Japan Expanded Clinical Study (ECS) to Provide Tofersen (BIIB067) to Patients With Amyotrophic Lateral Sclerosis (ALS) Associated with a Mutation in the Superoxide Dismutase 1 (SOD1) Gene

开始日期2024-06-25

申办/合作机构-

NCT04856982

/ Active, not recruiting临床3期

A Phase 3 Randomized, Placebo-Controlled Trial With a Longitudinal Natural History Run-In and Open-Label Extension to Evaluate BIIB067 Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation

The primary objective of this study is to evaluate the efficacy of tofersen in presymptomatic adult carriers of a superoxide dismutase 1 (SOD1) mutation with elevated neurofilament (NF). The secondary objectives of this study are to evaluate the safety and tolerability tofersen and to evaluate the effect of tofersen on pharmacodynamics (PD)/treatment response biomarkers when initiated prior to versus at the time of emergence of clinically manifest amyotrophic lateral sclerosis (ALS).

开始日期2021-05-17

申办/合作机构

Biogen, Inc.

NCT03764488

/ Completed临床1期

A Phase 1, Safety, Tolerability, and Distribution Study of a Microdose of Radiolabeled BIIB067 Co-administered With BIIB067 to Healthy Adults

The primary objective of the study is to evaluate the distribution in the central nervous system (CNS) of a microdose 99mTc-MAG3-BIIB067 co-administered with unlabeled BIIB067 (Tofersen). The secondary objective of the study is to assess the safety and tolerability of unlabeled BIIB067 co-administered with a microdose of 99mTc-MAG3-BIIB067 to healthy participants.

开始日期2018-12-20

申办/合作机构

Biogen, Inc.

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项与托夫生相关的文献（医药）

2025-06-01·MUSCLE & NERVE

Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis

Article

作者: Fanning, Laura ; Glass, Jonathan D. ; McDermott, Christopher ; Ladha, Shafeeq ; Lovett, Alexandra ; Cochrane, Thos ; Chiò, Adriano ; Bruneteau, Gaëlle ; Smirnakis, Karen ; Babu, Suma ; Karlsborg, Merete ; Ferguson, Toby A. ; Malek, Sohail ; Bucelli, Robert C. ; Mayl, Keith ; Fradette, Stephanie ; Inra, Jennifer ; Chary, Sowmya

ABSTRACT:

Introduction/Aims:

Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1‐ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1‐ALS.

Methods:

Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup.

Results:

Ten participants (approximately 7% of tofersen 100‐mg–treated trial participants) experienced a total of 12 serious neurologic AEs—4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life‐threatening or fatal.

Discussion:

Some antisense oligonucleotides (ASOs) have been described as having pro‐inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1‐ALS. Safety data from the open‐label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1‐ALS.

2025-05-01·Drug information journal

Regulatory, Translational, and Operational Considerations for the Incorporation of Biomarkers in Drug Development

Review

作者: Stankeviciute, Simona ; Hatcher, Heather ; Qu, Angela X ; Learn, Chris

BACKGROUND:

Biomarkers are an integral component in the drug development paradigm. According to the US Food and Drug Administration (FDA), a biomarker is "a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic intervention" (FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Glossary. 2016 [Updated 2021 Nov 29, cited 2024 Apr 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/ Co-published by National Institutes of Health (US), Bethesda (MD)). The European Medicines Agency (EMA) defines a biomarker as "an objective and quantifiable measure of a physiological process, pathological process or response to a treatment (excluding measurements of how an individual feels or functions" European Medicines Agency (EMA). Biomaker. 2020a. Available from: https://www.ema.europa.eu/en/glossary-terms/biomarker#:~:text=Biomarker-,Biomarker,an%20individual%20feels%20or%20functions . Several clinical biomarkers are well-documented and have been used routinely for decades in health care settings and have long been accepted as valid endpoints for drug approval (for example, blood pressure measurement as a biomarker for cardiovascular health) (European Medicines Agency (EMA). Assessment report, TAGRISSO. 2016. Available from: https://www.ema.europa.eu/en/documents/assessment-report/tagrisso-epar-public-assessment-report_en.pdf . Accessed 15 Apr 2024). Recently, novel biomarkers have been identified and validated to accelerate developing innovative therapies indicated for serious human diseases, for example targeted/immune therapies of cancer (Chen in Med Drug Discov 21:100174, 2024). As indicators of the efficacy of new pharmacological treatments or therapeutic interventions, biomarkers can improve clinical trial efficacy and reduce uncertainty in regulatory decision making (Bakker et al. in Clin Pharmacol Ther 112:69-80, 2022; Califf in Exp Biol Med 243:213-221, 2018; Parker et al. in Cancer Med 10:1955-1963, 2021).

METHODOLOGY:

This article describes case studies of recent drug approvals that successfully leveraged validated and non-validated biomarkers (i.e., tofersen for the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in adults; and osimertinib for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)).

CONCLUSIONS:

Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.

2025-05-01·MOLECULAR THERAPY

RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice

Article

作者: Harkins, Ashley L ; Furgal, Raymond ; Gilbert, James W ; Summers, Ashley ; McHugh, Nicholas ; Hassler, Matthew R ; Dogan, Elif O ; Henninger, Nils ; Brown, Robert H ; Belgrad, Jillian ; Greer, Paul ; Mocarski, Kit ; Godinho, Bruno M D C ; Weiss, Alexandra ; Rivera Flores, Iris Valeria ; Wightman, Nicholas ; Ferguson, Chantal ; Yamada, Nozomi ; Echeverria, Dimas ; Bramato, Brianna ; Khvorova, Anastasia ; Monopoli, Kathryn ; Yamada, Ken ; Cooper, David

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2%-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene suppression a promising approach, supported by preclinical data and the 2023 Federal Drug Administration (FDA) approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNA^SOD1 extended survival in SOD1-G93A ALS mice, increasing survival beyond that previously seen in these mice by ASO modalities, slowed disease progression according to the standard ALS preclinical endpoints, and attenuated ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.

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2025-06-17

·CPHI制药在线

一年143万！渐冻症迎来第一款对因治疗方案

关注并星标CPHI制药在线2025年6月10日6时，全球首款针对渐冻症的对因治疗药物托夫生，于北京大学第三医院（北医三院）开出首张处方。一名 43 岁女性患者接受托夫生注射液腰穿鞘内注射治疗，这一刻，中国渐冻症治疗史翻开了全新一页，全球首款针对病因的渐冻症药物完成了它在中国的首次注射。李女士因不明原因的进行性肌肉无力来到北医三院就诊，最终被确诊为SOD1-ALS患者。这种由超氧化物歧化酶1基因突变引发的渐冻症，仅占所有渐冻症患者的2%，却是中国渐冻症人群中最常见的致病基因。治疗结束后，北京大学第三医院神经内科主任、我国著名神经病学专家樊东升教授来到病房，亲自看望并慰问了这位具有特殊意义的首方患者。那天深夜，樊东升教授在朋友圈写道："一早一晚整了两件大事。"这简单的一句话背后，是一位医者对推动中国渐冻症治疗进步数十年的坚守，也是一位患者等待希望的不懈坚持。一、从对症到对因：渐冻症治疗的革命性突破肌萎缩侧索硬化症（ALS）被定义为一种进行性、致命的神经退行性疾病。它无情地攻击大脑和脊髓的运动神经元，导致肌肉无力，瘫痪，并最终夺走患者的生命。在托夫生出现前，渐冻症治疗领域经历了漫长而艰难的跋涉。近200年来，全球有1000多万人因为这种运动神经元病死亡，而治愈率始终为0。绝大多数患者在确诊后2至5年内死亡，医学界几乎束手无策。过去近30年间，全球仅有屈指可数的几种渐冻症药物获批：1995年：利鲁唑（力如太）上市，平均延长患者生命2-3个月。2015年：依达拉奉获批，仅对约5%的患者有效。2022年：Albrioza获得批准但随后因III期试验失败退出市场。这些药物都只能缓解症状、延缓疾病进展，却无法触及疾病的根本原因。医生和患者都像是在与时间进行一场必败的赛跑，手中却没有真正有效的武器。托夫生的问世，标志着渐冻症治疗从"对症"转向"对因"的革命性突破。作为全球首个且目前唯一获批用于SOD1-ALS成人患者的疾病修正治疗药物（DMT），托夫生的核心机制直击病因。SOD1 基因突变会产生异常的毒性蛋白，当这些毒性蛋白不断积累，就会引起细胞功能障碍，导致渐冻症患者出现神经退化和肌肉无力。托夫生通过靶向突变 SOD1 基因产生的 mRNA，可有效减少毒性 SOD1 蛋白的合成。托夫生作用机制，图源：参考资料5截至目前，已发现超过 40 个基因与渐冻症相关，可解释大约 70% 的家族性渐冻症和大约 15% 的散发性渐冻症的病因。其中 4 个基因的相关性最为显著：C9orf72、SOD1、FUS 和 TARDBP。"如果一名ALS患者被告知携带SOD1基因突变，已是不幸中的万幸，"樊东升教授解释道，"这类患者约占家族性ALS患者的四分之一，在全部ALS患者中约占2%，他们多从下肢开始起病，病程相对较长，生存期往往是散发型ALS患者的数倍。"根据中国的患病率调查，国内携带SOD1基因突变的ALS患者超过千人。然而，专家们对药效的期望保持着科学家的审慎。"但它不会出现'今天打明天就好'这种情况，"樊东升强调，"渐冻症患者肌肉萎缩无力等体征源于神经细胞丢失，目前没有任何一种药物可以在一夜之间完成人体修复。"神经细胞的修复需要时间，而托夫生的价值在于它能够延缓甚至阻止进一步的损伤，为神经系统的自我修复争取宝贵时间。托夫生注射液于2023年4月获美国FDA加速批准，随后在2024年9月获得中国国家药监局（NMPA）批准上市，正式进入我国。从海南博鳌乐城国际医疗旅游先行区的先行先试，到如今在全国范围内的临床应用，这款创新药物仅用了不到一年时间，反映了中国加速引入创新罕见病药物的政策利好。二、天价药费下的生命抉择：可及性与争议当医学突破遇上经济现实，一个无法回避的问题摆在眼前：生命的价值如何衡量？托夫生在美国的首年定价高达199,200美元（约合人民币143万元），患者第一年需使用14剂1。在中国，经北京康盟慈善基金会近50%的补贴后（该补贴仅面向内地中国籍患者），患者的首年自费价格降至约70万元，不到美国定价的一半。 "虽然补贴后的价格也较高，但渐冻症属于罕见病，研发成本非常高，出于保护创新的角度也不可能定成'白菜价'。"樊东升教授坦言。这一价格背后，反映了罕见病药物研发的经济现实--高昂的研发投入需要分摊到极少数患者群体上。另一个现实挑战是基因检测。目前，并非所有ALS患者都接受全外显子基因检测，这项检查需要自费数千元。而有家族遗传史的ALS患者，基因突变检出的阳性率较高。《2023肌萎缩侧索硬化（ALS）基因检测与咨询的循证共识指南》明确指出，所有ALS患者都应接受包括SOD1在内的基因检测。基因检测可帮助患者明确自身所患ALS是否与特定基因突变相关，对于疾病的精准诊断、预后判断和精准治疗具有重要意义。同时，托夫生的获批之路并非一帆风顺，其背后存在不容忽视的科学争议。2021年，渤健公司曾宣布托夫生注射液的III期临床试验未达到主要终点——在28周内，对患者的病情改善及延缓效果与安慰剂无显著差异。然而，FDA基于"替代终点"加速批准了该药物：生物标志物研究显示，受试者接受托夫生注射液注射12周后，其体内SOD1蛋白水平和神经丝轻链（NfL）水平显著降低。神经丝轻链水平是评估渐冻症进展的重要指标，其水平越高，渐冻症患者的病情进展越快，反之则越慢。这种加速审批机制在医学界引发了广泛讨论。对于某些严重疾病或未满足的医疗需求，FDA允许以"替代终点"为依据（而非实际临床疗效）批准药物尽快上市。同时，这类审批相应的要求是，需要对药物继续进行以实际临床疗效为重点的新临床试验。如果后续的临床试验未能证明该药物的临床获益，FDA有权撤销批准。图源：参考文献6值得一提的是，在中国临床试验注册中心官网以"托夫生"或其英文名称检索时发现，并无已注册的临床试验。这表明该药在国内很可能通过免临床途径获批上市。这种审批策略虽然加快了创新药物可及性，但也意味着中国患者使用该药的实际效果数据相对有限。图源：中国临床试验注册中心官网不过，长期数据带来了一线希望。根据渤健公司发布的1年期的整合性数据，早期使用托夫生注射液的患者在ALSFRS-R（一种用于评估ALS患者功能障碍进展的标准化工具）评分、肺活量（SVC）和手部功能（HHD）等方面显示出减缓疾病进展的趋势；对比先后接受安慰剂半年、托夫生注射液半年，以及接受托夫生注射液一年的对照组患者，后一组患者的病情改善及延缓效果也表现出统计学差异。三、中国渐冻症治疗的未来随着托夫生在国内的临床应用拉开帷幕，中国渐冻症治疗的图景正在发生深刻变化。在浙江，西湖大学医学院附属杭州市第一人民医院运动神经元病诊疗中心也完成了当地首针注射。更令人期待的是，国产渐冻症药物研发正在加速。"未来3到5年，国内就会有一批渐冻症药物获批。"樊东升教授预计。今年3月下旬，神济昌华宣布SNUG01--全球首款以TRIM72为靶点的基因治疗药物在美国获批临床试验，这是去年至今第4款在海外有临床进展的国产渐冻症药物。国产在研药物呈现出多元化的技术路线。"国产在研药物有不少值得期待的方向，既包括前沿的细胞和基因治疗（CGT），也包括传统的小分子药物、具有中国特色的中药治疗，"樊东升表示，"尽管这些产品获批还需要更多科学证据支撑，但国产药物的定价相对进口药物更低，有望让更多渐冻症患者用得起药、用得上药。"这一波研发浪潮背后，是中国社会对渐冻症关注度的整体提升。2019年，时任京东集团副总裁的蔡磊确诊渐冻症，引发社会对这一罕见病的广泛关注。患者积极参与临床试验、人工智能（AI）和大数据等技术的应用，也显著缩短了渐冻症新药的研发周期。北京大学第三医院神经内科在樊东升的带领下，已开设了渐冻症专病门诊和多学科诊疗（MDT）门诊，致力于为患者提供从基因筛查、精准诊断到个体化治疗的全流程服务，有效减少误诊误治，缩短确诊时间。樊东升教授强调："我们呼吁进一步推动基因检测与诊疗规范化，让更多符合条件的患者尽早受益于这一国际突破性疗法，把握治疗窗口期。"对于渐冻症，尤其是具有明确遗传背景（如SOD1突变）的患者，"早发现、早诊断、早治疗"至关重要。托夫生的出现，不仅是一款新药的诞生，更代表了神经退行性疾病治疗范式的转变。从1995年第一款仅能延长生命2-3个月的力如太，到如今直击病因的托夫生，科学家们一步步攻克着这个曾被视为绝症的领域。北京东方丝雨渐冻人罕见病关爱中心理事长王金环表示："长期以来，SOD1-ALS患者始终缺乏有效治疗手段，而这一突破性疗法的出现，为他们燃起了希望之火。我们呼吁社会各界持续关注罕见病群体，共同推动创新疗法的可及，让每一位患者都能更有底气地面对疾病挑战。""尽管价格不菲，但至少让患者有了尝试的希望，而不是让他们为了获得一些更加确定的积极结果，继续苦等数年。"一位医学协会首席科学官如是说。在科学与现实的平衡中，托夫生为特定基因型的渐冻症患者推开了一扇希望之门。随着国产药物的研发加速、医保政策的优化以及社会支持体系的完善，我们相信，这扇门将会向更多患者敞开。在人类与渐冻症的漫长斗争中，托夫生的第一针不仅注入了一位患者的椎管，更注入了整个医学界战胜神经退行性疾病的信心与勇气。在冰封的身体里，生命的微光正在顽强闪烁，而科学，正努力让这光芒更加明亮。参考资料：[1]https://mp.weixin.qq.com/s/1tmg7VN0pwZoQhS1sITjSw?mpshare=1&scene=1&srcid=0610oXhfdwNTOn7UM4J8Qiof&sharer_shareinfo=f882ca9f605d0a4fa380110d9003f2c9&sharer_shareinfo_first=f882ca9f605d0a4fa380110d9003f2c9&version=4.1.33.99589&platform=mac#rd [2]https://endpoints.news/biogen-prices-new-als-drug-at-more-than-14k-per-dose/ [3]https://www.ncbi.nlm.nih.gov/books/NBK594270 [4]https://en.wikipedia.org/wiki/ALS [5]https://www.als.org/navigating-als/living-with-als/fda-approved-drugs/tofersen [6]https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene [7]https://www.nmpa.gov.cn/zwfw/sdxx/sdxxyp/yppjfb/20241008142557142.html [8]https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program [9]The New York Times-F.D.A. Approves Alzheimer's Drug Despite Fierce Debate Over Whether It WorksEND领取CPHI & PMEC China 2025展会门票来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

基因疗法临床3期信使RNA

2025-06-16

·派真生物PackGene

一周要闻丨基因治疗要闻速递第153期

行业动态速览热点聚焦01基因疗法遭遇"寒冬"，FDA承诺给予支持基因疗法曾乘着投资者狂热之风达到极高估值，但商业化挑战已将其市值推入谷底，整个行业正经历"寒冬"。在上周举行的FDA圆桌会议上，FDA领导人承诺将加快审批速度并为该行业提供广泛支持。推荐阅读：点击文末【阅读原文】了解更多详情！02NEJM | AAV基因治疗严重血友病B，10名患者长达13年的安全性及疗效评估数据2025年6月12日，伦敦大学学院（University College London）Amit C. Nathwani教授团队在The New England Journal of Medicine发表标题为“Sustained Clinical Benefit of AAV Gene Therapy in Severe Hemophilia B”的研究论文，该研究主要对10名接受scAAV2/8-LP1-hFIXco基因治疗的严重血友病B患者进行了长达13年的随访，评估了治疗的安全性和疗效，结果显示单次给药后因子IX表达持久稳定，临床出血率和因子IX浓缩物使用显著降低，且未出现迟发性安全问题，证实了AAV基因治疗的长期有效性和安全性。推荐阅读：EJM | AAV基因治疗严重血友病B，10名患者长达13年的安全性及疗效评估数据03Nat Commun | 天津医科大学郝继辉团队报道AI驱动优化先导编辑器，扩展反向编辑窗口及增强保真度和效率2025年6月3日，天津医科大学肿瘤研究所和医院的郝继辉教授团队在Nature Communications期刊发表标题为“Prime editor with rational design and AI-driven optimization for reverse editing window and enhanced fidelity”的研究论文。该研究主要开发了一种名为反向先导编辑（reverse Prime Editing，rPE）的新策略，通过合理设计和人工智能驱动的优化，实现了在SpCas9引导下的3'方向DNA编辑，扩展了Prime编辑的高效编辑范围，并显著提高了编辑保真度和效率。推荐阅读：Nat Commun | 天津医科大学郝继辉团队报道AI驱动优化Prime编辑器，扩展反向编辑窗口及增强保真度和效率04Nature子刊：曹云龙团队利用病毒进化，预测并筛选广谱中和抗体2025 年 6 月 10 日，北大-清华生命科学联合中心/北京大学生物医学前沿创新中心/昌平实验室曹云龙团队联合中国科学院生物物理研究所王祥喜团队、美国 Moderna 公司 Laura Walker 团队发表研究论文。研究表明，将利用病毒进化预测来识别广谱中和抗体（bnAb）与 mRNA 递送技术的多功能性相结合，能够加快开发针对 SARS-CoV-2 以及可能具有大流行潜力的其他病原体的下一代抗体类应对措施。推荐阅读：Nature子刊：曹云龙团队利用病毒进化，预测并筛选广谱中和抗体05规范基因治疗、细胞治疗等先进治疗药品的管理，CDE发布《先进治疗药品的范围、归类和释义（征求意见稿）》为规范我国基因治疗、细胞治疗以及采用其他基于微生物、细胞、基因或组织工程等创新技术/方法生产的先进治疗药品的管理，推动产业高质量发展，国家药品监督管理局药品审评中心于2025年6月10日发布《先进治疗药品的范围、归类和释义（征求意见稿）》。该征求意见稿聚焦先进治疗药品的范围及归类，促进分级分类科学监管，助力监管与国际接轨，推动该类药品的研发申报及审评审批上市，促进产业高质量发展，更好地满足人民健康需求。推荐阅读：规范基因治疗、细胞治疗等先进治疗药品的管理，CDE发布《先进治疗药品的范围、归类和释义（征求意见稿）》06全球首个渐冻症精准治疗药物在中国商业上市，开启渐冻症“对因治疗”新纪元2025年6月10日，渤健中国宣布，创新药物托夫生注射液（商品名：凯盛迪™）正式在中国商业上市，意味着我国符合条件的渐冻症患者即将有机会用上这款创新药物。作为全球首个获批的肌萎缩侧索硬化（ALS，俗称“渐冻症”）精准治疗药物，托夫生注射液在国家罕见病防治战略及加快引入创新药物的利好政策的推动下，于去年9月在中国获批，用于治疗携带超氧化物歧化酶1（SOD1）基因突变的肌萎缩侧索硬化（ALS）成人患者。此次托夫生注射液在中国商业上市，填补了渐冻症治疗领域巨大未满足需求，开启了中国渐冻症精准诊疗新纪元。推荐阅读：全球首个渐冻症精准治疗药物在中国商业上市，开启渐冻症“对因治疗”新纪元07股价单日暴涨788%！AAV基因疗法抗衰研究取得突破2025年6月10日，美国生物遗传学公司Klotho Neurosciences（KLTO）对外发布一项关于AAV基因疗法抗衰的科研进展，其团队通过激活人体内被称为“长寿基因”的α-Klotho（s-KL）蛋白，成功在小鼠模型中实现寿命延长20%，并显著减缓多器官衰老进程。这一突破性研究发表于《Molecular Therapy》期刊，为抗衰老治疗领域开辟了新方向。推荐阅读：股价单日暴涨788%！AAV基因疗法抗衰研究取得突破08破译致命密码：首个SCA51神经退行性疾病模型及致病机理研究近日，暨南大学粤港澳中枢神经再生研究院杨甦/李世华和湘雅医院江泓团队发表研究论文。利用AAV载体递送系统结合基因编辑方法，成功构建了携带THAP11突变基因的转基因小鼠模型。该研究阐明了TREM2介导的小胶质细胞活化在polyQ疾病中的关键作用，为相关疾病的治疗提供了新的潜在靶点。推荐阅读：破译致命密码：首个SCA51神经退行性疾病模型及致病机理研究09祝贺神曦生物原位神经再生疗法全球首创应用于重度阿尔茨海默病患者近日，由中国科学技术大学附属第一医院（安徽省立医院）和神曦生物合作开展的NXL-001治疗阿尔茨海默病（老年痴呆）的IIT临床研究顺利完成首例受试者给药及1个月后的安全性访视。这是全球范围内将原位神经再生疗法首次应用于治疗重度阿尔茨海默病患者，为阿尔茨海默病患者带来新的希望。作为神曦生物的合作伙伴，派真生物对神曦生物这一重要进程表示热烈地祝贺！推荐阅读：祝贺神曦生物原位神经再生疗法全球首创应用于重度阿尔茨海默病患者10基因治疗的下一程，是“回到未来”AAV进化的终点，或许就是它的起点：不再局限于动物筛选，不再绕行于模型间的误差；直接回到人体，在人体中寻找最合适的载体，以此推动更安全、更精准、更有效的下一代AAV疗法。AAV的未来，不在模型中，而在人类自身中等待被发现。推荐阅读：AAV载体进化简史（4）：从理性设计、AI辅助衣壳设计到人体筛选创新突破01Nature Press | 暨南大学李斌团队开发新型mRNA递送平台——内吞体溶解性氯喹类优化脂质纳米颗粒（ecoLNPs）2025年5月7日，暨南大学第二临床医学院李斌团队在Nature Communications上发表了名为“Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing”研究论文。通过将氯喹特征结构与可电离脂质结合构建类氯喹脂质库，经过筛选优化得到 ecoLNPs，发现其在体外和体内均展现出高效的 mRNA 递送能力，还能介导基因组编辑，为 mRNA 递送系统的设计提供了新途径。推荐阅读：Nature Press | 暨南大学李斌团队开发新型mRNA递送平台——内吞体溶解性氯喹类优化脂质纳米颗粒（ecoLNPs）02JEM | 清华傅阳心/梁永团队开发膜锚定IL-12新型mRNA疫苗，激活全新T细胞抗肿瘤军团2025年6月6日，清华大学傅阳心/梁永团队在 Journal of Experimental Medicine 在线发表了题为“Membrane-IL12 adjuvant mRNA vaccine polarizes pre-effector T cells for optimized tumor control”的研究成果。该研究开发了编码膜型IL12（mtIL12）佐剂的新一代mRNA-LNP疫苗。该设计将mtIL12限制性表达在抗原呈递细胞表面，在诱导强效肿瘤特异性T细胞应答的同时，有效规避了传统IL-12带来的全身性副作用。该研究与宾夕法尼亚大学Christopher A. Hunter、Drew Weissman通讯在《Science immunology》发表的论文“An IL12 mRNA-LNP adjuvant enhances mRNA vaccine–induced CD8 T cell responses”同日在线，提示了基于细胞因子的新型mRNA-LNP疫苗的重大潜力。推荐阅读：JEM | 清华傅阳心/梁永团队开发膜锚定IL-12新型mRNA疫苗，激活全新T细胞抗肿瘤军团03mRNA技术新突破！Nat Commun｜mRNA纳米脂质粒让艾滋病“潜伏的敌人”无处可逃近日，一篇发表在国际杂志《Nature Communications》上题为“Efficient mRNA delivery to resting T cells to reverse HIV latency”的研究报告中，来自墨尔本大学等机构的科学家们通过研究探索了mRNA纳米脂质粒（LNP）如何成为逆转HIV潜伏的新希望。HIV病毒的潜伏状态是艾滋病治愈的最大障碍，传统抗逆转录病毒疗法（ART）虽能有效抑制病毒复制，却无法清除潜伏的病毒库。因此，寻找一种能激活HIV潜伏转录、进而清除感染细胞的新策略成为研究焦点。推荐阅读：mRNA技术新突破！Nat Commun｜mRNA纳米脂质粒让艾滋病“潜伏的敌人”无处可逃04Nat Cardiovasc Res | 郭宇轩/董尔丹团队开发新型基因开关技术DreAM控制基于AAV的心脏修复再生2025年6月13日，北京大学血管稳态与重构全国重点实验室的郭宇轩-董尔丹教授团队在Nature Cardiovascular Research杂志上以长文技术报告（technical report）形式在线发表题为“The drug-elicitable alternative splicing module for tunable vector expression in the heart”的文章。该文章报道了一种受FDA批准的口服小分子药物利司扑兰诱导的新型基因表达开关技术DreAM，在心肌梗死小鼠的心脏再生干预中显著提升了AAV基因治疗的有效性和安全性。推荐阅读：Nat Cardiovasc Res | 郭宇轩/董尔丹团队开发新型基因开关技术DreAM控制基于AAV的心脏修复再生资本速递01国内一基因治疗公司完成新一轮融资，专注于AAV等基因载体创新与临床应用6月12日，北京因诺惟康医药科技有限公司宣布完成数千万元的A+轮融资，本轮投资由天创资本领投，新投资人及老股东跟投。所募集的资金将主要用于公司产品管线的临床验证和推进以及基因递送平台的创新。推荐阅读：国内一基因治疗公司完成新一轮融资，专注于AAV等基因载体创新与临床应用0212.5亿！BioNTech收购CureVac，mRNA先驱成“先烈”近日，德国生物技术巨头BioNTech宣布以股票交易形式收购mRNA领域先驱CureVac，交易总额达12.5亿美元。根据协议，CureVac股东每持有1股股票可置换约5.46美元的BioNTech美国存托凭证（ADS），较CureVac前一日收盘价溢价55%。交易完成后，CureVac股东将持有BioNTech 4%-6%的股份，德国政府持有的13.32%股权也将通过交易退出。此次收购已获双方管理层一致批准，预计2025年内完成，需满足至少80%股权的最低接受门槛及监管审批。推荐阅读：12.5亿！BioNTech收购CureVac，mRNA先驱成“先烈”关于派真生物

基因疗法

2025-06-12

·PipelineReview

First patient dosed in pivotal Phase 3 REVEAL clinical study of ION582 in Angelman syndrome

– Completion of enrollment anticipated in 2026 – CARLSBAD, CA, USA I June 11, 2025 I Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced that the first participant has been dosed in the global Phase 3 REVEAL study, which is designed to evaluate the efficacy and safety of ION582, an investigational medicine for the treatment of people living with Angelman syndrome (AS), a serious and rare neurodevelopmental disorder that leads to significant physical and cognitive impairments. “Dosing the first person with Angelman syndrome in our pivotal REVEAL study marks an important milestone for this underserved community, who currently have no approved disease modifying treatments,” said Holly Kordasiewicz, Ph.D., senior vice president of neurology, Ionis. “This placebo-controlled study will evaluate ION582 in both children and adults with either UBE3A deletion or mutation and builds on earlier encouraging findings from our Phase 1/2 HALOS study. This milestone reflects our commitment to those impacted by Angelman syndrome and builds on our legacy of innovation in neurology including the development of SPINRAZA and QALSODY. With ION582, we continue to advance our leading wholly owned neurology pipeline, which includes eight medicines in clinical development across a range of rare and more prevalent diseases.” REVEAL ( NCT06914609 ) is a global, randomized, double-blind, placebo-controlled Phase 3 study that will enroll approximately 200 children and adults with AS that have a maternal UBE3A gene deletion or mutation. During the 52-week treatment period, participants will be randomized 2:1 to receive either ION582 or placebo. Participants in the active treatment groups will receive quarterly 40 mg or 80 mg doses of ION582. Following the treatment period, eligible participants will transition into the long-term extension portion of the study where all participants will receive ION582 for up to 2 years. The primary endpoint is improvement in expressive communication as assessed by the Bayley Scales for Infant and Toddler Development-4 (Bayley-4), an objective and direct clinician-administered assessment of clinical functioning. Deficits in expressive communication are reported to be the symptoms most challenging to caregivers of people with AS. Secondary endpoints include overall disease severity, cognition, communication, sleep, motor functioning and daily living skills, in addition to other exploratory endpoints. In the completed multiple ascending dose (MAD) portion of the Phase 1/2 open-label HALOS study, ION582 provided consistent and encouraging clinical improvement on all functional domains including communication, cognition and motor function and showed favorable safety and tolerability at all dose levels in the study. For more information on the REVEAL clinical study, please visit www.ionisrevealstudy.com and www.clinicaltrials.gov . About ION582 ION582 is an investigational RNA-targeted antisense medicine designed to inhibit the expression of the UBE3A antisense transcript (UBE3A-ATS) and increase production of UBE3A protein, for the potential treatment of Angelman syndrome (AS). The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) granted Orphan Drug designation to ION582. Additionally, the FDA granted Fast Track and Rare Pediatric designations to ION582. About Angelman Syndrome (AS) AS is a rare, genetic neurological disease that affects an estimated 1 in 21,000 people worldwide and is caused by the loss of function of the maternally inherited UBE3A gene. AS typically presents in infancy and is characterized by profound intellectual disability, balance issues, motor impairment and debilitating seizures. Most people with AS are unable to speak. Individuals with AS have a normal lifespan but require complete care from a caregiver. Some symptoms can be managed with existing medicines; however, there are no approved disease modifying therapies. About Ionis Neurology Ionis has been at the forefront of discovering and developing leading neurological disease medicines, including SPINRAZA ® (nusinersen), the first approved treatment for spinal muscular atrophy, WAINUA™ (eplontersen), a medicine to treat hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), and QALSODY ® (tofersen) for SOD1-ALS. The clinical-stage portfolio includes 13 therapies, of which eight are wholly owned by Ionis. Ionis’ investigational portfolio includes medicines for which there are few or no disease modifying treatments, such as rare diseases including Prion disease and Alexander disease and more common conditions such as Alzheimer’s and Parkinson’s disease. About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has six marketed medicines and a leading pipeline in neurology, cardiology, and select areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionis.com and follow us on X (Twitter), LinkedIn and Instagram . SOURCE: Ionis Pharmaceuticals

孤儿药临床3期快速通道上市批准

100 项与托夫生相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11811	-	-	DB14782

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
肌萎缩侧索硬化	欧盟	Biogen, Inc.	2024-05-30
肌萎缩侧索硬化	冰岛	Biogen, Inc.	2024-05-30
肌萎缩侧索硬化	列支敦士登	Biogen, Inc.	2024-05-30
肌萎缩侧索硬化	挪威	Biogen, Inc.	2024-05-30
1型肌萎缩侧索硬化	美国	Biogen MA, Inc.	2023-04-25

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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


NCT02623699 (FDA) 人工标引	临床3期	1型肌萎缩侧索硬化 SOD1 Mutation	108	QALSODY 100 mg (ITT population)	衊艱構鹹壓夢窪蓋壓遞(製築襯糧鹽範鏇簾憲膚) = 艱獵衊廠繭簾艱齋夢窪襯積繭窪淵繭糧餘憲醖 (選構廠鏇選壓鑰蓋壓憲 ) 更多	积极	2023-04-25
				Placebo (ITT population)	衊艱構鹹壓夢窪蓋壓遞(製築襯糧鹽範鏇簾憲膚) = 簾衊膚鬱淵鬱憲鹹糧鬱襯積繭窪淵繭糧餘憲醖 (選構廠鏇選壓鑰蓋壓憲 ) 更多
NCT02623699 (VALOR, Pubmed \| Br Dent J \| N Engl J Med) 人工标引	临床3期	1型肌萎缩侧索硬化 SOD1 Mutation	108	Tofersen	製餘壓廠廠築範遞窪衊(顧艱顧鹹觸夢積遞膚窪) = 鬱餘獵齋餘餘餘積觸艱襯鹽廠範鬱範構觸廠選 (鬱繭選製廠網選壓構獵 )	不佳	2022-09-22
				placebo	製餘壓廠廠築範遞窪衊(顧艱顧鹹觸夢積遞膚窪) = 獵襯憲繭鹹製艱醖襯窪襯鹽廠範鬱範構觸廠選 (鬱繭選製廠網選壓構獵 )
NCT02623699 (VALOR, Corporate Publications) 人工标引	临床3期	1型肌萎缩侧索硬化 SOD1	108	Tofersen	願窪餘淵繭鹽壓鹹夢鑰(築構壓艱鹹觸積鹹築選) = 鹹繭壓鑰範鏇範襯願衊窪簾積鹹壓鹹鑰壓鏇衊 (齋簾積壓鏇襯顧獵選淵 )	积极	2022-06-03
				Placebo	願窪餘淵繭鹽壓鹹夢鑰(築構壓艱鹹觸積鹹築選) = 鏇製壓憲築襯憲窪製遞窪簾積鹹壓鹹鑰壓鏇衊 (齋簾積壓鏇襯顧獵選淵 )
NCT02623699 (VALOR, Corporate Publications) 人工标引	临床3期	1型肌萎缩侧索硬化 SOD1 mutation	108	tofersen	齋繭築顧夢選淵衊艱鏇(鏇願鏇構鹹簾鏇醖糧遞) = 膚憲廠憲構憲選膚艱選餘積構範範構觸願製築 (衊鏇構鑰製獵廠鹽襯製 ) 更多	积极	2021-10-17
				Placebo	齋繭築顧夢選淵衊艱鏇(鏇願鏇構鹹簾鏇醖糧遞) = 築廠網齋鹹餘齋蓋蓋襯餘積構範範構觸願製築 (衊鏇構鑰製獵廠鹽襯製 ) 更多
NCT02623699 (VALOR, Pubmed \| Br Dent J \| N Engl J Med) 人工标引	临床1/2期	1型肌萎缩侧索硬化 SOD1 Mutation	50	Tofersen	淵糧艱範鹽壓齋顧構築(願糧壓鑰範憲鬱壓艱醖) = 願餘構鏇構衊觸獵範醖鬱鹽觸簾蓋製築襯鏇艱 (糧鑰築網衊遞簾憲膚鹹 ) 更多	积极	2020-07-09
				Placebo	願顧製壓選觸衊製餘簾(積壓願窪襯淵醖製鏇淵) = 鑰構積觸積願廠構遞鹽遞繭鹹積製餘遞觸鑰鏇 (積蓋淵繭窪壓觸鏇鑰廠 )
NCT01041222 (Pubmed) 人工标引	临床1期	1型肌萎缩侧索硬化 SOD1 Mutation	32	ISIS 333611	憲廠積願遞齋餘選鏇夢(鑰齋夢鹹鑰製夢壓齋鏇) = 顧憲構顧窪夢鏇選膚餘淵淵廠構顧簾製壓範衊 (憲鹹糧築醖夢壓淵蓋繭 ) 更多	积极	2013-05-01
				Placebo	-