排名前五的靶点	数量

KCa4.1(potassium sodium-activated channel subfamily T member 1)	2
Nav1.2(II型钠通道蛋白α亚基)	2
Sodium channels(钠通道)	1
T-type calcium channel(电压门控性T型钙通道家族)	1
VGSCs(电压门控钠离子通道)	1

关联

项与 Praxis Precision Medicines, Inc. 相关的药物

Ulixacaltamide

靶点

T-type calcium channel

作用机制

T-type calcium channel阻滞剂

在研机构

元羿生物科技（上海）有限公司 [+1]

原研机构

Praxis Precision Medicines, Inc.

在研适应症

特发性震颤 [+1]

非在研适应症-

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期-

PRAX-628

靶点

VGSCs

作用机制

电压门控钠离子通道阻滞剂

在研机构

Praxis Precision Medicines, Inc.

原研机构

Praxis Precision Medicines, Inc.

在研适应症

癫痫

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期-

Relutrigine

靶点

Sodium channels

作用机制

钠通道阻滞剂

在研机构

Praxis Precision Medicines, Inc.

原研机构

Praxis Precision Medicines, Inc.

在研适应症

SCN2A突变脑病 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期-

项与 Praxis Precision Medicines, Inc. 相关的临床试验

CTIS2024-514426-23-01 / Recruiting

- PRAX-628-102

开始日期2024-08-28

申办/合作机构

Praxis Precision Medicines, Inc.

NCT06087276 / Recruiting临床3期

Phase 3, Decentralized, Randomized, Double-Blind, Placebo Controlled, Parallel Design, Randomized Withdrawal, and Long-term Safety Study to Evaluate the Efficacy and Safety of Ulixacaltamide (PRAX-944) in Adults With Essential Tremor

The goal of this clinical study is to compare ulixacaltamide and placebo treatment in essential tremor. The main question it aims to answer is:
• Is ulixacaltamide a safe and efficacious treatment for patients with essential tremor?
Participants will be asked to participate in one of two clinical studies where they will be treated with either ulixacaltamide or placebo for a period of up to 12 weeks. After the controlled study completion, they will be eligible to participate in a long-term, open-label safety study and be treated with ulixacaltamide.

开始日期2023-11-02

申办/合作机构

Praxis Precision Medicines, Inc.

CTIS2022-502298-41-00 / Recruiting

A Phase 2, Double-Blind, Randomized Clinical Trial to Explore the Safety, Tolerability, Efficacy, and Pharmacokinetics of PRAX-562 in Pediatric Participants with Developmental and Epileptic Encephalopathies Followed by an Open-Label Extension - PRAX-562-221

开始日期2023-08-23

申办/合作机构

Praxis Precision Medicines, Inc.

100 项与 Praxis Precision Medicines, Inc. 相关的临床结果

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0 项与 Praxis Precision Medicines, Inc. 相关的专利（医药）

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项与 Praxis Precision Medicines, Inc. 相关的文献（医药）

2023-01-01·Frontiers in neurology

SCN1A channelopathies: Navigating from genotype to neural circuit dysfunction.

Review

作者: Petrou, Steven ; Bryson, Alexander

The SCN1A gene is strongly associated with epilepsy and plays a central role for supporting cortical excitation-inhibition balance through the expression of Na_V1.1 within inhibitory interneurons. The phenotype of SCN1A disorders has been conceptualized as driven primarily by impaired interneuron function that predisposes to disinhibition and cortical hyperexcitability. However, recent studies have identified SCN1A gain-of-function variants associated with epilepsy, and the presence of cellular and synaptic changes in mouse models that point toward homeostatic adaptations and complex network remodeling. These findings highlight the need to understand microcircuit-scale dysfunction in SCN1A disorders to contextualize genetic and cellular disease mechanisms. Targeting the restoration of microcircuit properties may be a fruitful strategy for the development of novel therapies.

2022-05-01·Molecular psychiatry1区 · 医学

Highly unstable heterogeneous representations in VIP interneurons of the anterior cingulate cortex

1区 · 医学

Article

作者: Jimenez, Jessica C ; Spevack, Eli D ; Kretsge, Lisa N ; Melzer, Sarah ; Wingfield, Kelly K ; Cho, Eun Seon ; Johnson, Connor ; Jinadasa, Tushare J ; Hausmann, Frances S ; Cruz-Martín, Alberto ; Sriram, Balaji ; Phadke, Rhushikesh A ; Fuchs, Erelle ; O'Connor, Alexandra ; Fournier, Luke A ; Velasco, Berta Escude ; Liu, Ruichen Sky ; Nguyen, Thanh P H ; Yeung, Charlotte ; Brack, Alison ; Yen, William W

A hallmark of the anterior cingulate cortex (ACC) is its functional heterogeneity. Functional and imaging studies revealed its importance in the encoding of anxiety-related and social stimuli, but it is unknown how microcircuits within the ACC encode these distinct stimuli. One type of inhibitory interneuron, which is positive for vasoactive intestinal peptide (VIP), is known to modulate the activity of pyramidal cells in local microcircuits, but it is unknown whether VIP cells in the ACC (VIP^ACC) are engaged by particular contexts or stimuli. Additionally, recent studies demonstrated that neuronal representations in other cortical areas can change over time at the level of the individual neuron. However, it is not known whether stimulus representations in the ACC remain stable over time. Using in vivo Ca²⁺ imaging and miniscopes in freely behaving mice to monitor neuronal activity with cellular resolution, we identified individual VIP^ACC that preferentially activated to distinct stimuli across diverse tasks. Importantly, although the population-level activity of the VIP^ACC remained stable across trials, the stimulus-selectivity of individual interneurons changed rapidly. These findings demonstrate marked functional heterogeneity and instability within interneuron populations in the ACC. This work contributes to our understanding of how the cortex encodes information across diverse contexts and provides insight into the complexity of neural processes involved in anxiety and social behavior.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Distinctivein vitrophenotypes in iPSC-derived neurons from patients with gain- and loss-of-functionSCN2Adevelopmental and epileptic encephalopathy

Article

作者: Menheniott, Trevelyan ; Jia, Linghan ; Apted, Danielle ; Berecki, Geza ; Nemiroff, Alex ; Mao, Miaomiao ; Pachernegg, Svenja ; Cuddy, Claire ; Rollo, Ben ; Heighway, Jacqueline ; Byars, Sean ; Reid, Christopher A ; Dalby, Kelley ; Maljevic, Snezana ; Mattei, Cristiana ; Petrou, Steven ; Mullen, Saul

SCN2Aencodes NaV1.2, an excitatory neuron voltage-gated sodium channel and a major monogenic cause of neurodevelopmental disorders, including developmental and epileptic encephalopathies (DEE) and autism. Clinical presentation and pharmocosensitivity vary with the nature ofSCN2Avariant dysfunction and can be divided into gain-of-function (GoF) cases with pre- or peri-natal seizures and loss-of-function (LoF) patients typically having infantile spasms after 6 months of age.We established and assessed patient induced pluripotent stem cell (iPSC) - derived neuronal models for two recurrentSCN2ADEE variants with GoF R1882Q and LoF R853Q associated with early- and late-onset DEE, respectively. Two male patient-derived iPSC isogenic pairs were differentiated using Neurogenin-2 overexpression yielding populations of cortical-like glutamatergic neurons. Functional properties were assessed using patch clamp and multielectrode array recordings and transcriptomic profiles obtained with total mRNA sequencing after 2-4 weeks in culture.At 3 weeks of differentiation, increased neuronal activity at cellular and network levels was observed for R1882Q iPSC-derived neurons. In contrast, R853Q neurons showed only subtle changes in excitability after 4 weeks and an overall reduced network activity after 7 weeksin vitro. Consistent with the reported efficacy in some GoFSCN2Apatients, phenytoin (sodium channel blocker) reduced the excitability of neurons to the control levels in R1882Q neuronal cultures. Transcriptomic alterations in neurons were detected for each variant and convergent pathways suggested potential shared mechanisms underlyingSCN2ADEE.In summary, patient iPSC-derived neuronal models of SCN2A GoF and LoF pathogenic variants causing DEE show specific functional and transcriptomic in vitro phenotypes.Significance statementSCN2Aencodes one of the major brain voltage-gated sodium channels, NaV1.2, and is a major monogenic cause of neurodevelopmental disorders, including severe infantile epilepsy and autism. SCN2A pathogenic variants cause either gain or loss of channel function, which correlates well with the clinical phenotype. Gain of function variants are associated with early-onset seizures with or without developmental delay, whereas loss of function results in late-onset severe epilepsy and/or autism. We used patient-derived induced pluripotent stem cells to generate neuronal cultures for two recurring SCN2A variants causing early and late seizure onset epilepsy. Identified electrophysiological and transcriptome changes compared to the isogenic control lines can be correlated with the distinguishable clinical phenotype.

128

项与 Praxis Precision Medicines, Inc. 相关的新闻（医药）

2024-09-26

·GlobeNewswire-Health Care

Praxis Precision Medicines presents on ulixacaltamide Essential3 program at the Movement Disorders Society 2024 International Congress

BOSTON, Sept. 26, 2024 (GLOBE NEWSWIRE) -- Praxis Precision Medicines, Inc. (NASDAQ: PRAX), a clinical-stage biopharmaceutical company translating genetic insights into the development of therapies for central nervous system (CNS) disorders characterized by neuronal excitation-inhibition imbalance, today announced the presentation of a poster and platform talk showcasing its Phase 3 clinical program evaluating ulixacaltamide for adults with essential tremor (ET) at the Movement Disorders Society (MDS) 2024 International Congress taking place in Philadelphia, Pennsylvania, September 27 – October 1, 2024. Praxis at MDS 2024 | Pennsylvania Convention Center Meet us at booth #1008 or head to one of our presentations listed below where we will share progress on our journey to develop a new ET therapy Essential3: An Innovative Multi-Study Phase 3 Program to Evaluate the Efficacy and Safety of Ulixacaltamide Platform Presentation Saturday, September 281:30 – 2:30 PM ET | Group 1: Clinical Trials | Meeting Room 204C Poster Presentation Sunday, September 291:00 – 3:00 PM ET | Poster #641 | Exhibit Hall A Materials will be made available on the Resources page of the Praxis website following presentation at MDS 2024: https://praxismedicines.com/resources/. About UlixacaltamideUlixacaltamide is a differentiated and highly selective small molecule inhibitor of T-type calcium channels designed to block abnormal neuronal burst firing in the Cerebello-Thalamo-Cortical (CTC) circuit correlated with tremor activity. Ulixacaltamide, the most advanced program within Praxis’ Cerebrum™ small molecule platform, is currently in development for the treatment of essential tremor. www.praxisessentialtremor.com. About Praxis Praxis Precision Medicines is a clinical-stage biopharmaceutical company translating insights from genetic epilepsies into the development of therapies for CNS disorders characterized by neuronal excitation-inhibition imbalance. Praxis is applying genetic insights to the discovery and development of therapies for rare and more prevalent neurological disorders through our proprietary small molecule platform, Cerebrum™, and antisense oligonucleotide (ASO) platform, Solidus™, using our understanding of shared biological targets and circuits in the brain. Praxis has established a diversified, multimodal CNS portfolio including multiple programs across movement disorders and epilepsy, with four clinical-stage product candidates. For more information, please visit www.praxismedicines.com and follow us on Facebook, LinkedIn, Instagram and Twitter/X. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws, including express or implied statements regarding Praxis’ future expectations, plans and prospects, including, without limitation, statements regarding the anticipated timing of Praxis’ clinical trials, the development of Praxis’ product candidates and the potential therapeutic effects of Praxis’ product candidates, as well as other statements containing the words “anticipate,” “believe,” “continue,” “could,” “endeavor,” “estimate,” “expect,” “anticipate,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “seek,” “should,” “target,” “will” or “would” and similar expressions that constitute forward-looking statements under the Private Securities Litigation Reform Act of 1995. The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation: uncertainties inherent in clinical trials; the expected timing of clinical trials, data readouts and the results thereof, and submissions for regulatory approval or review by governmental authorities; regulatory approvals to conduct trials; and other risks concerning Praxis’ programs and operations as described in its Annual Report on Form 10-K for the year ended December 31, 2023 and other filings made with the Securities and Exchange Commission. Although Praxis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on information and factors currently known by Praxis. As a result, you are cautioned not to rely on these forward-looking statements. Any forward-looking statement made in this press release speaks only as of the date on which it is made. Praxis undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.

临床3期寡核苷酸

2024-09-05

·GlobeNewswire-Health Care

Praxis Precision Medicines to Participate in Upcoming Investor Conferences

BOSTON, Sept. 05, 2024 (GLOBE NEWSWIRE) -- Praxis Precision Medicines, Inc. (NASDAQ: PRAX), a clinical-stage biopharmaceutical company translating genetic insights into the development of therapies for central nervous system (CNS) disorders characterized by neuronal excitation-inhibition imbalance, today announced that management will be attending and presenting at two upcoming conferences: H.C. Wainwright 26th Annual Global Investment ConferenceFormat: Fireside ChatPresentation date and time: September 9, 2024 at 12:00pm EDTLocation: Lotte New York Palace Hotel, New York, NYWebcast: here Baird Global Healthcare ConferenceFormat: Fireside ChatPresentation date and time: September 11, 2024 at 2:35pm EDTLocation: InterContinental Barclay Hotel, New York, NY The Company will be available for one-on-one meetings during these conferences. Interested investors should contact their respective H.C. Wainwright and/or Baird representatives to request meetings. A replay of the presentation will be posted, when available, to Praxis’ website on the “Events and Presentations” page under the investor section of the website for 90 days. About Praxis  Praxis Precision Medicines is a clinical-stage biopharmaceutical company translating insights from genetic epilepsies into the development of therapies for CNS disorders characterized by neuronal excitation-inhibition imbalance. Praxis is applying genetic insights to the discovery and development of therapies for rare and more prevalent neurological disorders through our proprietary small molecule platform, Cerebrum™, and antisense oligonucleotide (ASO) platform, Solidus™, using our understanding of shared biological targets and circuits in the brain. Praxis has established a diversified, multimodal CNS portfolio including multiple programs across movement disorders and epilepsy, with four clinical-stage product candidates. For more information, please visit www.praxismedicines.com and follow us on Facebook, LinkedIn and Twitter/X.

寡核苷酸

2024-09-05

·药融圈

季度综述：离子通道药物研发进展--中枢神经系统

▲10月26-27日成都中国临床试验产业发展大会点击免费报名注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。这一系列综述的主要焦点是突出离子通道临床药物开发中所取得的进展，这是靶点选择（Target selection）的关键性验证参数（Key Validation Parameter--KVP），当然我们还需要同时考虑其他因素，如人类遗传数据、药物设计中的冷冻电镜结构、相关动物和iPSC模型的可用性，以及每个适应症中医学和商业驱动因素：未被满足的临床需求一定是药物研发的底层驱动力和变现的力量。爱思益普电生理团队希望这些讨论有助于克服一个根深蒂固的执念：离子通道是“难以攻克”的药物研发靶点以及将历史失败归咎于靶点类别而非发现过程本身的倾向。我们都知道，无论靶点或开发方式如何，药物发现都是一段曲折且昂贵的旅程，因此重要的是要认识到离子通道调节剂进入临床试验的成功经验并从陷阱中吸取教训。让我们一起试试吧：大家的阅读以此带来的价值，是我们坚持这件事情的动力和源泉！！！在2024年的第二季度对于离子通道药物研发而言是具有突破性的。我们看到了国内外令人激动的进展。同样一些失败的案例也是颇具启发性质的。我们的综述，将围绕外周系统疾病（Peripheral disease indication）和中枢神经系统疾病（CNS disease indication）展开。这一部分主要集中在CNS疾病。 PART2. 中枢神经系统疾病（CNS disease indication） a 癫痫类疾病这个季度，癫痫这个领域出现了一些新的竞争者的消息，同时，一些长期从事抗癫痫离子通道药物研发项目的现有玩家也发布了正面和负面的临床数据。在这疾病领域中，出现了一个值得我们关注的玩家ES Therapeutics。他们在药物抵抗性癫痫患者的IIa期试验中发表了积极的疗效。ES 481是一种AMPA GluR TARPγ8辅助亚基抑制剂，但它并不是一种化学分子。它有着复杂的历史；最初由Cerecor（CERC 611）发现，并于与Eli Lilly合作研究其在癫痫中的临床前疗效（结果在2016年发表），之后公司更名为Avalo Therapeutics，然后在2020年将该资产出售给澳大利亚的ES Therapeutics，后者进行了IIa期试验（NCT04714996）。与接受安慰剂治疗的患者相比，该药物将每周发作次数减少了68-80%，而安慰剂组为38-49%，在75 mg BID的最高剂量下达到了边际统计显著性。这种复杂的故事在药物发现中相当有代表性。所以很高兴看到那些对有价值的化合物及其作用机制有信心的研究者们在经历了几次公司更迭后，最终为需要的患者取得了有希望的结果。另一个新加入的竞争者，也在研究AMPA GluR TARPγ8辅助亚基抑制剂，是Rapport Therapeutics，他们在5月EILAT XXVII会议上的摘要中公开了他们的第一个离子通道抗癫痫配体RAP-219（见https://www.eilatxvii.com/program-outline），在Rapport Therapeutics的官网中我们可以看到这个化合物设计到多个疾病管线。这也提示了这个靶点的潜在价值。（https://www.rapportrx.com/pipeline/） EILAT XXVII会议中同时披露的还有GRIN Therapeutics（Radiprodil NMDA 2B负向变构调节剂）、Praxis Precision Medicine的PRAX-628 Nav1.x阻断剂、Encoded和Stoke Therapeutics的Nav1.1基因疗法ETX101和STK-001、UniQure的AMT-260 GluR kainate miRNA沉默剂、Xenon的XEN1101和Biohaven的BHV-7000 Kv7.x开放剂、Autifony的Kv3.x正性调节剂，以及上述的ES Therapeutics ES-481 AMPA-R Tarp g8配体的介绍。RAP-219起源于Janssen在圣地亚哥的神经科学项目，并带有I期安全性数据；关于Rapport起源的更多细节可以在第3节找到。 2024年第二季度，癫痫领域的知名公司也发布了一些更新。首先是Xenon Pharmaceuticals，他们在全美神经学会会议上展示了他们完成的IIb期X-TOLE试验和Kv7.x开放剂XEN1101在局灶性癫痫患者中的开放标签扩展的数据。这些演讲的链接可以在这里访问，显示XEN1101通过在8周给药期间产生剂量依赖性和统计学上显著的发作频率降低，达到了其主要疗效终点，并且不良事件率低，没有心血管安全警示（这一点很重要，因为Kv7.1亚型在心脏中表达，并且是LQT1综合症的基础）。鉴于这种有希望且显著的疗效，几乎所有的初始参与者都参加了开放标签扩展，其中药物剂量为20 mg，继续在30个月内显著降低发作频率，但到分析期末只有一半的人仍然在使用，因为缺乏疗效（13.8%）、不良事件（12.0%）或患者撤回（12.0%）而中断。事后分析显示，在发作频率较低和/或服用较少抗癫痫药物的患者中，响应率更高（>50%），这可能解释了为什么有些人退出了。XEN1101现在正在进行3项III期试验，针对局灶性和强直-阵挛性发作。近日，Encoded Therapeutics在EILAT XXVII会议上就他们针对Dravet癫痫的Nav1.1基因疗法ETX101进行了演讲，并在2024年5月举行的美国基因与细胞治疗学会第27届年会上也进行了演讲，他们在那里专注于扩大AAV生产和表达以适应FIH临床剂量的挑战。该公司已经计划了一个复杂的全球I/II期试验项目，针对年轻的Dravet癫痫患者，目的是建立适当的剂量递增程序，并最终形成一种长期治疗方案，随着患者的成长，这种方案可能会有所调整。基于AAV的基因疗法最初的承诺现在已经达到了人类患者反应和安全问题的现实，例如抗原免疫反应，这可能会限制这些疗法只能一次性使用，因此确定正确的剂量方案（和AAV血清型）现在是迫切需要解决的问题，需要在不同的患者群体和治疗指征中进行解决。最后，我们从这个系列中的一个知名公司听到了一些负面消息：Marinus Pharmaceuticals一直在测试GABA-A PAM Ganaxolone作为难治性癫痫的静脉注射配方，但在4月份遇到了一个重大障碍，当时他们正在进行的III期试验的中期分析显示，这种药物在与主要终点相比时未能达到统计学意义。然而，它也未能跌破预先确定的“停止”点，因此公司决定继续进行试验，但不招募任何新患者，并等待2024年夏季之后完成试验的分析结果。这种药物已经作为Ztalmy上市，因为它在去年被批准用于治疗Cdkl5癫痫，所以并非一切都失去了，但显然一个负面结果将限制他们的患者群体和总收入。然而，5月份的更新显示，该公司正在进行削减，并已暂停任何进一步的Ganaxolone癫痫试验，等待完成的III期试验结果和随后的分析。 b 抑郁类疾病 Xenon对他们的Kv7.x PAM/开放剂XEN1101（现在已经更名为Azetukalner）有宏伟的计划，除了在第1节提到的正在进行的癫痫试验之外，他们还在重度抑郁症（MDD）中推进这种配体。这种药物候选在抑郁症患者的II期概念验证试验中表现不佳，未能与安慰剂相比达到统计学意义，但明显的剂量依赖性和在20 mg最高剂量下看到的“临床意义”的改善足以让公司宣布他们将继续推进，现在公司网站上有更多关于计划在2024年下半年开始的III期试验的细节。该公司还与西奈山医院的伊坎医学院合作，进行一项由研究者发起的II期概念验证平行臂安慰剂对照多中心研究，研究对象为60名MDD患者。在为重度抑郁症（MDD）开发临床离子通道药物方面也取得进展的是Neurocrine Biosciences，他们在2024年第二季度公布了有关GluR相关化合物并行临床项目的消息。首先是NBI-1065845（TAK-653），一种AMPA GluR PAM，在剂量范围的II期研究中显示出积极的疗效数据。这种首创药物候选的高剂量在第28天和第56天分别显著减少了标准抑郁评分量表测量的症状，达到了主要和次要终点，而低剂量则显示出相似但非显著的趋势。这种药物是通过与Takeda的一项交易（2020年预先支付1.2亿美元）独家获得的，用于开发后者的七个早期和中期精神病学配体，并且是在GPR139配体NBI-1065846在2023年第四季度的II期MDD试验失败后，第一个发布积极结果的药物。 Neurocrine Biosciences 在第二季度还宣布，他们的GluR NMDA NR2B选择性亚基NAM NBI-1070770已在重度抑郁症的II期试验中对首位患者进行了剂量给药，使用的是与他们AMPA MDD试验相同的抑郁症状评分调查。这种小分子化合物是2020年从Takeda授权的程序之一，因此Neurocrine似乎在这个交易上做得很好。还有一些其他公司正在研究用于治疗抑郁症的NMDA受体调的小分子化合物。从积极的方面来看，Gilgamesh Pharma宣布他们已经将他们的NMDA拮抗剂GM-1020推进到MDD的IIa期试验中，预计在2024年下半年会有中期结果。GM-1020包含了一种氯胺酮的重新配方，氯胺酮是一种竞争性NMDA受体拮抗剂，已被证明可以比传统的单胺类化合物更快地缓解抑郁症状，并且在治疗抵抗性患者中显示出显著的疗效，但它也展示了传统神经化学配体和最近对迷幻剂兴趣之间的交叉，Gilgamesh也在追求这一点。最后，有消息说NRx公司的NMDA的化合物在双相抑郁症的II/III期试验中失败了。NRX-101在6周治疗后未能达到上述提到的相同抑郁评分系统的主要终点，尽管该试验缺乏安慰剂组，而是将疗效与他们的药物替代品（用于精神分裂症患者的鲁拉西酮）进行了比较，这是由于他们的患者群体自杀风险高。然而，NRX-101在主要抑郁评分上取得了一些显著的降低，与对照组相似，并且还减少了自杀意念，因此公司决定进入一个更大规模的III期试验，重点是自杀终点。 c 精分类疾病 Newron的抗精神病药物Evenamide（NW-3509）在精神分裂症患者中的Ib期和IIa期积极数据；在2023年第四季度和2024年第一季度对2023年开始的II/III期试验进行了更新。现在结果已经公布，这些结果支持并改进了这些早期研究，满足了主要和次要终点。这种药物被定位为一种附加疗法，与现有的治疗如氯氮平联合使用，并显示出在4周的给药期间显著改善正面和负面症状并降低整体疾病严重程度，与安慰剂相比具有极佳的安全性和副作用概况。Evenamide是一种状态依赖性的电压门控Nav1.x通道阻断剂，在临床前试验中减少了谷氨酸突触传递和神经元兴奋性，并且声称与其他调节其他神经递质、5-羟色胺能和多巴胺能GPCRs的抗精神病药物协同作用。之前的开放标签试验显示，药物效果在6-12个月内维持甚至增加，症状减少了30-50%，因此现在正在计划一项为期1年的III期后续试验，希望这种新的抗精神病药物候选物能为治疗不足的患者群体带来显著的改善。 d 神经退行性疾病 Cerevance公司正在为肌萎缩侧索硬化症（ALS）和阿尔茨海默病开发的THIK1 K2P通道抑制剂CVN293，但现在它已正式成为临床候选药物，因为公司网站现在列出了一个正在进行的I期安全性试验，预计将在2024年第二季度公布结果（尽管在clinicaltrials.gov网站上还没有发现这一试验安排）。该公司还在2024年4月发表了一篇论文，描述了从高通量Ti influx assay测定中发现并优化CVN293的过程, 这一研究产生了一种强效且亚型选择性良好的抑制剂，专门针对小胶质细胞上的这种特定的K2P通道，能够减少中枢神经系统中NLRP3炎症体的激活和细胞因子的释放，这被认为是治疗各种神经退行性和神经炎症性疾病的一个非常有用的作用机制。相比之下，Sage Therapeutics采用一种更传统且长期运行的神经化学方法来治疗神经退行性疾病的尝试在2024年第二季度彻底崩溃了：GluR NMDA PAM SAGE-718（dalzanemdor）在帕金森病和亨廷顿病的II期临床试验中连续失败。公司原本计划在帕金森病、亨廷顿病和阿尔茨海默病中进行一系列中期临床试验，这些试验都计划在2024年公布结果，但在前两项试验中都遭遇了失败。首先报告的是帕金森病试验，与安慰剂相比，未能改善认知的主要终点或探索性的次要终点。这导致公司决定取消SAGE-718在帕金森病项目中的开发，但保持了对亨廷顿病的主要兴趣。然而，两个月后，他们透露亨廷顿病的II期试验也未能显示出与安慰剂相比在各种认知能力度量上的显著改善，尽管试验样本量较小，只有40名亨廷顿病患者和29名健康对照组。2024年7月的公司对第二季度的审查表明，他们仍在继续进行SAGE-718在AD和HD患者中增强认知的II期试验，这两项试验都应在2024年底报告结果，但已调整了第二项HD试验的主要终点，使用了一个特定的认知测试，这可能是在失败的试验中显示出最佳反应的测试。 e 特发性震颤 2024年第二季度，针对本态性震颤进行测试的临床候选药物有进展也有挫折，6月份宣布，Jazz Pharmaceuticals的T型Cav3.x阻断剂Suvecaltamide在一个最初于2021年开始的高级IIb期试验中失败。它未能达到主要和次要终点，但公司当时对30毫克最高剂量看到的一些非显著性改善持乐观态度，并正在等待一个于2022年开始的、针对帕金森病震颤患者的平行研究结果，该研究预计将在2025年第一季度报告，然后公司将决定这种药物的未来。Suvecaltamide（JZP385）是一种强效且状态依赖性但相对非选择性的Cav3.x家族成员阻断剂，就像第2节开头提到的ES Therapeutics的ES-481一样，它有着漫长而复杂的历史；最初由Merck在2010年代开发（作为MK-8998），并进行了针对与精神分裂症相关精神病的不成功临床试验，然后被授权给Cavion Therapeutics（作为CX-8998），并在Cavion被Jazz在2019年收购（预付款5250万美元）之前进一步测试用于本态性震颤，并被带入了这个IIb期试验。这是一种我们不熟悉的疾病类型。直到最近几年，由于Praxis Precision Medicines（PRAX-944）和Neurocrine Biosciences（NBI-827104）在他们的Cav3.x阻断剂方面的工作，才让我们对本态性震颤（Essential Tremor）作为离子通道治疗领域有所了解。Neurocrine的药物候选在2022年第四季度的II期试验中失败，但在也在罕见的儿童癫痫的小型II期试验中失败后才被取消。Praxis在2023年第一季度也遭遇了挫折，他们的II期本态性震颤试验未能达到主要终点，但该公司仍在继续推进Ulixacaltamide在2024年的III期试验。不幸的是，不好的消息还在继续，我们也关注到Sage Therapeutics和Biogen正在开发的GABA-A PAM SAGE-324在2024年第三季度的II期试验中未能实现疗效后已被放弃的最新消息。小结这一系列综述的主要焦点是突出离子通道临床药物开发中所取得的进展。这是爱思益普电生理团队做的一次尝试，希望可以对国内离子通道靶点的药物研发提供一些启发和帮助。由于数据的可得性，目前我们主要聚焦了国外的研发进展，后续我们也会不多的增加和汇总来自国内企业的进展和突破。版权声明：本文转自爱思益普，如不希望被转载的媒体或个人可与我们联系，我们将立即删除【关于药融圈】药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。

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