A Randomized, Double-blind, Placebo-Controlled, Multicenter Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of XEN1101 as Adjunctive Therapy in Focal-Onset Seizures - XPF-010-302

开始日期2023-10-13

申办/合作机构

Xenon Pharmaceuticals, Inc.

NCT05716100 / Recruiting临床3期

A Randomized, Double-blind, Placebo-Controlled, Multicenter Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of XEN1101 as Adjunctive Therapy in Focal-Onset Seizures

The X-TOLE3 Phase 3 clinical trial is a randomized, double-blind, placebo-controlled study that will evaluate the clinical efficacy, safety and tolerability of XEN1101 administered as adjunctive therapy in focal-onset seizures.

开始日期2023-05-09

申办/合作机构

Xenon Pharmaceuticals, Inc.

[+1]

NCT05718817 / Enrolling by invitation临床3期

A Multicenter, Open-label, Long-term, Safety, Tolerability, and Efficacy Study of XEN1101 in Subjects Diagnosed With Epilepsy

This study will evaluate the long term safety, tolerability, PK, and efficacy of XEN1101 25 mg QD taken orally in subjects with Focal Onset Seizures (FOS) or Primary Generalized Tonic-Clonic Seizures (PGTCS) for the treatment of seizures for up to 3 years.

开始日期2023-04-25

申办/合作机构

Xenon Pharmaceuticals, Inc.

[+1]

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100 项与 Azetukalner 相关的专利（医药）

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项与 Azetukalner 相关的文献（医药）

2023-11-01·JAMA neurology

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy

Article

Importance:

Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics.

Objective:

To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs).

Design, Setting, and Participants:

This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe.

Interventions:

Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose).

Main Outcomes and Measures:

The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted.

Results:

A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P &lt; .001 vs placebo; IQR, −80.4% to −16.9%) for 25 mg, 46.4% (P &lt; .001 vs placebo; IQR, −76.7% to −14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, −61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, −37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported.

Conclusions and Relevance:

The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs.

Trial Registration:

ClinicalTrials.gov Identifier: NCT03796962

2023-08-01·Acta pharmacologica Sinica

Functional characterization and in vitro pharmacological rescue of KCNQ2 pore mutations associated with epileptic encephalopathy.

Article

作者: Tian, Fu-Yun ; Li, Ping ; Yang, Chuan-Yan ; Shen, Yan-Wen ; Yang, Gui-Mei ; Gao, Zhao-Bing ; Yuan, Hui

Mutations in the KCNQ2 gene encoding K_V7.2 subunit that mediates neuronal M-current cause a severe form of developmental and epileptic encephalopathy (DEE). Electrophysiological evaluation of KCNQ2 mutations has been proved clinically useful in improving outcome prediction and choosing rational anti-seizure medications (ASMs). In this study we described the clinical characteristics, electrophysiological phenotypes and the in vitro response to KCNQ openers of five KCNQ2 pore mutations (V250A, N258Y, H260P, A265T and G290S) from seven patients diagnosed with KCNQ2-DEE. The KCNQ2 variants were transfected into Chinese hamster ovary (CHO) cells alone, in combination with KCNQ3 (1:1) or with wild-type KCNQ2 (KCNQ2-WT) and KCNQ3 in a ratio of 1:1:2, respectively. Their expression and electrophysiological function were assessed. When transfected alone or in combination with KCNQ3, none of these mutations affected the membrane expression of KCNQ2, but most failed to induce a potassium current except A265T, in which trace currents were observed when co-transfected with KCNQ3. When co-expressed with KCNQ2-WT and KCNQ3 (1:1:2), the currents at 0 mV of these mutations were decreased by 30%-70% compared to the KCNQ2/3 channel, which could be significantly rescued by applying KCNQ openers including the approved antiepileptic drug retigabine (RTG, 10 μM), as well as two candidates subjected to clinical trials, pynegabine (HN37, 1 μM) and XEN1101 (1 μM). These newly identified pathologic variants enrich the KCNQ2-DEE mutation hotspots in the pore-forming domain. This electrophysiological study provides a rational basis for personalized therapy with KCNQ openers in DEE patients carrying loss-of-function (LOF) mutations in KCNQ2.

2022-12-12·Expert opinion on pharmacotherapy

Current and future pharmacotherapy options for drug-resistant epilepsy

Review

作者: Mula, Marco ; Elkommos, Samia

INTRODUCTION:

Epilepsy is a common neurological condition, affecting over 70 million individuals worldwide.

AREAS COVERED:

The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies.

EXPERT OPINION:

Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.

项与 Azetukalner 相关的新闻（医药）

2024-09-09

·GlobeNewswire-Health Care

Xenon Showcases Azetukalner Data at 15th European Epilepsy Congress

Three presentations highlighting long-term data and improved quality of life outcomes in adults with focal onset seizures VANCOUVER, British Columbia and BOSTON, Sept. 09, 2024 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq:XENE), a neuroscience-focused biopharmaceutical company dedicated to discovering, developing, and delivering life-changing therapeutics for patients in need, today announced three poster presentations at the 15th European Epilepsy Congress (EEC) taking place in Rome, Italy. Azetukalner, a novel, potent Kv7 channel opener, is the most advanced, clinically validated potassium channel modulator in late-stage development for multiple indications, including focal onset seizures (FOS), primary generalized tonic-clonic seizures (PGTCS) and major depressive disorder (MDD). “We are excited for this opportunity to engage with leading epileptologists at EEC in Rome and share long-term azetukalner data from our ongoing X-TOLE open-label extension study. Azetukalner represents the only Kv7 potassium channel opener in clinical development that is supported by Phase 2b data as well as long-term efficacy and safety data in epilepsy patients,” stated Dr. Christopher Kenney, Chief Medical Officer of Xenon. “These data are particularly impressive given the baseline disease severity, with patients who are out to 30 months in the open-label extension study showing a greater than 90% reduction in median monthly seizure frequency, while approximately one in four patients on azetukalner for at least two years in the OLE have experienced a period of seizure freedom of a year or longer.” Dr. Kenney continued, “We are also presenting patient-reported survey data illustrating the substantial burden of illness for people living with epilepsy, with reduced quality of life, high seizure frequency and fatigue, as well as other comorbidities such as anxiety and depression, further underscoring the need for new medications to help people living with epilepsy.” Presentations at EEC: Poster #P282: Azetukalner (XEN1101), a Novel, Potent Kv7 Potassium Channel Opener: Interim Data From an Ongoing, Long‑Term, Open‑Label Extension of a Phase 2b Study (X‑TOLE) in Adults With Focal Onset SeizuresPresenter: Jacqueline A. French, New York University Grossman School of Medicine and NYU Langone Health, New York, NYSession Times: Daily from 1:30-3:00 pm CEST Poster #P281: Long-term, Quality of Life in Epilepsy Inventory-31 (QOLIE-31) Improvements in Adults With Focal Onset Seizures Treated With Azetukalner (XEN1101) in an Ongoing, Open-Label Extension of a Phase 2b study (X-TOLE)Presenter: Christian Brandt, Bethel Epilepsy Centre, Mara Hospital, University Hospital for Epileptology, Bielefeld, GermanySession Times: Daily from 1:30-3:00 pm CESTPoster Tour: S2 Clinical Neurophysiology/Drug Therapy Poster #P406: Non-seizure Symptoms, Mental Health Comorbidities, and Quality of Life in Patients Reporting Focal Onset SeizuresPresenter: Cynthia Harden, Xenon Pharmaceuticals Inc. Session Times: Daily from 1:30-3:00 pm CEST Posters will be available for viewing at the conference from Sunday, September 8 until Tuesday, September 10 at 4:00 pm CEST and will be added to the Xenon website consistent with conference guidelines. Xenon is also hosting a Scientific Exhibit at location SE1 and Booth #346. About Xenon Pharmaceuticals Inc.Xenon Pharmaceuticals (Nasdaq:XENE) is a neuroscience-focused biopharmaceutical company committed to discovering, developing, and commercializing innovative therapeutics to improve the lives of people living with neurological and psychiatric disorders. We are advancing a novel product pipeline to address areas of high unmet medical need, including epilepsy and depression. Azetukalner, our lead Kv7 channel opener, represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development for multiple indications. For more information, please visit www.xenon-pharma.com. About the Azetukalner Phase 3 Epilepsy ProgramXenon’s Phase 3 epilepsy program includes three ongoing Phase 3 clinical trials in focal onset seizures (FOS) and primary generalized tonic-clonic seizures (PGTCS). Designed closely after the Phase 2b X-TOLE clinical trial, the Phase 3 X-TOLE clinical trials are multicenter, randomized, double-blind, placebo-controlled studies evaluating the clinical efficacy, safety, and tolerability of 15 mg or 25 mg of azetukalner administered with food as adjunctive treatment in approximately 360 patients with FOS per study. The primary efficacy endpoint is the median percent change (MPC) in monthly seizure frequency from baseline through the double-blind period (DBP) of azetukalner compared to placebo. X-ACKT is a multicenter, randomized, double-blind, placebo-controlled study evaluating the clinical efficacy, safety, and tolerability of 25 mg of azetukalner administered with food as adjunctive treatment in approximately 160 patients with PGTCS. The primary efficacy endpoint is the MPC in monthly PGTCS frequency from baseline through the DBP of azetukalner compared to placebo. Safe Harbor StatementThis press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995 and Canadian securities laws. These forward-looking statements are not based on historical fact, and include statements regarding the timing of and potential results from clinical trials; the potential efficacy, safety profile, future development plans in current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partners’ product candidates; the efficacy of our clinical trial designs; our ability to successfully develop and achieve milestones in our azetukalner and other pipeline and development programs; and our ability to successfully develop and obtain regulatory approval of azetukalner and our other product candidates. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events, or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: clinical trials may not demonstrate safety and efficacy of any of our or our collaborators’ product candidates; promising results from pre-clinical development activities or early clinical trial results may not be replicated in later clinical trials; our assumptions regarding our planned expenditures and sufficiency of our cash to fund operations may be incorrect; our ongoing discovery and pre-clinical efforts may not yield additional product candidates; any of our or our collaborators’ product candidates, including azetukalner, may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; regulatory agencies may impose additional requirements or delay the initiation of clinical trials; the impact of market, industry, and regulatory conditions on clinical trial enrollment; the impact of competition; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; as well as the other risks identified in our filings with the U.S. Securities and Exchange Commission and the securities commissions in British Columbia, Alberta, and Ontario. These forward-looking statements speak only as of the date hereof and we assume no obligation to update these forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements. “Xenon” and the Xenon logo are registered trademarks or trademarks of Xenon Pharmaceuticals Inc. in various jurisdictions. All other trademarks belong to their respective owner. Contacts: For Investors:Chad FugereVice President, Investor Relations(857) 675-7275investors@xenon-pharma.com For Media:Colleen AlabisoSenior Vice President, Corporate Affairs(617) 671-9238media@xenon-pharma.com

临床2期临床3期

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。

临床结果临床研究

2024-08-12

·GlobeNewswire-Health Care

Xenon Expands Leadership Team with Matthew D. Ronsheim, Ph.D. as Chief Operating Officer

VANCOUVER, British Columbia and BOSTON, Aug. 12, 2024 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq:XENE), a neuroscience-focused biopharmaceutical company dedicated to discovering, developing, and delivering life-changing therapeutics for patients in need, today announced the appointment of Matthew D. Ronsheim, Ph.D. as Chief Operating Officer and a member of the Xenon senior executive team. In this new role, Dr. Ronsheim will lead Chemistry, Manufacturing and Controls (CMC), Program Management and Quality Assurance and as a member of the senior executive team will be responsible for providing strategic and operational leadership for the Company’s pipeline of small molecule programs with a focus on preparation for the commercial launch of azetukalner. “Matt joins Xenon at an exciting time of growth where his extensive operational, pharmaceutical development and manufacturing expertise will help support the advancement of our Phase 3 epilepsy and MDD programs, planning for regulatory submissions and commercialization, while also progressing our broad portfolio of pre-clinical assets that will fuel future growth,” stated Ian Mortimer, President and Chief Executive Officer of Xenon. Dr. Ronsheim has 25 years of experience bringing important medicines from discovery through clinical development, global regulatory filings and approvals, and commercial launch and supply. Before joining Xenon, Dr. Ronsheim was President of Innoviva Specialty Therapeutics, having previously served as their Chief Technical Officer. Prior to this, Dr. Ronsheim was President of Entasis Therapeutics, which was acquired by Innoviva, Inc. in 2022. Throughout his career, he has held leadership roles overseeing research, CMC, pharmaceutical development, and commercialization at companies including Merck/Cubist Pharmaceuticals, Enanta Pharmaceuticals, and Forest Laboratories. Dr. Ronsheim’s industry contributions and leadership have contributed to delivering important therapies across several disease areas including central nervous system disorders. Dr. Ronsheim holds a B.S. in Chemistry from Southern Connecticut State University and a Ph.D. in Synthetic Organic Chemistry from the University of New Hampshire. “I am thrilled to join Xenon to support the future development and commercialization of azetukalner given its compelling profile in both epilepsy and depression with a broad Phase 3 program underway,” said Dr. Matt Ronsheim, Chief Operating Officer of Xenon. “I am also excited about the opportunity to deliver on Xenon’s promise of a next-generation ion channel modulators with the advancement of multiple Kv7, Nav1.7 and Nav1.1 molecules creating opportunities for development across a broad range of CNS indications.” About Xenon Pharmaceuticals Inc. Xenon Pharmaceuticals (Nasdaq:XENE) is a neuroscience-focused biopharmaceutical company committed to discovering, developing, and commercializing innovative therapeutics to improve the lives of people living with neurological and psychiatric disorders. We are advancing a novel product pipeline to address areas of high unmet medical need, including epilepsy and depression. Azetukalner, our lead Kv7 channel opener, represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development for multiple indications. For more information, please visit www.xenon-pharma.com. Safe Harbor Statement This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995 and Canadian securities laws. These forward-looking statements are not based on historical fact, and include statements regarding the timing of and potential results from clinical trials; the potential efficacy, safety profile, future development plans in current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partners’ product candidates; the efficacy of our clinical trial designs; our ability to successfully develop and achieve milestones in our azetukalner and other pipeline and development programs; our ability to successfully develop and obtain regulatory approval of azetukalner and our other product candidates. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events, or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: clinical trials may not demonstrate safety and efficacy of any of our or our collaborators’ product candidates; promising results from pre-clinical development activities or early clinical trial results may not be replicated in later clinical trials; our assumptions regarding our planned expenditures and sufficiency of our cash to fund operations may be incorrect; our ongoing discovery and pre-clinical efforts may not yield additional product candidates; any of our or our collaborators’ product candidates, including azetukalner, may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; regulatory agencies may impose additional requirements or delay the initiation of clinical trials; the impact of market, industry, and regulatory conditions on clinical trial enrollment; the impact of competition; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; as well as the other risks identified in our filings with the U.S. Securities and Exchange Commission and the securities commissions in British Columbia, Alberta, and Ontario. These forward-looking statements speak only as of the date hereof and we assume no obligation to update these forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements. “Xenon” and the Xenon logo are registered trademarks or trademarks of Xenon Pharmaceuticals Inc. in various jurisdictions. All other trademarks belong to their respective owner. Contacts: For Investors:Chad FugereVice President, Investor Relations(857) 675-7275investors@xenon-pharma.com For Media:Colleen AlabisoSenior Vice President, Corporate Affairs(617) 671-9238media@xenon-pharma.com

高管变更并购临床3期

100 项与 Azetukalner 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
强直阵挛性癫痫	临床3期	美国	Xenon Pharmaceuticals, Inc.	2023-02-14
强直阵挛性癫痫	临床3期	澳大利亚	Xenon Pharmaceuticals, Inc.	2023-02-14
强直阵挛性癫痫	临床3期	保加利亚	Xenon Pharmaceuticals, Inc.	2023-02-14
强直阵挛性癫痫	临床3期	加拿大	Xenon Pharmaceuticals, Inc.	2023-02-14
强直阵挛性癫痫	临床3期	克罗地亚	Xenon Pharmaceuticals, Inc.	2023-02-14
强直阵挛性癫痫	临床3期	捷克	Xenon Pharmaceuticals, Inc.	2023-02-14
强直阵挛性癫痫	临床3期	意大利	Xenon Pharmaceuticals, Inc.	2023-02-14
强直阵挛性癫痫	临床3期	波兰	Xenon Pharmaceuticals, Inc.	2023-02-14
强直阵挛性癫痫	临床3期	葡萄牙	Xenon Pharmaceuticals, Inc.	2023-02-14
强直阵挛性癫痫	临床3期	西班牙	Xenon Pharmaceuticals, Inc.	2023-02-14

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03796962 (X-TOLE, CTgov)	临床2期	癫痫部分性发作 \| 癫痫发作	325	XEN1101 (25 mg XEN1101)	鹽鹹鑰獵構壓膚範網願(選齋遞衊顧鑰齋壓積醖) = 鹹鏇淵簾積鏇餘網衊繭齋膚鏇築廠醖鏇鬱鬱遞 (鑰窪網襯襯衊鏇艱齋簾, 構壓廠壓繭鏇鹹衊齋觸 ~ 廠鹽膚夢襯觸齋鏇衊襯) 更多	-	2024-09-24
				XEN1101 (20 mg XEN1101)	鹽鹹鑰獵構壓膚範網願(選齋遞衊顧鑰齋壓積醖) = 壓夢膚壓膚窪憲製構鑰齋膚鏇築廠醖鏇鬱鬱遞 (鑰窪網襯襯衊鏇艱齋簾, 願積製鏇餘齋鹽遞壓構 ~ 齋衊構窪憲繭襯蓋壓廠) 更多
NCT05376150 (X-NOVA, Company_Website) 人工标引	临床2期	重度抑郁症	168	Azetukalner 10mg	壓獵蓋餘選衊繭獵簾願(衊蓋廠憲衊艱憲願鹽鏇) = 獵廠鏇鬱壓願廠餘構艱簾衊憲鹽淵衊齋壓壓範 (鏇餘願鹹觸齋蓋夢齋鏇 )	积极	2024-05-28
				Azetukalner 20mg	壓獵蓋餘選衊繭獵簾願(衊蓋廠憲衊艱憲願鹽鏇) = 艱齋憲窪繭構淵網夢襯簾衊憲鹽淵衊齋壓壓範 (鏇餘願鹹觸齋蓋夢齋鏇 ) 更多
NCT03796962 (X-TOLE, AES2023) 人工标引	临床2期	癫痫部分性发作	325	XEN1101	醖窪廠廠窪淵蓋選鏇襯(簾鏇糧艱壓網糧壓襯鬱) = 範選壓齋鏇築繭窪衊醖鬱夢餘範願網顧膚簾衊 (蓋觸顧顧夢齋鑰鹽鑰觸 )	积极	2023-12-03
				Placebo	醖窪廠廠窪淵蓋選鏇襯(簾鏇糧艱壓網糧壓襯鬱) = 範簾鹹遞築網憲艱膚鏇鬱夢餘範願網顧膚簾衊 (蓋觸顧顧夢齋鑰鹽鑰觸 )
NCT03796962 (X-TOLE, AES2023) 人工标引	临床2期	癫痫部分性发作	170	XEN1101 (overall)	夢蓋醖製憲築構願糧艱(鹽廠蓋淵簾憲鏇遞鏇夢) = 鬱醖範鑰夢艱願築繭夢簾憲觸構襯繭夢壓齋積 (範壓選衊艱壓壓網糧遞 ) 更多	积极	2023-12-03
				XEN1101 (seizure-free group)	夢蓋醖製憲築構願糧艱(鹽廠蓋淵簾憲鏇遞鏇夢) = 獵蓋艱醖憲繭鏇顧鹹夢簾憲觸構襯繭夢壓齋積 (範壓選衊艱壓壓網糧遞 ) 更多
NCT03796962 (X-TOLE, AES2023) 人工标引	临床2期	癫痫部分性发作	275	XEN1101	網鹹鹽膚選範夢窪築顧(網網憲願膚遞鏇餘窪廠) = The most common reasons for discontinuation were lack of efficacy (13.1%), adverse events (12.0%), and study withdrawal by patient (11.3%). 鏇壓範糧繭鏇觸齋夢膚 (齋鑰蓋繭構蓋簾醖廠鬱 ) 更多	积极	2023-12-02
NCT05376150 (X-NOVA, Corporate Publications) 人工标引	临床2期	重度抑郁症	168	XEN1101 10 mg	糧鬱糧築衊鹹襯齋夢簾(鹽憲鑰衊顧築遞淵鏇獵) = 壓築壓鏇餘夢簾築築衊糧廠積構襯膚鏇淵選餘 (窪蓋鏇築鑰艱簾構淵簾 )	积极	2023-11-27
				XEN1101 20 mg	糧鬱糧築衊鹹襯齋夢簾(鹽憲鑰衊顧築遞淵鏇獵) = 鹽衊觸廠構淵鑰憲膚網糧廠積構襯膚鏇淵選餘 (窪蓋鏇築鑰艱簾構淵簾 ) 更多
NCT03796962 (X-TOLE, pubmed) 人工标引	临床2期	癫痫部分性发作	325	XEN1101 25 mg	製獵齋願觸築膚淵醖衊(鏇壓築蓋膚艱齋觸觸願) = 餘衊獵願願獵顧範範鬱淵襯鏇築醖積艱膚憲壓 (窪糧願淵鬱願選窪遞鏇, -80.4 ~ -16.9)	积极	2023-10-09
				XEN1101 20 mg	製獵齋願觸築膚淵醖衊(鏇壓築蓋膚艱齋觸觸願) = 膚醖鬱艱網範鑰觸糧醖淵襯鏇築醖積艱膚憲壓 (窪糧願淵鬱願選窪遞鏇, -76.7 ~ -14.0)
IEC2023	临床2期	癫痫部分性发作	275	XEN1101 20 mg QD	繭廠顧淵顧窪憲鹽廠窪(鏇繭餘鏇廠遞齋鏇選淵) = 11.6% 鬱醖製衊製鏇鹽觸鑰壓 (醖鹽醖膚築壓鏇遞鹽壓 ) 更多	积极	2023-09-04
				Placebo
X-TOLE (AAN2023)	临床2期	癫痫部分性发作	285	XEN1101 20 mg	糧築選築獵壓鏇鹽範蓋(餘積鏇遞齋蓋獵鹽壓繭) = The most common TEAEs were dizziness, headache, somnolence, weight increased, fall, gait disturbance, fatigue, confusional state, aphasia, and memory impairment. No TEAEs of pigmentary abnormalities were reported. Two patients experienced TEAEs of urinary retention (1 mild, 1 moderate, possibly drug related, but both patients continued the medication) 願顧糧鬱窪鬱齋鑰襯蓋 (繭築憲鹹選糧襯鏇鹽糧 ) 更多	-	2023-04-25
X-TOLE (AAN2022)	临床2期	癫痫部分性发作	325	XEN1101 10mg	遞構壓襯廠鏇夢鑰鹹鹹(餘製壓遞鑰醖夢顧製艱) = 獵鑰範膚繭顧衊製餘願蓋鑰襯範願鹽簾鏇願膚 (壓簾遞鹽鏇艱醖壓淵糧 ) 更多	积极	2022-05-03
				XEN1101 20mg	壓鑰廠蓋獵憲蓋獵繭衊(鏇艱衊蓋積選襯構憲構) = 選膚鏇廠夢網繭觸衊選願衊窪衊鑰憲夢艱餘選 (選鏇蓋鹽網網鏇製構窪 )