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–Dose-escalating study will evaluate the safety, tolerability and exposure of STK-002 in people with ADOA– –Changes in visual function, ocular structure and quality of life to be evaluated as secondary objectives– –ADOA is the most common inherited optic nerve disorder and is primarily caused by variants in the OPA1 gene that result in progressive and irreversible vision loss– 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 announced that the first patient has been dosed in the Phase 1 OSPREY study of STK-002, an investigational medicine for the treatment of Autosomal Dominant Optic Atrophy (ADOA). ADOA is a rare genetic disease that causes progressive and irreversible vision loss in both eyes starting in the first decade of life. Approximately 80 percent of people with ADOA are symptomatic by age 10, and approximately half are expected to become legally blind. There are currently no approved treatments for ADOA. “Data from our natural history study suggest that for some people affected by ADOA, the disease progresses more rapidly than previously thought. Based on a growing understanding of the disease biology, we believe that increasing naturally occurring OPA1 protein may help restore vision in people with ADOA,” said the lead principal investigator of the study Dr. Patrick Yu-Wai-Man, M.D., Ph.D., Professor of Ophthalmology at the University of Cambridge and honorary consultant neuro-ophthalmologist at Addenbrooke’s Hospital, Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, United Kingdom. “There are currently no medicines available for people living with ADOA, and there is a lot of interest in this study from the ADOA community given the potential for STK-002 to restore vision by addressing the root cause of the disease.” The OSPREY study is a Phase 1, dose-escalating open-label study of children and adults ages 6 to 55 who have an established diagnosis of ADOA and have a confirmed disease-causing variant in the OPA1 gene. The primary objectives for the study are to assess the safety and tolerability of single ascending doses of STK-002, as well as to determine the exposure in blood. Secondary objectives are to assess changes in visual function, ocular structure and quality of life after single doses of STK-002. The OSPREY study follows a standard dose escalation design with participants enrolled into sequential cohorts receiving increasing dose levels of STK-002. Dose escalation of the first four cohorts will continue through 2026 and early 2027, pending safety and tolerability assessments. Data from the OSPREY study will help to inform potential future development of STK-002. “ADOA is a haploinsufficient disease, one of many that we believe are ideally suited for our ASOs that are designed to increase naturally occurring protein levels to improve health,” said Barry Ticho, M.D., Ph.D., Chief Medical Officer of Stoke Therapeutics. “We are pleased to be expanding our approach into a new disease area, leveraging our learnings from Dravet syndrome and applying them to the development of a potential disease-modifying medicine for people living with ADOA.” The OSPREY study is actively recruiting in the United Kingdom and Germany. Additional European sites are expected to activate in the coming months. About Autosomal Dominant Optic Atrophy (ADOA) ADOA is the most common inherited optic nerve disorder, affecting approximately one in 30,000 people globally with a higher incidence of one in 10,000 in Denmark due to a founder effect. It is a rare disease that causes progressive and irreversible vision loss in both eyes starting in the first decade of life. Severity can vary and the rate of vision loss can be difficult to predict. Approximately half of people with ADOA fail driving standards and up to 46% are registered as legally blind. More than 400 different disease-causing OPA1 variants have been reported in people diagnosed with ADOA. Currently there are no approved treatments for people living with ADOA. About STK-002 STK-002 is a proprietary antisense oligonucleotide (ASO) in clinical development for the treatment of ADOA. Stoke believes that STK-002 has the potential to be the first disease-modifying therapy for people living with ADOA. An estimated 65% to 90% of ADOA cases are caused by variants in the OPA1 gene, most of which lead to a haploinsufficiency resulting in 50% OPA1 protein expression and disease manifestation. STK-002 is designed to upregulate OPA1 protein expression by leveraging the non-mutant (wild-type) copy of the OPA1 gene to restore OPA1 protein expression with the aim to maintain or improve vision in people with ADOA. Stoke has generated preclinical data demonstrating proof-of-mechanism and proof-of-concept for STK-002. STK-002 has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) as a potential new treatment for ADOA. A Phase 1 study (OSPREY) of STK-002 in people with ADOA is now underway. About the Phase 1 OSPREY Study The OSPREY study is a Phase 1, dose-escalating open-label study of children and adults ages 6 to 55 who have an established diagnosis of ADOA and have a confirmed disease-causing variant in the OPA1 gene. The primary objectives for the study are to assess the safety and tolerability of single ascending doses of STK-002, as well as to determine the exposure in blood. Secondary objectives are to assess changes in visual function, ocular structure and quality of life after single doses of STK-002. The OSPREY study follows a standard dose escalation design with participants enrolled into sequential cohorts receiving increasing dose levels of STK-002. Dose escalation of the first four cohorts will continue through 2026 and early 2027, pending safety and tolerability assessments. Data from the OSPREY study will help to inform potential future development of STK-002. The OSPREY study is actively recruiting in the United Kingdom and Germany. Additional European sites are expected to activate in the coming months. For more information on the OSPREY study, please visit: 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 naturally-occurring protein levels. Stoke’s first medicine in development, zorevunersen, has demonstrated the potential for disease modification in patients with Dravet syndrome and is currently being evaluated in a Phase 3 study. Stoke’s initial focus are diseases of the central nervous system and the eye that are caused by a loss of ~50% of normal protein levels (haploinsufficiency). Proof of concept has been demonstrated in other organs, tissues, and systems, supporting broad potential for Stoke’s proprietary approach. Stoke is headquartered in Bedford, Massachusetts. For more information, visit . 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 ability of STK-002 to treat the underlying cause of ADOA and maintain or improve vision; and the timing, details and expected progress of clinical trials for STK-002. Statements including words such as “anticipate,” “potential”, “could,” “expect,” “plan,” “will,” “may” or similar words 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 Stoke’s results to differ materially from those expressed or implied by such forward-looking statements, including, but not limited to, risks and uncertainties related to: Stoke’s ability to advance, obtain regulatory approval and ultimately commercialize its product candidates; that if Stoke’s collaborators were to breach or terminate their agreements, it would not obtain the anticipated financial or other benefits; the possibility that Stoke and its collaborators may not be successful in their development of product candidates and that, even if successful, they may be unable to successfully commercialize such product candidates; 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; Stoke’s ability to protect its intellectual property; Stoke’s ability to fund development activities and achieve development goals into 2028; and the other risks and uncertainties described under the heading “Risk Factors” in Stoke’s Annual Report on Form 10-K for the year ended December 31, 2024, its quarterly reports on Form 10-Q, and the other documents it files with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Stoke undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. Contacts Media & Investor Contacts: Susan Willson Vice President, Corporate Communications swillson@stoketherapeutics.com 415-509-8202 Doug Snow Director, Communications & Investor Relations IR@stoketherapeutics.com 508-642-6485

编者按：世界癫痫日定于每年二月的第二个星期一。当前，尽管已有多种疗法获批用于治疗癫痫，但仍未能充分满足患者的临床需求。因此，全球范围内持续开展针对该疾病的创新疗法探索，以期为患者提供更优的治疗选择。作为一种中枢神经系统（CNS）疾病，癫痫的新药研发面临若干固有挑战，包括复杂的疾病机制以及药物递送需克服血脑屏障限制等。作为医药创新的赋能者，药明康德已构建起完善的CNS能力体系，覆盖从早期筛选到IND申报的全流程。凭借丰富经验与深厚积累，药明康德致力于加速全球合作伙伴包括癫痫新药在内的CNS药物研发进程，助力客户早日将创新疗法带给患者。 今日（2026年2月9日）为世界癫痫日。该疾病日由国际癫痫署和国际抗癫痫联盟共同发起，旨在提高公众对癫痫的认识，减少社会对癫痫患者的歧视，促进癫痫研究和改善患者的生活质量。 癫痫是一种常见的神经系统疾病，其特征是癫痫发作或阵发的异常行为、感觉，有时甚至丧失意识。研究表明，癫痫的发病机制与离子通道、突触间传递和连接的改变有关，造成这些改变的主要原因是神经元的兴奋与抑制失衡。基于此，全球范围内正在探索各种创新疗法，旨在为患者带来更好的治疗选择。 通过公开渠道梳理，全球范围内有数十款新药正在针对癫痫相关适应症开展临床研究，药物类型以小分子药物为主，此外还包括反义寡核苷酸（ASO）、抗体、细胞和基因疗法等。 图片来源：123RF 2025年癫痫新药研发领域迎新进展 在刚刚过去的2025年，癫痫新药研发领域也取得诸多新进展，相关新药以小分子和寡核苷酸药物为主，靶点涵盖SCN1A、GABA、KCNQ2/3、NMDA、TARPγ8、Kv7.2/Kv7.3等。 以下列举该领域的部分新进展： 2025年12月，Praxis Precision Medicines宣布在研小分子药物relutrigine治疗携带SCN2A和SCN8A基因变异的发育性和癫痫性脑病（DEEs）患者的EMBOLD研究注册队列取得积极结果。Relutrigine的作用机制为精确调控钠离子通道（NaV）活性，有望在疾病状态下对NaV通道的过度兴奋性实现更高选择性调节，从而潜在为这类重症癫痫患者提供更具针对性的治疗选择。2025年7月，relutrigine还获美国FDA授予突破性疗法认定，用于治疗DEEs儿科患者。该项授予正是基于EMBOLD临床2期试验结果：在第11个月时，患者平均癫痫发作减少约90%，无癫痫发作的持续时间也显著延长，平均达到67天，而基线期仅为3天。 2025年10月，渤健（Biogen）与Stoke Therapeutics公司共同宣布了针对Dravet综合征的在研ASO药物zorevunersen的最新研究进展。Dravet综合征是一种严重且进展性的遗传性癫痫。最新公布的两年分析数据显示，接受zorevunersen治疗的Dravet综合征患者在认知和行为方面持续改善，这与一项同样为期两年的自然病史研究中患者几乎无改善的结果形成鲜明对比。在为期三年的OLE研究中，临床医生和护理人员分别报告了95%的患者整体临床状况得到改善。Zorevunersen旨在通过增强SCN1A基因非突变（野生型）拷贝的功能，提升脑细胞中NaV1.1蛋白的表达，从而针对Dravet综合征的根本病因发挥作用。2025年2月，渤健与Stoke Therapeutics宣布就该产品的开发和商业化达成合作。 2025年10月，Ovid Therapeutics宣布其下一代GABA-氨基转移酶（GABA-AT）抑制剂OV329在健康受试者中开展的1期研究获得积极顶线结果。研究结果进一步证实OV329能够进入大脑、与靶点结合并产生与GABA水平升高一致的生物学调节作用，从而有望抑制导致发作的高兴奋性。根据此结果，Ovid计划将OV329推进至难治性局灶性癫痫发作的2a期研究。 2025年9月，挚盟医药宣布其在研的新一代KCNQ2/3钾离子通道开放剂CB03-154，在中国获批开展针对难治性癫痫的2期临床试验，研究将针对18-70岁局灶性癫痫成人患者。钾离子（K+）通道是分布最广、种类最多的一类离子通道，主要参与调节神经元的兴奋性及动作电位发放的频率和振幅。研究表明，CB03-154具有良好的化学和代谢稳定性、体外和体内抗癫痫活性和药效、药代性质及安全性，同时也具有更为特异的离子通道选择性，有望克服第一代药物存在的安全性问题。 2025年3月，Bloom Science公司公布了其在研口服疗法BL-001在一项涉及32名健康成年人的1期试验中的疗效和安全性结果。BL-001是一种口服给药的活生物治疗产品，旨在模拟生酮饮食的治疗效果。临床前数据表明，该产品在癫痫模型中复制了生酮饮食的治疗效果，并进一步展示了其对γ-氨基丁酸（GABA）和其他关键生物能途径的调节作用，以抑制癫痫发作的关键驱动因素——过度兴奋性。该产品目前正在针对Dravet综合征和肥胖开展1期临床研究。 2025年2月，GRIN Therapeutics宣布FDA已授予其在研疗法radiprodil突破性疗法认定，用于治疗携带功能获得性突变的GRIN相关神经发育障碍患者的癫痫，这是一组由GRIN基因突变引起的罕见小儿神经发育障碍。针对该适应症，radiprodil目前已经进入关键性3期临床研究阶段。Radiprodil是一款选择性靶向N-甲基-D-天冬氨酸（NMDA）受体亚型2B（GluN2B）的负向别构调节剂。在1b期临床研究中，符合条件的癫痫患者的中位可计数运动性癫痫发作频率较基线减少了86%。 2025年1月，Rapport Therapeutics公司公布了RAP-219的正电子发射断层扫描（PET）试验结果。RAP-219是一种临床阶段的AMPA受体负变构调节剂，被设计为对AMPA相关蛋白TARPγ8具有高效力和选择性，旨在通过选择性靶向TARPγ8实现神经解剖学特异性，有望作为局灶性癫痫等疾病的潜在差异化疗法。该产品具有较长的半衰期（8-14天）和很小的药物相互作用，使其非常适合多药治疗，且有可能提供更好的活性、耐受性和更高的治疗指数，从而为更多的患者提供持续的治疗益处。 除了上述临床研究进展，2025年抗癫痫领域还迎来其他方面的新进展。比如，在授权合作方面：2025年8月，Jazz Pharmaceuticals与Saniona宣布达成全球许可协议。Saniona将授予Jazz对SAN2355的全球独家开发权，同时将获得4250万美元的前期付款，并有资格根据开发和监管里程碑获得高达1.925亿美元的款项，以及获得高达8亿美元的潜在商业里程碑付款。SAN2355是一种选择性小分子Kv7.2/Kv7.3钾通道激活剂，主要用于癫痫及其他潜在适应症的开发，该产品旨在克服非选择性Kv7靶向化合物的局限性。 新锐融资方面同样迎新进展：比如：6月，Actio Biosciences宣布完成6600万美元B轮融资。该公司主导管线之一ABS-1230为一款KCNT1抑制剂，拟开发治疗KCNT1相关癫痫及其他遗传性癫痫；4月，Neurona Therapeutics宣布完成1.02亿美元的超额融资。该公司正在推进治疗耐药性内侧颞叶癫痫的主要候选药物NRTX-1001，这是一种源于人类多能干细胞的再生细胞候选疗法。这些完全分化的中间神经元分泌抑制性神经递质GABA，可以持久存在并提供长期的GABA信号，以修复过度兴奋的神经网络；4月，纽欧申医药宣布完成数千万美元的A轮融资。该公司核心产品NS-041（选择性KCNQ2/3通道激动剂）已经推进至局灶性癫痫的2期概念验证研究阶段；3月，Montara Therapeutics宣布完成2000万美元超额认购的种子轮融资。Montara公司旨在彻底改变脑靶向药物的发现和开发，该公司计划在未来12个月内推动其主要罕见癫痫项目进入IND；1月，Atalanta Therapeutics宣布完成9700万美元的B轮融资，该公司的研发管线中包含多款治疗中枢神经系统疾病的RNAi疗法，其中ATL-201是用于治疗KCNT1相关癫痫（由KCNT1基因出现功能获得性突变引起的早发性癫痫）的在研疗法，旨在降低KCNT1水平并正常化神经元的兴奋性。 除了上述进展，2025年癫痫新药研发领域还迎来其他新进展，限于篇幅，此处不再一一介绍。很高兴看到在产业界通力合作下，更多创新成果正在加速从实验室走向临床，为疾病治疗开辟新的路径。 一体化CRDMO赋能平台助力合作伙伴加速创新疗法研发 作为一种CNS疾病，癫痫领域的新药研发面临一些固有挑战，比如疾病机制复杂、药物入脑受到血脑屏障的限制等等。作为全球医药创新的赋能者，药明康德始终坚持赋能全球合作伙伴，凭借一体化、端到端的CRDMO赋能平台，致力于加速全球合作伙伴的CNS药物研发进程，加速创新疗法的落地。 比如，针对CNS新药研发领域的特殊挑战，药明康德建立了多项CNS专属的药物代谢与药代动力学（DMPK）能力。例如，其“漏斗（Funnel）”体外检测模型展现出高度准确性，能够有效区分可穿透血脑屏障的药物与因被动扩散能力不足或受外排转运蛋白影响而无法进入的药物，帮助合作伙伴快速识别潜力候选疗法，从而高效推进研发进程。 除了早期筛选，药明康德还为合作伙伴提供多样化的定制化研究策略，包括脑室内或鞘内给药、微透析技术、在啮齿类和大型动物模型中进行脑脊液连续采样、精确解剖和分离近20种不同脑区组织，以及利用全身自显影（QWBA）全面展示药物在脑内的分布。这些能力不仅应用于小分子药物，也广泛支持蛋白质、寡核苷酸等大分子药物，从早期筛选直至IND申报。 展望未来，随着对癫痫等神经系统疾病的基础研究不断深入，以及药物递送技术持续创新，该领域的新药研发有望迎来快速发展。药明康德也将继续发挥一体化、端到端的CRDMO平台优势，赋能全球合作伙伴在神经系统疾病领域的药物开发，共同加速将前沿科研成果转化为造福患者的突破性治疗方案。 参考资料： [1] 穿越血脑屏障！数百款小分子新药正在临床开发，帕金森病等患者有望迎来新曙光！.From https://mp.weixin.qq.com/s?__biz=MzUxMTY5MzM5OQ==&mid=2247581827&idx=1&sn=0b4b300ebc5f4954d8cd776905aa6595&chksm=f8332187e02fb13ef8027d435865e39a0ad99652488c38507151421dbc0b8d5334e7e8b45044#rd 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号回复“转载”，获取转载须知。