single dose of rapastinel (3mg/kg IV) was assessed in rats using the Porsolt, open field and ultrasonic vocalization assays. Cognitive enhancement was examined using the Morris water maze, positive emotional learning, and contextual fear extinction tests. LTP was assessed in hippocampal slices. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex. Significant antidepressant-like or cognitive enhancing effects were observed that lasted for at least one week in each model. Rapastinel facilitated LTP 1day-2weeks but not 4weeks post-dosing. Biweekly dosing with rapastinel sustained this effect for at least 8weeks. A single dose of rapastinel increased the proportion of whole-cell NMDAR current contributed by NR2B-containing NMDARs in the hippocampus 1week post-dosing, that returned to baseline by 4weeks post-dosing. The NMDAR antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked the antidepressant-like effect of rapastinel 1week post dosing. A single injection of rapastinel also increased mature spine density in both brain regions 24h post-dosing. These data demonstrate that rapastinel produces its long-lasting antidepressant effects via triggering NMDAR-dependent processes that lead to increased sensitivity to LTP that persist for up to two weeks. These data also suggest that these processes led to the alterations in dendritic spine morphologies associated with the maintenance of long-term changes in synaptic plasticity associated with learning and memory.

项与 Naurex, Inc. 相关的新闻（医药）

2024-09-12

·药精通Bio

全球在研小分子抗抑郁症新药盘点

Apimostinel CAS : 1421866-48-9 机理：NMDA受体部分激动剂状态：II期（IV）和I期（口服）临床试验开发者：Allergan 也称为NRX-1074，是一种最初由Naurex开发的用于治疗抑郁症的药物-但目前正在由Naurex和Allergan（收购Naurex）共同研究。该药物对NMDA受体具有选择性的部分激动剂的功能，特别是在甘氨酸结合位点的变构位点。虽然Apimostinel表现出GLYX-13（另一种正在由Naurex开发的药物）相似的作用机制，但它与GLYX-13的不同之处在于其重量更显着。一项比较分析表明，按重量计，Apimostinel的效力是GLYX-13的数千倍。之前我已经讨论了使用NRX-1074来治疗抑郁症的潜在好处，并提到它起效快，没有拟精神病作用并且似乎耐受良好。初步证据表明，服用Apimostinel后，抑郁症状可能在24小时内消失。此外，Apimostinel的情绪增强作用似乎是剂量依赖性的，因此更高剂量的抗抑郁作用更为明显。值得一提的是，在早期试验中，单剂量的Apimostinel提供的缓解抑郁症状的症状要比SSRIs持续数周的缓解率更高。 BTRX-246040 CAS : 1307245-86-8 机理: NOC 受体拮抗剂状态: Phase II 开发者: BlackThorn Therapeutics 该药物最初由礼来公司进行研究，但现在似乎与黑刺李疗法联系在一起，并有了一个新的化学名称。2016年发表的一项概念验证研究报告称，LY-2940094(40毫克)是安全的，耐受性好，对治疗人类抑郁症有效——持续时间超过8周。它作为一种抗抑郁药物的初步疗效通过格里-汉密尔顿抑郁评分量表(GRID-Hamilton Depression Rating scale)从基线到8周的17个总分的显著变化得到证明。此外，研究还发现LY-2940094在治疗的第一周内改变了对情绪刺激的处理——在情绪测试系列中，对积极面部表情相对于消极面部表情的认知增强就是证据。LY-2940094的初步调查数据是第一批显示NOP受体拮抗剂治疗抑郁症的潜力的数据。关于BTRX-246040是否将继续用于治疗重度抑郁症，还是将其作为治疗其他神经系统疾病的治疗手段而接受调查，还存在一些争议。然而，与大多数抗抑郁药物相比，BTRX-246040表现出独特的作用机制。拮抗NOC受体似乎能增加大脑几个区域的单胺浓度，增强神经发生，并调节下丘脑-垂体-肾上腺轴的激活。 CERC-301 CAS : 808732-98-1 机理: NMDA 受体 (NR2B-selective) 拮抗剂状态: Phase II 开发者: Cerecor 2013年，FDA授予CERC-301“快速通道指定”，作为抑郁症和自杀意念的潜在辅助治疗药物。药效学研究表明，CERC-301对NMDA受体NR2B亚基具有高选择性拮抗作用。它对NMDA受体NR2B亚基的选择性亲和性被认为可以最大限度地降低与其他非选择性NMDA受体拮抗剂共同发生的拟精神分裂效应(如药物诱导的精神病)的可能性。 CERC-301的显影剂Cerecor表明，CERC-301具有快速的抗抑郁活性，从而在给药几分钟或几小时内就能缓解抑郁症状，而不是几天或几周。来自CERC-301试验的初步数据表明，该药物耐受性良好且安全。许多人认为，CERC-301是正在开发的治疗抑郁症的NMDA拮抗剂中最有前途的。 CERC-501 CAS : 1174130-61-0 机理: KOR 拮抗剂状态: Phase III 开发者: Janssen CERC-501是美国礼来公司首次研发的药物，名为LY-2456302。然而，在2015年2月，礼来公司将LY-2456302卖给了Cerecor公司，后者将其更名为CERC-501。2016年，CERC-501作为一种抗抑郁II期临床试验难治性抑郁症患者达到效果。截至2017年8月，Cerecor将CERC-501出售给了Janssen Pharmaceuticals，后者正在继续开发其作为抑郁症的辅助疗法和药物滥用障碍的干预疗法。药效学评估显示，CERC-501是一种选择性的、短效的KOR (kappa阿片受体)拮抗剂。研究表明，激活kappa类阿片受体(KORs)会引发烦躁、幻觉和精神幻像效应——同时也会强化神经化学系统，与奖赏缺乏综合症、慢性压力和重度抑郁症有关。用CERC-501拮抗kappa阿片受体(KOR)可能通过抵消已有的kappa阿片受体激活而促进抗抑郁效果。CERC-501与其他抗抑郁药(如SSRIs)联合使用可产生协同情绪增强作用(或比单独使用任何一种药物效果更好)。有报道称，在三期临床试验中，CERC-501的副作用不严重。 Liafensine (DB104) CAS:1198790-53-2 机理: SNDRI 状态: Phase II 开发者: Denovo Biopharma Liafensine (DB104)，原名BMS-820836，是一种SNDRI(5 -羟色胺-去甲肾上腺素-多巴胺再摄取抑制剂)或三层再摄取抑制剂，最初由AMRI开发，授权给百时美施贵宝治疗重度抑郁症。通过二期临床试验，该药物表现出与依西酞普兰(即依地普仑)和度洛西汀(即欣百达)相似的疗效。但百时美施贵宝终止其开发，主要原因是其疗效并不明显优于依地普乐和欣百达。它的疗效相对于副作用和滥用潜力可能是Liafensine 被百时美施贵宝停止开发的原因。2017年，Denovo Biopharma获得了Liafensine的许可权，三重再摄取抑制剂的二期临床试验仍在继续。 JNJ-39393406 CAS : 953428-73-4 机理: Alpha-7 nAChR 调制器状态: Phase II 开发者: Janssen JNJ-39393406用于治疗重度抑郁症和戒烟。与目前市场上大多数抗抑郁药相比，JNJ-39393406的独特之处在于，它仅作为-7烟碱乙酰胆碱受体的选择性正变构调制器(PAM)。药效学研究表明，该药物不会与-4-beta-2或-3-beta-4尼古丁乙酰胆碱受体或- 5-HT3受体相互作用。更重要的是，药物似乎并没有与62种受体和酶相互作用。截至2018年2月，JNJ-39393406正在进行治疗重度抑郁症和尼古丁戒断的II期临床试验。JNJ-39393406以前被研究作为阿尔茨海默病和精神分裂症的干预措施，但是，经评估后被放弃了。 Ansofaxine (LY03005) CAS : 916918-84-8 机理: SNDRI 状态: Phase I 开发者: 绿叶制药盐酸Ansofaxine(LY03005)是绿叶制药集团开发的用于治疗中重度抑郁症的三重摄取抑制剂(5 -羟色胺-去甲肾上腺素-多巴胺)。对Ansofaxine的药效学评价表明，它具有SNDRI的作用，是去文拉法辛的前药。然而，与去文拉法辛(即Pristiq)相比，Ansofaxine在同时调节血清素和去甲肾上腺素的同时，具有显著的多巴胺能效应。到目前为止，Ansofaxine已经在两个人体试验中进行了评估，分别有72名和48名参与者。从现有的I期试验数据来看，Ansofaxine在40毫克至160毫克的剂量下似乎具有良好的耐受性和安全性。绿叶制药集团认为，与目前市面上的抗抑郁药相比，这种新药的副作用更少，起效更快。 MIN-117 CAS : 310392-93-9 机理: SDRI 状态: Phase II 开发者: Minerva Neurosciences MIN-117是一种血清素-多巴胺调制器，由Minerva神经科学公司开发用于治疗重度抑郁症。其作用机制针对受体和转运体的结合，包括:α- 1a受体;α-1B受体;5-HT2A受体;SERT(羟色胺转运体);和DAT(多巴胺转运体)。具体来说，MIN-117被证明是一种5-HT1A和5-HT2A拮抗剂;血清素和多巴胺再摄取抑制剂;α- 1a和α- 1b肾上腺素能受体调节剂。 Minerva神经科学提示MIN-117旨在解决重性抑郁症伴有共病焦虑或焦虑症状的患者的未控制症状。开发人员推测MIN-117将比目前市场上的大多数抗抑郁药物反应更快、更安全、耐受性更好。目前MIN-117作为干预抑郁症的临床试验正处于II期。 Seltorexant (MIN-202) CAS : 1293281-49-8 机理: Orexin-2 拮抗剂状态: Phase II (complete) 开发者: Minerva Neurosciences & Janssen Seltorexant，又称MIN-202 (Minerva)和JNJ-42847922或JNJ-922 (Janssen)，是一种正在研究中的小分子、选择性orexin受体拮抗剂，由Minerva神经科学和Janssen开发。临床试验正在评估Seltorexant对重度抑郁症和失眠的治疗效果。据开发人员介绍，Seltorexant可以阻断大脑中促进觉醒的神经元的激活，特别是通过与orexin 2 (Orx-2)受体结合。 NSI-189 CAS : 1270138-40-3 机理: 神经发生诱导物状态: Phase III (?) 开发者: Neuralstem Inc. NSI-189是由Neuralstem公司开发的一种实验性药物，用于治疗重度抑郁症、认知障碍和神经退行性疾病。NSI-189是通过超过10000个化合物筛选，以确定哪些在体外(细胞)诱导最大程度的神经发生。NSI-189在体外和啮齿类动物中都表现出了疗效，随后将在患有重度抑郁症的人身上进行测试。在II期临床试验中，NSI-189通过降低220名重性抑郁症患者的MADRS评分而未能达到其主要终点。NSI-189仍将继续接受神经系统和中枢神经系统疾病的治疗评估，包括:神经病、缺血性中风和认知障碍。 Rapastinel (GLYX-13) CAS : 117928-94-6 机理: NMDA 受体调制器状态: Phase III 开发者: Allergan Rapastinel(原名GLYX-13)是Allergan公司开发的一种药物(在收购Allergan之前由Naurex公司进行测试)，作为治疗耐药性抑郁症(或对2种或2种以上一线干预无效的抑郁症)的辅助干预手段。这种药物在口服时是不活跃的，而在静脉注射时是特别设计的。它在NMDA受体复合物的甘氨酸亚基的变构位点起选择性、适度的局部激动剂(混合拮抗剂/激动剂)的作用。初步证据表明Rapastinel作用快速，并产生长期的抗抑郁反应。此外，Rapastinel似乎是通过抑制和增强NMDA受体介导的信号转导而增强认知功能的。无论动物年龄多大，给动物服用Rapastinel能增强记忆和学习能力，还能促进神经保护作用。 Rapastinel被归类为一种glyxin化合物，来源于修改单克隆抗体的结构，调节NMDA受体，称为“B6B21”。基于初步的试验数据，Rapastinel是治疗难治性抑郁症最有希望的治疗手段之一。 SAGE-217 CAS : 1632051-40-1 机理: GABAA受体调制器状态: Phase III 开发者: Sage Therapeutics Sage -217是由Sage Therapeutics公司研发的一种研究性化学药物，用于治疗重度抑郁症和产后抑郁症，以及帕金森病、失眠和癫痫的原发性震颤。据Sage Therapeutics公司介绍，Sage -217是一种合成的孕烷神经类固醇，它是GABAA受体的一种正变构调制器。SAGE-217的目标是改进并继承Brexanolone ——另一种圣人治疗抑郁症的药物，目前已进入临床试验阶段。在用于治疗女性产后抑郁症(PPD)患者的3期试验ROBIN中，达到了试验的主要和次要终点。重症抑郁三期失败。 Travivo (Gepirone ER) CAS:83928-66-9;83928-76-1 机理: 5-HT1A 选择性部分激动剂状态: 等待 FDA 批准开发者: Fabre-Kramer Pharmaceuticals Travivo (Gepirone ER)是一种抗抑郁药物，最初因疗效问题被FDA多次拒绝。它第一次被否决是在2004年，然后在2007年再次被否决。FDA在2015年审查了Gepirone的数据，推翻了他们最初对该药物的排斥——给予了有利的评价。2016年3月FDA对Travivo (Gepirone ER)治疗重度抑郁症的疗效进行了有利的规定。参考原文：30+ New Antidepressants (2018): Drugs In Clinical Trials TIS2024第四届自免疾病细胞疗法与干细胞疗法论坛重磅来袭，点击图片查看重磅嘉宾，合作详询：王晨 180 1628 8769 （扫码立即报名获取TIS2024免费票）

临床2期快速通道临床1期并购

2024-05-08

·PRNewswire

Alcyone Therapeutics Announces Appointment of Dr. Norbert Riedel as Chairman of the Board and Dr. Kathrin Meyer as Chief Scientific Officer and Head of Research & Development

--Key Additions to Executive Team as Alcyone Continues Clinical Progress-- LOWELL, Mass., May 8, 2024 /PRNewswire/ -- Alcyone Therapeutics, a clinical-stage biotechnology company pioneering next-generation precision genetic therapies for complex neurological conditions, today announces appointments of Norbert Riedel, Ph.D., a skilled and experienced biopharmaceutical executive, as the Chairman of its Board of Directors, and Kathrin Meyer, Ph.D., a leader in development and clinical translation of genetic therapies for the central nervous system (CNS), as Alcyone's new Chief Scientific Officer and Head of R&D. "I am delighted and honored to join the board of Alcyone Therapeutics," said Dr. Riedel. "The company is developing innovative precision genetic therapies for diseases of the central nervous system and has obtained highly promising clinical results using its proprietary intrathecal drug delivery platform. I am very excited about the programs we have in development to address the significant unmet patient needs in several neurological indications." "Developing neurological genetic therapies demands both a highly precise biological mechanism of action and effective delivery to the central nervous system. At Alcyone, we're uniquely positioned to merge optimized delivery and biodistribution with next-generation gene expression technology. This combination has the potential to revolutionize patient care, offering safer, more accessible, and more effective treatments. I'm thrilled to be a part of Alcyone, contributing to the advancement of therapies that can truly make a difference in the lives of patients and their families," said Dr. Meyer. "With a history of innovation in developing technologies for the treatment of CNS disorders, Alcyone is rapidly advancing the development of novel precision genetic therapies for X-linked diseases, including a next-generation Rett Syndrome therapy and precision delivery and biodistribution systems," said PJ Anand, Chief Executive Officer of Alcyone Therapeutics. "Drs. Riedel and Meyer bring extraordinary skills and an immense network in the development of life-altering therapies as well as significant and relevant experience in the building of innovative companies. We are excited to welcome them to Alcyone as we embark on our next stage of growth. Dr. Riedel has decades of leadership experience in large healthcare companies and in the biotechnology industry with a proven track record in successful company building, fundraising, and developing therapeutics across multiple indications for the CNS. His extensive industry experience includes roles as President and CEO of Aptinyx Inc., President and CEO of Naurex which was acquired by Allergan, and corporate Vice President and Chief Science and Innovation Officer at Baxter International. Dr. Riedel holds a Ph.D. and a Diploma in Biochemistry from the University of Frankfurt and serves on the boards of Jazz Pharmaceuticals, Eton Pharmaceuticals, and the Illinois Biotechnology Innovation Organization. Until its acquisition by Abbvie, he is also a member of the board of directors of Cerevel Therapeutics Holdings. Dr. Kathrin Meyer is a pioneer in the research and clinical development of novel therapies for the CNS. Until recently, Dr. Meyer was a Principal Investigator at Nationwide Children's Hospital, Abigail Wexner Research Institute Center for Gene Therapy, and an Assistant Professor at The Ohio State University in Ohio. During Dr. Meyer's post-doctoral research and then tenure at Nationwide Children's, she played a key role in the successful first-in-human translation of several genetic therapies, including Zolgensma®, intrathecal Zolgensma®, Batten's disease, Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) and Charcot Marie Tooth type 2 (CMT2S). She is a co-inventor of Alcyone's miREX™ microRNA gene expression platform with a focus on Rett Syndrome and other X-linked disorders. Dr. Meyer holds a Ph.D. in the area of molecular and cellular biology from the University of Bern in Switzerland. About Alcyone Therapeutics Alcyone Therapeutics is a clinical-stage biotechnology company pioneering next-generation precision gene-based therapies for neurological conditions. The company integrates innovation in neuroscience and precision dosing platforms to deliver transformative therapies to patients. Alcyone leverages the synergy between Falcon™, the company's proprietary intrathecal precision dosing and biodistribution platform and novel genetic therapeutic platforms. Falcon™ incorporates deep knowledge of cerebral spinal fluid (CSF) dynamics, computational modeling, and bioengineering. This comprehensive approach optimizes central nervous system dosing and delivery to better target the pathophysiology and anatomy specific to various neurological diseases. Alcyone's X-reactivation genetic therapy platform was developed at the Abigail Wexner Research Institute at Nationwide Children's Hospital (AWRI) and the University of Virginia and allows expression and upregulation of X-linked genes for the treatment of X-linked disorders including Rett Syndrome. Alcyone has a license and collaboration agreement with a large-cap biopharmaceutical company to evaluate its novel CNS delivery device to improve patient experience and access to neurological antisense oligonucleotide (ASO) genetic therapies. For more information, visit . Media and Investor Contact PJ Anand, Chief Executive Officer Alcyone Therapeutics 978-709-1946 [email protected] SOURCE Alcyone Therapeutics

高管变更并购引进/卖出寡核苷酸

2024-04-02

·研发客

CNS如何用AI找精准患者？| 行业观察

// 从1期临床至上市成功率仅有5.9%的CNS药物，AI为其开辟了新机遇，包括难以在CNS领域应用的靶向疗法。“知识驱动的常规药物研发模式在CNS领域遭遇瓶颈期，加之过去15年积累的疾病组学和药物临床大数据，因而给予了数据驱动CNS药物研发新契机。”普百思生物创始人包杨欢如是分析。利用AI驱动CNS疾病研发，目前国内外均已有企业布局，且已有部分成果出现：一是从已有研究数据中筛选和验证老药的新途径，预测药物联用组合的疗效和副作用；二是发现新靶点和新机理；三是为特定患者亚群匹配更可能有效的药物。筛选生物标志物多年的基因组和遗传学研究表明，除了ALS、亨廷顿病、家族性AD等只有少数几种亚型，大部分CNS疾病的风险基因有上百个，每个都对发病产生一定程度的贡献，且各致病基因间相互关系并不清楚。这也意味着，类似针对“驱动基因”的肿瘤靶向疗法在CNS领域很难推广开来，给CNS疾病新机理的开发增加了更多难度。但也正是各类CNS疾病之间存在很强的关联性，底层生物学致病机制存在相通之处，包杨欢认为，CNS药物研发应着重靶向这些机制，即CNS疾病的“靶向疗法”。连接这些疾病的底层机制是什么？包杨欢做出解释。普百思创始人包杨欢在中枢神经上游的压力应激、神经免疫炎症和下游的神经突触损伤三个通路中，各类疾病都存在相同之处，例如抑郁症、精神分裂、双向情感障碍、阿尔茨海默病等疾病，压力激素失调、神经免疫炎症指标偏高、神经突触损伤导致的认知受损，在相当一部分患者中能检测出来，这正是“靶向疗法”瞄准的精准亚群。以“房屋着火”解释三个通路的原理。“房屋着火”时，最明显标志是中游的“火焰”，这是目前研究较多的方向，例如精神类药物靶向的神经递质和AD药物靶向的错误折叠蛋白。而如果只针对火焰，可能暂时扑灭，但无法完全解决问题。上游没被熄灭的“火源”（应激和炎症）容易复燃，下游对房屋造成的损伤没被修复（突触、神经、髓鞘损伤），疾病也不能完全被治愈。以神经突触损伤通路为例。当突触功能损伤后易导致认知功能障碍，斯坦福大学研究人员在重度抑郁症（MDD）中发现一类认知受损亚群，占MDD患者约27%，且对常规治疗反应不佳。该领域中已有企业开启研究，Alto Neuroscience公司的ALTO-100就是治疗以神经认知损伤为特征的MDD患者。由此也体现出生物标志物筛选的重要性，富集出与有效药物发挥疗效相匹配的亚群。富集用药人群越精准，临床获益越好。ALTO-100的2a数据显示，单药治疗时，81%神经认知受损的患者获得临床应答，而一般患者只有38%。另一款以脑电生物标志物为特征的ALTO-300，其2a期临床试验发现，通过生物标志物识别的患者与无生物标志物的患者，两者的临床缓解分别是47%与27%。而生物标志物的应用并非一帆风顺，但在不断研究中也给临床进展不顺的项目带来了希望。索元生物2017年从BMS引入治疗难治性抑郁症的DB104后，历经3年至2020年才发现生物标志物DGM4。在DGM4阳性的病人中，DB104的抗抑郁效果极为显著。用于治疗重度抑郁症（MDD）的zelquistinel同样充满波折，产品最初由Naurex发现，后辗转经过艾尔建、艾伯维，最后被Gate Neurosciences引进，目前已经完成了多项1期脑电图生物标志物研究，将在2a期临床中利用EEG生物标志物平台，深入探索产品对MDD亚群的疗效。挑战老药新用相比针对精准亚群的靶向疗法，“老药新用”研发策略是更多CNS企业选择的开发思路。事实上，很多老机制老靶点只是在临床阶段被研究多年，并未上市，只是科学研究意义上的“老”。例如KarXT中的组分xanomeline，最早于上世纪90年代开发，因不良反应被放弃，2018年才被Karuna重启与trospium组成复方制剂。包杨欢认为，未来5~8年有可能上市的新药将还是这些“老面孔”。老药新用是建立在过往几十年积累的大量试验数据和临床经验基础上，寻找有初步疗效数据的老靶点、老分子的机会。另外，鲁白教授和管小明博士共同创立的福贝生物，在与英矽智能2021年达成的AI平台合作中，也采用了老药新用策略。由英矽智能PandaOmics平台开发的FB1006，已启动IIT并完成64例患者入组。拓展阅读中国新药猎手｜遇见鲁白（上）中国新药猎手｜遇见鲁白（下）英矽智能：AI全程推动研发的样本根据普百思的统计，2019年至今，已有6款老药新用获批的CNS药物（见下表）。如，治疗产后抑郁症（PPD）的zuranolone由四氢孕酮改良而来，先改良为注射液brexanolone于2019年获批，后再制成口服制剂zuranolone于2023年批准上市。zuranolone是老药新用中微改良的典型案例。另一种常见模式是联用，受访两位专家也更看重联用方式。阿斯诺来创始人周显波谈到，老药的联用主要解决两类问题。一类是利用其中一个药物解决另一个药物的缺陷和副作用。例如被BMS收购的KarXT，是利用trospium缓解蕈毒胆碱M1/M4受体双激动剂xanomeline的毒副作用，1期临床数据显示加入trospium后确实能使药物副作用下降46%。另一款药物Axsome的Auvelity，是利用安非他酮解决右美沙芬的代谢问题，提高右美沙芬的生物利用度。阿斯诺来创始人周显波另一类是两个药物协同发挥作用。AMX0035是苯丁酸钠+牛磺酸二醇两个组分联合的老药，两款老药获批多年，因此安全性已获得验证，联合后发现产品能改善线粒体功能和内质网的健康状态、延缓神经细胞死亡，在ALS治疗中看到积极疗效，从而获得FDA批准。“联用效果更好的原因是，CNS疾病具有致病位点多、患者异质性高的特点，同时靶向多个位点的药物或者不同机制的药物联用，往往效果更好，副作用更小，复发率更低。”包杨欢如是解释。而两款老药如何在增加疗效同时减少副作用，发挥协同效果，是周显波谈到的老药新用在实际研究过程中遇到的挑战之一。例如近期AMX0035被宣布3期验证性研究失败，开发公司Amylyx表示将撤市该产品。拓展阅读Relyvrio失败对渐冻症药物试验设计的启示另一项挑战是专利问题，包括如何获取老药专利，以及联用后的新组合药物的专利保护问题。包杨欢认为，很多人把老药等同于没有专利保护，事实上国际已上市的老药新用都有一整套IP保护策略，也就是说，其他公司很难在近期简单仿制。新趋势：表型筛选目前进入临床阶段的大多数企业还是从老机制、老靶点出发，但总有企业致力于寻找新机理、新靶点，并在原始创新途中获得关注和机遇。成立于2015年的AI药物发现公司Verge Genomics，就不断获得MNC青睐：2021年与礼来达成价值近7亿美元的合作，共同开发ALS创新疗法；2023年9月，与阿斯利康的罕见疾病部门Alexion建立高达8.4亿美元的合作，寻找和验证不常见的新药物靶点。不仅如此，礼来和默克还参与了Verge近1亿美元B轮融资。吸引MNC不断加码的是Verge的ConVERGE平台，其特点是利用机器学习直接分析源于人体组织的基因组数据以发现新兴靶点，而不是动物模型数据。首个研发产品VRG50635创新性靶向PIKfyve，是治疗ALS的潜力靶点，可恢复ALS患者神经元的内溶酶体功能，并在ALS相关运动神经元变性模型中的多项临床前研究中显示出疗效，2024年1月启动了1b期概念验证研究。从Verge身上能看到，致力于新靶点的CNS药物研发还存在潜力和机遇。同时，国内的原始创新企业也在冉冉升起。国内企业中，卓凯生物的05061是全球首个抑制遗忘分子Rac1活性的阿尔茨海默症新药，通过果蝇表型筛选平台以表型筛选的方式研发而来。阿斯诺来引进的AN1001同样是通过表型筛选而来，是全球唯一口服通过肠道分布GPCR靶向迷走神经的多肽药物，2022年已在澳洲完成1期临床。据周显波介绍，AN1001是通过迷走神经脑肠轴起效，因此能避开血脑屏障阻碍，1期临床结果显示，产品已观察到脑电波量效关系的改变，安全性和生物学活性已得到初步验证。可以看到，卓凯生物和阿斯诺来药物研发的共同特点是通过表型筛选发现新药，也代表了目前CNS药物研发的新趋势。海外进展较快从已公开信息发现，在CNS新药研发应用AI并取得初步积极的临床数据方面，海外企业的进展较快。Alto Neuroscience管线中有6款产品进入临床阶段，其中ALTO-100和ALTO-300已分别在超过200名患者完成临床2a期试验，并均推进至2b期。两款均已在2a期研究中取得积极结果，以ALTO-300为例，产品给药后，通过脑电生物标志物识别出的部分患者在抑郁症状上观察到明显的临床改善和更高的缓解率。Neumora Therapeutics公司有4款产品进入临床阶段，其中治疗重度抑郁症（MDD）的NMRA-140已启动3期临床，另一项治疗精神分裂症的NMRA-266，分子机制与艾伯维收购Cerevel的潜力药物emraclidine相同，靶向新型毒蕈碱M4受体。有意思的是，这两家公司均成立于2019年，仅成立4年后已成功推动产品进入临床，且Neumora于2023年在纳斯达克上市，Alto则于近期成功登陆纽交所。产品的快速推进和IPO进度，将为其他CNS开发企业提供参考的样本。编辑 | 姚嘉yao.jia@PharmaDJ.com 总第2081期访问研发客网站可浏览更多文章www.PharmaDJ.com

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药物(靶点)	适应症	全球最高研发状态

雷帕替奈 ( NMDA receptor )	重度抑郁症更多	终止
Apimostinel ( NMDA receptor )	精神分裂症更多	终止
NRX-1059 ( NMDA receptor )	精神分裂症更多	终止
NRX-1050 series (Naurex) ( NMDA receptor )	抑郁症更多	无进展
Zelquistinel ( NMDA receptor )	重度抑郁症更多	无进展