Soticlestat

背景：尽管已有超过30种获批的抗发作药物，但约三分之一的癫痫患者仍存在耐药性，且发育性和癫痫性脑病是癫痫治疗学中尚未满足的最大需求之一。过去十年中，在癫痫遗传学、新疾病模型、药物筛选进步以及创新治疗模式的驱动下，ASMs的发现发生了实质性的重新定向。目的：本研究旨在回顾具有新型或差异化作用机制的临床阶段ASMs研发管线，按分子靶点进行组织，同时将近期监管方面的成功及具有指导意义的失败案例置于向基于机制、精准及潜在疾病修饰疗法更广泛转变的背景中。发现：一项2024年的管线分析确定了200多种处于临床前或临床开发阶段的癫痫疗法；在本次文献检索的截止日期（2026年6月30日）前，超过40种化合物已进入II期或III期，其中大多数针对DEEs。功能状态选择性钠通道调节已成为一项主要的概念进展，并得到了汇聚的机制证据和早期临床证据的支持，以relutrigine（PRAX-562）和vormatrigine（PRAX-628）为例，前者是一种优先抑制持续性电流的抑制剂，目前针对SCN2A/SCN8A-DEEs的监管决定尚在待定中，后者在开放标签试验中显示出巨大疗效，但在对照（盲法）试验中未能重现。研究人员在此总结的几项疗效数据来源于大会报告、中期分析或开放标签扩展研究，尚待经过完整的同行评审发表。并行的进展包括选择性Kv7通道开启剂azetukalner；双机制基准药物cenobamate；胆固醇-24-羟化酶抑制（soticlestat）；选择性5-羟色胺受体激动（bexicaserin）；谷氨酸能精准药物；亚型选择性GABAA受体调节剂（darigabat, ganaxolone）；以及基因靶向疗法（zorevunersen, elsunersen）。在结节性硬化复合体中进行症状前干预，为在基因明确的人群中延缓和降低癫痫发病率提供了早期的单试验临床概念验证；但这不应等同于已确立的疾病预防。结论：当前研发管线反映了从广谱对症药物向机制主导、基因型匹配及潜在疾病修饰治疗的持续转变。这种转变因早期信号与随机试验证实之间持续存在的转化鸿沟，以及大量支持性证据的初步状态而有所缓和。引言与概念框架癫痫影响着全球约5000万人，尽管过去三十年间治疗手段增加了一倍以上，但仍有30-40%的患者在适当的药物治疗后仍无法实现无发作。一旦产生耐药性，难以通过增加广谱抗发作药物（ASMs）来克服，且目前获批的ASMs主要依赖于钠通道阻滞、增强GABA能、钙通道调节和突触囊泡蛋白结合等有限的机制。过去十年中，cenobamate和fenfluramine的成功证明了超越常规机制的新药具有显著优势，这促使研发重心转向了真正的新型靶点、基于综合征和基因型的精准治疗，乃至旨在阻止或改变癫痫发生的疾病修饰疗法。当代研发管线反映了三种汇聚的治疗范式：机制差异化的小分子、针对遗传定义癫痫的精准疗法、以及从症状性发作抑制向能够改变癫痫发生或疾病自然史的干预措施的转变。需要注意的是，许多研发中的药物具有浓度依赖的次要药理作用，其功能选择性并不等同于绝对的分子特异性。方法学与证据来源框架这是一项叙述性综述，涵盖了截至2026年6月30日的文献、临床试验注册库及监管记录。研究人员优先纳入了具有新型或差异化机制的临床阶段疗法，特别是II/III期项目。由于大量管线数据未发表于同行评审文献，研究人员为每条实质性声明分配了七类证据来源，涵盖了同行评审的随机对照试验、开放标签研究、临床前研究、会议摘要、中期分析、试验注册记录和监管记录。当代ASM研发管线全景当代癫痫疗法管线包含200多项研发计划。靶点虽然在神经递质系统和离子通道上仍有锚点，但已显著拓宽，涵盖了5-羟色胺、大麻素受体以及mTOR通路和泛素蛋白连接酶UBE3A等。治疗模式日益多样化，小分子占四分之三，反义寡核苷酸（ASOs）、RNA疗法、基因疗法等占四分之一。此外，研发重心已明显转向发育性和癫痫性脑病，这类由罕见单基因突变引起的难治性癫痫具有极高未满足需求，且基因匹配的精准方法在此领域更具可操作性。电压门控钠通道：功能状态选择性与持续电流钠通道调节领域最新的概念进展在于功能状态的选择性。与广泛阻滞瞬时钠通道的经典药物不同，新型药物优先选择性结合病理状态下产生持续电流（INaP）的兴奋过度的通道构象，从而扩大治疗窗口并提高耐受性。Relutrigine（PRAX-562）是一种优先抑制INaP的口服小分子，在SCN2A和SCN8A相关DEEs的II期EMBOLD研究中，中期分析显示出压倒性疗效，已提交新药申请并获优先评审。然而，同类的Vormatrigine（PRAX-628）在开放标签II期RADIANT研究中显示出56.3%的发作频率降低，但在随后的盲法对照试验POWER1中却未达到主要终点，这凸显了转化鸿沟。其他策略还包括针对SCN8A-DEE的选择性NaV1.6抑制剂NBI-921352，以及通过ASO降低SCN2A表达的Elsunersen（PRAX-222）。钾通道：KV7开启剂及相关调节剂开启神经元KV7（KCNQ）钾通道能够稳定静息膜电位并减少重复放电。Azetukalner（XEN1101）是一种偏好KV7.2/7.3的第二代开启剂。在IIb期X-TOLE研究中，它显著降低了局灶性发作频率，且在III期试验中达到了主要终点。尽管其选择性是相对的，且可能产生全身性系统效应，但它仍是极具前景的钾通道调节剂。GABAA受体调节：亚型选择性及神经甾体新型“GABAkines”被设计为保留抗发作 efficacy 同时避免经典苯二氮?类药物的镇静和耐受副作用。Darigabat（CVL-865）作为α2/3/5亚型选择性的正向变构调节剂已进入II期试验。神经活性类固醇如Ganaxolone，靶向突触外受体，已获批用于CDKL5缺乏症，并正在难治性癫痫持续状态中进行评估。谷氨酸受体调节针对谷氨酸受体的调节包括针对GluN2B亚型的负向变构调节剂Radiprodil，主要用于治疗GRIN基因变异导致的遗传性脑病。此外还有靶向mGlu5的拮抗剂和mGlu2的正向变构调节剂，展现了针对特定受体亚型的精准干预潜力。5-羟色胺能机制鉴于fenfluramine在Dravet综合征中的疗效，5-HT受体药物成为开发热点。Bexicaserin（LP352）作为一种高亲和力的5-HT2C激动剂，在针对DEEs的Ib/2a期试验中显著降低了运动性发作，且规避了对5-HT2B的心脏毒性，目前已在III期开发阶段。新型正交小分子机制Soticlestat（TAK-935）通过抑制脑特异性的胆固醇-24-羟化酶降低NMDA受体介导的过度兴奋，尽管III期试验未达主要终点，但其机制仍具研究价值。Cenobamate通过结合持久钠电流抑制和GABAA受体调节的多模态机制，成为证实多靶点优势的重要参考。其他新型机制涵盖了抑制神经炎症、调节氧化应激和糖酵解等广泛领域。基因靶向及分子疗法基因疗法是针对单基因癫痫最具变革性的前沿。Zorevunersen（STK-001）通过靶向增加SCN1A转录来恢复Dravet综合征中NaV1.1的表达量，其中期研究显示出了发作频率的持久降低及认知改善的可能，目前正在开展假手术对照的III期试验。此外，通过AAV载体上调基因表达的ETX-101和抑制UBE3A反义转录的ION-582等，均标志着向干预遗传病因转变。从发作抑制到疾病预防与修饰领域的终极目标是预防或改变癫痫发生过程本身。在结节性硬化复合体中，EPISTOP试验在临床前电生理变化期即启动干预，证明了延长首次发作时间和降低癫痫发生率的可能，这是疾病修饰的首个临床概念验证。然而，真正的疾病修饰要求有证据表明在停药后自然史被更改，目前管线中尚无药物达到此标准。转化鸿沟：开放标签的承诺与随机现实的差距Relutrigine与Vormatrigine截然不同的命运模式在领域内反复出现。开放标签研究中动辄75-90%的发作减少率，往往因背景效应、回归平均值及样本留存偏差而存在夸大。当进入盲法、随机、对照试验时，由于安慰剂效应的不稳定、患者群体的显著异质性及剂量的不当选择，早期信号往往无法重现。这对于新型机制药物的评估提出了警示，必须依赖设计严谨的对照试验。对当代抗发作药物研发的批判性评估现阶段研发方法仍需改进。开放标签放大效应需要被警惕，需将其与对照数据明确区分。以基因型作为机制前提存在风险，同一基因的不同功能变异需要相反的药物作用。临床试验终点不仅限于运动性发作频率，亦需结合神经发育和功能评估。小样本和多重性分析容易导致结果不稳定和误读。剂量选择和靶点结合度不足是后期失败最常见的原因，需要引入脑电生物标志物予以确证。同时，阴性试验结果的透明发表对于整个领域总结经验至关重要。讨论与未来方向当前管线反映了癫痫治疗从经验性症状控制向基于机制和基因型的精准治疗和潜在疾病修饰疗法的转变。这些新型药物旨在补充和完善现有治疗体系。临床研发需整合适应性试验设计、数字生物标志物和长期的对照随访。未来的综合管理将依赖于机制导向的药物、外科手术和神经调控技术的有机结合。

First-ever oral direct KCC2 activator, OV4071, advancing in an ongoing Phase 1 studyInitiated Phase 2 proof-of-concept and photosensitivity studies for OV329, a next-generation GABA-AT inhibitorA newly-formed portfolio company with funds advised by Perceptive Advisors acquired global rights to soticlestat; Ovid secured equity in the company and the potential to receive regulatory and sales milestone payments and royalties upon successStrengthened executive leadership team with appointment of Kevin Norrett as Chief Business Officer and Eliseo Salinas, MD, as Executive R&D AdvisorCash, cash equivalents and marketable securities were $169.8 million as of June 30, 2026; expected financial runway into 2029 NEW YORK, Aug. 13, 2026 (GLOBE NEWSWIRE) -- Ovid Therapeutics Inc. (Nasdaq: OVID), a biopharmaceutical company dedicated to pioneering better, gentler medicines for brain disorders with significant unmet need, today provided business updates including financial results for the second quarter ended June 30, 2026. “Ovid is focused on the execution of multiple near-term clinical, proof-of-concept studies across our differentiated pipeline,” said Meg Alexander, President and Chief Executive Officer. “Our team is well positioned to realize the potential of KCC2 direct activation and GABA aminotransferase inhibition for many intractable disorders of the brain. Additionally, through the recent transaction with Perceptive Advisors and Takeda, Ovid has the potential to realize value from our interests in soticlestat, which may provide future capital to Ovid and most importantly, advance a meaningful therapy to epilepsy patients who can benefit.” PIPELINE AND BUSINESS UPDATES KCC2 direct activator portfolio: OV4071 advancing in Phase 1 study: Ovid continues to progress OV4071 through an ongoing Phase 1 study in healthy volunteers. The Phase 1 study is intended to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of this first-ever oral direct potassium-chloride cotransporter 2 (KCC2) activator. Data from the study are expected to support initiation of a Phase 2 proof-of-concept study in acute schizophrenia in 2027 and provide insights into future development across additional high-value central nervous system (CNS) indications. A growing body of pharmacodynamic and translational data demonstrates OV4071’s ability to restore excitatory/inhibitory (E/I) balance across more than 40 disease models, including psychosis, cognition and behavioral dysfunction with results meeting or exceeding marketed traditional antipsychotics. In preclinical studies, OV4071 also demonstrated favorable properties and no evidence of sedation. OV4071 is supported by a translational biomarker strategy designed to help guide and de-risk clinical development. Ketamine challenge study: Building on the encouraging Phase 1 results thus far and as a part of the clinical development plan, Ovid intends to initiate a ketamine challenge study of OV4071 in the second half of 2026 to further characterize potential pharmacodynamic effects and proof-of-mechanism using electrophysiology and biomarkers. The study is designed to reproduce biological and neurotransmitter surges of glutamate and dopamine in a healthy volunteer to assess key biomarkers relevant to schizophrenia and other potential indications.KCC2 portfolio expansion; advancing next-generation compounds to support broad CNS therapeutic potential: Ovid has a discovery engine focused on identifying novel KCC2 direct activator molecules that are amenable for oral and injectable administration and moving them into IND-enabling studies. OV329 next-generation GABA-AT inhibitor: Phase 2 initiated with proof-of-concept studies underway, supporting continued development across multiple seizure disorders Ovid continues to advance OV329, its next-generation 4-aminobutyrate aminotransferase (GABA-AT) inhibitor, through proof-of-concept studies designed to establish the program's clinical potential across multiple seizure disorders. OV329 acts as a GABA-AT inhibitor and this represents a mechanism of action that has been previously validated in multiple seizure disorders. Building upon robust cortical inhibition that was established in human healthy volunteers, the Company is expanding development into multiple indications, including treatment-resistant focal onset seizures (FOS), tuberous sclerosis complex (TSC)-associated seizures and infantile spasms (IS). Initiated Phase 2 randomized, placebo-controlled study evaluating efficacy, safety and tolerability in treatment-resistant FOS: Ovid has received regulatory clearance across multiple regions and has initiated the dose-confirmatory study to evaluate seizure reduction efficacy, safety and tolerability of OV329 in people living with treatment-resistant FOS. This global study is designed with registrational-level rigor to potentially support multiple future seizure indications for OV329. The study is anticipated to be completed in the second half of 2027.Exploratory proof-of-mechanism photosensitivity study: Ovid has received regulatory clearances and has initiated a photo stimulation study to evaluate the anti-convulsant effect of multiple potential doses of OV329. The Company intends to test three doses of OV329, including 5, 7 and 9 milligrams, and anticipates results near year end 2026.Proof-of-concept studies in developmental epileptic encephalopathies (DEEs), TSC and IS: Ovid is in the process of initiating development programs for OV329 to assess proof of safety and anti-convulsant effect in TSC-associated seizures and IS using a weight-based pediatric formulation, which is independent from the adult fixed-dose tablets being tested in FOS. The Company expects to initiate a proof-of-concept safety and signal-finding study in the fourth quarter of 2026 to evaluate OV329 in patients with TSC-associated seizures. This study will help inform the dosing strategy for a subsequent study in IS, which is anticipated to commence in 2027. GABA-AT inhibition has previously been established as an effective mechanism of action in these DEEs, and OV329 is designed to be a GABA-AT inhibitor with a favorable safety, tolerability and efficacy profile. BUSINESS STRATEGY AND CORPORATE UPDATES Recent Events Strengthened leadership team: In July 2026, Ovid strengthened its executive leadership team to support the Company’s next phase of development. Kevin Norrett, MS, MBA, was appointed Chief Business Officer to lead business and corporate development and strategic partnerships. Charles Carter, MS, MBA, was promoted to Chief Financial Officer, succeeding Jeffrey Rona, who will remain an advisor to the Company through the end of 2027. Eliseo Salinas, MD, MSc, joined as Executive R&D Advisor, providing strategic and operational guidance for the Company’s research and development programs, and Victoria Fort was promoted to Chief Strategy Officer, leading enterprise strategy, investor relations and operational growth initiatives. Appointed additional board director: In June 2026, Ovid appointed Anna Greka, MD, PhD, a globally recognized physician-scientist, academic leader and biotech entrepreneur, to its Board of Directors. Dr. Greka chairs Ovid’s Science and Technology Committee and serves as a member of the Compensation Committee. Potential monetization of soticlestat interests: Ovid and Takeda assigned global intellectual property rights in soticlestat to a new privately held company (“NewCo”) launched by Perceptive Advisors to develop and commercialize the program for all potential indications, including developmental and epileptic encephalopathies, such as Dravet syndrome. Ovid has always believed in soticlestat’s potential to meaningfully improve the treatment paradigm for people with rare epilepsies, and NewCo was launched to carry this program forward with the focus and resources needed to reach these patients who are currently underserved by existing therapies. As part of the transaction, Ovid is eligible to receive up to $294.5 million in potential clinical, regulatory and commercial milestone payments, a portion of which is payable to Ligand under Ovid’s previously disclosed, royalty monetization agreement, as amended; and may receive low- to mid-single digit royalties on net sales of soticlestat if commercialized. Soticlestat has received Orphan Drug and Rare Pediatric Disease designation from the U.S. Food and Drug Administration. In April 2026, the Series A warrants issued by the Company in connection with its October 2025 private placement expired. The aggregate number of common shares underlying the Series A warrants was 38,481,325, and investors elected to exercise the warrants into 33,597,860 shares of the Company’s common stock for $1.40 per share and 4,883,465 pre-funded warrants for $1.399 per share, resulting in proceeds to the Company of approximately $53.9 million. Second Quarter 2026 Financial Results Cash, cash equivalents and marketable securities as of June 30, 2026 totaled $169.8 million.Research and development expenses were $10.0 million for the second quarter ended June 30, 2026, compared to $6.5 million for the same period in 2025. The increase is primarily related to elevated preclinical and clinical study activities on the OV329 and OV4071 programs.General and administrative expenses were $6.5 million for the second quarter ended June 30, 2026, as compared to $4.9 million for the same period in 2025. The increase between the periods was comprised of accounting and audit, legal, business development and other professional fees, offset by a decrease in payroll and related expenses resulting from lower headcount between the periods as well as recognition of approximately $0.4 million of severance and talent acquisition costs in the quarter ended June 30, 2025.Total operating expenses were $16.4 million for the second quarter ended June 30, 2026, as compared to $11.3 million for the same period in 2025.Ovid reported a net loss of $15.0 million, or basic and diluted net loss per share attributable to common stockholders of $0.08, for the three months ended June 30, 2026, as compared to a net loss of $4.7 million, or basic and diluted net loss per share attributable to common stockholders of $0.06, for the same period in 2025. About Ovid Therapeutics Ovid Therapeutics Inc. is a New York-based biopharmaceutical company dedicated to pioneering better, gentler medicines for the brain. The Company discovers and develops differentiated, small molecule medicines for neurological and neuropsychiatric disorders with significant unmet need. Ovid is developing: OV329, a next-generation GABA-aminotransferase inhibitor, as a potential therapy for treatment-resistant FOS and DEEs, including TSC and IS; and OV4071 and others within a library of compounds that directly activate the KCC2 transporter, for multiple CNS disorders. For more information about these and other Ovid research programs, please visit www.ovidrx.com. Forward-Looking Statements This press release includes certain disclosures by Ovid that contain “forward-looking statements” including, without limitation, statements regarding the expected timing of initiation, completion and results and data of Ovid’s ongoing and planned clinical studies; the reproducibility and durability of any favorable results initially seen to date in clinical trials; the potential use and development of OV4071, other compounds from Ovid’s library of direct activators of KCC2 and OV329; the potential opportunity for soticlestat, including the potential to receive milestone payments and royalties upon success; Ovid’s expectations regarding the duration of its cash runway and the expectation that it will support Ovid’s operations and development programs; the potential opportunity and ability to achieve full therapeutic potential of OV4071, other compounds from Ovid’s library of direct activators of KCC2 and OV329; Ovid’s clinical pipeline strategy and plans for future clinical studies; and other statements that are not historical fact. You can identify forward-looking statements because they contain words such as “anticipates,” “believes,” “expects,” “intends,” “may,” “plan,” “potentially,” and “will,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances). Forward-looking statements are based on Ovid’s current expectations and assumptions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that may differ materially from those contemplated by the forward-looking statements, which are neither statements of historical fact nor guarantees or assurances of future performance. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, without limitation, uncertainties inherent in the preclinical and clinical development and regulatory approval processes, impediments to Ovid’s ability to achieve expected benefits of cost-savings efforts, risks related to Ovid’s ability to achieve its financial objectives, and the risk that Ovid may not be able to realize the intended benefits of its business strategy. Additional risks that could cause actual results to differ materially from those in the forward-looking statements are set forth under the caption “Risk Factors” in Ovid’s most recently filed Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (“SEC”), and in subsequent and future filings Ovid makes with the SEC. Any forward-looking statements contained in this press release speak only as of the date hereof, and Ovid assumes no obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. Condensed Consolidated Statements of OperationsUnaudited (in thousands, except share and per share data)For The Three Months EndedJune 30, 2026 For The Three Months EndedJune 30, 2025Revenue: License and other revenue$733 $6,272 Total revenue 733 6,272 Operating expenses: Research and development 9,957 6,465 General and administrative 6,474 4,880 Total operating expenses 16,431 11,345 Loss from operations (15,698) (5,073)Other income (expense), net 689 389 Loss before provision for income taxes (15,009) (4,684)Provision for income taxes — — Net loss$(15,009) $(4,684)Net loss per share of Series A preferred stock, basic and diluted$— $(64.73)Weighted-average Series A preferred stock shares outstanding, basic and diluted — 1,250 Net loss per share of common stock, basic and diluted$(0.08) $(0.06)Weighted-average common stock shares outstanding, basic and diluted 197,453,293 71,109,514 Select Condensed Consolidated Balance Sheet DataUnaudited (in thousands)June 30, 2026 December 31, 2025Cash, cash equivalents and marketable securities$169,769 $90,447Working capital(1) 113,636 66,080Total assets 231,973 150,934Total stockholders’ equity 209,889 130,660(1)Working capital defined as current assets less current liabilities Contact Investor Relations & MediaInvestors@ovidrx.com202.361.0445