Brain Abscess

摘要：为应对由大流行引起的紧迫性，COVID-19疫苗被迅速开发并获得批准。当时市场上没有特定的法规。因此，监管机构紧急适应了这些疫苗。现在大流行的紧急情况已经过去，是时候考虑与这种快速批准相关的安全问题了。COVID-19 mRNA疫苗的作用机制应将其归类为基因治疗产品（GTPs），但监管机构已将其排除在外。作为疫苗，它们已经接受的一些测试在纯度、质量和批次均质性方面产生了不符合标准的结果。由于它们被归类为疫苗，mRNA及其蛋白质产品的广泛和持久的生物分布尚未完全研究，这引发了安全问题。上市后研究表明，mRNA能够进入母乳，可能对母乳喂养的婴儿产生不良影响。鉴于药物警戒数据库中报告的不良事件，应研究长期表达、基因组整合、向生殖细胞系的传递、精子、胚胎/胎儿和围产期毒性、遗传毒性和致癌性。还应对潜在的水平传播进行评估。应进行深入的疫苗警戒。我们期望这些控制措施对于在非大流行背景下开发的未来的mRNA疫苗是必需的。 1.引言 药品和疫苗的监管是一个鲜为人知但非常重要的课题。事实上，作为一项原则，健康产品必须经过非常严格的控制，以控制其有效性和安全性。抗COVID-19 mRNA疫苗是市场上的首批mRNA疫苗。mRNA疫苗代表了一类新型疫苗，应该比传统疫苗接受更多的控制，因为它们基于几种新技术。尽管定义不完全，mRNA疫苗的作用机制应该将它们归类为基因治疗产品（GTP）。但是，作为针对传染病的mRNA疫苗已被美国和欧盟法规排除在GTP监管之外。2020年之前没有针对mRNA疫苗的具体法规。“当前的指南要么不适用，要么没有提及RNA治疗，要么没有广泛接受的定义”。因此，监管机构不得不采取紧急程序来监控这些产品的测试，即滚动审查。在滚动审查中，数据在完整数据包可用之前就可以提交和审查，并且已经要求对这一新平台进行特定控制。本研究的目的是将GTP法规要求的控制措施与实际应用于mRNA COVID-19疫苗的控制措施进行比较。一些GTP所需的控制措施可能没有用于mRNA COVID-19疫苗，可能是因为需要迅速开发SARS-CoV-2疫苗的大流行紧急情况。将讨论由于缺少这些控制而可能出现的潜在安全问题。这一点尤为紧迫，因为制造商计划用mRNA疫苗替换某些“经典”疫苗，从流感疫苗开始。事实上，赛诺菲正在启动首个基于mRNA的季节性流感疫苗候选产品的临床试验，Moderna正在进行多项mRNA疫苗的临床试验（COVID-19、流感、人类偏肺病毒、副流感、RSV、HCoV、CMV、EBV、HSV、水痘、疱疹、HIV、寨卡病毒、尼帕病毒），特别是流感疫苗的3期试验。正在进行一项针对mRNA-LNP流感疫苗的1期临床试验。对于这些流感疫苗，不应适用紧急批准，也不应超出这些额外研究的要求。此外，正在宣布癌症“疫苗”（例如，Moderna和默克正在合作试验mRNA-4157/V940，一种与Keytruda——一种针对程序性细胞死亡受体PD-1的单克隆抗体结合使用的抗黑色素瘤“疫苗”）通过增强人体免疫系统检测和抗击肿瘤细胞的能力，通过阻断PD-1与其配体PD-L1和PD-L2之间的相互作用，从而激活抗T细胞反应，特别是抗肿瘤反应。我们必须对与治疗药物相关的疫苗一词非常警惕，特别是关于适用于它们的法规。这些治疗药物不是针对传染病的疫苗，因此必须继续遵守GTP法规。 2.抗COVID-19 mRNA的当前监管 2.1. mRNA抗COVID-19的作用机制将它们定义为GTP及其作为疫苗的命运 尽管定义不完全，mRNA疫苗的作用机制应该将它们归类为基因治疗产品（GTP）；它们是核酸，旨在使疫苗接种者的细胞产生抗原，诱导产生抗体。这种作用机制与监管机构对GTP的定义完全对应。根据EMA CHMP报告（人类用药产品委员会）：“活性成分由mRNA组成，翻译成SARS-CoV-2的刺突蛋白抗原；LNP保护RNA并在肌肉注射后使宿主细胞转染；S蛋白诱导适应性免疫反应”。根据FDA，基因治疗是基于改变活细胞的遗传物质的医疗干预。细胞可以通过直接给予受试者的基因疗法在体内改变。根据EMA 2009，GTP：(a)包含一种活性成分，该成分包含或由用于或施用于人类的重组核酸组成，目的是调节、修复、替换、添加或删除遗传序列；(b)在其治疗、预防或诊断效果中，直接与其所包含的重组核酸序列或该序列的遗传表达产物有关。但mRNA也符合疫苗的定义；然而，在某种程度上存在不兼容性。2005年WHO指南授予基于核酸的疫苗疫苗地位（“在接种活载体或核酸或体外化学合成的抗原后，在接种宿主内体内产生的抗原”）。根据法国国家药品安全局（ANSM，Saint-Denis，法国）的定义，疫苗是一种预防性药物，由一个或多个称为抗原的生物来源活性成分组成，用于预防疾病。根据CDC，疫苗是一种用于刺激身体对疾病的免疫反应的制剂。根据欧洲法规，疫苗是能够产生主动免疫的产品，包含能够诱导对传染病原的主动免疫的抗原。根据EMA，COVID-19辉瑞疫苗的活性成分是mRNA：它不是抗原。因此，根据欧洲和法国药典，mRNA不应被视为疫苗，因为它们不包含抗原。 此外，根据它们的作用机制，mRNA疫苗可以被视为前药；这是模仿前药一词的新词，前药指的是一种药物，经过给药后，会被生物体转化为药理活性药物。事实上，根据mRNA的原理，它必须被接种疫苗者的细胞翻译成蛋白质（注射的物质不是引起主动免疫的物质）。根据FDA，mRNA疫苗对应于前药的第一类，即被细胞转化为活性药物的物质。这种前药属性可能意味着除了疫苗外还需要额外的控制措施。然而，FDA和EMA都没有对mRNA抗COVID-19疫苗的这些资质做任何引用。 2.2. 作为针对传染病的疫苗，mRNA已被美国和欧盟法规排除在GTP监管之外 1998年，FDA已经声明，用作预防性疫苗的重组DNA材料不包括在基因治疗指导中。2007年，FDA根据DNA质粒疫苗是否用于预防传染病来区分它们；没有用于传染病预防的DNA质粒受到基因治疗产品的监管，而针对传染病的DNA质粒疫苗则受到另一套法规的监管，该法规受到GTP法规的启发。2013年，FDA确认基因治疗产品的监管不适用于针对传染病的疫苗。在1996年关于用于预防传染病的DNA质粒的文件中，明确指出（与所有FDA指南一样）没有建立后续要求：这些是非约束性的建议。因此，本研究将主要基于EMA文件；尽管EMA指南没有法律约束力，申请者需要为任何偏离提供理由。 根据EMA，自2009年以来，“基因治疗药品不应包括针对传染病的疫苗”。这一排除在2015年得到确认。有关预防传染病的核酸法规的历史，见表1。这种排除带来了一个逻辑问题，因为并非所有基于RNA的产品都具有相同的监管地位，正如Guerriaud和Kohli所指出的。 2.3. 需要强调立法的矛盾 根据欧盟（EU）立法，基于RNA的药物目前可以根据不同的监管地位进行分类，对于疫苗来说，取决于它们的目标（是否针对传染病），对于其他药物，则取决于它们的获取方式（化学或生物学）。这种分类决定了为获得市场授权必须进行的控制和研究。因此，针对传染病的mRNA疫苗不被视为基因治疗产品（第162页）和，而用于治疗癌症的mRNA疫苗是GTMPs（基因治疗药品，是ATMPs，先进治疗药品的一部分）；事实上，根据CAT（先进疗法委员会），mRNA是GTMPs，因此必须进行完整的药代动力学研究。 因此，Moderna和BioNTech期望它们的产品被监管为基因疗法是令人惊讶的。Moderna公司在其2020年第二季度证券交易委员会（SEC）文件中承认，“目前，FDA认为mRNA是基因治疗产品”。此外，BioNTech创始人Ugur Sahin在2014年的一篇文章中表示，“可以预期mRNA药物的分类是生物制品、基因疗法或体细胞疗法”。因此，COVID-19 mRNA疫苗的地位制造商自己也没有很好地理解。 EMA法规必须参考WHO关于疫苗非临床评估的指南。根据EMA，“与欧盟指南不同，WHO指南还包括含有活载体或核酸的疫苗。这被认为是适当的，因为许多需要解决的非临床方面对于传统疫苗和含有活载体或自由DNA的疫苗是共同的”。这与EMA在2016年同一份文件中指定的从GTP法规中排除核酸疫苗相矛盾，因为EMA指出，核酸疫苗的特定方面必须根据GTP法规进行研究。 2020年，WHO指出了管理mRNA疫苗法规的不明确性。为解决这一监管问题，WHO于2020年12月20日发布了一份指导文件草案，用于评估mRNA疫苗的质量、安全性和有效性，其中包括疫苗的制造和控制以及它们的非临床评估。WHO承认，COVID-19 mRNA疫苗的生产详细信息尚不可用。此外，基于基因的生物制品的安全性和有效性控制尚未标准化，一些细节仍然是专有的，并未公开披露。鉴于这些不确定性，WHO认为不可能制定具体的国际指南或建议，需要一些监管灵活性。 2.4. 为什么mRNA疫苗被排除在基因产品监管之外？ 根据Guerriaud和Kohli，“很难确切回答为什么针对传染病的疫苗被排除在外。疫苗的定义自1975年以来没有改变，那个时期还没有针对癌症的‘疫苗’”；它们是能够产生针对传染病的主动免疫的药剂。当时，唯一存在的疫苗是针对传染病的疫苗，目前对疫苗的定义仅限于针对传染病的免疫药物。因此，一种抗癌药物绝不能被称为“疫苗”。值得注意的是，基于慢病毒的治疗性艾滋病疫苗，作为基因疗法，因为它们整合到基因组中，也被排除在基因疗法之外。可以假设申请人认为该产品既有治疗作用又有预防作用，但文件在EMA网站上不可用。 从公共卫生的角度来看，并且知道被视为疫苗的抗COVID-19 mRNA没有经过GTP所需的所有严格控制（见下文），人们可能会反对说，针对世界上大多数健康人群的产品应该比针对少数罕见疾病或癌症患者（这次涉及数百万人）的GTP受到更严格的监管。此外，根据EMA，“由于疫苗在大多数情况下是给予大量健康个体的，因此需要进行扎实的非临床安全评估”。 这种排除可能有监管解释；这个决定部分是因为疫苗的作用机制与其他药品非常不同，部分是为了确保所有疫苗都由同一个委员会审查（人类用药产品委员会—CHMP），EMA的疫苗专家（疫苗科学咨询小组（SAG-V））和疫苗工作组。 2.5. 作为疫苗考虑的mRNA所需的控制措施 疫苗通常属于EMA定义的人用药物，因此必须经过这些产品的相应控制；药品的监管涉及良好生产规范（GMP）。这些GMP在2001年的EMA文件中详细说明，并在2012年更新，适用于包括疫苗在内的所有人用药物（第117页）。这些GMP涉及，除其他外，对于临床前研究的环境风险评估、产品和原料的特性（纯度和质量）、它们的控制和稳定性、生产方法、药理学研究（例如，定量组成、生产过程描述、药典中未列出的原料、活性物质的鉴定和检测、作用机制、生物活性的体外或体内测试—如果成品中无法检测—毒性、致癌性、生殖和胚胎/胎儿毒性、药代动力学、药效学—药物对生理学的修改—有效性和产品安全性）。对于新的辅料，化学、制药和生物学信息应与活性物质提供的信息相同（第135页）。WHO对一般疫苗推荐相同类型的控制。 有关产品质量、纯度、稳定性、生产方法、生殖和胚胎/胎儿毒性以及致癌性的GMP将在下文讨论。尽管这些GMP适用于所有人用药物，但通常不适用于疫苗。 药代动力学是生物体对药物的作用，即药物的命运，从其进入生物体到离开，其吸收、生物利用度、分布、代谢和排泄随时间的演变。“通常不需要对疫苗进行药代动力学研究。然而，当使用新的给药系统或疫苗含有新型佐剂或辅料时，可能适用此类研究”。根据2016年的文件，对于EMA，规定应遵循WHO的规定。WHO指南明确指出，药效学研究也可能扩展到佐剂的药理学，并且在新配方的情况下必须考虑分布研究。当使用新的添加剂时，如果其毒理学数据不可用，则应首先对单独的添加剂进行毒性研究，并将结果按照新化学实体的指南进行记录。 EMA还要求对使用新配方的疫苗进行额外研究；2006年的文件适用于“表达外来抗原的DNA疫苗”，指出“通常不需要对疫苗进行药代动力学研究。然而，当使用新的给药系统或疫苗含有新型佐剂或辅料时，可能适用此类研究”。这份文件是在将针对传染病的核酸疫苗从GTP法规中排除之前制定的。我们将看到，为抗COVID-19 mRNA提供的药代动力学研究是不完整的。 2.6. 作为前药所需的控制 FDA指出，前药因其或多或少完全转化为活性物质以及毒性问题而带来的特殊问题。根据FDA，需要定义前药如何显著地为活性药物的毒性概况做出贡献，特别是作为转化和作用部位的函数。 对于mRNA疫苗，生物学转化发生在许多细胞类型和所有器官中（见下文），而期望的目标，即免疫，只会在免疫细胞中发生。然而，mRNA疫苗没有被归类为前药，因此不必经过有关转化和作用部位的控制。 2.7. 基于GTP法规的额外控制 鉴于大流行紧急情况，疫苗审查流程已被修改和加速，以滚动审查的形式进行。在滚动审查中，数据在完整数据包可用之前就可以提交和审查。这种方法需要赞助商和卫生当局之间更紧密的合作和更密集的互动。从EMA报告中可以推断，EMA已经调整了疫苗法规，并要求某些特定于基因治疗产品的控制。这是从Moderna的EPARs和辉瑞的滚动审查的分析中得出的。 尽管没有针对mRNA疫苗的具体法规，EMA还是增加了以下产品质量控制：通过RT-Sanger测序确定身份（对于Spikevax）和下一代测序（对于Comirnaty）；总RNA含量（UV）、纯度（RP-HPLC）；产品相关杂质（RP-HPLC）；50%盖帽的百分比（RP-UPLC）；PolyA尾RNA的百分比（Spikevax的RP-HPLC，Comirnaty未完全描述）和残留DNA模板（qPCR）。 然而，根据2021年的报告，第一份报告中报告的一些特定义务（例如，未描述的作用机制）尚未完成。关于杂质，应指定细菌内毒素的测定方法。在澳大利亚监管机构TGA的文件中未指定发现的内毒素水平，一些批次在批次发布时仍在评估中。接受的限制是12.5 EU/mL。 关于产品质量，体外转录方法描述不足，mRNA的特性不令人满意；评估截短和修饰mRNA的方法必须更详细。效力测试不满意，体外表达测试需要更新。如果Poly(A)尾的长度和百分比部分保持不变，REC20未完成。如果提供了3个月的稳定性数据，期望6个月的数据，截短的mRNA和截短的蛋白表达的存在没有得到充分的探索。EMA要求澄清作用机制。 因此，根据EMA报告，EMA要求的GTP所需控制的结果不充分。 3.抗COVID-19 mRNA未受GTP法规约束所需的控制  3.1. 产品质量 关于产品质量，基因治疗产品（GTPs）需要经过特定控制，这些控制对于非基因药物并未提及。在这些控制中，内毒素水平没有具体提供（见上文），并且核酸与载体的相互作用也没有被研究。应通过适当的方法确认特定特征的存在/缺失，例如CpG序列：这一点没有提供。产品相关杂质（删除、重排、杂交或突变序列、氧化、脱聚）的研究和定量没有提供。在最终的基因治疗药物产品（GTMP）中应尽可能避免使用抗生素抗性基因，如果不可避免，应提供理由（这一点没有理由）。“如果不可避免，在首次临床研究之前，应进行研究，以解决抗性基因在人体细胞中的非预期表达”；这些研究尚未进行。 关于美国FDA，应参考负责监管这些产品的CBER（生物制品评估和研究中心）指南，它只发布非约束性建议，以及2013年的指导，总体上，它对EMA施加了相同的标准。 3.2. 药代动力学 根据欧盟，GTMP需要特定的测试或试验来评估基因组整合和生殖系传播的风险，即使这种整合不太可能，就像RNA的情况一样。GTMP需要特定的测试或试验来评估插入性突变、致癌性、胚胎/胎儿和围产期毒性以及长期表达的风险，这些测试尚未进行。 对于GTMP，EMA要求对核酸和载体颗粒/输送系统进行广泛的研究，包括生物分布、剂量研究、潜在目标毒性、确定获得生物活性的目标器官、与结构改变蛋白表达相关的毒性、生殖毒性（对于这些研究，测试必须遵循ICH M3文件）、重复毒性和环境中的排泄。这些研究对于含有DNA的产品是必需的，因为该文件是在2006年起草的，当时没有考虑mRNA疫苗。重复毒性没有得到充分的研究，因为只计划了两次疫苗剂量。必须强调药代动力学研究，这些研究通常对疫苗不是必需的，除非它们基于新配方或疫苗含有新型佐剂或辅料。这种研究的需求必须由监管当局逐案评估。此外，“标准的吸收/分布/代谢和排泄研究对GTMPs可能不相关”。例如，应考虑作为最坏情况的给药途径（例如，静脉注射，代表GTMP广泛传播的效果）。对于GTPs，预期进行脱落研究，解决在体内的排泄和传播，包括持久性、清除和动员的研究。生物分布研究还应解决转基因产品的药代动力学研究（例如，表达的蛋白）。从这个角度来看，制造商提供的研究似乎是不完整的（见第4节）。 3.3. 未进行生物药品控制 EMA和欧盟委员会一样，认为“RNA衍生产品应被视为生物产品，即使它们不是来自生物来源”。根据欧洲法规，对于生物药品，必须提供生物活性列表，并且必须考虑生殖功能、胚胎胎儿和围产期毒性以及突变和致癌潜力的研究。正如上文所见，这些测试尚未进行，并且活性成分—mRNA—的生物活性没有得到充分的描述。 3.4. 临床研究 在动物模型中进行脱落研究（通过分泌物和排泄）将用于估计人类脱落的可能性和程度，并指导设计临床脱落研究。如果基因产品是一种在血液循环中排泄的蛋白质，则应包括临床药代动力学研究。需要调查向第三方传播的可能性，或者提供不这样做的理由。应评估剂量反应效应。对于GTP，还必须解决精液中的脱落问题；监管机构的报告中没有提到这种可能的排泄。 应仔细评估遗传毒性问题，包括插入性突变和随后的致癌性，在相关的体外/体内模型中。免疫抑制，人类肿瘤发生的一个原因，必须进行调查。根据Spikevax EPAR，没有提交致癌性、插入性突变或体内研究中的肿瘤发生性。如果育龄期妇女将暴露于GTMP，则可能需要胚胎胎儿和围产期毒性研究。 3.5. 疫苗警戒 根据EMA，GTMP有义务在药品过期后30年内提供安全性和有效性数据，这超出了传统药物警戒的要求。根据FDA对GTP的法规，对于新的临床疾病，如新的恶性肿瘤、现有神经系统疾病的新发生或加重、先前风湿病或其他自身免疫性疾病的新发生或加重、血液疾病的新发生和新的感染（可能与产品相关），必须至少进行5年的长期不良事件跟踪。 根据欧洲法规，风险管理计划中应包括长期跟踪安全性和有效性的策略。关于传统疫苗，不良事件的观察期通常仅为几周。Brighton Collaboration负责监测疫苗的安全性和风险/效益比，已发布一般疫苗选定不良事件的监测指南。跟进时间有时会指定，但很少超过2个月，根据FDA COVID-19疫苗药物警戒研究，接种个体的跟踪时间长达42天。 4.讨论  4.1. 未进行的前药所需控制 如果抗COVID-19 mRNA被归类为前药，它们将不得不经过有关转化和作用部位的控制。因此，将检测到从mRNA翻译的刺突蛋白不仅存在于注射mRNA的肌肉的免疫细胞中。这一点将在第4.3.1节中讨论。 4.2. 一般疫苗所需的某些测试结果不满意 4.2.1. 药物物质纯度 这不是讨论mRNA控制结果的地方，但仅就产品纯度而言似乎很重要。EMA要求人用产品的纯度为95%；根据EMA，辉瑞最终产品的纯度因生产过程而异。根据通过FOIA获得的“评估员滚动审查关键评估报告”（第81页和第102页），详细说明了先前文件，产品纯度在上市时远低于95%，接受标准为50%。在另一份通过FOIA获得的文件中，这一阈值为58%（第38页）。在2022年针对奥密克戎变体的Moderna疫苗报告中，EMA再次要求重新评估是否需要调整活性物质的纯度规格限制。对于新配方，这些产品纯度缺陷是值得质疑的。 值得注意的是，OCABR进行的批次放行程序没有检测到任何批次异质性。OCABR提供的文件没有指明参考实验室对产品的身份、效力和完整性进行的控制。然而，已经发表了批次毒性的异质性，这可能源于成分的异质性。 4.2.2. 药物物质杂质 残留DNA模板的规格是基于WHO的建议：每剂不超过10纳克DNA。这一限制最初由FDA在1985年设定为每剂疫苗10皮克，后由WHO在1986年提高到每剂100皮克，然后在1996年提高到每剂10纳克。WHO指出，在设定此限制时应考虑要给予的总剂量数。基于这些考虑，并假设最大剂量为30微克，商业放行标准为每毫克RNA ≤330纳克DNA（第103页）。然而，EMA请求提供有关线性DNA模板和定量方法的更多信息。在EMA报告中，残留DNA模板和ds-RNA检测结果在不同批次之间高度异质，尽管远低于接受限制。重新评估未来在非大流行期间评估的mRNA疫苗的检测方法和限制将是明智的。鉴于个人将接受的COVID-19 mRNA疫苗的最终剂量数尚不清楚，这一点尤其正确。 4.2.3. 抗生素抗性基因存在引起的问题 用于mRNA生产的DNA质粒包含一个卡那霉素抗性基因（第26页）。鉴于药物物质中DNA的显著和可变数量，人们担心抗性基因可能被整合到人体消化道细菌或体细胞中。如果抗COVID-19 mRNA受到GTP法规的约束，这些研究就已经进行了。因此，对所有药物和疫苗所需的控制没有给出关于产品纯度和质量的完全满意的结果。 4.3. 未执行的GTP所需控制：由mRNA药代动力学引起的安全问题 4.3.1. 抗COVID-19 mRNA的药代动力学 新疫苗配方所需的药代动力学控制没有完全执行。遗憾的是，没有完全进行完整的药代动力学研究，因为EMA指出，文献中的几份报告表明，LNP配方的RNA可以相当非特异性地分布到脾脏、心脏、肾脏、肺和大脑等多个器官[11]（第54页）。此外，独立的上市后研究表明，mRNA在许多器官中分布并持续数周。mRNA的产物，即刺突蛋白，也在血液中循环数周。在接种疫苗后3周死亡的人的大脑和心脏中发现了刺突蛋白。在接种疫苗后100天，发现刺突蛋白在皮肤病变中。因此，从药代动力学的角度来看，制造商提供的产品研究似乎是不完整的，因为它们未能检测到这种广泛的生物分布和持久性。 对于辉瑞，只研究了纳米颗粒的单独组分的生物分布。EMA指出，根据对GTP（Patisiran数据）类似组分的研究，可以预期人类半衰期为20-30天，纳米颗粒脂质完全消除需要4-5个月。应该在装载mRNA的完整纳米颗粒上研究生物分布，特别是因为临床前研究已经显示所有器官中的生物分布。根据Spikevax-EPAR，生物分布、遗传毒性和重复毒性研究是使用编码除SARS-CoV-2刺突外的蛋白质的mRNA进行的。这与GTP法规不兼容，因为EMA要求在GTMP中对转基因进行分布研究。这些生物分布数据本应加强某些基本GTP控制的需求。实际上，EMA要求，在出现长期表达迹象、非预期基因组整合和肿瘤发生的情况下，必须进行调查。持续时间和表达应通过RT-PCR和免疫学检测和/或检测功能性蛋白的检测来确定。必须监测转基因的过度表达。鉴于可以大量生产刺突蛋白，有时甚至超过严重COVID-19患者中循环的数量，这一点应该受到控制。疾病期间和疫苗接种后达到的刺突浓度比较表明，在严重COVID-19期间，观察到的中位浓度为50皮克/毫升，最高为1纳克/毫升。在严重的COVID-19感染期间，可以检测到高达135皮克/毫升的S1刺突蛋白水平，通常在6到50皮克/毫升之间。在mRNA疫苗接种后，通常观察到高达150皮克/毫升的浓度，但在疫苗诱导的血小板减少的个体中可能达到10纳克/毫升。 4.3.2. 这种广泛的生物分布本应使执行GTP所需的控制成为必需 生殖系整合 需要调查垂直生殖系的可能性（在性腺中的信号、在配子中的信号、精液分离研究和整合分析），特别是因为EMA强调了更广泛的生物分布模式，卵巢和睾丸中低度和可测量的放射性。GTMP需要基因组整合研究。2009年明确指出，对于预计无法整合的基因治疗药品，如果产品生物分布表明存在生殖系传播的风险，则必须进行整合研究。2005年的一份文件，专门针对基因转移载体和裸DNA的生殖系传播研究，明确指出只有DNA，而不是RNA，被假定为存在生殖系修改的风险。这一断言可以根据两篇出版物提出质疑，首先，SARS-CoV-2 RNA可以整合到基因组中；其次，疫苗mRNA可能能够整合到体外培养的人类细胞基因组中。尽管有争议，但这些结果可能会倾向于要求对mRNA进行基因组整合研究，特别是因为刺突mRNA也转移到细胞核。 遗传毒性 针对Moderna进行的大鼠临床前遗传毒性研究显示了不确定的结果（第21页）。结论是“总体而言，由于肌肉注射后的系统暴露最小，暴露持续时间有限，体外结果为阴性，因此对人类遗传毒性的风险被认为很低”。鉴于暴露不仅限于肌肉，暴露持续时间也不限于，继续这些研究将是明智的。正如EMA对GTP的法规所指明的那样，“如果发现阳性结果，将需要进行额外的测试以确保产品的安全性”。 生殖和发育毒性 根据一份通过FOIA获得的有关Moderna疫苗非临床试验的文件，接种大鼠的胎儿中出现了骨骼变异（一个或多个肋骨结节和一个或多个波浪形肋骨，对F1代的存活或生长发育没有影响），但并未被视为不利。然而，强调它们出现在母体毒性的同时，与大鼠肋骨发育最敏感的时期相关。 根据从澳大利亚和日本监管机构获得的文件，辉瑞的临床前试验中也发现了骨骼畸形。腰椎肋骨增多的发生率在治疗组中高于对照组，但被认为与治疗无关。两种类型的mRNA疫苗胎儿异常的一致性本应导致更详细的研究。 根据FDA对纳米药物的药代动力学 对于新的辅料，化学、制药和生物学信息应与活性物质提供的信息相同（第135页）。此外，根据Hemmrich和McNeil[68]的说法，LNP组分的状态令人困惑，根据FDA的说法；它们被视为“起始材料”（因此不是辅料）或作为“非活性成分”（因此是辅料）的文件，然而，根据FDA本身的说法，它们应被视为活性成分。根据同一作者的说法，开发人员必须证明新成分的安全性，“长期使用的辅料可能需要6个月的重复剂量毒理学研究和2年的致癌性研究”。实际上，制造商只打算接种两剂疫苗，但一些人群目前正在接受多达六剂疫苗，间隔几个月。必须评估含有mRNA、活性物质的完整纳米颗粒的稳定性、毒性和生物分布，而不是隔离的脂质组分，与已经进行的相反（Moderna和Pfizer已经部分评估了纳米颗粒中脂质的生物分布，或含有用于抗COVID-19疫苗的mRNA的其他纳米颗粒）。 如果FDA将这些mRNA归类为GTPs，将解决这些模糊性，因为FDA建议评估GTP输送程序的风险（在临床前试验中评估血液、脑脊液、生殖系、心脏和大脑中的生物分布，载体的持久性）。FDA还要求评估可能的水平传播，即从患者传播到家庭成员和卫生保健提供者的具有复制能力的载体（即脱落）。即使载体不是具有复制能力的病毒，也应适用此要求。 4.4. 临床研究 如上所示，刺突蛋白已被证明在血液中循环良好，因此本应进行排泄研究。CHMP指出，没有关于疫苗通过胎盘转移或在乳汁中排泄的数据（第56页）。独立于制造商的研究表明，在注射后的第一周，疫苗mRNA进入了乳汁，根据FDA的报告，母乳喂养的婴儿的不良影响可能是由于这种传递。与COVID-19 mRNA疫苗中类似的纳米颗粒已被证明能够在小鼠中穿过胎盘屏障。应进行广泛的临床前和临床研究，探索这种在乳汁中和通过胎盘的传递。 应进行致癌性、肿瘤发生性和免疫抑制研究，因为有两项研究表明mRNA疫苗可能诱导免疫耐受。此外，刺突蛋白可能与肿瘤抑制因子相互作用（第53页）。因此，明智的做法是在体内探索肿瘤发生效应，并长期监测接种疫苗的个体是否发生癌症，特别是因为已有建议癌症可能被mRNA疫苗重新激活，或者可能在mRNA疫苗接种后发展。 4.5. 疫苗警戒 GTP法规要求对不良效应进行非常长期的监测。这对于mRNA疫苗来说很难实现，因为EMA已要求在疫苗接种后24个月对不良事件进行跟踪，指出安慰剂组中有相当数量的参与者接种了疫苗，这使得这种跟踪更加困难（第14、114和138页）。Moderna宣布，“截至2021年4月13日，所有安慰剂参与者都已提供Moderna COVID-19疫苗，其中98%的人已经接种了疫苗”。 EMA要求的药物警戒跟踪的最新日期是2024年3月31日，远低于FDA对GTP的不良事件长期跟踪5至15年，以及EMA的30年。除了EMA要求的广泛药物警戒计划外，我们可以要求加强监测。由于临床试验中的安慰剂组已接种疫苗，这些长期不良效应的监测可以通过回顾性观察性研究进行，比较参与者的疫苗接种状态的病理发生率。关于腺病毒载体的两篇出版物表明，基因治疗载体的长期效应，尽管它们不是特定的mRNA载体，清楚地说明了研究的缺乏和潜在的长期风险。 FDA和EMA建议长期监测GTPs可能的不良效应，特别是对于某些疾病（癌症、血液学、神经系统、风湿病和感染）。正如上文所见，有报告称在抗COVID-19 mRNA疫苗接种后出现新的或重新激活的癌症。还有报告称在GTPs给药后特别要监测的疾病案例。这里只是一些例子，因为不可能全面。关于血液学疾病，有报道称骨髓抑制和再生障碍性贫血。对于神经系统疾病，有报道称脑炎、脑炎、脱髓鞘和自身免疫性神经系统疾病。风湿病、新的自身免疫性风湿病、类似自身免疫的肌病以及新的或加剧的炎症性疾病也有报道。 2021年，在大规模疫苗接种活动开始后，有报道称脑脓肿复发，以及mRNA疫苗后的非COVID肺炎。EMA指出，正在进行一项干预研究，以评估辉瑞疫苗在孕妇中的安全性和耐受性；尽管实际研究完成日期是2022年7月15日，但没有结果发表，这是不幸的。 5.结论  尽管COVID-19 mRNA疫苗的作用原理符合基因治疗产品（GTPs）的定义，但它们已被监管机构（美国FDA和EMA）从GTPs的监管中排除，并受到针对传染病的疫苗的监管。这种排除没有给出任何科学或伦理上的理由，并且法规中仍然存在不一致之处。例如，根据欧洲和法国法规，疫苗必须含有抗原，这对于mRNA疫苗来说并非如此。这些产品可以被视为“前疫苗”。实际上，mRNA疫苗不含有抗原，而是使接种疫苗的人产生抗原。因此，它们可以被归类为前药或“前疫苗”。应为这类产品制定特殊法规，强调效力控制，即感兴趣的抗原的质量、数量、持续时间和表达位点，以及这种抗原的毒性。 正如2020年初提出的，SARS-CoV-2刺突蛋白与肾素-血管紧张素系统相互作用，并具有公认的毒性，这种毒性在COVID-19之前就已知，并已得到确认。 根据欧洲法规，疫苗是人用药品，因此必须经过相同的控制，但并非所有这些控制通常都适用于针对传染病的疫苗。在应用到mRNA的控制方面，值得注意的是，产品的纯度低于任何药品的要求：这对于一种新的配方和作用原理来说是值得质疑的。此外，批次异质性可能没有通过批次放行程序被检测到。与这种新配方相关的杂质可能会带来安全问题；需要重新评估用于制造RNA的模板中污染DNA的存在和数量，以及ds-RNA。污染模板DNA中抗生素抗性基因的存在也引起了安全问题。 通常不需要对疫苗进行药代动力学研究，除非是新配方，这里就是这种情况。然而，在这个领域进行广泛的研究是必要的，因为它们没有检测到mRNA及其产品——刺突蛋白在疫苗接种者体内的广泛分布和持久性，mRNA在母乳中的传递，以及可能通过接种疫苗的母亲的胎盘传递。GTP法规要求对完整配方（装载mRNA的脂质纳米颗粒对应于药品）进行这些深入研究。 由于这种广泛和持久的生物分布，应该进行GTPs所需的基本测试，关于：遗传毒性风险、基因组整合和生殖系传播、插入性突变、致癌性、胚胎/胎儿和围产期毒性、长期表达、重复毒性和环境排泄（例如，在精液中的脱落）。 GTPs的长期安全性监测需要进行数年，而疫苗通常只进行几周。鉴于药品和表达蛋白的持久性，这应该是不可接受的。抗癌症疗法和mRNA疫苗的已知结果可能会让我们预见到安全性和有效性问题。在抗癌症mRNA的情况下，绝大多数开放标签临床试验是在极少数患者身上进行的，结果要么未公布，要么为负面。随机研究也显示出负面结果，报告治疗组中不良事件更频繁。关于传染病，两项封装在LNPs中的mRNA疫苗试验显示了显著的不良效应。一项针对狂犬病的mRNA疫苗试验显示了比经典疫苗更多的不良效应，经典疫苗已经很反应原性，特别是淋巴细胞减少（这种效应也发现在抗COVID-19 mRNA疫苗中）。一项流感疫苗试验在人类中显示了严重的不良效应（31名受试者仅观察了43天，至少发现了4起严重不良事件）。在一项针对HIV的非随机试验中，一些患者的反应出奇地不完整。根据另一项针对15名参与者的HIV试验对比安慰剂，免疫反应不满意且持续时间有限。BioNTech的创始人Ugur Sahin本人警告不要使用密码子优化，这可以改变翻译速度并导致错误折叠。他还强调了非自然核苷酸的潜在毒性。他还提到了肌肉注射mRNA的广泛生物分布。他提醒我们，我们应该担心在自身免疫疾病患者中出现针对自身mRNA抗体的出现。 监管机构的作用是确保药品的安全性和有效性。COVID-19大流行紧急情况加速了COVID-19疫苗的生产和临床使用的时间表；因此，某些安全方面可能没有得到完全解决。因此，重要的是在未来考虑到这些方面，以免破坏公众对疫苗的普遍信心。 WHO在2023年5月初宣布结束COVID-19大流行紧急阶段，但将继续授权使用紧急使用清单（EUL）程序。疫苗的紧急授权应通过顺利过渡转变为预认证。然而，应该就这种过渡到mRNA疫苗的常规使用开展广泛的公共讨论，而不是使它们受到GTPs所需的控制。 在EMA旨在规范从2023年起新疫苗临床评估的文件中，没有提到mRNA疫苗，仍然指定疫苗含有抗原；因此，该文件将不适用于不含抗原的mRNA疫苗。再次指出，当使用新的给药系统或疫苗含有新型佐剂或辅料时，非临床药代动力学研究可能适用。为mRNA疫苗特别明确这些点是很遗憾的。2021年初的一篇文章强调了需要进一步研究以确保mRNA疫苗的质量、有效性和安全性；这些产品上市之前就已撰写。在临床前试验的详细结果和上市后阶段发布的安全数据的基础上，澄清应要求哪些额外的控制似乎很重要。 将来，应该讨论所有基于mRNA的产品是否应受到相同的法规和控制，无论它们是否被视为疫苗。当治疗性mRNA旨在用于代表人类一小部分的病人时，对其进行严格控制，而将针对健康人群大多数的mRNA疫苗排除在这些控制之外，这是没有道理的。 为了推动人用及兽用疫苗行业交流，共同探讨该领域的最新研发进展、产业化现状及未来发展趋势，生物制品圈联合四叶草会展将于2024年8月16日-17日在苏州共同举办“第三届新型疫苗研发峰会”。诚邀全国相关领域专家、学者和企业家共享学术盛会。现将有关事宜通知如下。 名称：2024第三届新型疫苗研发峰会 时间：2024年8月16-17日（周五-周六） 地点：苏州（酒店定向通知） 主办单位：四叶草会展、生物制品圈 媒体支持：药时空、抗体圈、细胞基因研究圈 会议费用：点击二维码即可查询。 报名方式：扫描下方二维码→ 填写表格 → 报名成功（报名志愿者，免交报名费，承担一定工作任务）！ 转发分享福利：疫苗研发企业、科研院校和监管机构人员，前30位报名人员转发分享会议信息可免费参会（不含餐饮）报名后，扫描下方二维码加工作人员微信后，发送截图即可。 组委会获得报名信息后，根据报名信息进行初筛，并进一步与报名者沟通确认，实现精准邀请，最终有机会进入大会微信群（严格审核通过）。 大会日程 已经确定的报告人 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Continuous Kesimpta® treatment for up to six years showed sustained efficacy in recently diagnosed (≤3 years) treatment-naïve people living with relapsing multiple sclerosis (RMS) in an analysis of the ALITHIOS open-label extension study1 Similar efficacy outcomes were demonstrated in a separate analysis of continuous Kesimpta treatment for up to six years in the overall ALITHIOS study population2 Switch from teriflunomide to Kesimpta resulted in significant improvements across several efficacy outcomes such as annualized relapse rate and MRI lesion activity in both analyses1,2 Treatment with Kesimpta for up to six years continues to be well tolerated with consistent safety outcomes, supporting the favorable benefit-risk profile of Kesimpta in RMS2 EAST HANOVER, N.J., April 17, 2024 /PRNewswire/ -- Novartis today announced data from the ALITHIOS open-label extension study showing sustained efficacy of first-line, continuous Kesimpta® (ofatumumab) treatment for up to six years in recently diagnosed – defined as starting treatment within three years of initial diagnosis – treatment-naïve people living with relapsing multiple sclerosis (RMS).1 These efficacy outcomes included 44% fewer relapses; 96.4% and 82.7% reductions in MRI lesions (Gd+ T1 and neT2), respectively; and 24.5% and 21.6% fewer 3- and 6-month confirmed disability worsening (CDW) events, respectively, versus those who switched to Kesimpta from teriflunomide.1 A separate analysis of the overall ALITHIOS population showed similar efficacy with continuous Kesimpta treatment, which was also well-tolerated with a consistent safety profile up to six years.2 These data will be presented at the American Academy of Neurology (AAN) 2024 Annual Meeting held in Denver, Colorado and virtually on April 13-18, 2024. "Our analysis of treatment-naïve people who were recently diagnosed with relapsing multiple sclerosis found that first-line use of Kesimpta for up to six years provided long-term benefits, including fewer relapses, profoundly suppressed MRI lesion activity, and fewer disability worsening events," said principal investigator Gabriel Pardo, M.D., Founding Director of the Multiple Sclerosis Center of Excellence at Oklahoma Medical Research Foundation. "While measurable improvements were also seen in patients switching to Kesimpta later on, the delay in irreversible disability worsening was not fully realized in the switch group compared to those starting on Kesimpta first, reinforcing the value of introducing the treatment to patients earlier." "We are extremely pleased to share the new data from ALITHIOS, which adds to the growing body of evidence of Kesimpta as an efficacious and well-tolerated option for people living with RMS," said Norman Putzki, M.D., Development Unit Head, Neuroscience & Gene Therapy, Development, Novartis Pharmaceuticals Corporation. "Novartis is committed to addressing the biggest challenges for people living with MS through relentless discovery, development, and delivery of potentially transformative medicines with the goal of achieving complete disease control." Study Results In the first analysis, the low annualized relapse rate (ARR) experienced by recently diagnosed treatment-naïve (RDTN) people living with RMS receiving continuous Kesimpta during the core Phase III trials was further reduced in the ALITHIOS open-label extension study, from 0.104 to 0.050 (52.0% reduction), corresponding to an adjusted ARR of one relapse per 20 years.1 Rates of 3- and 6-month progression independent of relapse activity (PIRA) with first-line Kesimpta were also lower versus switch.1 The observed rapid increase in the proportion of participants with no evidence of disease activity (NEDA-3) with continuous first-line Kesimpta treatment was maintained up to six years.1 In RDTN people living with RMS initially randomized to teriflunomide, improvements across several efficacy outcomes were seen after switching to Kesimpta, including significant reductions in ARR (71.3%) and in MRI lesion activity (Gd+ T1: 98.5% reduction; neT2: 93% reduction), and rapid increase in rates of NEDA-3.1 However, rates of 3- and 6-month CDW events remained higher compared to patients receiving continuous Kesimpta, indicating that the efficacy benefit of first-line Kesimpta on delaying disability worsening was not fully achieved in the switch group.1 Across both continuous and switch groups, nine out of 10 participants achieved NEDA-3 at Year 6.1 Similar results were seen in the second analysis, which looked at the overall ALITHIOS population.2 Data showed sustained efficacy of continuous Kesimpta up to six years, including low ARR (49.9% reduction between core Phase III trials and extension phase), suppression of MRI lesion activity (Gd+ T1: 56.7% reduction; neT2: 89.3% reduction), sustained reduction of 6-month CDW events (14.1%, relative to the switch group), lower rates of 6-month PIRA, and sustained high rates of NEDA-3.2 People switching from teriflunomide to Kesimpta experienced reductions in ARR (73.8%) and MRI lesion activity (Gd+ T1: 97.7% reduction; neT2: 91.8% reduction) and a rapid increase in NEDA-3 rates during the extension period.2 Six-month CDW rates remained higher compared to patients receiving continuous Kesimpta, again highlighting an efficacy benefit of first-line Kesimpta on delaying disability worsening that was not fully achieved in the switch group.2 At Year 6, NEDA-3 status was achieved in nine out of 10 participants in both the continuous and switch groups.2 The study also found that treatment with Kesimpta for up to six years was well-tolerated with no unexpected safety signals identified.2 The rates of adverse events (AEs), serious AEs, serious infections, and malignancies remained stable with no increased risks over six years.2 The overall rates of AEs and serious AEs up to six years of Kesimpta treatment were consistent between the core Phase III trials and the ALITHIOS extension study.2 The most common AEs were infections (COVID-19 [34.3%], nasopharyngitis [20.6%], upper respiratory tract infection [14.9%], and urinary tract infection [14.4%]).2 The incidence of serious infections remained stable over time and did not increase with Kesimpta treatment up to six years.2 Mean serum immunoglobulin G (IgG) levels remained stable up to six years of treatment and the majority of patients (97.2%) had lgG levels above the lower limit of normal (LLN).2 Mean serum immunoglobulin M (IgM) levels decreased over time but remained above the LLN for the majority of patients (65.9%).2 No clinically meaningful association was observed between IgG/IgM levels below the LLN and risk of serious infections.2 About Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by myelin destruction and axonal damage in the brain, optic nerves and spinal cord.3 MS, which affects around 2 million people worldwide, can be characterized into four main types: clinically isolated syndrome (CIS), relapsing-remitting (RRMS), secondary progressive (SPMS) and primary progressive (PPMS).4,5 The various forms of MS can be distinguished based on whether a patient experiences relapses (clearly defined acute inflammatory attacks of worsening neurological function), and/or whether they experience progression of neurologic damage and disability from the onset of the disease.3 About Kesimpta® (ofatumumab) Kesimpta is a targeted, precisely dosed and delivered B-cell therapy that provides the flexibility of self-administration for adults with relapsing forms of multiple sclerosis (RMS). Kesimpta is the first fully human anti-CD20 monoclonal antibody (mAb) self-administered by a once-monthly injection, delivered subcutaneously (SC) in RMS.6, 7, 8 The treatment regimen was designed and tested to enhance safety and tolerability and minimize the risk of systemic injection-related reactions.6 Initial doses of Kesimpta are at Weeks 0, 1 and 2, with the first injection performed under the guidance of a healthcare professional. Monthly Kesimpta 20 mg doses are associated with rapid reduction and near-complete peripheral B-cell depletion, with no significant effect on pharmacokinetics due to body weight.6 As shown in preclinical studies, Kesimpta is thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion.9 The selective mechanism of action and SC administration of Kesimpta allows precise delivery to the lymph nodes, where B-cell depletion in MS is needed, and preclinical studies have shown that it may preserve the B-cells in the spleen.10 Data from the ASCLEPIOS I/II core studies demonstrate Kesimpta's efficacy and favorable safety and tolerability profile in RMS participants and the ALITHIOS open-label extension study provides additional support with up to 6 years of data.2,11 The at-home administration of Kesimpta by monthly doses of 20 mg/0.4mL with an autoinjector (Sensoready®) also matches the preferences of many people living with MS due to its ease of use and supports patients to be compliant with, and persistent on the therapy over time.6 Kesimpta was originally developed by Genmab and licensed to GlaxoSmithKline; Novartis obtained rights for ofatumumab from GlaxoSmithKline in all indications, including RMS, in December 2015.12 Kesimpta has been approved for the treatment of relapsing forms of multiple sclerosis in over 90 countries worldwide with more than 100,000 patients treated as of March 2024. Novartis in Neuroscience At Novartis, in Neuroscience, we are committed to understanding and solving some of the most burdensome neurological conditions to improve the quality of life for patients and their caregivers, and to make a positive impact on society. We aim to lead the discovery, development and delivery of innovative medicines to create a transformational impact for people living with severe neurological conditions by changing the course of disease progression. Through innovation, partnerships and community engagement, we have been tackling neurological conditions for >80 years, launching transformative treatments which have made meaningful differences to millions of people worldwide. We continue to collaborate on the development of industry-leading innovative medicines for multiple sclerosis, and in the areas of neuroimmunology, neurodegeneration, and neuromuscular/rare diseases. To ensure patients everywhere can benefit from these life-changing therapies, we work closely with key stakeholders across the world to ensure rapid access and sustainable accessibility to our medicines, with the aim of providing the best treatment choices for each person's unique journey. KESIMPTA Indication KESIMPTA is a prescription medicine used to treat adults with relapsing forms of multiple sclerosis (MS) including clinically isolated syndrome (CIS), relapsing-remitting disease, and active secondary progressive disease. It is not known if KESIMPTA is safe or effective in children. Important Safety Information Who should not take KESIMPTA? Do NOT take KESIMPTA if you: have an active hepatitis B virus (HBV) infection. have had an allergic reaction to ofatumumab or life-threatening injection-related reaction to KESIMPTA. What is the most important information I should know about KESIMPTA? KESIMPTA can cause serious side effects such as: Infections. Serious infections, which can be life-threatening or cause death, can happen during treatment with KESIMPTA. If you have an active infection, your health care provider (HCP) should delay your treatment with KESIMPTA until your infection is gone. KESIMPTA taken before or after other medicines that weaken the immune system may increase your risk of getting infections. Tell your HCP right away if you have any infections or get any symptoms including painful and frequent urination, nasal congestion, runny nose, sore throat, fever, chills, cough, or body aches. HBV reactivation. If you have ever had HBV infection, it may become active again during or after treatment with KESIMPTA (reactivation). If this happens, it may cause serious liver problems including liver failure or death. Before starting KESIMPTA, your HCP will do a blood test to check for HBV. They will also continue to monitor you during and after treatment with KESIMPTA for HBV. Tell your HCP right away if you get worsening tiredness or yellowing of your skin or the white part of your eyes. Progressive Multifocal Leukoencephalopathy (PML). PML may happen with KESIMPTA. PML is a rare, serious brain infection caused by a virus that may get worse over days or weeks. PML can result in death or severe disability. Tell your HCP right away if you have any new or worsening neurologic signs or symptoms. These may include weakness on one side of your body, loss of coordination in arms and legs, vision problems, changes in thinking and memory, which may lead to confusion and personality changes. Weakened immune system. KESIMPTA taken before or after other medicines that weaken the immune system could increase your risk of getting infections. Before you take KESIMPTA, tell your HCP about all your medical conditions, including if you: Have or think you have an infection including HBV or PML. Have ever taken, currently take, or plan to take medicines that affect your immune system. These medicines could increase your risk of getting an infection. Have had a recent vaccination or are scheduled to receive any vaccinations. You should receive any required 'live' or 'live-attenuated' vaccines at least 4 weeks before you start treatment with KESIMPTA. You should not receive 'live' or 'live-attenuated' vaccines while you are being treated with KESIMPTA and until your HCP tells you that your immune system is no longer weakened. Whenever possible, you should receive any 'non-live' vaccines at least 2 weeks before you start treatment with KESIMPTA. Talk to your HCP about vaccinations for your baby if you used KESIMPTA during your pregnancy. Are pregnant, think that you might be pregnant, or plan to become pregnant. It is not known if KESIMPTA will harm your unborn baby. Females who can become pregnant should use birth control (contraception) during treatment with KESIMPTA and for 6 months after your last treatment. Talk with your HCP about what birth control method is right for you during this time. Are breastfeeding or plan to breastfeed. It is not known if KESIMPTA passes into your breast milk. Talk to your HCP about the best way to feed your baby if you take KESIMPTA. Tell your HCP about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I use KESIMPTA? See the detailed Instructions for Use that comes with KESIMPTA for information about how to prepare and inject a dose of KESIMPTA and how to properly throw away (dispose of) used KESIMPTA Sensoready pens or prefilled syringes. Use KESIMPTA exactly as your HCP tells you to use it. Your HCP will show you how to prepare and inject KESIMPTA the right way before you use it for the first time. Do not inject into areas where the skin is tender, bruised, red, scaly or hard. Avoid areas with moles, scars, or stretch marks. KESIMPTA may cause serious side effects including: Injection-related reactions. Injection-related reactions are a common side effect of KESIMPTA. Injecting KESIMPTA can cause injection-related reactions that can happen within 24 hours (1 day) following the first injections and with later injections. There are two kinds of reactions: at or near the injection site: redness of the skin, swelling, itching, and pain. Talk to your HCP if you have any of these signs and symptoms. that may happen when certain substances are released in your body: fever, headache, pain in the muscles, chills, tiredness, rash, hives, trouble breathing, swelling of the face, eyelids, lips, mouth, tongue and throat, and feeling faint, or chest tightness. Contact your HCP right away if you experience any of these signs and symptoms, especially if they become worse or you have new severe signs of reactions after subsequent injections. It could be a sign of an allergic reaction, which can be serious. Low immunoglobulins. KESIMPTA may cause a decrease in some types of antibodies. Your HCP will do blood tests to check your blood immunoglobulin levels. The most common side effects of KESIMPTA include: Upper respiratory tract infection, with symptoms such as sore throat and runny nose, and headache. Headache. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit , or call 1-800-FDA-1088. Please see full Prescribing Information including Medication Guide. Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "would," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people's lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide. Reimagine medicine with us: Visit us at and and connect with us on LinkedIn, LinkedIn US, Facebook, X/Twitter, X/Twitter US and Instagram. References Pardo G, Hauser SL, Bar-Or A, et al. Longer-term (up to 6 Years) Efficacy of Ofatumumab in People with Recently Diagnosed and Treatment-Naïve Relapsing Multiple Sclerosis. Oral presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting; April 13-18, 2024; Denver, CO. Wiendl H, Hauser SL, Nicholas J, et al. Longer-term Safety and Efficacy of Ofatumumab in People With Relapsing Multiple Sclerosis for Up to 6 Years. Poster presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting; April 13-18, 2024; Denver, CO. Guthrie EW. Multiple sclerosis: A primer and update. Adv Studies Pharm. 2007;4(11):313-317. Multiple Sclerosis International Federation. Atlas of MS 2013-Mapping Multiple Sclerosis Around the World. Accessed August 12, 2020. National MS Society. Types of MS. Accessed January 18, 2023. Hauser SL, Kappos L, Bar-Or A, et al. The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment. Neurol Ther. 2023;12(5):1491-1515. doi:10.1007/s40120-023-00518-0 Kesimpta Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corp; September 2022. Bar-Or A, Fox E, Goodyear A, et al. Onset of B-cell depletion with subcutaneous administration of ofatumumab in relapsing multiple sclerosis: results from the APLIOS bioequivalence study. Poster presentation at: ACTRIMS; February 2020; West Palm Beach, FL. Smith P, Kakarieka A, Wallstroem E. Ofatumumab is a fully human anti-CD20 antibody achieving potent B-cell depletion through binding a distinct epitope. Poster presentation at: ECTRIMS; September 2016; London, UK. Smith P, Huck C, Wegert V, et al. Low-dose, subcutaneous anti-CD20 therapy effectively depletes B-cells and ameliorates CNS autoimmunity. Poster presentation at: ECTRIMS; September 2016; London, UK. Cohen, JA, Hauser SL, Zielman R., et al. Effect of Longer-term Ofatumumab Treatment on Disability Progression and Brain Volume Change. Poster presentation at: AAN; April 2023; Boston, US. Genmab Press Release: Genmab announces completion of agreement to transfer remaining ofatumumab rights. December 21, 2015. Accessed January 18, 2023. # # # SOURCE Novartis Pharmaceuticals Corporation

Results from the Phase III study showed that subcutaneous (SC) injection was consistent with IV infusion and demonstrated near-complete suppression of relapse activity (97%) and MRI lesions (97.2%) through 48 weeks The twice-yearly, 10-minute SC injection has the potential to expand the usage of Ocrevus to treatment centers without IV infrastructure or with IV capacity limitations U.S. FDA and EMA accepted filings based on the data from OCARINA II, with EU approval anticipated mid-2024 and U.S. approval anticipated September 2024 SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today data from the Phase III OCARINA II study (S31.006) of Ocrevus® (ocrelizumab), an investigational twice-yearly, 10-minute subcutaneous (SC) injection. Results showed near-complete suppression of clinical relapses and brain lesions in people with relapsing or primary progressive multiple sclerosis (RMS or PPMS) which reinforce the potential benefits of this investigational formulation. Treatment with Ocrevus SC led to rapid and sustained B-cell depletion in the blood. The data will be presented as an oral presentation at the 76th American Academy of Neurology (AAN) Annual Meeting taking place April 13-18 in Denver and has been recognized as an abstract of distinction by the AAN scientific committee. “With a full year of data demonstrating near-complete suppression of relapse activity and minimal progression of lesion development, this 10-minute subcutaneous Ocrevus injection shows results that are consistent with the long-established benefits of intravenous Ocrevus,” said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. “We look forward to continuing ongoing conversations with regulatory bodies worldwide to potentially bring an additional treatment option to more people living with MS, in a shorter injection time.” Updated, longer-term results showed that Ocrevus SC injection (920 mg; n=236; both treatment arms [OCR SC/SC and OCR IV/SC]) resulted in near-complete suppression of relapse activity (97.2% had no relapse during the treatment phase) and MRI up to 48 weeks with an ARR of 0.04, and most patients having no T1 gadolinium-enhancing (T1 Gd+) lesions and no new/enlarging T2 lesions. These lesion types are markers of active inflammation and burden of disease, respectively. Additionally, in exploratory patient reported outcome measures (n=52) patients reported a high level of satisfaction (92.3% were satisfied or very satisfied) and convenience (90.1% felt it was convenient or very convenient) with Ocrevus SC injection. “Updated results from OCARINA II further underline the potential benefits of subcutaneous Ocrevus for patients with both relapsing and progressive forms of MS,” said Scott Newsome, D.O., lead author, Johns Hopkins University School of Medicine. “Patients treated with subcutaneous Ocrevus experienced appropriate B-cell suppression and impressive near-complete suppression of new inflammatory disease activity. These results demonstrate the potential of subcutaneous Ocrevus as a treatment option that can be matched to the individual needs of people with MS and healthcare professionals.” Additional data continued to show that the safety pro Ocrevus SC injection was consistent with the well-established safety pro Ocrevus IV infusion. No new safety signals were identified for Ocrevus SC. The most common adverse events in the Ocrevus SC group were injection reactions (51.5% of all exposed patients), including erythema (34.8%; skin redness or irritation), pain (17.2%), swelling (9.4%) and pruritus (5.6%; skin itching), all of which were either mild or moderate and none of which led to treatment withdrawal. A total of seven serious AEs were experienced by three (2.6%) and four (3.4%) patients in the Ocrevus SC injection and IV infusion groups, respectively. The OCARINA II abstract was selected as an abstract of distinction by the AAN, based on the quality of the study and the interest to the neurology community. The twice-yearly, 10-minute SC injection has the potential to expand the usage of Ocrevus to treatment centers without IV infrastructure or with IV capacity limitations. Data from the Phase III OCARINA II trial were submitted to health authorities around the world following the first presentation of these results during ECTRIMS-ACTRIMS 2023. Both the European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) have accepted Genentech’s submissions, with a target decision date of mid-2024 for the EMA and September 2024 for the FDA. More than 300,000 people with MS have been treated with Ocrevus IV globally. Ocrevus IV is approved in more than 100 countries across North America, South America, the Middle East, Eastern Europe, Asia, Australia, Switzerland, the United Kingdom and the EU. Genentech is committed to advancing innovative clinical research programs to broaden the scientific understanding of MS, further reducing disability progression in RMS and PPMS and improving the treatment experiences for those living with the disease. There are more than 30 ongoing Ocrevus clinical trials designed to help us better understand MS and its progression. Follow Genentech on X via @Genentech and on LinkedIn as Genentech and keep up to date with AAN 2024 news and updates by using the hashtag #AANAM. About the subcutaneous formulation of Ocrevus (ocrelizumab) The investigational subcutaneous formulation combines Ocrevus with Halozyme Therapeutics’ Enhanze® drug delivery technology. Ocrevus is a humanized monoclonal antibody designed to target CD20-positive B cells, a specific type of immune cell thought to be a key contributor to myelin (nerve cell insulation and support) and axonal (nerve cell) damage. This nerve cell damage can lead to disability in people with MS. Based on preclinical studies, Ocrevus binds to CD20 cell surface proteins expressed on certain B cells, but not on stem cells or plasma cells, suggesting that important functions of the immune system may be preserved. The Enhanze drug delivery technology is based on a proprietary recombinant human hyaluronidase PH20 (rHuPH20), an enzyme that locally and temporarily degrades hyaluronan – a glycosaminoglycan or chain of natural sugars in the body – in the subcutaneous space. This increases the permeability of the tissue under the skin, allowing space for large molecules like Ocrevus to enter, and enables the subcutaneous formulation to be rapidly dispersed and absorbed into the bloodstream. Ocrevus IV is the first and only therapy approved for both RMS (including relapsing-remitting MS [RRMS] and active, or relapsing secondary progressive MS [SPMS], in addition to clinically isolated syndrome [CIS] in the U.S.) and PPMS. Ocrevus IV is administered by intravenous infusion every six months. The initial dose is given as two 300 mg infusions given two weeks apart. Subsequent doses are given as single 600 mg infusions. About the OCARINA II study OCARINA II is a Phase III, global, multicenter, randomized study evaluating the pharmacokinetics, safety and radiological and clinical effects of the subcutaneous formulation of Ocrevus compared with Ocrevus intravenous (IV) infusion in 236 patients with relapsing MS (RMS) or primary progressive MS (PPMS). The primary endpoint is non-inferiority in area under the serum concentration time curve (AUC) from day 1 to 12 weeks after subcutaneous injection compared to IV infusion. Secondary endpoints include maximum serum concentration (Cmax) of Ocrevus, the total number of active, gadolinium-enhancing T1 lesions at 8 and 12 weeks, and new or enlarging T2 lesions at 12 and 24 weeks, as well as safety and immunogenicity outcomes. Exploratory endpoints include patient-reported outcomes. About multiple sclerosis Multiple sclerosis (MS) is a chronic disease that affects more than 2.8 million people worldwide. MS occurs when the immune system abnormally attacks the insulation and support around nerve cells (myelin sheath) in the central nervous system (brain, spinal cord and optic nerves), causing inflammation and consequent damage. This damage can cause a wide range of symptoms, including muscle weakness, fatigue and difficulty seeing, and may eventually lead to disability. Most people with MS experience their first symptom between 20 and 40 years of age, making the disease the leading cause of non-traumatic disability in younger adults. People with all forms of MS experience disease progression – permanent loss of nerve cells in the central nervous system – from the beginning of their disease even if their clinical symptoms aren’t apparent or don’t appear to be getting worse. Delays in diagnosis and treatment can negatively impact people with MS, in terms of their physical and mental health, and contribute to the negative financial impact on the individual and society. An important goal of treating MS is to slow, stop and ideally prevent disease activity and progression as early as possible. Relapsing-remitting MS (RRMS) is the most common form of the disease and is characterized by episodes of new or worsening signs or symptoms (relapses) followed by periods of recovery. Approximately 85% of people with MS are initially diagnosed with RRMS. The majority of people who are diagnosed with RRMS will eventually transition to secondary progressive MS (SPMS), in which they experience steadily worsening disability over time. Relapsing forms of MS (RMS) include people with RRMS and people with SPMS who continue to experience relapses. Primary progressive MS (PPMS) is a debilitating form of the disease marked by steadily worsening symptoms but typically without distinct relapses or periods of remission. Approximately 15% of people with MS are diagnosed with the primary progressive form of the disease. Until the FDA approval of Ocrevus, there had been no FDA-approved treatments for PPMS. About Genentech in Neuroscience Neuroscience is a major focus of research and development at Genentech. Our goal is to pursue groundbreaking science to develop new treatments that help improve the lives of people with chronic and potentially devastating diseases. Genentech and Roche are investigating more than a dozen medicines for neurological disorders, including MS, spinal muscular atrophy (SMA), neuromyelitis optica spectrum disorder (NMOSD), Alzheimer’s, Huntington’s, Parkinson’s, acute ischemic stroke, Duchenne muscular dystrophy and Angelman syndrome. Together with our partners, we are committed to pushing the boundaries of scientific understanding to solve some of the most difficult challenges in neuroscience today. About Genentech Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit . Indications and Important Safety Information What is Ocrevus? Ocrevus is a prescription medicine used to treat: Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults Primary progressive MS, in adults. It is not known if Ocrevus is safe or effective in children. Who should not receive Ocrevus? Do not receive Ocrevus if you have an active hepatitis B virus (HBV) infection. Do not receive Ocrevus if you have had a life-threatening allergic reaction to Ocrevus. Tell your healthcare provider if you have had an allergic reaction to Ocrevus or any of its ingredients in the past. What is the most important information I should know about Ocrevus? Ocrevus can cause serious side effects, including: Infusion reactions: Infusion reactions are a common side effect of Ocrevus, which can be serious and may require you to be hospitalized. You will be monitored during your infusion and for at least 1 hour after each infusion of Ocrevus for signs and symptoms of an infusion reaction. Tell your healthcare provider or nurse if you get any of these symptoms: itchy skin rash hives tiredness coughing or wheezing trouble breathing throat irritation or pain feeling faint fever redness on your face (flushing) nausea headache swelling of the throat dizziness shortness of breath fatigue fast heart beat These infusion reactions can happen for up to 24 hours after your infusion. It is important that you call your healthcare provider right away if you get any of the signs or symptoms listed above after each infusion. If you get infusion reactions, your healthcare provider may need to stop or slow down the rate of your infusion. Infection: Infections are a common side effect. Ocrevus increases your risk of getting upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes infections. Serious infections can happen with Ocrevus which can be life-threatening or cause death. Tell your healthcare provider if you have an infection or have any of the following signs of infection including fever, chills, a cough that does not go away, or painful urination. Signs of herpes infection include cold sores, shingles, genital sores, skin rash, pain, and itching. Signs of more serious herpes infection include: changes in vision, eye redness or eye pain, severe or persistent headache, stiff neck, and confusion. Signs of infection can happen during treatment or after you have received your last dose of Ocrevus. Tell your healthcare provider right away if you have an infection. Your healthcare provider should delay your treatment with Ocrevus until your infection is gone. Hepatitis B virus (HBV) reactivation: Before starting treatment with Ocrevus, your healthcare provider will do blood tests to check for hepatitis B viral infection. If you have ever had hepatitis B virus infection, the hepatitis B virus may become active again during or after treatment with Ocrevus. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure or death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop receiving Ocrevus. Weakened immune system: Ocrevus taken before or after other medicines that weaken the immune system could increase your risk of getting infections. Progressive Multifocal Leukoencephalopathy (PML): PML is a rare brain infection that usually leads to death or severe disability, and has been reported with Ocrevus. Symptoms of PML get worse over days to weeks. It is important that you call your healthcare provider right away if you have any new or worsening neurologic signs or symptoms that have lasted several days, including problems with: thinking eyesight strength balance weakness on 1 side of your body using your arms or legs Decreased immunoglobulins: Ocrevus may cause a decrease in some types of immunoglobulins. Your healthcare provider will do blood tests to check your blood immunoglobulin levels. Before receiving Ocrevus, tell your healthcare provider about all of your medical conditions, including if you: have ever taken, take, or plan to take medicines that affect your immune system, or other treatments for MS. have ever had hepatitis B or are a carrier of the hepatitis B virus. have had a recent vaccination or are scheduled to receive any vaccinations. You should receive any required ‘live’ or ‘live-attenuated’ vaccines at least 4 weeks before you start treatment with Ocrevus. You should not receive ‘live’ or ‘live-attenuated’ vaccines while you are being treated with Ocrevus and until your healthcare provider tells you that your immune system is no longer weakened. When possible, you should receive any ‘non-live’ vaccines at least 2 weeks before you start treatment with Ocrevus. If you would like to receive any non-live (inactivated) vaccines, including the seasonal flu vaccine, while you are being treated with Ocrevus, talk to your healthcare provider. If you have a baby and you received Ocrevus during your pregnancy, it is important to tell your baby’s healthcare provider about receiving Ocrevus so they can decide when your baby should be vaccinated. are pregnant, think that you might be pregnant, or plan to become pregnant. It is not known if Ocrevus will harm your unborn baby. You should use birth control (contraception) during treatment with Ocrevus and for 6 months after your last infusion of Ocrevus. Talk with your healthcare provider about what birth control method is right for you during this time. are breastfeeding or plan to breastfeed. It is not known if Ocrevus passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Ocrevus. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. What are the possible side effects of Ocrevus? Ocrevus may cause serious side effects, including: Risk of cancers (malignancies) including breast cancer. Follow your healthcare provider’s instructions about standard screening guidelines for breast cancer. Inflammation of the colon, or colitis: Tell your healthcare provider if you have any symptoms of colitis, such as: Diarrhea (loose stools) or more frequent bowel movements than usual Stools that are black, tarry, sticky or have blood or mucus Severe stomach-area (abdomen) pain or tenderness These are not all the possible side effects of Ocrevus. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. For more information, go to or call 1-844-627-3887. Please see additional Important Safety Information throughout and click here for the full Prescribing Information and Medication Guide. View source version on businesswire.com: Contacts Media Contact: Michelle McCourt, (650) 467-6800 Advocacy Contact: Lily Rose Atherton, (650) 690-5573 Investor Contacts: Loren Kalm, (650) 225-3217 Bruno Eschli, +41 61 68 75284 Source: Genentech View this news release online at: