003(Xinchuan Biotechnology)

作者｜知乎@西山含黛   * 后台回复【 ADC定点偶联 】可获取本文相关资料！今天我们讨论ADC的定点偶联。ADC的偶联方式主要分为两大类：随机偶联和定点偶联，定点偶联方式主要包括工程化半胱氨酸的引入、链间二硫键桥接偶联、非天然氨基酸、酶辅助偶联和糖型重塑等。目前，国内采用定点偶联方法构建ADC的(部分)公司包括尚健生物、新码生物、和元艾迪斯、新港生物、百力司康、康源久远、普方生物、爱科瑞思、迈威生物、维立志博等（排名不分先后）。本文我们对他们的ADC定点偶联管线及技术平台进行分析。  01  尚健生物作为创新驱动型生物制药企业致力于创新生物药开发与商业化，聚焦于肿瘤治疗创新型抗体药物开发，并逐步向自免、抗病毒感染等领域拓展，产品管线涉及单抗、双抗(BIMA技术平台)、ADC药物。SG2918 (注射用)是尚健生物自主研发的全球同类首创ADC药物，是其在ADC领域布局的首个项目[1]。SG2918靶向肿瘤免疫治疗的潜力靶点-白细胞免疫球蛋白样受体亚家族B成员4 (Leukocyte immunoglobulin-like receptor subfamily B member 4, LILRB4)，LILRB4在多种肿瘤细胞中表达，包括实体瘤和血液肿瘤[2]。关于SG2918的信息披露较少，其采用定点偶联方式和新型可裂解连接子，有效载荷为微管蛋白抑制剂-MMAE，具备良好的血液稳定性，能介导旁观者效应。该款ADC的作用机制包括ADCC(抗体依赖的细胞毒作用)、T淋巴细胞刺激剂，尝试通过调节机体免疫系统，发挥抗肿瘤效应。SG2918的非临床研究结果显示，其抗肿瘤活性明确，安全性可控；单独给药在多种肿瘤模型中发挥显著抗肿瘤活性，并可与抗PD-1抗体联合应用，协同发挥抗肿瘤活性。2023年7月29日，SG2918临床试验申请获得国家药品监督管理局（NMPA）受理(CXSL2300526)，拟定适应症为恶性肿瘤，该项目是全球同靶点首个申报临床的ADC药物。2023年10月27日，尚健生物首次公示注射用SG2918的国内I期临床试验(CTR20233441)，评估其在晚期恶性肿瘤患者中的安全性、耐受性和初步有效性并探索最大耐受剂量(MTD)和最大给药剂量(MAD)；2023年12月12日，尚健生物在Clinicaltrials.gov网站上注册了SG2918的I期临床试验(NCT06167486)，除涉及其安全性、耐受性和初步有效性评估外，还涉及剂量递增/扩展试验，预计2025年12月初步完成。  02  新码生物为浙江医药下属控股子公司，于2017年初成立，主要致力于生物制品的研发生产，其中涉及ADC的方面包括毒素合成、偶联等。新码生物利用基因密码子扩增技术(genetic code expansion，GCE)向蛋白质中引入含有特殊基团的非天然氨基酸(ncAAs)，对蛋白质进行定点修饰，改变蛋白质的功能、稳定性、半衰期等特征，并可用于创新型生物药的开发。目前，该公司在这方面取得一系列成果，如PEG定点偶联重组人白细胞介素-2 (IL-2)制备长效重组蛋白(CN117417292A)、小分子毒素定点偶联单抗开发ADC等。由此可见，非天然氨基酸具有非常重要的作用和非常广泛的应用领域。专利CN117417292A提供一种含有杂芳基的ncAA (图1A)，其制备重组蛋白时的蛋白表达量更高，利用羟胺和醛基进行偶联(肟化)反应时合成效率也更高，应用性更好，制备工艺简便，无需高昂成本，适宜于大规模生产。利用该方法实现了PEG与IL‑2的精确定点偶联，进而实现了IL‑2在体内半衰期的延长，并且有利于肿瘤的免疫治疗。专利CN113582881B/CN113548984B分别提供了含有苯环、烷基链的ncAA (图1B、C)，利用GCE构建含有特定ncAA的Trastuzumab，通过肟化反应将含有羟胺基团的毒素(DM1‑PEG‑ONH2)引入到抗体构建相应的ADC，与含有ncAA的Trastuzumab相比，ADC的IC50值分别低3、4.5倍，肿瘤杀伤效果得到显著提升。 图1. 专利CN117417292A、CN113582881B、CN113548984B概述新码生物自研管线包括BCN001/002/003，具体细节批露较少；与Ambrx合作研发的ARX-788/305信息披露较多。BCN001靶向HER2，用于治疗HER2+复发性乳腺癌和胃癌等，目前已在国内、新西兰、澳大利亚开展Ⅰ期临床研究，国内已顺利推进至Ⅰ期临床研究后期。ARX-788采用的ncAA为pAF，靶向HER2，通过不可裂解的Linker与AS269偶联，DAR~1.9[3]。2023年3月2日，新码生物宣布ARX-788针对HER2+局部晚期/转移性乳腺癌的II/III期试验ZMC-ARX788-211达到期中分析的界值，可以停止研究；与对照组相比ARX-788可以显著延长PFS，并具有显著的统计学差异。2024年2月2日，浙江医药表示ARX-788的产品进度尚未达到下一个披露里程碑(即“收到药品注册、生产许可”)，公司正在努力推进该产品的上市进程。ARX-305与ARX-788源于同一平台，ARX-305靶向CD70[4]，于2022年10月28日完成国内Ⅰ期临床试验(CTR20222161)首例患者给药(FIH)。  03  烟台市和元艾迪斯生物医药科技有限公司(和元艾迪斯)是和元生物旗下子公司，成立于2018年6月，致力于癌症靶向治疗创新抗体药物的研发，其发展也得到了荣昌生物制药(烟台)有限公司的投资。该公司ADC业务领域主要涉及新型Linker-payload的开发(Zapadcine，扎帕迪尼)，采用二硫键桥接技术构建靶向TRAILR2 (WO2019157973A1)的ADC[5]。专利WO2019157973A1通过二硫基桥接技术构建靶向TRAILR2的Zapadcine-1a/3a (mAb-Py-VC-PAB-MMAD/MMAE)、Zapadcine-1c/3b (mAb-Py-MAA-MMAD/MMAE，图2A)，所选抗体为Zaptuzumab。采用各类TRAILR2高表达的淋巴细胞白血病细胞系(Jurkat E6-1，裸鼠皮下移植瘤)、肺癌细胞系(NCI-H460和NCI-H1975，裸鼠移植瘤)、肝癌细胞系(SMMC-7221，裸鼠移植瘤)、卵巢癌细胞系(A2780，裸鼠移植瘤)和胰腺癌(Mia PaCa-2，裸鼠移植瘤)模型，评估Zapadcine-1a/3a对各类肿瘤细胞和正常细胞的细胞毒作用。Zapadcine-1a/3a在中高剂量组展现出良好的抗肿瘤效果，高剂量组可出现完全缓解的现象(图2B)。在人急性淋巴细胞白血病(ALL)的PDX模型中表现出显著且剂量依赖性地抑制急性淋巴细胞白血病的肿瘤生长，其安全性可以接受。 图2. Zapadcine-1a/1c/3a/3b及其体内抗肿瘤活性(部分)Zapadcine-1a对ALL表现出优异的抗肿瘤活性，但由于MMAD比Auristatin家族的其他成员毒性更大使其安全窗相对较小。经过结构优化与筛选，和元艾迪斯发现了新的候选ADC，Zaptuzumab-Py-VC-PAB-MMAE，命名为Oba01，虽然二硫键桥接认为是定点偶联技术，但Oba01的HIC分析表明其DAR值分布不均一。与Zapadcine-1a相似，Oba01在体外和体内均以剂量依赖性方式显着抑制DR5+淋巴细胞白血病的肿瘤生长；在大鼠和食蟹猴的急性和慢性毒性研究中，与Zapadcine-1a相比，其安全窗明显更大，表明Oba01具有出色的临床前耐受性和良好的安全性[6]。2020年12月7日，Oba01临床试验申请获得国家药品监督管理局（NMPA）受理，Oba01为国内唯一的DR5靶向ADC药物。2023年10月16日，Oba01进行Ⅰ期临床试验(NCT06083870)，用于DR5+转移性非小细胞肺癌(mNSCLC)的治疗，目前处于招募患者阶段。  04  新港生物是上海新理念生物医药科技有限公司的全资子公司(100%持股创建)。自2011成立以来，便致力于肿瘤免疫领域的抗体药物及ADC药物的研发，其定点偶联技术包括BiM (DAR~4)、TriM (DAR~3)、TetraM (DAR~2)技术。BiM技术采用特有的三齿形连接子构建ADC，属于链间二硫键桥接技术。将一个连接子与三齿型连接子偶联得到三齿型连接子-连接子(T-L)，T-L与药物分子(D)偶联得到三齿型连接子-连接子-药物(T-LD)，抗体链间二硫键被还原产生共8个巯基基团，T-LD与还原后的抗体巯基交联，生成部分/全部交联的抗体药物偶联物(图3A)。与Herceptin相比，CN103933575B中所构建的ADC对人乳腺癌细胞株(SK-BR-3)增殖有明显的抑制作用。 图3. 三齿型连接子(A)、四马来酰亚胺型连接子(B)及其ADC的构建应用TetraM技术采用四马来酰亚胺型连接子(CN107652219B，图3B)结构中含有四个马来酰亚胺基团，可以同时偶联抗体(Herceptin类似物，抗体H)链间的Cys残基或其它氨基酸残基，通过简单的化学方法与抗体偶联。与传统的偶联方式相比，应用这种连接子得到的偶联物主要组分为DAR～2的组分(可达90％以上)，DAR值分布非常窄，因此生成的ADC均一性得到了很大程度的提高，利用该方法制备的ADC均具有良好的细胞增殖抑制作用。利用上述两种专利中的方法构建靶向CD79b的ADC药物，通过DAR值的改变评估其抗肿瘤效果(CN111116745B)。其中，AS11259-ADC-001 (三齿型连接子，DAR~4.0)的抗肿瘤活性较优。在此专利中也诞生出NBT508注射液，具体与之呼应的代号笔者不得而知。2021年9月17日，NBT508作为国内首个CD79b靶向新药，其临床试验申请(IND)获得国家药品监督管理局药品审评中心(CDE，NMPA)批准，用于治疗复发/难治性B细胞非霍奇金淋巴瘤，并已启动I期临床试验(CTR20211604)。除NBT508外，新理念生物医药ADC在研管线涉及NBT828 (乳腺癌)、NBT528 (霍奇金淋巴瘤)、NBT558 (小细胞肺癌)、NBT568 (卵巢癌)、NBT578 (肺/胃癌)[7]。  05  百力司康于2017年12月成立，专注于抗肿瘤生物创新药的研发和产业化，其生物创新药临床前研究平台包括先导抗体的设计和筛选、定点偶联抗体的基因工程设计及改造、以及有效载荷及连接子的设计和筛选。百力司康的定点偶联技术可见专利WO2022105873A1，主要是通过基因工程技术将抗体进行改造，在抗体的特定区域引入Cys，后续经还原与抗体进行偶联。该专利涉及两种引入Cys的方法，一是对抗体CH1区域的142位丝氨酸突变成Cys (S142C)；对于IgG2而言，CH1区域的142位为天然Cys。二是在抗体Hinge区域CPPCP序列上游引入一对Cys残基，使得抗体多出一对链间二硫键(HG3)。ELISA实验表明利用该方法构建的工程化抗体对其结合活性不产生影响。在该专利中利用靶向EGFR的工程化抗体BR0301/0302进行ADC的构建，新引入的HG3较其他链间二硫键对还原条件(TCEP)更敏感，使其成为主要的偶联位点，与Mal-PEG2-VC-PAB-Eribulin (艾立布林)偶联得到ADC BB0500-2g/2n，DAR2的ADC占比70-80%；Hinge区域改造的HG3序列经不同的还原和偶联条件可以获得DAR~2主导的ADC产物。BB0500-2f/2g在EGFR高/低表达细胞系(A341/NUGC3)均展现出较强的细胞杀伤作用。百力司康基于专利WO2022105873A1中定点偶联技术构建了多款ADC在研产品，其中BB-1701/1705/1709已进入临床阶段。2023年5月底，BB-1701公布其临床Ⅰ期临床试验(NCT04257110)结果[8]，BB-1701在高达2.6 mg/kg的剂量下通常具有良好的耐受性，并且在HER2过表达实体瘤患者中显示出有希望的抗肿瘤活性；五月初，百力司康宣布与卫材(Eisai)就BB-1701达成具有战略合作选择权的临床试验合作协议。BB-1705于2022年6月开展Ⅰ期临床试验(NCT05217693)，用于局部晚期/转移性实体瘤的治疗，预计2025年底公布临床试验结果。2022年10月27日，BB-1709一期临床试验申请(IND)获得FDA批准；2023年01月28日，BB-1709的IND获得NMPA批准(CXSL2200580)。2023年12月15日，据CDE官网显示靶向HER2的BB-1710获批临床(CXSL2300678)，拟用于治疗局部晚期或转移性实体瘤。  06  普方生物创始于美国西雅图，聚焦实体瘤治疗领域，布局差异化的创新靶向药物ADC和其他抗体类药物。普方生物具有自主研发的新型亲水性载荷连接子Sesutecan，与抗体偶联后产物高度均一(DAR8)。基于专利CN116036303A的内容，笔者认为Sesutecan应是专利中提及的LD038 (图4)，并在专利中公布了其制备方法；除此之外，普方生物自主研发的新型亲水性Linker-drugs (LD)还包括LD163、LD206等。专利CN116036303A通过Trastuzumab与Linker-Payload进行ADC的构建，经TCEP还原后偶联得到Trastuzumab-LD038，经SEC‑HPLC测得Trastuzumab‑LD038的纯度为98％，采用LCMS测得DAR值为8.0。并将Trastuzumab‑LD038命名为PRO1102。利用该专利中构建的ADC对HER2+肿瘤细胞株HCC1954(乳腺癌)、SK‑OV‑3(卵巢癌)、JIMT‑1(乳腺癌)和Capan‑1(胰腺癌)小鼠异种移植模型中进行体内抗肿瘤活性研究，相比于trastuzumab‑deruxtecan (8, DAR~6.5)、trastuzumab‑emtansine (4, DAR~4.1)、trastuzumab‑vedotin (4, DAR~3.7)，PRO1102在多个肿瘤模型中显示出更强的肿瘤抑制效果(图4B)。以上数据PRO1102，在不改变抗体亲和性的基础上，提高了ADC对肿瘤靶细胞的杀伤力。 图4. PRO1102结构及其活性评价(部分)此外，PRO1102在具有中度和低度HER2表达的癌细胞中保有活性，这表明其有可能使更广泛的HER2表达癌症患者受益。在大鼠中评估了PRO1102的药代动力学，PRO1102在循环中稳定，其分布与亲本抗体相似；在小鼠中评估了耐受性，在与有效的抗肿瘤活性相关的PRO1102剂量水平下，PRO1102具有良好的耐受性[9]。目前，PRO1102处于临床前研究阶段，披露信息较少，且官网在研管线中并未公布，期待后续能有较好的研究结果。  07  爱科瑞思(Adcoris)成立于2021年5月，专注于开发新一代ADC及AXC疗法的临床阶段生物制药公司，以满足肿瘤学和自身免疫性疾病领域未满足的需求。Adcoris的尖端新药研发平台由三大支柱组成：专有的高活性有效负载(PHAP™)，可裂解的柔性连接子(CLEFS™)、多功能位点特异性缀合(MuSC™)，加速ADC产品的开发与转化。专利CN107029244B公布该公司靶向HER2的ADC-ZV0203 (ADC2122)的构建方法，该专利原始申请人为浙江昭华生物医药有限公司。经K-Lock技术将帕妥珠单抗(Pertuzumab)与高活性微管蛋白抑制剂DUO5通过缬氨酸-瓜氨酸二肽连接子定点偶联，该偶联方法利用抗体分子中赖氨酸上氨基残基进行成酰胺反应制备ADC，所得ZV0203的DAR为2，分布均一(图5A)。经肽图分析发现采用K‑lock方法偶联的ADC，其Payload主要偶联于抗体轻链恒定区的第81位赖氨酸。体内活性研究表明，ZV0203对小鼠体内BT474乳腺癌、Calu‑3肺癌移植瘤的抑制效果明显，疗效优于已经上市的T‑DM1 (图5B)。 图5. ZV0203结构及其抗肿瘤活性研究爱科瑞思在2023 ESMO会议中公布ZV0203的初步Ⅰ期临床试验数据(NCT05423977)。作为全球首款获批临床的帕妥珠单抗ADC，ZV0203在HER2高表达的肿瘤患者中，在中等及以上剂量水平(2.7 mg/kg、3.6 mg/kg)具有良好的安全性、耐受性和抗肿瘤活性[10]。目前，该项目即将进行Ⅰb/Ⅱa临床剂量拓展研究。  08  迈威生物创始于2017年，以抗体药物靶点发现与分子发现为起点，覆盖成药性研究、临床前研究、临床研究和生产转化等药品研发全周期的创新体系。其中，ADC药物开发平台依据两项第三代抗体偶联药物技术而构建，即桥连定点偶联技术和分散型定点偶联技术(CN108101825B、CN109810039B)。IDDC™ (Interchain-Disulfide Drug Conjugate)是迈威生物自主开发的新一代定点偶联技术平台，由定点偶联工艺DARfinity™、定点连接子接头IDconnect™、新型载荷分子Mtoxin™以及条件释放结构LysOnly™等多项系统化核心专利技术组成(图6)。相比随机偶联技术，该类偶联技术偶联过程可靠，偶联产物更加均一，反应后经纯化获得的抗体偶联物终产品优于其他桥连定点技术开发的ADC药物，且与其他类型的抗体偶联药物相比具有更优的药代动力学和药理毒理特征。 图6. IDDC™技术平台针对肿瘤领域，迈威生物开发多款ADC产品，包括9MW2821、9MW2921、7MW3711等。其中，9MW2821基于IDDC™开发，Payload为MMAE[11]；具有良好的肿瘤结合能力及靶向特异性，以及更加均一的组分，更加均一稳定的结构，更加优异的肿瘤递送能力。作为国内首个、全球第二个获批进入临床试验靶向Nectin-4的ADC创新药，其研究进展较快。2024年1月9日，迈威生物开展9MW2821的Ⅲ期临床试验(NCT06196736)，在既往接受过PD-(L)1抑制剂和含铂化疗的局部晚期或转移性尿路上皮癌患者中评估9MW2821与化疗的研究。靶向Trop-2的ADC创新药9MW2921于2023年八月进行Ⅰ/Ⅱ期临床试验(NCT05990452)，用于晚期实体瘤的治疗。2024年2月18日，迈威生物宣布靶向B3-H3的ADC创新药7MW3711临床试验申请正式获得FDA的批准，可针对晚期恶性实体瘤患者开展临床试验；此前，7MW3711已在国内开展临床试验(CTR20232441)，评估其在晚期实体瘤患者中的安全性和耐受性，确定最大耐受剂量(MTD)和/或II期推荐剂量(RP2D)，并初步评估在选定瘤种中的有效性。  09  维立志博成立于2014年，致力于具有自主知识产权的治疗肿瘤和其他重大疾病的抗体新药研发，目前已经拥有二十多个新型肿瘤免疫、自免、ADC治疗抗体项目组成的丰富研发管线。公司官网仅公布了单抗、双抗的研发管线，针对ADC领域的研究管线未予披露。专利CN110577600B公布了维立志博ADC的构建方法-链间二硫键桥接技术(图7)。采用新型双取代马来酰亚胺连接子将强细胞毒活性Payload和抗抗磷脂酰肌醇聚糖蛋白3(GPC3)的抗体(GPC3‑6)进行偶联得到GPC3‑6‑BL20E。该类连接子可选择性与二硫键同时作用，从而大大提高偶联物的物质均一性。细胞实验表明GPC3‑6‑BL20E对人肝癌细胞(HepG2、Huh‑7、SMMC‑7721)、人乳腺癌细胞(MDA‑MB‑231、MDA‑MB‑486)、人肺癌细胞NCI‑H1975、卵巢癌细胞SKOV‑3和人肾腺癌细胞786‑O均能产生抗肿瘤细胞增殖活性，且比未偶联的GPC3‑6更为有效的抑制表达GPC3受体的细胞增殖。后续，随着研究的进展，GPC3‑6‑BL20E应该会有更多的信息披露。 图7. 专利CN110577600B简述免责声明：本文仅作信息交流之目的，文中观点不代表个人立场，亦不代表个人支持或反对文中观点。本文并非治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。欲有所明，终有所蔽。欢迎各位批评指正(dyc21@mails.tsinghua.edu.cn)，谢谢！ 主要参考文献 1. https://www.sumgenbio.com/?c=Service&a=nav&id=347.2. Yang, T., et al., LILRB4, an immune checkpoint on myeloid cells. Blood Sci, 2022. 4(2): p. 49-56.3. Skidmore, L., et al., ARX788, a Site-specific Anti-HER2 Antibody-Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1-resistant Breast and Gastric Cancers. Mol Cancer Ther, 2020. 19(9): p. 1833-1843.4. Skidmore, L., et al., Preclinical characterization of ARX305, a next-generation anti-CD70 antibody drug conjugate for the treatment of CD70-expressing cancers. Brain, 2023. 65: p. 0.040.5. Zhang, S., et al., A novel anti-DR5 antibody-drug conjugate possesses a high-potential therapeutic efficacy for leukemia and solid tumors. Theranostics, 2019. 9(18): p. 5412-5423.6. Zhang, S., et al., Preclinical evaluation of a novel antibody-drug conjugate targeting DR5 for lymphoblastic leukemia therapy. Mol Ther Oncolytics, 2021. 21: p. 329-339.7. http://www.newbiotherapeutics.com/list/?26_1.html.8. Ma, F., et al., A first-in-human, open label, multiple dose, dose escalation, and cohort expansion phase I study to investigate the safety, tolerability, pharmacokinetics and antitumor activity of BB-1701 in patients with locally advanced/metastatic HER2-expressing solid tumors. 2023, American Society of Clinical Oncology.9. Wang, L., et al., Abstract 1758: The preclinical pharmacology of PRO1102, a novel exatecan-based HER2-directed antibody-drug conjugate with robust anti-tumor activity. Cancer Research, 2022. 82(12_Supplement): p. 1758-1758.10. Lin, F., et al., 438P Phase I study of ZV0203, a first in class pertuzumab ADC, in patients with HER2+ advanced solid tumors. Annals of Oncology, 2023. 34: p. S365.11. Zhou, W., et al., Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers. Molecular Cancer Therapeutics, 2023. 22(8): p. 913-925.  2024活动预告  3月8-9日，XDC唯新不破！2024 BiG ADC专题研讨会  关键词：  临床适应症拓展；靶点&立项；双抗ADC；联用策略；下一代linker-payload；核药▼▌更多分享嘉宾即将揭晓参会注册▼会议门票：审核制(免费)；含1场主论坛+4场分论坛，不含餐晚宴门票：费用：2800元/人；含1场主论坛+4场分论坛，3月8日晚宴、3月9日午餐会员/特邀：审核制(免费，仅限BiG会员/特邀嘉宾)；权益同晚宴门票共建Biomedical创新生态圈！如何加入BiG会员？

- Supply agreement supports Viridian’s development of potential first- and best-in-class subcutaneous therapies for treatment of thyroid eye disease (TED) - - Ypsomed brings strong track record of drug-device combination approvals engineered with its proprietary YpsoMate self-injection technology - WALTHAM, Mass.--(BUSINESS WIRE)-- Viridian Therapeutics, Inc. (NASDAQ: VRDN), a biotechnology company focused on discovering and developing potential best-in-class medicines for serious and rare diseases, and Ypsomed AG (SIX: YPSN), the leading developer and manufacturer of injection and infusion systems for self-medication have signed a supply agreement for Ypsomed’s customizable YpsoMate 2.25 autoinjector pen device with a fill volume of 2.0 milliliters. As part of the agreement, Ypsomed will customize and supply YpsoMate 2.25 patient-administered delivery devices to support Viridian’s development of investigational subcutaneous therapy candidates for the treatment of thyroid eye disease (TED). “Developing a subcutaneous therapy is an essential part of our vision to offer the most comprehensive set of therapeutic options to the TED community. Following our lead intravenous candidate, a subcutaneous therapy would bring much needed convenience to care givers and patients while potentially expanding the TED medicines market,” said Scott Myers, President and CEO of Viridian. “Thus, it’s critical that we continue to improve our therapy by packaging it in a delivery device that is as convenient and user-friendly as possible. We engaged in a rigorous selection process and concluded that, based on its strong track record of drug-device combination approvals in multiple disease areas, Ypsomed is the ideal partner to supply such a device. We’re very much looking forward to working with them.” “We are very pleased that, together with Viridian, we may provide people affected by TED access to an innovative drug,” said Ulrike Bauer, Chief Business Officer Delivery Systems at Ypsomed. “It shows that with our platform approach, we are able to quickly and efficiently customize autoinjectors that optimally support users in the administration of their medicine.” About Viridian’s Thyroid Eye Disease Pipeline (VRDN-001, -002, and -003) Viridian’s lead product candidate, VRDN-001, is a differentiated monoclonal antibody targeting the insulin-like growth factor-1 receptor (IGF-1R), a clinically and commercially validated target for the treatment of thyroid eye disease (TED). In preclinical studies, VRDN-001 was shown to be a full antagonist of IGF-1R, with more complete receptor blockade than other anti-IGF-1R antibodies, including the only currently approved TED therapy. Data from the Phase 2 portion of the ongoing trial established clinical proof-of-concept for VRDN-001 delivered intravenously (IV) in patients with active and chronic TED. VRDN-001 was generally well tolerated in the trial. The THRIVE Phase 3 trial in patients with active TED is ongoing, and the Company is currently recruiting for its second Phase 3 trial, called THRIVE-2, in patients with chronic TED. The Company is also advancing three candidates (VRDN-001 SC, VRDN-002, and VRDN-003) designed for administration as a convenient, low-volume, subcutaneous (SC) injection for the treatment of TED. Viridian’s goal is to bring a best-in-class IV therapy followed by a first- and best-in-class SC therapy to the market for the treatment of the TED. VRDN-001, -002, and -003 are investigational therapies that are not approved for any use in any country. About TED TED is a serious and debilitating rare autoimmune disease that causes inflammation within the orbit of the eye that can cause double vision, pain, and potential blindness. TED is a progressive disease consisting of an initial active phase, followed by a transition to a secondary chronic phase. According to estimates, more than 50,000 and 200,000 people suffer from active and chronic TED, respectively, in the United States and Europe. About Viridian Therapeutics Viridian Therapeutics is a biopharmaceutical company focused on engineering and developing potential best-in-class medicines for patients with serious and rare diseases. Viridian’s expertise in antibody discovery and engineering enables it to develop differentiated therapeutic candidates for previously validated drug targets in commercially established disease areas. Viridian is advancing multiple candidates in the clinic for the treatment of patients with thyroid eye disease (TED). The Company is conducting two global Phase 3 trials called THRIVE and THRIVE-2 to evaluate the safety and efficacy of VRDN-001 in patients with active or chronic TED. In addition to its program for intravenously administered VRDN-001, the Company is advancing three candidates for its subcutaneous strategy with the goal of providing a more conveniently administered therapy to patients with TED. Viridian is also developing multiple preclinical assets in autoimmune and rare diseases. Viridian is based in Waltham, Massachusetts. For more information, please visit . Follow Viridian on LinkedIn and twitter. About Ypsomed AG Ypsomed is the leading developer and manufacturer of injection and infusion systems for self-medication and a renowned diabetes specialist with over 35 years’ experience. As a leader in innovation and technology, it is a preferred partner of pharmaceutical and biotech companies for pens, autoinjectors and pump systems for administering liquid medications. Ypsomed presents and markets its product portfolios under the umbrella brands mylife Diabetescare directly to patients or via pharmacies and hospitals as well as under YDS Ypsomed Delivery Systems in business-to-business operations with pharmaceutical companies. Ypsomed has its headquarters in Burgdorf, Switzerland, and operates a global network of manufacturing sites, subsidiaries, and distributors. The Ypsomed Group employs over 2,200 employees. For more information, please visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of words such as, but not limited to, "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "might," "plan," "potential," "predict," "project," "should," "target," "will," or "would" or other similar terms or expressions that concern our expectations, plans and intentions. Forward-looking statements include, without limitation, statements regarding our expectations, strategies, plans and intentions. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations, and assumptions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Such forward-looking statements are subject to a number of material risks and uncertainties including but not limited to: the potential efficacy and safety of VRDN-001, VRDN-002, and VRDN-003 for the treatment of Thyroid Eye Disease (TED), the results of ongoing or future clinical trials; the timing, progress and plans for our ongoing or future research, pre-clinical and clinical development programs; including the clinical trials for VRDN-001, VRDN-002, and VRDN-003, our ability to develop a subcutaneous formulation (SC); our plan regarding a lead SC candidate and our expectations regarding a delivery device supply partnership and other risks and uncertainties, including those risks set forth under the caption "Risk Factors" in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 8, 2023 and other subsequent disclosure documents filed with the SEC. Any forward-looking statement speaks only as of the date on which it was made. Neither the Company, nor its affiliates, advisors, or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date hereof.