Migalastat Hydrochloride

天然产物（NPs）历来是药物研发的重要基石，从古代草药疗法到吗啡、奎宁等具有里程碑意义的药物，均源于天然产物的发现。20世纪中期，天然来源抗生素的发现进入"黄金时代"，随后其应用逐步扩展至其他治疗领域。然而，到20世纪末，随着合成化学、分子生物学等技术的迅速发展，天然产物在药物研发中的核心地位逐渐被多元化的技术路径所替代。 本文系统梳理了2014年以来获批的天然产物衍生（NP-D）药物，并分析了截至2024年底处于临床研发阶段的候选药物，旨在客观评估天然产物在当代药物研发体系中的实际地位与价值。 研究显示，2014年1月至2025年6月期间，全球共有58款天然产物相关药物获批上市，其中包括45个天然产物及其衍生物新化学实体（NCEs），以及13个天然产物-抗体偶联药物（NP-ADCs）。进一步对2014–2024年全球批准的579种药物进行分析（其中NCEs为388种，占67%；新生物实体NBEs为191种，占33%），根据本研究的界定标准，共有56种药物（占总数的9.7%）被归类为天然产物或其衍生物，具体包括44个NCEs（占总批准数的7.6%，占NCEs的11.3%）和12个NP-ADCs（占总批准数的2.1%，占NBEs的6.3%）。从年度趋势来看，自2014年起，新型NP-D NCEs与NP-ADCs的年批准数量在0至8款之间波动，年均批准约5款。 此外，研究还识别出截至2024年12月底处于临床试验或注册审评阶段的125种天然产物及其衍生化合物。值得关注的是，其中33种化合物具有全新的药效骨架，但过去十五年间仅有1种全新骨架被发现。本综述指出，尽管天然产物在整体药物研发中的比重有所下降，其持续贡献仍不容忽视，并呼吁重新重视以生物活性为导向的天然产物分离、鉴定及机制研究，以拓展先导化合物的发现空间。 1. 引言 天然产物（NPs）在医学史上具有重要地位，其粗提物作为传统药物已沿用数百年。这些药物至今仍在全球范围内发挥重要作用，尤其在发展中国家，它们仍是医疗保健体系的重要组成部分。19世纪是药物发现的关键转折点，纯化技术的出现使得吗啡、奎宁、毛果芸香碱、地高辛、水杨苷和麻黄碱等化合物得以从植物中分离。20世纪早中期，合成药物的兴起促使天然产物、合成化学和疫苗在现代医学中形成动态互动。这一趋势在抗生素研究中尤为显著：1930年代合成磺胺类药物的发现推动了青霉素的研发（1942年首次临床应用），进而引发了对微生物源抗生素的广泛探索。1940年代，短杆菌素、Gramicidin S、Gramicidin D、杆菌肽、链霉素和金霉素相继被发现。这一时期常被称为"抗生素的黄金时代"，开启了长达约30年以天然产物为核心的抗生素及其他治疗领域研究。 然而，20世纪末的技术进步彻底改变了药物研发模式。天然产物曾是先导化合物的主要来源，如今已成为药物发现工具箱中的选项之一。进入21世纪的首个25年，生物药（表1）显著崛起，其影响力已与小分子药物相当。例如，2014年全球批准的47种药物中生物药占10种（21.3%），而2024年批准的75种药物中生物药增至32种（42.7%）（图1）1,2。值得注意的是，天然产物在抗体-药物偶联物（ADCs）中作为"弹头"发挥了新作用。在此背景下，一个关键问题浮出水面：天然产物先导化合物的发现与药物开发，应如何适应这一不断演变的制药版图？ 图1 2014–2024年全球获批新化学实体（NCEs）与新生物实体（NBEs）的分类统计 在本综述中，"天然产物（NP）"特指从天然来源（包括海洋与陆生植物、微生物及海洋动物）中分离获得的、结构明确的小分子纯品，例如萜类、聚酮化合物、多肽、脂质及混合生物合成来源的化合物。通常与初级代谢相关或主要发挥营养功能的分子（如甾体、胆汁酸、氨基酸、唾液酸、前列腺素、类视黄醇、激素、核苷以及人体蛋白质和蛋白质片段）不在讨论范围内。在图示中，天然产物结构以蓝色标注，天然产物衍生化合物则以黑色表示。已获批天然产物衍生药物的适应症拓展研究在第2.2节中讨论，但不纳入整体统计分析。 本文涉及的化合物按分子属性分为三类（天然产物NP、天然产物衍生化合物NP-D、天然产物-抗体偶联药物NP-ADC），并按生产工艺分为三大类别（表1），同时明确定义了新化学实体（NCEs）与新生物实体（NBEs）。将化合物属性与生产工艺分类独立分析，不同于本系列既往综述的框架3–6，这一调整旨在简化分析流程，同时便于深入探讨生产工艺细节。 表1 法规、化合物和制造类别 符合以下任一标准的化合物未被纳入本次分析：（1）临床试验注册信息显示试验已于2021年12月31日或之前完成，且无活跃研发计划证据；（2）临床开发已终止；（3）化合物已被开发方从研发管线中移除且未进行授权。此外，COVID-19疫情对临床试验及企业资金投入的冲击也已纳入考量。尽管已对公开数据进行全面分析，部分天然产物及天然产物衍生化合物（尤其是临床研发早期阶段的项目）可能未被涵盖。需要说明的是，临床试验格局与企业参与情况动态变化，建议读者通过企业官网、临床试验注册平台及最新文献获取最新信息。 本综述系统梳理了2014年1月至2025年6月期间全球获批的天然产物（NP）、天然产物衍生药物（NP-D）及天然产物-抗体偶联药物（NP-ADC）（第2节，表2和表3）；进而对截至2024年12月31日处于临床评估或注册阶段的NP、NP-D与NP-ADC，按疾病领域进行分类阐述：感染性疾病（第3节）、神经系统疾病（第4节）、心血管与代谢疾病（第5节）、免疫性及炎症相关疾病（第6节）和肿瘤学（第7节）。针对进入II期及以上临床试验的含天然产物衍生弹头的ADC药物，在第7.3节专门讨论。此外，本文还详细分析了这些化合物的给药途径及其先导天然产物结构来源（第8节），并在第9节总结了处于研发后期阶段的NP-D化合物及具有新颖药效团的临床候选药物。 2. 2014年1月至2025年6月全球获批的NP、NP-D及NP-ADC药物 2.1 NP衍生药物概述 2014年1月至2025年6月期间，全球共批准58款天然产物（NP）相关药物，其中45款为NP及NP-D类新化学实体（NCEs）（表2），13款为NP-抗体偶联药物（NP-ADCs）（表3）。在45款NCEs中，6款为直接天然产物（NPs），39款为NP衍生药物（NP-Ds），其生产工艺包括3款基于生物质合成、18款半合成及24款全合成。45款NCEs中有9款属于全新作用机制的人用药物类别（表2），而13款NP-ADCs中有2款采用首创型"弹头"结构（表3）。 表2 2014年1月1日至2025年6月30日期间获批的NP衍生小分子药物 本节按治疗领域（第2.1.1–2.1.5节）简要介绍2014–2024年间批准的55款NP衍生药物及其结构特征，并分别在第3.1、第6及第7.3节中说明截至2025年6月获批的3款NP-D药物（那氟霉素3.01、阿科尔 Tremon 6.06和替利索妥珠单抗维多汀7.55）。 全球药物批准趋势分析 根据2014–2024年全球批准的NCE与NBE药物数据1,2,8–27，其可分为NP/NP-D NCEs、NP-ADCs及其他NCEs/NBEs（图1）。此期间共批准579款新药，包含388款（67%）NCEs和191款（33%）NBEs。其中： 44款NCEs为NP或NP-D药物（占总批准数7.6%，占NCEs的11.3%）； 12款NBEs为NP-ADCs（占总批准数2.1%，占NBEs的6.3%）； 按本综述的NP定义，共有56款（9.7%）药物属于NP、NP-D或NP-ADC类别。若将甾体、胆汁酸、氨基酸等排除在外的类天然分子纳入统计，此比例将进一步升高。 关键趋势解读（图1） NCEs数量小幅增长：过去十年NCEs批准量较此前14年总体略有上升，但2022–2023年因新冠疫情出现回落； NBEs显著增加：近10年NBE类药物批准数量大幅上升； NP衍生药物稳定输出：2014–2024年间，NP衍生NCEs与NP-ADCs年批准量在0–8款之间波动，年均约5款； NP-ADCs前景可期：自2014年以来已有13款NP-ADCs获批（表3），且后期临床及注册阶段候选药物众多（第7.3节），预计未来数量将持续增加。 表3 2014年1月1日至2025年6月30日期间获批的NP-ADCs药物 2.1.1 用于治疗感染性疾病的新型天然产物（NP）及天然产物衍生药物（NP-D） 在此期间共有15款新型抗感染药物获批上市，其中包括： 11款抗菌药物（含1种β-内酰胺酶抑制剂） 2款抗真菌药物 1款抗病毒药物 1款抗寄生虫药物 （一）抗菌药物 按药物类别划分，具体包括： 四环素类（3种）： 艾拉环素（eravacycline, 2.18）34 沙瑞环素（sarecycline, 2.20）35 奥马环素（omadacycline, 2.29）36 糖肽类（2种）： 达巴万星（dalbavancin, 2.02）37 奥利万星（oritavancin, 2.07）38 β-内酰胺类（2种）： 头孢地尔（cefiderocol, 2.23）39 舒罗培南酯羟丙基（sulopenem etzadroxil, 2.43）40 β-内酰胺/β-内酰胺酶抑制剂复方（1种）： 恩美他唑巴坦（enmetazobactam, 2.40）41 氨基糖苷类（1种）： 普拉佐米星（plazomicin, 2.17）42 截短侧耳素类（1种）： 来法莫林（lefamulin, 2.22）43 大环内酯混合物（1种）： 卡里霉素（carrimycin, 2.24a–2.24c）44,45 （二）抗真菌药物 伊布雷沙芬净（ibrexafungerp, 2.30）46,47： 属新型Fungerp类化合物49 雷扎芬净（rezafungin, 2.35）48： 属已确立的棘白菌素类50 （三）抗病毒药物 斑蝥素（cantharidin, 2.39）作为局部外用抗病毒药物，获批用于治疗传染性软疣（一种DNA痘病毒感染）51。该药物早有应用历史，既见于中医传统疗法52，亦于1950年代在欧美用于抗疣治疗53。 （四）抗寄生虫药物 莫西菌素（moxidectin, 2.15）为一种由兽用驱虫药转换用途而来的抗寄生虫药物54。 2.1.2 用于治疗神经系统疾病的新型NP与NP-D药物 地那布啡癸二酸酯（dinalbuphine sebacate, 2.13）为阿片类镇痛药纳布啡的前体药物，用于术后疼痛治疗55。 萨米多芬（samidorphan, 2.29）与奥氮平的复方制剂获批用于治疗精神分裂症及双相情感障碍56，其中萨米多芬的加入旨在减轻奥氮平常见的体重增加副作用。 沙诺美林（xanomeline, 2.42）57为槟榔碱衍生物58，可作用于M1与M4毒蕈碱型乙酰胆碱受体，曾用于阿尔茨海默病及精神分裂症的研究，但因严重副作用于1998年终止开发。后续研究发现将其与非选择性毒蕈碱拮抗剂曲司氯铵（trospium chloride）59联用可降低不良反应60，该复方于2024年9月获批用于治疗精神分裂症。 2.1.3 用于治疗心血管与代谢疾病的新型NP-D药物 共14款新型NP-D药物获批用于心血管与代谢疾病治疗，主要包括： 11种根皮苷衍生物61：用于2型糖尿病治疗，包括： 恩格列净（empagliflozin, 2.03） 伊格列净（ipragliflozin, 2.04） 鲁格列净（luseogliflozin, 2.05） 托格列净（tofogliflozin, 2.06） 厄格列净（ertugliflozin, 2.11） 雷格列净碳酸乙酯（remogliflozin etabonate, 2.25） 亨格列净（henagliflozin, 2.27） 贝格列净（bexagliflozin, 2.33） 索格列净（sotagliflozin, 2.36） 依那格列净（enavogliflozin, 2.38） 贾那格列净（janagliflozin, 2.41） 米加拉司他（migalastat, 2.09）：为1-脱氧野尻霉素衍生物，获批用于法布里病治疗62。 沃拉帕沙（vorapaxar, 2.01）：作为首创类药物用于血栓性心血管事件预防，其结构源于植物生物碱himbacine的对映体63,64。 麦芽酚铁（ferric maltol, 2.10）：用于缺铁性贫血治疗，系麦芽酚衍生物的首个临床应用实例65；麦芽酚本身以往仅作为药用辅料或食品风味增强剂使用。 2.1.4 用于治疗免疫性、炎症性及相关疾病的新型NP-D药物 纳洛昔醇（naloxegol, 2.08）66与那地麦定（naldemedine, 2.14）67为吗啡衍生物，用于治疗阿片类药物引起的便秘。 西波尼莫德（siponimod, 2.21）与依曲莫德（etrasimod, 2.37）为多球壳菌素（myriocin）衍生物，分别获批用于多发性硬化症68及重度溃疡性结肠炎69治疗。 伏环孢素（voclosporin, 2.28）为环孢菌素衍生物，获批用于狼疮性肾炎治疗70。 两款首创类药物： 他匹那罗（tapinarof, 2.32）为二苯乙烯类化合物，用于斑块型银屑病治疗71。 奥马维酮（omaveloxolone, 2.34）为齐墩果酸衍生物，获批用于弗里德赖希共济失调治疗72。 2.1.5 新型NP、NP-D及NP-ADC抗癌药物 2014年以来获批的两款首创类抗癌药物： 米哚妥林（midostaurin, 2.12）73：星孢菌素衍生物。 普利西普辛（plitidepsin, 2.16）74,75：从海鞘Aplidium albicans中分离得到的环状缩肽。 其他NP-D抗癌药物： 卢比奈克丁（lurbinectedin, 2.26）为曲贝替定（trabectedin, 7.45）类似物，其合成以氰化萨夫拉辛B（源自荧光假单胞菌）为关键中间体76,77。 乌替隆（utidelone, 2.31）（depoxythilone，埃博霉素D）属埃博霉素类78，该类此前仅有伊沙匹隆获批。 淫羊藿苷元（icaritin, 2.44）为从淫羊藿属植物中分离的异戊烯化黄酮醇，亦是淫羊藿苷类衍生物的肠道代谢产物79–81，2022年在中国获批用于肝细胞癌的预防与治疗。 抗体偶联药物（ADC）进展 2014至2024年间共批准12款ADC药物（表2），其发展基于此前已获批的三款ADC药物基础： 吉妥珠单抗奥佐米星（2000年，美国，弹头：卡奇霉素，靶点：CD33） 维布妥昔单抗（2011年，美国，弹头：海兔毒素MMAE，靶点：CD30） 曲妥珠单抗美坦新（2013年，美国，弹头：美登素DM1，靶点：HER2） 12款ADC中，7款采用上述NP-D弹头（卡奇霉素×1、海兔毒素×5、美登素×1），其余5款使用新型NP来源弹头（喜树碱类×4、安曲霉素×1）。本节提供了奥加珠单抗奥佐米星（inotuzumab ozogamicin, 2.37）和朗妥昔单抗泰西兰（loncastuximab tesirine, 2.38）的结构示例，其他NP来源弹头的代表性案例详见第7.3节。 2.2 已获批天然产物（NP）及天然产物衍生药物（NP-D）的后期研发进展 替比培南匹酯（Tebipenem pivoxil） 已上市药物新适应症 III期临床试验 2009年首次在日本上市（商品名：Orapenem®） Spero Therapeutics与GSK正在开展一项III期临床试验（NCT06059846），评估其用于治疗复杂性尿路感染（cUTI），旨在推动该药在亚洲以外市场获批。试验于2025年5月因中期分析确认其疗效不劣于静脉注射用亚胺培南-西司他丁而提前终止82,83。 氨曲南-阿维巴坦复方（Emblaveo®） 新复方制剂 已获批 由单环β-内酰胺类抗生素氨曲南（1984年首次上市）与β-内酰胺酶抑制剂阿维巴坦（2015年上市）组成。2024年3月获欧洲药品管理局（EMA）批准，用于治疗： 复杂性腹腔内感染 复杂性尿路感染 医院获得性肺炎 治疗选择有限的需氧革兰氏阴性菌感染 参考：84,85 利福布汀静脉制剂（BV100） 新剂型开发 II期临床试验完成 口服制剂于1992年首次获批用于分枝杆菌感染 BioVersys AG开发的静脉制剂已完成一项II期临床试验（NCT06059846），评估其治疗碳青霉烯类耐药鲍曼不动杆菌引起的严重感染的潜力86。 大麻二酚（Cannabidiol）与屈大麻酚（Dronabinol） 已上市药物新适应症 多项II/III期临床试验进行中 大麻二酚（2018年FDA批准用于癫痫）和屈大麻酚（1985年FDA批准用于化疗相关恶心呕吐）目前正在进行多项II期和III期临床试验，评估其在其他神经系统疾病中的应用。 金雀花碱（Cytisine / Cytisinicline） 老药新用 全球多项II/III期临床试验 该药物自1960年代起已在苏联和东欧国家使用87，并在其他少数国家获批上市88,89。目前正在全球范围内开展多项II期和III期临床试验，评估其辅助戒烟疗效。 待续 ACD/Labs作为一款专业的化学分析软件平台 将大数据与人工智能技术结合 在天然产物化学研究领域提供了多方位的支持！ 1、基于碳谱数据库的天然产物结构排重 基于核磁碳谱数据库检索来快速确认已知化合物的结构或者得到骨架参考信息，是目前天然产物结构解析工作中一个重要的手段，能有效提高结构定性的效率！ACD碳谱数据库已经收录了130多万的天然产物及类天然产物的核磁碳谱信息，是目前最大的天然产物核磁碳谱数据库，为天然产物的结构排重、辅助结构鉴定提供了强有力的支持！ 了解更多 2、基于MS数据的天然产物识别 MS Structure ID Suite基于样品组分的高分辨质谱数据，通过Molecules Formula Generator工具快速计算化合物的精确分子组成，结合目前最大的天然产物数据库COCONUT2.0进行检索，并可结合色谱保留时间参数及质谱碎片特征对候选结构进行筛选分析，以获得最优结果。 了解更多 3、人工智能助力天然产物结构解析 ACD/Structure Elucidator软件作为CASE技术应用的佼佼者，经过20多年的技术打磨及功能完善，已经为全球不同领域的用户解决了超过1000多个复杂化合物结构解析的难题，并且接近有100篇文献报道了该软件技术的应用。 另外，基于多谱图同步处理技术(NMR Sync)，ACD软件可帮助我们更快地对整套谱图进行标峰处理；基于Combined Concurrent Verification (CCV)和Unbiased Verification(UBV)技术可实现同分异构体的快速确认。软件可实现一键自动标峰、结构-谱图自动归属验证打分、一键导出详细、专业的报告等功能，为核磁解析的研究者大大提升工作效率！ 了解更多 4、专业的化合物谱图数据库管理平台 对天然产物化学研究领域而言，有效地把已有的化学实验数据(尤其是化学结构、原始谱图文件等)进行电子化储存、管理，无疑对后续的实验有很大的帮助，如实现结构排重、避免重复实验、快速查询数据等。从实验室管理的角度而言，对不同实验人员产生的实验数据电子化储存的规范化、统一化也尤为重要，有利于科研数据的有效积累，形成实验室内部的知识库。ACD/Spectrus平台为此提供了强有力的帮助！ 了解更多 5、基于成药性质的天然产物结构改造  ACD/Percepta从分子结构出发，可快速、准确地预测化合物的物理化学性质、 ADME/Tox 性质。用户也可以基于化合物的 ADME-Tox 性质对先导化合物进行结构优化和设计，从而得到满足成药性要求的目标物，加快新药项目研发。 了解更多 广州凯美科信息技术有限公司是一家以化学信息学软件为核心业务的企业。公司成立于2019年10月，竭诚为国内医药、化工、食品等领域用户提供高质量的化学信息学软件解决方案和技术服务。作为加拿大ACD/Labs公司在国内的合作伙伴，我们在化合物结构鉴定、化学信息管理、色谱方法开发、化合物成药性评价、药物分子设计、分子模拟等方面累积了丰富的服务经验，并且得到广泛好评。 产品包括(点击查看详情)： ✅ 化合物波谱解析系列   ✅ 化合物成药性预测 ✅ 化合物性质预测系列   ✅ 色谱方法开发系列 ✅ 实验室化学信息管理 —————————————————— ✅ 智能解析｜👉 [申请核磁/质谱解析软件演示]✅ 疑难攻坚｜📩 [提交疑难数据，获取专家支援]✅ 购买升级｜💼 [单位采购/版本更新/技术培训] 📢 联系我们：▔▔▔▔▔▔▔▔▔▔▔🧑 产品经理｜胡炽文📲 电话/微信｜18680221948📮 服务邮箱｜hcw@chemico.com.cn🌍 官网直达｜www.chemico.com.cn 扫码咨询

Totality of data supports potential for isaralgagene civaparvovec as a one-time, durable treatment of the underlying pathology of Fabry disease to provide meaningful, multi-organ, clinical benefits above current standards of care STAAR study demonstrated positive mean annualized estimated glomerular filtration rate (eGFR) slope at 52-weeks across all dosed patients in the study, which U.S. Food and Drug Administration (FDA) has agreed will serve as primary basis of approval Isaralgagene civaparvovec showed a favorable safety and tolerability profile Sangamo intends to submit a Biologics License Application (BLA) in 2026 under the Accelerated Approval pathway RICHMOND, Calif., Sept. 04, 2025 (GLOBE NEWSWIRE) -- Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine company, today announced detailed data from the registrational Phase 1/2 STAAR study evaluating isaralgagene civaparvovec, or ST-920, a wholly owned investigational gene therapy for the treatment of adults with Fabry disease. These data were presented at the International Congress of Inborn Errors of Metabolism 2025 (ICIEM2025) in Kyoto, Japan, on September 4, 2025, in a poster presentation (Poster Ref: P-662). These data are also available on Sangamo’s website on the Presentations page. “These STAAR study data demonstrate the potential for ST-920 to provide meaningful clinical benefits to Fabry disease patients,” said Dr John Bernat, M.D., Ph.D., University of Iowa and investigator of the Phase 1/2 STAAR study. “The positive mean eGFR slope at both one and two years, which compares favorably to approved Fabry treatments, alongside stable cardiac function, are exciting developments, particularly given the decline in renal and cardiac function traditionally seen with Fabry patients. The ability for patients to discontinue the use of burdensome enzyme replacement therapies further supports the potential of ST-920 as a single-dose, durable treatment option for people living with Fabry disease.” “Fabry disease is a debilitating and multifaceted condition, for which there is a serious unmet medical need,” said Nathalie Dubois-Stringfellow, Ph. D, Chief Development Officer at Sangamo. “We are excited by the potential of ST-920 to provide long-lasting clinical benefits to a wide range of Fabry disease patients. Improvements in renal function and stable cardiac function, alongside quality of life and additional clinical benefits, show the ability of ST-920 to address the underlying pathology of Fabry disease and provide a potentially transformative treatment for Fabry disease patients. We look forward to sharing these data with health authorities.” Updated Phase 1/2 STAAR Study Results (as of April 10, 2025 cut-off date) Efficacy (32 dosed patients followed at least 12 months) A positive mean annualized eGFR slope of 1.965 mL/min/1.73m2/year (95% confidence interval (CI): -0.153, 4.083) at 52-weeks was observed across all 32 dosed patients. This compares favorably to a meta-analysis of publications of approved Fabry treatments (Fabrazyme, Replagal and Galafold). Furthermore, a mean annualized eGFR slope at Week 104 of 1.747 mL/min/1.73m2/year (95% CI: -0.106, 3.601) was observed for the 19 patients who have achieved 104-weeks of follow-up. Supportive mean annualized eGFR slopes were also observed across a variety of patient subgroups, including gender, baseline ERT status, Fabry disease type and baseline eGFR, showing consistency in effect across Fabry patients in the study. Stable cardiac function was observed, including left ventricular mass (LVM), left ventricular mass index (LVMI), left ventricular myocardial global longitudinal strain (GLS), T1 and T2 mapping, end-diastolic and end-systolic volumes that remained stable over at least one year. Durability of effect was demonstrated with elevated expression of alpha-galactosidase A (α-Gal A) activity maintained for up to 4.5 years for the longest treated patient. All 18 patients who began the study on Enzyme Replacement Therapy (ERT) had been withdrawn from ERT and remained off ERT as of the data cutoff date1. Plasma lyso-Gb3 levels in these patients remained generally stable following ERT withdrawal. Of the 10 patients who had measurable titers of total antibodies (TAb) or neutralizing antibodies (Nab) against α-Gal A associated with ERT at baseline, TAb or NAb titers decreased markedly in nine patients and became undetectable in eight following treatment. Improvements in disease severity were reported in the Fabry Outcome Survey adaptation of the Mainz Severity Score Index (FOS-MSSI) age-adjusted score, with 22 patients showing improvements in their total MSSI score at 12 months and nine patients improving their FOS-MSSI disease category at the last assessment. Statistically and clinically significant improvements in the short form-36 (SF-36) quality of life scores were observed including role-physical +14.8 (95% CI: 7.3, 22.4, p=0.0003), vitality +9.6 (95% CI: 3.9, 15.2, p=0.0017), bodily pain +9.0 (95% CI: 2.3, 15.7, p=0.0104), social functioning +7.8 (95% CI: 2.0, 13.6, p=0.0100), general health +7.4 (95% CI: 2.0, 12.8, p=0.0091), and physical component scores +4.2 (95% CI: 1.8, 6.6, p=0.0014), at week 52 compared to baseline. Statistically significant improvements were seen in the gastrointestinal symptom rating scale (GSRS) compared to baseline. Safety (all dosed patients): Isaralgagene civaparvovec demonstrated a favorable safety and tolerability profile in the study, without the requirement for preconditioning. The majority of adverse events were grade 1-2 in nature. The most common treatment-emergent adverse events (TEAEs) were pyrexia (60.6% of participants), COVID-19 (36.4%), headache (30.3%), and nasopharyngitis (33.3%). All TEAEs resolved in response to clinical management and there were no safety-related study discontinuations and no deaths. Sangamo believes these data support the potential for isaralgagene civaparvovec as a one-time, durable treatment of the underlying pathology of Fabry disease, to provide meaningful clinical benefits above current standards of care and will form the basis for an anticipated BLA submission under the Accelerated Approval pathway as early as the first quarter of 2026. The STAAR study enrolled male and female patients who were either on ERT, were ERT pseudo-naïve (defined as having been off ERT for six or more months), or were ERT-naïve. The median age of patients enrolled in the study was 42, with a median duration of follow-up of 24 months and the longest treated patient having achieved 4.5 years of follow-up. Isaralgagene civaparvovec has been granted Orphan Drug, Fast Track and RMAT designations from the FDA, Orphan Medicinal Product designation and PRIME eligibility from the European Medicines Agency and Innovative Licensing and Access Pathway from U.K. Medicines and Healthcare products Regulatory Agency. Sangamo is advancing BLA preparation activities for isaralgagene civaparvovec, while continuing to engage in business development negotiations for a potential Fabry commercialization agreement. A Current Report on Form 8-K summarizing the Phase 1/2 STAAR study data will be filed by Sangamo, and this press release is subject to the further detail provided in that Form 8-K. About the STAAR Study The Phase 1/2 STAAR study is a global open-label, single-dose, dose-ranging, multicenter clinical study designed to evaluate isaralgagene civaparvovec, or ST-920, a gene therapy product candidate in patients with Fabry disease. Isaralgagene civaparvovec requires a one-time infusion without preconditioning. About Fabry Disease Fabry disease is a lysosomal storage disorder caused by mutations in the galactosidase alpha gene (GLA), which leads to deficient alpha-galactosidase A (α-Gal A) enzyme activity, which is necessary for metabolizing globotriaosylceramide (Gb3). The buildup of Gb3 in the cells can cause serious damage to vital organs, including the kidney, heart, nerves, eyes, gut and skin. Symptoms of Fabry disease can include decreased or absent sweat production, heat intolerance, angiokeratoma (skin blemishes), vision problems, kidney disease, heart failure, gastrointestinal disturbance, mood disorders, neuropathic pain and tingling in the extremities. About Sangamo Therapeutics Sangamo Therapeutics is a genomic medicine company dedicated to translating ground-breaking science into medicines that transform the lives of patients and families afflicted with serious neurological diseases who do not have adequate or any treatment options. Sangamo believes that its zinc finger epigenetic regulators are ideally suited to potentially address devastating neurological disorders. Moreover, Sangamo’s SIFTER capsid discovery platform is advancing delivery to the central nervous system in preclinical studies. Sangamo is also progressing next generation genome editing through its modular integrase (MINT) platform. Sangamo’s pipeline includes multiple partnered programs and programs with opportunities for partnership and investment. To learn more, visit www.sangamo.com and connect with us on LinkedIn and Twitter/X. 1 Since the data cutoff date, a physician has decided to resume ERT for one of their treated patients who had withdrawn from ERT. This patient, who received ST-920 more than two and a half years ago, maintained supraphysiological levels of a-Gal A activity, and their lyso-Gb3 levels were generally stable as of the data cutoff date. Forward-Looking Statements This press release contains forward-looking statements regarding Sangamo’s current expectations. These forward-looking statements include, without limitation, statements relating to: the safety and efficacy and therapeutic and commercial potential of isaralgagene civaparvovec; the potential for isaralgagene civaparvovec to qualify for the FDA’s Accelerated Approval program, including the adequacy of data generated in the Phase 1/2 STAAR study to support any such approval; expectations concerning the potential BLA submission for isaralgagene civaparvovec, and the timing of such submission; Sangamo’s plans to seek a commercialization partner for ST-920; and other statements that are not historical fact. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, risks and uncertainties related to Sangamo’s lack of capital resources and need for substantial additional funding to execute its operating plan and to continue to operate as a going concern, including the risk that Sangamo will be unable to obtain substantial additional funding on acceptable terms or at all or collaboration partners necessary to advance its preclinical and clinical programs, in particular for its Fabry disease program and to otherwise operate as a going concern, in which case Sangamo may be required to cease operations entirely, liquidate all or a portion of its assets and/or seek protection under the U.S. Bankruptcy Code; the uncertain timing and unpredictable nature of clinical trial results, including the risk that the therapeutic effects observed in the latest clinical data from the Phase 1/2 STAAR study will not be durable in patients and that final clinical trial data from the study will not validate the safety and efficacy of isaralgagene civaparvovec, including that the 104-week data from such study will not verify the clinical benefit of isaralgagene civaparvovec or support FDA approval, and that the patients withdrawn from ERT will remain off ERT; the effects of macroeconomic factors or financial challenges, including as a result of the ongoing overseas conflicts, tariffs, geopolitical instability, inflation and fluctuations in interest rates, on the global business environment, healthcare systems and business and operations of Sangamo and its collaborators; the research and development process; the unpredictable regulatory approval process for product candidates across multiple regulatory authorities; reliance on results of early clinical trials, which results are not necessarily predictive of future clinical trial results, including the results of any registrational trial of Sangamo’s product candidates; the potential for technological developments that obviate technologies used by Sangamo; Sangamo’s reliance on collaborators and Sangamo’s potential inability to secure additional collaborations; Sangamo’s ability to achieve expected future financial performance. All forward-looking statements about Sangamo’s future plans and expectations, including Sangamo’s development plans for its product candidates, are subject to Sangamo’s ability to secure adequate additional funding. There can be no assurance that Sangamo and its current or potential future partners will be able to develop commercially viable products. Actual results may differ materially from those projected in these forward-looking statements due to the risks and uncertainties described above and other risks and uncertainties that exist in the operations and business environments of Sangamo and its collaborators. These risks and uncertainties are described more fully in Sangamo’s Securities and Exchange Commission, or SEC, filings and reports, including in Sangamo’s Annual Report on Form 10-K for the year ended December 31, 2024, as supplemented by its Quarterly Report on Form 10-Q for the quarter ended June 30, 2025, each filed with the SEC, and future filings and reports that Sangamo makes from time to time with the SEC. Forward-looking statements contained in this announcement are made as of this date, and Sangamo undertakes no duty to update such information except as required under applicable law. Contacts Investor Relations Louise Wilkie ir@sangamo.com Media Inquiries Melinda Hutcheon media@sangamo.com Source: Sangamo Therapeutics, Inc.