An Open-label, Nonrandomized, Phase 3 Study to Evaluate the Efficacy and Safety of Soticlestat in Participants With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have Been Exposed to Fenfluramine

The purpose of this study is to check how soticlestat impacts symptoms of Dravet syndrome [DS] and Lennox-Gastaut syndrome [LGS] in participants who have been exposed to fenfluramine.

开始日期2024-04-25

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

NCT05602818

/ Completed临床1期

A Phase 1, Randomized, Double-Blind, Double-Dummy, Active- and Placebo-Controlled, 5-Way Crossover Study Evaluating the Abuse Potential of Soticlestat (TAK-935) in Healthy Adult Nondependent Recreational Drug Users With Central Nervous System Depressant Experience

The main aim is to evaluate the relative abuse potential of soticlestat in healthy adults who has used central nervous system (CNS) depressants for recreational nontherapeutic reasons.

开始日期2022-11-15

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

NCT05309902

/ Withdrawn临床1期

A Phase 1, Double-Blinded, Placebo- and Active-Controlled, Randomized Study to Investigate the Potential of Soticlestat to Prolong the QTc Interval in Healthy Adult Participants

The main aim is to see if soticlestat has any effect in the heart rate.
Participants will receive 4 doses of soticlestat in tablets and will complete some assessment which include to record activity of the heart and collection of blood samples.
Then, the clinic will contact the participants 14 days after their final dose of soticlestat to check if they have any health problems.

开始日期2022-10-11

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

100 项与 Soticlestat 相关的临床结果

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100 项与 Soticlestat 相关的转化医学

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100 项与 Soticlestat 相关的专利（医药）

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项与 Soticlestat 相关的文献（医药）

2024-11-01·NEUROSCIENCE RESEARCH

Characterization of soticlestat, a novel cholesterol 24-hydroxylase inhibitor, in acute and chronic neurodegeneration models

Article

作者: Fujimoto, Shinji ; Nishi, Toshiya ; Hasegawa, Shigeo ; Kondo, Shinichi ; Watanabe, Sayuri

We investigated whether soticlestat (TAK-935), a newly discovered cholesterol 24-hydroxylase (CH24H) inhibitor now in phase 3 clinical trials for Dravet and Lennox-Gastaut syndromes, has effects on neurodegeneration in both chronic and acute animal models associated with glutamate hyperexcitation. Soticlestat was administered at doses that approximately halve 24S-hydroxycholesterol in both experiments. In the kainic acid (KA)-induced acute hippocampal degeneration model, soticlestat ameliorated inflammatory cytokine expression, hippocampal degeneration, and memory impairment. We ruled out the possibility that soticlestat directly interferes with KA binding to the KA receptor, or that 24S-hydroxycholesterol modulates KA receptor signaling, by conducting receptor binding and cell death assays. In the PS19 chronic degeneration model of tauopathy, treatment effects were observed in neurodegeneration markers. Notably, there was a significant correlation between the levels of brain 24S-hydroxycholesterol and a proinflammatory cytokine, tumor necrosis factor-α, which is implicated in cognitive decline and lowering of seizure threshold. This is the first study demonstrating that CH24H inhibition can alleviate neurodegeneration concomitant with neuroinflammation. Herein, we discuss the interplay among 24S-hydroxycholesterol production, neuroinflammation, and excitotoxicity. Effects on neurodegeneration and neuroinflammation demonstrated in two preclinical models suggest that soticlestat is effective in ameliorating seizures and addressing cognitive dysfunction in seizure disorders.

2024-10-01·EPILEPSIA

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development

Article

作者: White, H. Steve ; Johannessen, Svein I. ; Perucca, Emilio ; Tomson, Torbjörn ; Koepp, Matthias J. ; Bialer, Meir ; Perucca, Piero

Abstract:

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5–8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy‐related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3‐specific potassium channel opener in development for the treatment of focal seizures, generalized tonic–clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5‐HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit‐containing N‐methyl‐D‐aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain‐of‐function mutations in the GRIN1, −2A, ‐2B, or ‐2D genes; soticlestat (TAK‐935), a selective inhibitor of cholesterol 24‐hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome; and STK‐001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo‐controlled adjunctive‐therapy trial. For the other compounds, adequately powered placebo‐controlled efficacy trials have not been completed to date.

2024-09-01·Expert Opinion on Drug Discovery

Innovative drug discovery strategies in epilepsy: integrating next-generation syndrome-specific mouse models to address pharmacoresistance and epileptogenesis

Review

作者: Hawkins, Nicole A ; Barker-Haliski, Melissa

INTRODUCTION:

Although there are numerous treatment options already available for epilepsy, over 30% of patients remain resistant to these antiseizure medications (ASMs). Historically, ASM discovery has relied on the demonstration of efficacy through the use of 'traditional' acute in vivo seizure models (e.g. maximal electroshock, subcutaneous pentylenetetrazol, and kindling). However, advances in genetic sequencing technologies and remaining medical needs for people with treatment-resistant epilepsy or special patient populations have encouraged recent efforts to identify novel compounds in syndrome-specific models of epilepsy. Syndrome-specific models, including Scn1a variant models of Dravet syndrome and APP/PS1 mice associated with familial early-onset Alzheimer's disease, have already led to the discovery of two mechanistically novel treatments for developmental and epileptic encephalopathies (DEEs), namely cannabidiol and soticlestat, respectively.

AREAS COVERED:

In this review, the authors discuss how it is likely that next-generation drug discovery efforts for epilepsy will more comprehensively integrate syndrome-specific epilepsy models into early drug discovery providing the reader with their expert perspectives.

EXPERT OPINION:

The percentage of patients with pharmacoresistant epilepsy has remained unchanged despite over 30 marketed ASMs. Consequently, there is a high unmet need to reinvent and revise discovery strategies to more effectively address the remaining needs of patients with specific epilepsy syndromes, including drug-resistant epilepsy and DEEs.

项与 Soticlestat 相关的新闻（医药）

2024-11-04

·生物制药小编

癫痫药物的春天来了？

癫痫治疗领域再次迎来重磅交易。近日，灵北制药宣布以26亿美元的价格，收购Longboard Pharmaceuticals。后者的核心管线是bexicaserin，一款高选择性的5-HT2C超级激动剂，用于治疗难治性癫痫DEE，已完成二期临床并获得突破疗法认证。收购消息传出后，Longboard股价大涨超50%。年初至今，由于公布bexicaserin 1b/2a期研究的积极顶线数据，其股价一路上涨，涨幅超过888%。灵北制药是丹麦精神疾病与神经系统疾病领域先驱，也是为数不多专注于CNS疾病的制药公司之一。大手笔收购Longboard，也意味着其在神经学和罕见疾病这片充满挑战却又极具潜力的领域中，更进一步。尽管失败如影随形，但是，随着越来越多药企尝试征服这一CNS研发高地，或许，正如阿尔兹海默症般，经历数十载漫长黑夜，癫痫药物的开发正在迎来春天。严重未满足的临床需求癫痫是最常见的中枢神经系统疾病（CNS）之一，影响着全球5000多万人。作为一种高致残性的慢性神经系统疾病，癫痫以其发作的不可预测性对患者生活造成极大影响。对于患者来说，治疗首选方案是抗癫痫发作药物（ASMs），这也是最基础、最重要的治疗手段。过去几十年，已有超过20种ASMs问世，从第一代演变至第三代，然而，疗效有限、副作用明显等问题依然影响着癫痫患者的治疗效果，是目前ASMs亟待解决的问题。比如，第一代ASMs包括苯巴比妥、苯妥英钠、卡马西平、丙戊酸、氯硝西泮等。这些药物在早期的癫痫治疗中发挥了重要作用，但其副作用较为明显，如嗜睡、头晕、恶心等，并且药物之间的相互作用较多，需要严格控制剂量和监测不良反应。而第二代ASMs如加巴喷丁、拉莫三嗪、托吡酯、左乙拉西坦、普瑞巴林等。相比第一代药物，副作用有所减少，药物间的相互作用也较少，是目前治疗的主流。但是，在过去的30年中，二代ASMs的广泛使用似乎并未使癫痫药物治疗的整体疗效和耐受性得到提高。近几年上市的三代ASMs，能否打破目前的停滞状态还有待于进一步观察。与之相比，还有一类患者的治疗困境尤为突出。尽管WHO指出70%的癫痫患者通过ASMs治疗可达到消除癫痫发作，但仍有约30%的患者对现有ASMs不敏感，癫痫发作无法得到有效控制，称为难治性癫痫。这类患者由于异质性、耐药性导致可选择的药物十分匮乏。典型如全球神经系统疾病负担的第三大元凶——DEEs。这也是灵北制药此次收购布局的领域。 DEEs是一组罕见的神经系统疾病，通常在婴儿期发作，具有难治性癫痫发作和发育迟缓和/或倒退的特征。同时DEEs涵盖了超过25种不同的综合征，包括Dravet综合征（DS）、Lennox-Gastaut综合征（LGS）、结节性硬化症（TSC）、CDKL5缺乏症（CDD）等，其中仅有4种有获批药物。虽然这些综合征单独被认为是孤儿病，但据估计在美国大约有22万患者受到DEEs综合征的影响。作为一组疾病，其总体发病率达到（0.27～0.54）/1000例新生儿，癫痫发作的影响还伴随到他们的儿童、成年时期，甚至可能导致过早死亡或者避免死亡但留下严重的神经系统残疾。而在治疗方面，大多数DEE患者采用多种药物联合治疗，并随时间更换药物。然而，几乎所有患者都经历了多次癫痫发作和治疗相关的副作用。换句话说，DEEs治疗领域存在严重未满足的临床需求，需要更多更好的治疗选择。潜在破局者bexicaserin 灵北制药此次收购Longboard，看中的就是bexicaserin有成为DEEs领域破局者的潜力。 Bexicaserin是由Longboard研发的新型口服、高选择性、中枢作用的5-HT2C超级激动剂，正在开发用于治疗与DEE相关的癫痫发作，例如Dravet综合征、Lennox-Gastaut综合征、结节性硬化症、CDKL5缺乏症和其他癫痫性疾病。 5-HT是一种重要的脑内神经递质，与神经元的兴奋-抑制平衡密切相关，其受体包含多种亚型。其中5-HT2C受体，是一种G蛋白偶联受体，这也是Longboard一直专注的成药靶点，已被确定为治疗肥胖和其他CNS疾病(如精神分裂症和药物成瘾)的有效药物靶点。但是，由于5-HT2C受体与其他两个5-HT2亚型(5-HT2A和5-HT2B)具有约50%的序列相似性，因此导致大量药物存在脱靶效应，或因选择性差从而与5-HT2A、5-HT2B结合，产生幻觉和心脏瓣膜病等副作用。比如2020年获批用于治疗Dravet综合征的5-HT2激动剂Fintepla，其药物标签上有一个黑框警告，该药物的活性成分与瓣膜性心脏病和肺动脉高压的风险有关。因此，开发高选择性5-HT2C受体激动剂，作为潜在治疗DEEs药物更具前景。临床前试验已经验证了bexicaserin的5-HT2C受体高选择性以及相比内源性5-HT能诱导更强的细胞反应。与Fintepla相比，bexicaserin对5-HT2C受体的选择性增加，从而减少了与5-HT2A和5-HT2B激动剂相关的潜在不良反应的可能性。今年1月，Longboard公布了bexicaserin 1b/2a期研究的积极顶线数据，结果显示：在主要疗效终点方面，在DEE研究人群中，bexicaserin使可数运动性癫痫发作的中位数减少53.3%，远高于安慰剂组的20.8%。另外，Longboard还公布了在DS、LGS和其他DEE亚组中的数据，癫痫发作的中位数降低分别为72.1%、48.1%和61.2%。这一数据，与此前Fintepla治疗DS的三期临床数据不相上下。而在安全性方面，bexicaserin表现似乎更优。此前Fintepla各组患者经历了至少一次严重TEAE，bexicaserin最常见的不良事件则是嗜睡、食欲下降、便秘、腹泻和嗜睡。数据公布后，Longboard的股价一路上涨，截至收购消息公布前，涨幅已经接近600%，而年初至今，其股价涨幅超过888%。 7月，bexicaserin获得FDA突破性疗法认定，用于2岁以上DEEs患者的治疗。9月以来，Longboard正式开启了bexicaserin针对DS的Ⅲ期试验。优秀的临床表现也成功吸引了灵北制药入局，并对其报以厚望，计划在2028年第四季度正式推出，预计bexicaserin全球销售额达到15-20亿美元。灵北制药总裁Charl van Zyl表示，此次收购是“变革型的交易”，将成为灵北神经罕见病的基石，有可能推动未来十年的发展。癫痫药物的春天来了？由于血脑屏障阻碍、致病机制不明、缺乏有效疾病模型等原因，包括癫痫在内的CNS疾病新药研发困难重重。幸运的是，包括Longboard在内的biotech在不断努力，包括灵北制药、艾伯维、武田等大药企的加入，也在不断增强我们对于征服该领域的信心。去年底，艾伯维宣布以87亿美元收购Cerevel，后者管线较多，其中之一包括Darigabat，用于治疗难治性癫痫和恐慌症，已经进入2期临床。整体来看，除了前文提及的bexicaserin、Fintepla，还有一些已上市以及很多处于研究中的新型抗癫痫药物。根据DelveInsight公司提供的数据，目前有超过75家药企在开发癫痫药物，在研药物超过90个。可以说，这些新一代ASMs的研究和开发为癫痫患者提供了更多治疗选择。而去年以来，癫痫领域在基础、临床研究方面取得了诸多进展。比如加拿大药企Xenon，其核心管线XEN1101是一款新型小分子Kv7.2/Kv7.3钾通道开放剂，主要开发适应症是癫痫和抑郁症。 Kv7.2/Kv7.3电压门控钾通道在大脑神经元轴突周围和轴突上的表达，是一个特别有吸引力的靶点。这些抑制性离子通道在靠近动作电位阈值的神经膜去极化对抗癫痫的过度兴奋起着制约作用，增强Kv7.2/Kv7.3通道开放的药物已被证明能减少癫痫发作。2011年，瑞替加滨被FDA批准为治疗癫痫的抗惊厥药物，但由于存在严重的皮肤及视网膜色素沉积等毒副作用，已经退市。与之相比，XEN1101有更高的体外和体内活性，瑞替加滨需要每天给药三次，而XEN1101每天给药一次，且没有色素沉积等问题。临床二期数据显示，XEN1101高剂量组癫痫发作频率相比基线降低52.8%，而安慰剂组只有18.2%。国内方面，上海药物所研发的派恩加滨同样瞄准这一靶点。而与瑞替加滨相比，派恩加滨的化学性质、活性、药代和安全性特征均显著优化，没有色素沉积风险。临床一期试验证明其具有良好的安全和代谢特性，目前出于二期阶段。再比如，Epidiolex是一种首创运用大麻成分的抗癫痫疗法，也是首个获批用于DS的药物，其主要成分大麻二酚（CBD）是一种多靶点分子，被证实具有明显抗癫痫活性。不过，CBD抗癫痫作用的分子机制仍不清楚，其可能的治疗靶点包括离子通道、转运体和跨膜信号蛋白，具体抗癫痫作用的机制仍有待研究。而最新研究显示，LPI-GPR55信号传导通路是CBD抗癫痫靶点的潜在调节因子，在联合用药方面，CBD也为对GABAAR调节剂（例如苯二氮卓类药物）无效的难治性癫痫患者提供了一种潜在的治疗选择。而在新机制研究方面，武田制药8.65亿美元收购而来的胆固醇24羟化酶（CH24H）抑制剂soticlestat，属于一个全新的抗癫痫作用机制，是通过抑制CH24H活性，减少胆固醇转化为24S-羟基胆固醇，从而降低谷氨酸能通路的兴奋性，减少癫痫发作。积极的二期试验结果为DS和LGS患者提供了新的药物选择的可能性，尤其是那些对现有药物不敏感的患者。然而，三期试验双双折戟。总体来看，目前在研治疗方法主要针对遗传学、离子通道和其他神经递质，以及其他潜在性FIC干预措施，比如干细胞、肠道微生物组、AAV9基因疗法等在进行早期研究，也为患者带来了更多新希望。从趋势来看，癫痫新疗法的研究不再局限于发作的控制，而是包括从发病机制的根源上改变癫痫发作的治疗及预后情况。总结需要承认的是，尽管新的突破每天都有可能发生，但这尚无法彻底改变CNS疾病新药研发的困境。就在上半年，一些药企在研癫痫新药遭遇失败。4月份，Addex宣布ADX71149在治疗对左乙拉西坦或布瓦西坦反应不佳的局灶性癫痫发作的2期研究失败；6月份，Marinus公司口服抗癫痫药物Ztalmy的静脉制剂ganaxolone治疗难治性癫痫持续状态开展的试验失败；武田的soticlestat，在治疗LGS及DS这两种难治性癫痫综合征的三期试验均未达主要终点；对此，武田表示，在16周的治疗中，治疗应答率、护理人员和临床医生对病情改善的总体印象以及癫痫发作强度和持续时间尺度都发生了显著变化。总体数据呈积极趋势，希望与监管机构商讨下一步行动。在号称“研发黑洞”的CNS领域，也的确需要武田这种屡败屡战的精神。期待新的革命性突破，早日到来。

并购临床2期

2024-10-14

·MedCity News

Lundbeck’s Neuro-Rare Pipeline Lands Cornerstone Drug via $2.6B Longboard Pharma Acquisition - MedCity News

Neuroscience drug developer Lundbeck is expanding its scope to epilepsy via the $2.6 billion acquisition of Longboard Pharmaceuticals, a company whose lead asset is in late-stage clinical development for a rare, inherited seizure disorder that has few approved treatments. According to deal terms announced Monday, Lundbeck will pay $60 in cash for each Longboard share, representing a 54.2% premium to the biotech’s closing stock price on Friday and a 77% premium to the stock’s average price for the month of September. When La Jolla, California-based Longboard went public in 2021, it priced shares at $16 apiece. Longboard’s lead drug candidate, bexicaserin, is in development for developmental and epileptic encephalopathies (DEEs), a group of disorders that include the rare epilepsies Dravet syndrome and Lennox-Gastaut syndrome. The oral small molecule is an agonist of the 5-HT2C receptor, whose roles include regulating seizure severity. This receptor is already targeted by Fintepla, a UCB drug approved to treat seizures associated with Dravet and Lennox-Gastaut. But Fintepla’s label carries a black box warning for cardiovascular complications. Bexicaserin is designed to selectively target 5-HT2C without also hitting other receptors that can cause adverse effects. presented by Health IT Accelerating Claim Processing: Strategies to Shorten the Life of a Claim These strategies and practices can significantly shorten the life cycle of claims, leading to quicker resolutions and improved financial outcomes. By Greenway Health Jazz Pharmaceuticals’ cannabis-derived Epidiolex, approved for Dravet, Lennox-Gastaut, and tuberous sclerosis complex, has no black box warning. Some high-profile efforts in DEEs have encountered setbacks. In June, Takeda Pharmaceutical reported its drug candidate soticlestat failed separate placebo-controlled Phase 3 tests in Dravet and Lennox-Gastaut. Longboard had been making the case that bexicaserin can stand apart from other approaches to treat epilepsies. In January, the biotech reported Phase 1b/2a data showing a median 53.3% reduction in seizure frequency in patients with DEEs during the 75-day treatment period, results that had the company making claims of best-in-class potential. Shares of the biotech soared more than 300% after that data report. Bexicaserin’s efficacy results are holding up so far. According to a Lundbeck investor presentation, nine-month open-label data show a 57.7% reduction in countable motor seizures. In September, Longboard began a global Phase 3 test enrolling Dravet patients age 2 and older. This clinical trial is part of a broader program planned to evaluate the drug in about 480 patients who have a range of DEEs. The Longboard pipeline also includes LP659, a modulator of the S1P receptor that has potential applications in neuroinflammatory disorders. A Phase 1 single-ascending dose study has been completed but plans for a Phase 1 multiple-ascending dose study are subject to resolution of a partial clinical hold. Both bexicaserin and LP659 were licensed from Arena Pharmaceuticals. presented by Sponsored Post The Promise of Value-Based Care and MedTech Innovation Monica Vajani, Executive Director for mHUB’s MedTech Accelerator, discusses how mHUB is helping innovators transition healthcare towards value-based care. By Monica Vajani - mHUB Lundbeck focuses on neuroscience drugs. The Copenhagen-based company’s top-selling product is Rexulti, a schizophrenia and depression drug that last year expanded its approved uses to include agitation caused by Alzheimer’s disease. The product accounted for 4.5 billion Danish krone (about $661 million) in revenue last year, a 16% increase compared to the prior year, according to the company’s annual report. Within neuroscience, Lundbeck executives have identified rare neurological diseases as an opportunity for pipeline expansion. Lundbeck projects a fourth quarter 2028 launch for bexicaserin. The company estimates the drug could achieve peak sales of $1.5 billion to $2 billion. “This transformative transaction will become a cornerstone in Lundbeck’s neuro-rare franchise, with a potential to drive growth into the next decade,” Lundbeck President and CEO Charl van Zyl said in a prepared statement. “Bexicaserin addresses a critical unmet need for patients suffering from rare and severe epilepsies, for which there are very few good treatment options available.” The boards of directors of both Lundbeck and Longboard have approved the acquisition, which still needs the majority of Longboard’s outstanding voting shares to be tendered. The deal also must pass regulatory muster. The transaction is expected to close by the end of this year. Image: Getty Images, Iaremenko

临床3期并购上市批准临床结果临床1期

2024-09-17

·精准药物

核心产品出问题，biotech股价暴跌76%

PREFACE 前言股市，向来是一场惊险无比的资本游戏，一夜暴富的美梦和血本无归的幻灭，在确定性和不确定性中不断上演。而对于专业性极强的创新药股票，每次暴涨或是暴跌，都是投资人对于公司管线估值的最新判断。 2024年初以来，因为临床研发失败而导致股价暴跌的biotech公司不在少数，甚至在同一天内有三家biotech公司同时遭重：5月6日，GlycoMimetics、Lyra Therapeutics、EyePoint Pharmaceuticals三家公司宣布旗下核心产品临床失利，股价应声暴跌，分别下跌了月83%，87%，43%。这样的“股价”惨案，仍在不断上演。 01 两项临床3期研究失败 Ovid暴跌76% 癫痫是一种常见的发作性神经系统疾病，被世界卫生组织列为神经系统五大难治性疾病之一，也是神经系统疾病中仅次于脑血管疾病的第二大疾病。根据WHO数据显示，全球大约有5000万癫痫患者，其中发病率最高的患者群体是儿童。而Lennox-Gastaut综合征（LGS）、Dravet综合征（DS）是两种发病于儿童早期，罕见、严重、难治的癫痫综合征，会造成癫痫相关的严重认知和发育障碍，存在巨大的未满足的临床需求。 2018年，FDA首次批准了GW Pharmaceuticals公司旗下的Epidiolex治疗年龄在2岁及以上的LGS和DS患者，面对一片蓝海，Epidiolex在2020年的销售额已经达到5亿美元。面对蓝海和不菲的市场蛋糕，全球药企在LGS和DS治疗领域不断的投入资源。 2021年，武田以8.56亿美元的总价以及额外的销售额提成收购了Ovid Therapeutics，从而获得了后者在研管线——胆固醇24羟化酶（CH24H）抑制剂soticlestat的全球开发和商业化权益，彼时这款药物已经在改善DS和LGS患者的癫痫发作上展现出了不菲的潜力。 Soticlestat在成为epidiolex的有力竞争者的同时，也非常契合武田全球长期增长战略规划，因而武田也是在全球范围内大力推进soticlestat的临床研究。但新药研发，总是九死一生，尤其是对于CNS疾病来说，更是难上加难，临床后期试验无法延续此前治疗效果的案例比比皆是。当地时间6月17日，武田公布了soticlestat治疗DS和LGS患者的两项临床3期试验SKYLINE研究和SKYWAY研究初步结果。 SKYLINE研究结果显示，soticlestat组治疗DS患者并未达到主要终点；SKYWAY研究结果显示，soticlestat组治疗LGS患者未能达到减少运动跌倒发作的主要终点两项3期临床失败，已经基本上宣告了soticlestat的失败，也同时宣告着对Ovid Therapeutics公司身价起主要支撑作用的后续巨额里程碑付款与销售额提成化为了乌有。因而美股投资人也是“毫不留情”，Ovid Therapeutics股价当天大跌76%，市值仅剩5600万美元。 Soticlestat的失败为CH24H靶点蒙上了阴影，也给Ovid公司带来了致命的打击。但面对DS和LGS患者发作负担和治疗耐药等多个方面仍未满足的临床需求，仍需各方投入资源探索新药物。 02 “难啃”的癫痫流水的biotech 血脑屏障的阻碍，致病机理不明确，缺乏有效的疾病模型等等原因，让CNS新药的开发困难重重。癫痫作为CNS疾病之一，亦是如此。据不完全统计，在抗癫痫新药的开发上，今年以来已有至少三家公司折戟临床，并且股市给出的结果都是：暴跌。除上文提到的Ovid Therapeutics外，另外两家公司为Marius Pharmaceuticals和Addex Therapeutics。 Marius Pharmaceuticals 当地时间2024年4月15日，Marius宣布旗下ganaxolone治疗难治性癫痫持续状态（refractory status epilepticus，RSE）的临床3期试验RAISE研究的中期分析没有达到预设的终止标准，Marius股价当天大跌近83%。但在公布中期分析结果的同时，Marius还给投资者们留了一些希望，即独立数据监测委员会建议继续开展试验，等待顶线结果再决定是否继续开发ganaxolone。 Ganaxolone是一款GABAA受体正变构调节注射剂，口服混悬制剂ZTALMY于2022年3月18日获FDA批准用于2岁及以上细胞周期蛋白依赖性激酶样5（CDKL5）缺乏导致的癫痫患者。根据Marius最新季报显示，ZTALMY在2024年第一季度的销售额在740-760万美元之间，截至第一季度末，Marius在手的现金及现金等价物约为1.133亿美元，今年支撑公司运营至2024年年末。随着核心管线研发失利，现金流喊急，Marius也不得不寻求裁员自保，5月8日，Marius宣布裁员20%，以求延长现金流。 Addex Therapeutics 当地时间2024年4月29日，Addex宣布旗下ADX71149治疗左乙拉西坦（levetiracetam）或布立西坦（brivaracetam）反应不良的局灶性癫痫发作患者的临床2期研究没有达到主要终点。 ADX71149是一款选择性代谢型谷氨酸2型（mGlu2）受体正变构调节剂，此前杨森制药公司以1.09亿欧元的总金额以及两位数的销售额分成引进了该药物。受此消息影响，Addex美股股票当天大跌53%，截至目前最新的市值仅为854万美元。在一个季度内，三家开发抗癫痫新药的biotech在核心管线临床开发失利后，股价暴跌，将CNS新药研发之难体现的淋漓尽致，但不可否认的是CNS疾病患病人群众多，市场需求巨大，也将继续催生更多新靶点、新机制药物的出现。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

并购临床3期临床成功临床失败

100 项与 Soticlestat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11590	-	-	-

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
CDKL5缺乏症	临床3期	美国	武田（中国）国际贸易有限公司	2021-10-28
CDKL5缺乏症	临床3期	美国	Bushu Pharmaceuticals Ltd.	2021-10-28
CDKL5缺乏症	临床3期	美国	Takeda Development Center Americas, Inc.	2021-10-28
CDKL5缺乏症	临床3期	日本	Bushu Pharmaceuticals Ltd.	2021-10-28
CDKL5缺乏症	临床3期	日本	Takeda Development Center Americas, Inc.	2021-10-28
CDKL5缺乏症	临床3期	日本	武田（中国）国际贸易有限公司	2021-10-28
CDKL5缺乏症	临床3期	澳大利亚	Takeda Development Center Americas, Inc.	2021-10-28
CDKL5缺乏症	临床3期	澳大利亚	武田（中国）国际贸易有限公司	2021-10-28
CDKL5缺乏症	临床3期	澳大利亚	Bushu Pharmaceuticals Ltd.	2021-10-28
CDKL5缺乏症	临床3期	比利时	Takeda Development Center Americas, Inc.	2021-10-28

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临床结果

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分期

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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


NCT04938427 (SKYWAY \| TAK-935-3002, CTgov)	临床3期	Lennox-Gastaut综合征	270	Placebo (Placebo)	夢選製艱構獵膚製製構(憲繭醖繭範範繭遞餘鏇) = 艱鹹糧選選構選鑰壓製壓鏇簾鬱獵獵齋簾網鹽 (鹽蓋醖淵膚壓鬱齋範糧, 觸鏇願糧積餘艱鹽衊餘 ~ 憲積餘製網願餘願膚鹹) 更多	-	2024-08-21
				Soticlestat (Soticlestat)	夢選製艱構獵膚製製構(憲繭醖繭範範繭遞餘鏇) = 鬱範遞鬱觸糧鏇鬱糧構壓鏇簾鬱獵獵齋簾網鹽 (鹽蓋醖淵膚壓鬱齋範糧, 窪壓鹹壓選獵繭壓鏇獵 ~ 膚夢觸餘積繭鑰膚繭構) 更多
NCT04938427 (SKYWAY \| TAK-935-3002, Company_Website) 人工标引	临床3期	Lennox-Gastaut综合征	-	Soticlestat+standard of care	選鬱製淵廠鏇鑰鑰繭糧(齋衊遞醖鏇觸網淵蓋願) = Soticlestat missed the novel primary endpoint of reduction from baseline in Major Motor Drop (MMD) seizure frequency as compared to placebo. 夢鬱鏇製網壓範鏇範鑰 (獵壓繭夢遞艱築襯齋顧 ) 未达到更多	不佳	2024-06-17
				Placebo+standard of care
NCT04940624 (SKYLINE \| TAK-935-3001, Company_Website) 人工标引	临床3期	Dravet综合征	-	soticlestat plus standard of care	膚鬱窪憲鹽鹹繭觸鹹鏇(壓選壓鏇淵鏇鬱鹽鹹築): P-Value = 0.06 未达到更多	不佳	2024-06-17
				placebo plus standard of care
NCT05098054 (CTgov)	临床1期	肝损伤 \| 肝功能衰竭	36	Soticlestat (Severe HI: Soticlestat 300 mg)	夢夢鹹襯繭膚觸膚鹹夢(壓鑰構願鹽選醖鹽夢構) = 鹽壓網積鏇鏇蓋鬱窪餘願窪鑰夢淵選製衊觸窪 (選簾醖範願齋構艱齋壓, 壓範觸鏇糧淵襯築夢製 ~ 選簾範糧襯簾醖顧繭遞) 更多	-	2024-02-02
				Soticlestat (Moderate HI: Soticlestat 300 mg)	夢夢鹹襯繭膚觸膚鹹夢(壓鑰構願鹽選醖鹽夢構) = 製衊鏇淵顧遞壓遞觸繭願窪鑰夢淵選製衊觸窪 (選簾醖範願齋構艱齋壓, 醖願窪齋顧夢餘鏇鑰醖 ~ 衊膚鑰製衊鏇夢繭選願) 更多
NCT05098041 (CTgov)	临床1期	-	15	Rifampin+Soticlestat	憲遞廠獵繭製築簾選淵(壓襯鹹艱醖選鑰繭糧夢) = 廠鹹鏇製糧構艱襯衊鏇淵廠網鹹鹹襯範顧憲餘 (鏇網壓夢範鹽廠遞簾製, 夢積積襯窪觸淵鏇製構 ~ 糧觸鹹鑰衊憲簾構壓憲) 更多	-	2023-11-22
NCT05064449 (CTgov)	临床1期	-	28	itraconazole+Soticlestat	製繭選鬱糧廠鏇繭築餘(願網鏇鏇淵鑰廠積築糧) = 憲夢鏇醖鏇艱膚鹹鏇鑰醖壓醖壓醖獵鹹範鑰願 (齋鹽壓繭鑰蓋夢夢齋鑰, 範鬱鹽廠顧網顧鹹膚選 ~ 夢製顧構遞鏇願艱夢廠) 更多	-	2023-10-03
NCT03635073 (ENDYMION 1, IEC2023)	临床2期	Dravet综合征	-	Soticlestat ≤300 mg twice daily	簾廠遞簾襯夢網繭膚觸(醖鏇獵範憲襯鬱顧衊醖) = 鑰蓋構繭選築範簾選獵醖廠鏇積顧餘製淵顧齋 (積鏇網鑰範鬱鏇鬱鏇淵 ) 更多	积极	2023-09-04
				Placebo	簾廠遞簾襯夢網繭膚觸(醖鏇獵範憲襯鬱顧衊醖) = 網顧壓選繭憲顧襯範選醖廠鏇積顧餘製淵顧齋 (積鏇網鑰範鬱鏇鬱鏇淵 ) 更多
NCT03635073 (ENDYMION 1, AAN2023)	临床2期	Dravet综合征 \| Lennox-Gastaut综合征	-	Soticlestat ≤300 mg BID	構鏇選醖觸餘觸積衊選(鹹觸選選襯鬱衊夢糧窪) = 齋衊鏇窪遞獵觸範鹹襯積淵憲衊築選廠獵淵餘 (願糧淵膚餘獵夢淵壓製 ) 更多	-	2023-04-25
				Placebo	構鏇選醖觸餘觸積衊選(鹹觸選選襯鬱衊夢糧窪) = 衊艱齋壓鏇範壓顧廠醖積淵憲衊築選廠獵淵餘 (願糧淵膚餘獵夢淵壓製 ) 更多
NCT03694275 (ARCADE, Pubmed)	临床2期	CDKL5缺乏症 \| Crouzon综合征伴黑棘皮症	20	Soticlestat	願築願蓋願醖積築製鑰(夢襯醖製夢艱簾鹽選淵) = 築廠廠蓋鹹範獵選醖淵製顧醖窪鏇壓齋積遞鹹 (構鹹願蓋淵齋範築繭積 ) 更多	-	2023-04-01
NCT03650452 (ELEKTRA, Pubmed) 人工标引	临床2期	Lennox-Gastaut综合征 \| Dravet综合征辅助	141	Soticlestat	顧築鹹壓選鏇艱顧夢願(淵餘觸積構憲築鬱獵衊): difference = -30.21, P-Value = 0.0008	积极	2022-07-16
				Placebo