Zorevunersen sodium

“You may have the opportunity to put them on a more neurotypical pathway to develop,” Stoke\'s CEO said. “There’s not many medicines that give back function in a disease where there is no function after a certain age.”\n For children with Dravet syndrome, a rare, severe genetic disease characterized by fever-related seizures and intellectual disability, developmental delays begin after the first few years of normal development. Stoke Therapeutics is developing a drug designed to reduce seizures and restore some of their lost developmental function.“These children grow neuro-typically up to ages 18 months or 24 [months], but once they reach that period in life, they’re in a stable state—they don’t grow,” Ian Smith, CEO of Stoke Therapeutics, told Fierce Biotech. The company is one of a handful of players with a clinical-stage asset taking aim at the rare disease, with current treatments focused on seizure management and lifestyle modifications. “So, when you’re 10, 15, 20 years old, you’re still in a two-year-old state,” Smith explained about people living with Dravet syndrome. “You may not be able to talk, you don’t recognize your parents, you can’t acknowledge your name, you can’t take yourself to the toilet.”“There’s many features of a Dravet child, but it’s like they’re effectively an 18-month to two-year-old all their life, while they may have an adult body,” he added.Stoke and Biogen’s zorevunersen, an investigational antisense oligonucleotide, is designed to boost functional NaV1.1 protein production in brain cells from the non-mutated copy of the SCN1A gene. The drug is made to treat the underlying cause of Dravet syndrome, which is caused primarily by SCN1A haploinsufficiency.“I really do believe this medicine not only reduces seizures but actually causes these children, that unfortunately, are flatlining after two years old—they might start to sprout off that flatline of neurotypical development,” Smith said.“You may have the opportunity to put them on a more neurotypical pathway to develop,” he continued. “There’s not many medicines that give back function in a disease where there is no function after a certain age.” In the clinic, Smith said the company is seeing seizure reductions of up to 85% in addition to standard-of-care medicines.In two open-label phase 1/2 studies, zorevunersen, in combination with standard-of-care antiseizure medicines, demonstrated durable reductions in seizures and improvements across multiple measures of cognition and behavior, according to results published this month in The New England Journal of Medicine. One of those measures is an assessment known as, Vineland-3, which evaluates changes in adaptive behavior, such as motor skills and receptive communication, among others. These changes can be tied to increased independence and safety for the patients. Out of 81 total patients enrolled across the two trials, 75 have entered the open-label extension (OLE) program. Looking at the three-year OLE data, Smith said the Vineland scores demonstrate robust improvements. “Dravet syndrome arrives without warning for families, just as it did for our family more than 25 years ago when my son began having seizures,” Mary Anne Meskis, CEO of the nonprofit Dravet Syndrome Foundation, said in a March 4 release announcing the data publication.“While awareness, diagnosis and medical care have advanced significantly over the years, the realities of Dravet syndrome remain severe and life-altering for patients and their families,” Meskis explained. “A treatment that could help someone like my son dress himself independently or better communicate with his parents would profoundly change the cadence and quality of our everyday lives.” In Stoke’s phase 1/2 studies, most adverse events (AEs) were mild or moderate, with one patient experiencing a suspected unexpected serious AE related to zorevunersen. Another patient withdrew from the study after experiencing an AE.Two patients died from sudden unexpected death in epilepsy (SUDEP), and one from malnutrition—all unrelated to zorevunersen.  “SUDEP is unfortunately common with this disease,” Smith said, citing the fact that one out of five children with Dravet syndrome don’t reach 18 years of age, largely because of SUDEP. Stoke has already started a phase 3 program for zorevunersen, in which no SUDEPs have been reported to date, according to Smith.  The path forward  Stoke is currently recruiting patients for the phase 3 study, dubbed Emperor. The biotech anticipates enrolling a total of 150 patients across the U.S., U.K. and Japan to be enrolled by the second quarter of this year, with data expected to support a rolling new drug application slated for mid-2027. The sham-controlled study’s main goal is to reduce seizures at 28 weeks, with a secondary endpoint based around Vineland scores at Week 52.“There was an initial anticipation that the study may take a year to 18 months to recruit,” Smith said. “We anticipate fully recruiting all patients into the study by the second quarter of this year, which means it will have taken eight to 10 months.”The CEO credited Stoke’s strong presence at medical conferences and advocacy work for speeding up the enrollment time. “The whole timeline for the company over the last year was probably accelerated by close to a year and so, and I think that’s a function of education around the severity of Dravet, but also what our medicine is doing beyond just seizure reductions,” Smith said. Zorevunersen has nabbed breakthrough, orphan drug and rare pediatric disease designations from the FDA. When asked about current controversies surrounding the agency’s rare disease decisions, such as uniQure’s heated back-and-forth over the FDA’s request for another sham-controlled trial in Huntington’s, Smith said he wasn’t concerned about Stoke’s regulatory path. “I do think that [FDA commissioner Marty] Makary is leading a very progressive FDA in a way that I do think he wants change,” Smith said. “I think he’s very genuine to, you know, having faster approvals, evidence-based medicine, real-world data, doing natural history comparison studies.That being said, Smith said he believes the agency is “struggling to execute on the ground.” “Now, I can’t comment on specific examples of different companies, but I can comment on our company because we’ve had interactions with them, and we\'ve had all the data on the table with the FDA,” the CEO said. “We have great interactions with them.”Smith said the agency did exhibit “regulatory flexibility,” asking if Stoke “wanted to move our patients all onto medicine and not have a sham-control trial and measure the endpoints at month six—just seizures.”“We declined because we wanted to have a label that shows what our medicine does in the kind of a more neurotypical benefit as well,” he said.Smith’s insight is interesting given the agency’s recent push for placebo- or sham-controlled trials, even in rare diseases that impact very small populations.  Stoke’s drug is being developed with Biogen, which paid out $165 million cash early last year to gain exclusive rights to commercialize zorevunersen outside of the U.S., Canada and Mexico. Biogen will cover 30% of external clinical development costs and is offering the biotech up to $385 million in milestone payments. Other players in Dravet syndrome include Encoded Therapeutics’ gene therapy, Harmony Bioscience’s late-stage clemizole hydrochloride and Lundbeck’s oral 5-HT2C receptor superagonist. Besides pipeline medicines, UCB’s Fintepla and Jazz’s Epidiolex are approved to treat seizures in patients with Dravet syndrome.

电压门控钠通道（NaV）是可兴奋细胞（包括神经元、肌细胞和心肌细胞）产生动作电位的核心分子机器。 随着分子生物学的飞速发展，传统的“单一钠通道”概念已被九种具有不同组织分布、生物物理特性及病理功能的亚型（NaV1.1–NaV1.9）所取代。这九种亚型在癫痫、疼痛、心律失常及肌肉疾病中扮演着的关键作用。 分子图谱的重构：九种亚型的多样性 1. 结构保守性与功能差异性 电压门控钠通道是由一个形成孔道的α亚基和辅助性的β亚基组成的异三聚体复合物。α亚基包含四个同源结构域（DI-DIV），其中S1-S4构成电压感应模块，S5-S6构成孔道模块。 尽管九种人类NaV通道（NaV1.1至NaV1.9）在整体三级结构上高度保守（序列相似性>50%），但其氨基酸序列的细微差异导致了截然不同的生物物理特性（如激活/失活电压依赖性）和组织表达谱。 2. 组织分布的精密分工 中枢神经系统（CNS）： NaV1.1、NaV1.2、NaV1.3和NaV1.6主要表达于大脑。其中，NaV1.1特异性地富集于抑制性中间神经元，对维持兴奋-抑制平衡至关重要；NaV1.6则是成熟节点（Nodes of Ranvier）和轴突起始段（AIS）远端的主要亚型，负责动作电位的发起与传导。 周围神经系统（PNS）： NaV1.7、NaV1.8和NaV1.9高度特异性地表达于背根神经节（DRG）和三叉神经节的感觉神经元中，是痛觉信号传递的关键驱动力。 肌肉组织： NaV1.4主导骨骼肌的收缩，而NaV1.5则是心肌细胞动作电位上升相的主要贡献者。 这种精确的时空表达模式，使得针对特定亚型的药物开发成为可能，从而在治疗效果与副作用之间找到最佳平衡点。 中枢神经系统疾病：基因缺陷到精准修复 Dravet综合征与NaV1.1的功能恢复 Dravet综合征是一种严重的发育性癫痫性脑病（DEE），主要由SCN1A基因的功能缺失（LOF）突变引起，导致抑制性中间神经元中NaV1.1表达不足。传统的治疗手段往往束手无策，甚至可能加重病情。 反义寡核苷酸（ASO）的突破：Stoke Therapeutics开发的ASO药物STK-001（zorevunersen），利用TANGO（靶向核基因输出增强）技术，特异性地结合SCN1A前体mRNA中的“毒外显子”（exon 20N），阻止其被剪接进入成熟mRNA，从而避免无义介导的mRNA降解（NMD）。单次给药即可显著增加NaV1.1蛋白表达，大幅减少癫痫发作并提高生存率。 基因疗法的探索：Encoded Therapeutics开发的ETX101通过AAV载体递送工程化转录因子，特异性上调抑制性神经元中的内源性SCN1A基因表达，目前也已进入临床试验阶段。     表1：NaV通道与人类疾病关系 心脏与肌肉疾病：老药新用与机制创新 心律失常的精准干预 NaV1.5（SCN5A）的功能异常是长QT综合征3型（LQT3）和Brugada综合征的主要原因。LQT3：NaV1.5失活受阻引起持续的钠电流增加。目前主要使用晚期钠电流抑制剂进行治疗，如美西律（Mexiletine）和雷诺嗪（Ranolazine）等，但缺乏高度特异性的新药。 Brugada综合征：通常由NaV1.5功能缺失引起。奎尼丁（Quinidine）是目前的标准治疗药物，但其疗效不一且副作用明显。最新的基因治疗策略尝试通过过表达伴侣蛋白MOG1来增加细胞膜表面的NaV1.5数量，在动物模型中成功挽救了Brugada表型。 疼痛管理：非阿片类镇痛的新纪元 NaV1.7：痛觉的“音量旋钮” NaV1.7因其在痛觉神经元中的关键作用及先天性无痛症（CIP）患者的存在，被视为理想的镇痛靶点。 研发困境与希望：尽管早期的芳香族磺酰胺类化合物（如PF-05089771）在临床试验中因药效或药代动力学问题受挫，但新一代化合物（如GEN-3565）通过优化外周限制性分布，展现了更好的前景。 毒素衍生物：基于河豚毒素（TTX）和石房蛤毒素（STX）骨架改造的高选择性NaV1.7抑制剂（如ST-2427）正在临床试验中，旨在利用其独特的孔道阻断机制实现强效镇痛。 2. NaV1.8：里程碑式的突破 NaV1.8在动作电位的上升相中起主导作用，是另一个极具潜力的靶点。Suzetrigine (VX-548) 的获批：Vertex Pharmaceuticals开发的NaV1.8选择性抑制剂Suzetrigine（商品名Journavx）在多项III期临床试验中表现出优异的急性镇痛效果，且安全性良好，不具成瘾性。FDA已批准其用于治疗中重度急性疼痛，标志着数十年来非阿片类镇痛药研发的重大突破。 慢性痛的挑战：尽管在急性痛中表现卓越，Suzetrigine在糖尿病神经痛等慢性痛模型中的疗效仍需进一步验证，提示急慢性疼痛机制可能存在差异。 3. 其他亚型与联合策略 NaV1.9因其独特的持续性电流特性也被关注，但受限于表达系统的困难，药物开发进展较慢。此外，研究提示联合阻断NaV1.7和NaV1.8可能产生协同效应，克服单一靶点的疗效天花板。    表2：开发中的NaV靶点药物 未来展望：迈向亚原子时代的精准医疗 1. 结构生物学驱动的药物设计 冷冻电镜（Cryo-EM）技术的进步使得科学家能够解析NaV通道与药物、毒素结合的原子级结构。这不仅揭示了已知药物的结合位点（如NaV1.7 DIV-VSD区的正交位点），还为理性设计具有更高选择性和亲和力的下一代抑制剂提供了精确模板。 2. 超越小分子：多元化治疗模态RNA靶向疗法：除了ASO，基于ADAR的RNA编辑技术和CRISPR-Cas9基因编辑正在成为治疗遗传性通道病的新兴工具，有望实现一次性治愈。 蛋白质相互作用干扰：针对CRMP2等调控NaV通道trafficking 的蛋白进行干预，提供了一种间接调节通道功能的创新策略。 生物制剂：抗体、纳米抗体及工程化多肽毒素因其极高的亚型选择性，正成为研发热点。 3. 非兴奋细胞的新疆域 最新研究发现，NaV通道（如NaV1.7）在软骨细胞等非兴奋细胞中也发挥关键作用，调控骨关节炎的进程。这一发现极大地拓展了NaV通道作为药物靶点的疾病谱，预示着其在退行性疾病治疗中的巨大潜力。 结  语电压门控钠通道的研究已进入一个前所未有的黄金时代。从对九种亚型功能的精细解析，到ASO、基因疗法及高选择性小分子的成功应用，我们正逐步摆脱“一刀切”的治疗模式，迈向针对特定分子机制的精准医疗新时代。 随着Suzetrigine的获批和更多候选药物的涌现，人类有望彻底改变癫痫、慢性疼痛及心律失常等疾病的治疗格局，为患者带来更安全、更有效的生命希望。