Zorevunersen sodium

正文共：2386字 1图 预计阅读时间：5分钟 由于患者招募困难，卫材终止了一项三期临床试验。 美东时间2024年11月17日，知名行业媒体《Endpoints News》发文称，卫材终止了旗下Lorcaserin（氯卡色林）用于辅助治疗Dravet综合征的三期MOMENTUM 1研究（NCT04572243）。 根据美国临床试验数据库（ClinicalTrials.gov）查询，目前MOMENTUM 1研究已处于终止状态，并提示该状态并非由于任何安全性或有效性原因导致。 关于Dravet综合征 Dravet综合征（Dravet syndrome ，DS），为婴儿期起病的难治性癫痫综合征，由法国医生Charlotte Dravet在1978年首次报道，既往又称婴儿严重肌阵挛癫痫。 DS是一种罕见的癫痫性脑病，根据国外文献报道DS患病率为1/40000~1/20000（也有文献报道为发病率为1/15700~1/40900）占3岁以内婴幼儿癫痫的8%。2018年，该疾病被列入国家第一批罕见病目录（编号：105号）。 DS发病主要由遗传因素决定，其主要致病基因为钠离子通道α1亚单位基因SCN1A突变，此外如SCN1B、GABRG2等基因也可能与Dravet综合征有关。 目前，DS暂无治愈方法，治疗主要是对症支持治疗，旨在减少癫痫发作的频率和强度。常用药物包括丙戊酸、司替戊醇、芬氟拉明、药用级大麻二酚、托吡酯等。 其中，芬氟拉明作为一种5-HT2C受体激动剂，最早（1973年）被批准用于减肥，1997年因严重心脏毒性而停用。后来其较低剂量被重新启用，治疗一些癫痫性脑病：2020 年，美国和欧盟先后批准芬氟拉明作为DS治疗的添加药物。 相同命运的氯卡色林 此次，卫材终止的氯卡色林与芬氟拉明同为5-羟色胺（5-HT，又称血清素）受体激动剂。 其研发历程也颇为相似。氯卡色林原研为Arena，2012年获FDA批准上市用于减肥治疗，商品名Belviq。后因市场表现一般，Arena于2017年将其权益卖给了卫材。 值得一提的是，基于芬氟拉明的前车之鉴。FDA在批准Belviq时要求生产商开展一项随机、双盲、安慰剂对照的上市后研究，以评估氯卡色林的心血管风险。这项研究有12000例参与者，为期5年，于2018年6月结束。 因此，氯卡色林是完成FDA要求的长期心脏安全研究的第一种新型减肥药物。只不过，FDA在对其安全性数据进行审查时发现，服用氯卡色林的患者被确诊为癌症的人数更多（462， 7.7% vs 423, 7.1%）。 2020年1月，FDA要求Belviq，Belviq XR从美国市场撤市。这对卫材而言，称得上无妄之灾。尽管癌症风险增高的原因还不明确，FDA也无法断定氯卡色林就是直接的致癌原因，但撤市已成定局。 后者激流勇进，前者寸步难行 芬氟拉明在肥胖症失利之后，在癫痫性脑病中“复活”。那么氯卡色林，理应也可走通这条路径。 2020年，卫材在与FDA协商后启动了氯卡色林治疗DS的三期MOMENTUM 1研究。当时目标是在美国招募58名受试者，如今4年过去，卫材还在招募在面临招募困境。 根据《Endpoints News》报道，卫材一位的发言人通过电子邮件表示，“随着其他经FDA批准的疗法可用于治疗这一复杂的疾病（DS），招募患者进行试验性治疗变得极其困难。” 目前，针对DS的治疗涌现了各种新型治疗方式，包括但不限于：Stoke的反义寡核苷酸（ASO），STK-001；Longboard的5-HT2C受体超激动剂Bexicaserin；Encoded的AAV9介导的候选基因调控疗法，ETX101。 其中，Bexicaserin已进入临床三期阶段。它虽然与氯卡色林、芬氟拉明同为5-HT2C受体激动剂，但却显示出对5-HT2C受体的选择性增加。 具体而言，5-HT2受体次家族有A、B、C三种亚型，研究发现，中枢5-羟色胺主要通过作用于脑内5-羟色胺2C受体（5-HT2C）起到调节食欲的作用，这也是其减重的原因。 而5-HT2A与5-HT2B激动，可能导致致幻活性与心脏毒性相关不良反应。芬氟拉明与右芬氟拉明的退市，便与同时激动5-HT2B导致的肺动脉高压和心脏瓣膜异常有关。 至于氯卡色林，今年4月是我国列入第二类精神药品目录。此前（2013年），该药物已被FDA列入《管制物质法案》附表Ⅳ管理。 以目前的科研水平结合当前商业价值，几经波折的氯卡色林，或许不值得继续投入资源。 参考资料： 1.Eisai terminates Phase 3 trial of Dravet drug, citing recruitment challenges（Endpoints News） 2.clinicaltrials.gov 3.Dravet 综合征诊断与治疗的中国专家共识（癫痫杂志） 4.Wirrell E C, Laux L, Donner E, et al. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel[J]. Pediatric Neurology,2017,68:18-34 5.田小娟，张月华. Dravet综合征治疗和预后研究进展[J]. 中国实用儿科杂志,2017(10):789-793 6.新列管药“氯卡色林”的由来（中国禁毒报） 7.其他公开资料 封面图来源：pixabay 主管说没有预算，这个局怎么破？这里可以24小时免费观看FDA、EMA培训录像，自己不断成长，还不麻烦公司！~ 2024-11-17 第四届佛山创新药论坛圆满落幕，行业领袖共绘“BD出海与投融资”新未来 2024-11-16 FDA要变天！特朗普正式提名罗伯特·肯尼迪领导卫生与公众服务部 2024-11-15 版权声明/免责声明 本文为原创文章。 本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。 文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。 如有任何问题，请与我们联系。 衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 点击查看更多精彩！

BEDFORD, Mass.--( BUSINESS WIRE )-- Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company dedicated to restoring protein expression by harnessing the body’s potential with RNA medicine, today reported financial results for the third quarter of 2024 and provided business updates including those related to zorevunersen, the Company’s proprietary antisense oligonucleotide (ASO) which is in development by Stoke as the first potential medicine to address the genetic cause of Dravet syndrome. “We are headed into a busy year-end as we prepare to share new data which is representative of our proposed Phase 3 dosing regimen and complete our regulatory discussions toward alignment on that study design,” said Edward M. Kaye, M.D., Chief Executive Officer of Stoke Therapeutics. “Key to our regulatory discussions are the assessments of behavior and cognition in patients with Dravet syndrome. In our studies of zorevunersen, we have demonstrated substantial and sustained effects across multiple measures of disease, starting within the first year of treatment. These data give us confidence in our Phase 3 planning and the potential for zorevunersen to go beyond seizure management by addressing the root cause of the disease.” The Company announced today that it has submitted abstracts for presentation at the American Epilepsy Society meeting taking place December 6-10, in Los Angeles, California. Included among these planned presentations are new data from all patients treated in the clinical studies with initial 70mg doses followed by 45mg maintenance dosing in studies of zorevunersen. A Phase 3 regimen of two or three loading doses of 70mg followed by maintenance doses of 45mg is currently under discussion with global regulatory agencies. As the Company continues to focus on zorevunersen as its lead program, it will delay the start of the Phase 1 study of STK-002, its clinical candidate for the treatment of autosomal dominant optic atrophy (ADOA). Recent Program Highlights and Upcoming Milestones In August, the Company announced that the U.S. Food and Drug Administration (FDA) has removed the Partial Clinical Hold on zorevunersen. In September, the Company shared data from the Phase 1/2a and open-label extension (OLE) studies of zorevunersen in children and adolescents with Dravet syndrome at the 15 th European Epilepsy Congress (EEC). Company management will present at the Jefferies London Healthcare Conference on Wednesday, November 20, at 6:30am EST (11:30am GMT). A live webcast of the presentation will be available on the Investors & News section of Stoke’s website. The Company expects to present data at the American Epilepsy Society (AES) 2024 Annual Meeting, pending acceptance of the abstracts. The Company plans to provide an update on Phase 3 registrational plans for zorevunersen by year-end. Third Quarter 2024 Financial Results As of September 30, 2024, the Company had $269.2 million in cash, cash equivalents, and marketable securities. Revenue recognized for upfront license fees and services provided from the License and Collaboration Agreement with Acadia Pharmaceuticals for the three months ended September 30, 2024 was $4.9 million, compared to $3.3 million for the same period in 2023. Net loss for the three months ended September 30, 2024 was $26.4 million, or $0.47 per share, compared to $24.5 million, or $0.55 per share, for the same period in 2023. Research and development expenses for the three months ended September 30, 2024 were $22.2 million, compared to $20.3 million for the same period in 2023. General and administrative expenses for the three months ended September 30, 2024 were $12.7 million, compared to $10.3 million for the same period in 2023. Year-to-Date 2024 Financial Results Revenue recognized for upfront license fees and services provided from the License and Collaboration Agreement with Acadia Pharmaceuticals for the nine months ended September 30, 2024 was $13.9 million, compared to $6.0 million for the same period in 2023. Net loss for the nine months ended September 30, 2024 was $78.5 million, or $1.48 per share, compared to $77.7 million, or $1.78 per share, for the same period in 2023. Research and development expenses for the nine months ended September 30, 2024 were $65.7 million, compared to $60.5 million for the same period in 2023. General and administrative expenses for the nine months ended September 30, 2024 were $36.0 million, compared to $30.7 million for the same period in 2023. The increase in operating expenses for the three and nine month periods ending September 30, 2024 over the same periods in 2023 primarily relates to increases in costs associated with personnel, third party contracts, consulting, facilities and other costs associated with development activities for zorevunersen and STK-002, research on additional therapeutics and growing a public corporation. About Dravet Syndrome Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures, beginning within the first year of life. Dravet syndrome is difficult to treat and has a poor long-term prognosis. Complications of the disease often contribute to a poor quality of life for patients and their caregivers. The effects of the disease go beyond seizures and often include intellectual disability, developmental delays, movement and balance issues, language and speech disturbances, growth defects, sleep abnormalities, disruptions of the autonomic nervous system and mood disorders. The disease is classified as a developmental and epileptic encephalopathy due to the developmental delays and cognitive impairment associated with the disease. Compared with the general epilepsy population, people living with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy, or SUDEP. There are no approved disease-modifying therapies for people living with Dravet syndrome. One out of 16,000 babies are born with Dravet syndrome, which is not concentrated in a particular geographic area or ethnic group. About Zorevunersen (STK-001) Zorevunersen is an investigational new medicine for the treatment of Dravet syndrome currently being evaluated in ongoing clinical trials. Stoke believes that zorevunersen, a proprietary antisense oligonucleotide (ASO), has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome. Zorevunersen is designed to upregulate Na v 1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological Na v 1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. Zorevunersen has been granted orphan drug designation by the FDA and the EMA, and rare pediatric disease designation by the FDA as a potential new treatment for Dravet syndrome. About Stoke Therapeutics Stoke Therapeutics (Nasdaq: STOK), is a biotechnology company dedicated to restoring protein expression by harnessing the body’s potential with RNA medicine. Using Stoke’s proprietary TANGO (Targeted Augmentation of Nuclear Gene Output) approach, Stoke is developing antisense oligonucleotides (ASOs) to selectively restore protein levels. Stoke’s first compound, zorevunersen (STK-001), is in clinical testing for the treatment of Dravet syndrome, a severe and progressive genetic epilepsy. Dravet syndrome is one of many diseases caused by a haploinsufficiency, in which a loss of ~50% of normal protein levels leads to disease. Stoke is pursuing the development of STK-002 for the treatment of autosomal dominant optic atrophy (ADOA), the most common inherited optic nerve disorder. Stoke’s initial focus is haploinsufficiencies and diseases of the central nervous system and the eye, although proof of concept has been demonstrated in other organs, tissues, and systems, supporting its belief in the broad potential for its proprietary approach. Stoke is headquartered in Bedford, Massachusetts with offices in Cambridge, Massachusetts. For more information, visit https://www.stoketherapeutics.com/ . Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to: the Company’s current or future financial position and liquidity; the ability of zorevunersen (STK-001) to treat the underlying causes of Dravet syndrome and reduce seizures or show improvements in behavior and cognition at the indicated dosing levels or at all; and the timing and expected progress of clinical trials, data readouts, regulatory meetings, regulatory decisions and other presentations. Statements including words such as “expect,” “plan,” “will,” “continue,” or “ongoing” and statements in the future tense are forward-looking statements. These forward-looking statements involve risks and uncertainties, as well as assumptions, which, if they prove incorrect or do not fully materialize, could cause our results to differ materially from those expressed or implied by such forward-looking statements, including, but not limited to, risks and uncertainties related to: the Company’s ability to advance, obtain regulatory approval of, and ultimately commercialize its product candidates, including zorevunersen; the timing of data readouts and interim and final results of preclinical and clinical trials; the receipt and timing of potential regulatory decisions; positive results in a clinical trial may not be replicated in subsequent trials or successes in early stage clinical trials may not be predictive of results in later stage trials; the Company’s ability to fund development activities and achieve development goals, including expectations regarding its collaboration with Acadia Pharmaceuticals; the Company’s ability to protect its intellectual property; the direct or indirect impact of global business, political and macroeconomic conditions, including inflation, interest rate volatility, cybersecurity events, uncertainty with respect to the federal budget, instability in the global banking system and volatile market conditions, and global events, including public health crises, and ongoing geopolitical conflicts, such as the conflicts in Ukraine and the Middle East; and other risks and uncertainties described under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2023, its quarterly reports on Form 10-Q, and the other documents it files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and the Company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. Financial Tables Follow Stoke Therapeutics, Inc. and subsidiary Consolidated balance sheets (in thousands, except share and per share amounts) (unaudited) September 30, December 31, 2024 2023 Assets Current assets: Cash and cash equivalents $ 150,016 $ 191,442 Marketable securities - current 89,184 9,952 Prepaid expenses 9,837 11,320 Restricted cash - current 75 — Interest receivable 691 64 Other current assets 3,809 2,561 Total current assets $ 253,612 $ 215,339 Marketable securities - long-term 29,952 — Restricted cash - long-term 494 569 Operating lease right-of-use assets 4,928 6,611 Property and equipment, net 4,333 5,823 Total assets $ 293,319 $ 228,342 Liabilities and stockholders’ equity Current liabilities: Accounts payable $ 2,485 $ 1,695 Accrued and other current liabilities 15,768 13,815 Deferred revenue - current portion 31,612 15,309 Total current liabilities $ 49,865 $ 30,819 Deferred revenue - net of current portion 8,291 33,074 Other long term liabilities 3,050 4,884 Total long term liabilities 11,341 37,958 Total liabilities $ 61,206 $ 68,777 Stockholders’ equity Common stock, par value of $0.0001 per share; 300,000,000 shares authorized, 52,941,191 and 45,918,233 shares issued and outstanding as of September 30, 2024 and December 31, 2023, respectively 5 5 Additional paid-in capital 712,290 561,433 Accumulated other comprehensive income (loss) 166 (24 ) Accumulated deficit (480,348 ) (401,849 ) Total stockholders’ equity $ 232,113 $ 159,565 Total liabilities and stockholders’ equity $ 293,319 $ 228,342 Stoke Therapeutics, Inc. and subsidiary Consolidated statements of operations and comprehensive loss (in thousands, except share and per share amounts) (unaudited) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Revenue $ 4,894 $ 3,308 $ 13,941 $ 5,978 Operating expenses: Research and development 22,205 20,271 65,710 60,453 General and administrative 12,692 10,271 35,950 30,712 Total operating expenses 34,897 30,542 101,660 91,165 Loss from operations (30,003 ) (27,234 ) (87,719 ) (85,187 ) Other income (expense): Interest income (expense), net 3,545 2,651 9,668 7,321 Other income (expense), net 28 41 (448 ) 125 Total other income (expense) 3,573 2,692 9,220 7,446 Net loss $ (26,430 ) $ (24,542 ) $ (78,499 ) $ (77,741 ) Net loss per share, basic and diluted $ (0.47 ) $ (0.55 ) $ (1.48 ) $ (1.78 ) Weighted-average common shares outstanding, basic and diluted 56,341,074 44,266,017 52,991,015 43,669,987 Comprehensive loss: Net loss $ (26,430 ) $ (24,542 ) $ (78,499 ) $ (77,741 ) Other comprehensive gain: Unrealized gain on marketable securities 181 232 190 1,028 Total other comprehensive gain $ 181 $ 232 $ 190 $ 1,028 Comprehensive loss $ (26,249 ) $ (24,310 ) $ (78,309 ) $ (76,713 )