Vedolizumab

引言：从“用什么药”到“如何决策” 过去十年，UC的治疗版图经历了前所未有的扩张：在抗TNF之外，抗整合素、抗IL-12/23p40与IL-23p19抗体、JAK抑制剂、S1P受体调节剂相继进入临床，抗TL1A等新靶点也已步入后期研发。当这些先进治疗（advanced therapy, AT）不断把疗效与"疾病清除"的标准推高，在这样一个日益丰富的治疗格局中，不同的治疗手段处在各自什么位置？ 这种复杂性在中度（moderate）UC身上尤为突出——它恰好横跨“轻-中度”与“中-重度”两条不同的指南治疗路径的交界。对这部分患者，临床需要面对的是一组相互关联的决策。 本文邀请到来自上海交通大学医学院附属上海市第一人民医院的曾悦主任，基于近年的最新证据，对中度UC的治疗决策做一次系统的再思考。在治疗手段空前丰富的今天，真正的临床命题已不再是“传统药物是否还有位置”，而是如何在一条环环相扣的决策链上，为每一类患者做出取舍——从精准分层，到传统治疗的优化，再到升级先进治疗的依据，最后到升级之后是否保留传统药物。本文沿这条脉络展开，将视角落在“在恰当的时点、为恰当的患者、匹配恰当的手段”这一科学判断上。 一、 “中度UC”的分层 一切治疗决策的起点是对疾病的精准分层。然而“中度”本身长期缺乏统一定义：法国Caron等发表于United European Gastroenterol J的系统综述发现，近二十年相关试验中用于界定“轻-中度”的评分多达6种，cut-off各异，最常用的UCDAI也仅见于不到一半（41%）的临床试验。这意味着同样被标记为“中度”的患者，实际炎症负荷可能从接近轻度一直跨越到需要积极干预的较重区间。 2025年更新的美国胃肠病学会（ACG）指南因此强调，疾病严重度应当是多维度的综合判定：①患者报告结局；②炎症负荷（内镜MES/UCEIS、FC、CRP、白蛋白）；③疾病病程（住院、激素需求、药物失败）；④疾病影响（HRQoL与社会功能）（图1）。 落到可操作的指标上，这四个维度各有抓手：症状层面可用部分Mayo评分或简化临床结肠炎活动指数（SCCAI）动态追踪；内镜层面，MES 2分（明显红斑、血管纹理消失、脆性增加伴糜烂）或UCEIS约4–6分大致对应“中度”活动；生物标志物层面，粪钙卫蛋白持续>250 µg/g提示活动性肠道炎症，CRP升高与低白蛋白血症则进一步提示较高的炎症负荷与不良预后倾向；而病变范围（蒙特利尔分型E1直肠、E2左半结肠、E3广泛型）既影响严重度判断，也直接决定给药途径的选择。 图1  “中度”UC的多维分层框架（ACG 2025）与UCEIS内镜严重度分级。“轻-中度”与“中-重度”是不同的治疗分类，moderate恰位于交界。 这一区分直接决定治疗路径的走向：偏轻的“中度”往往通过优化传统治疗即可控制；偏重的“中度”则可能更早需要先进治疗。判断一例患者偏向哪一端，可参考一组公认的不良预后线索：广泛型病变、内镜下深溃疡、CRP升高或低白蛋白血症、粪钙卫蛋白持续高水平、发病年龄较轻、确诊后短期内即需激素或呈激素依赖、以及显著的症状与生活质量负担——具备越多此类特征，越提示“偏重”一端、宜更早考虑升级；反之则更可能通过优化传统治疗达标。 此外，内镜评分并非分层的唯一维度：VARSITY研究事后分析（Khan等2026）显示，内镜MES 1分但组织学仍活动（Geboes>3.2）者，其第52周的组织-内镜黏膜改善（24.1% vs. 24.8%）、内镜缓解（29.1% vs. 31.0%）与临床缓解（48.1% vs. 58.4%）均与传统轻-中度UC相当，提示这部分“内镜偏轻、组织学偏重”的患者若仅凭内镜评估可能被低估，组织学维度有助于进一步细化分层。 二、治疗选择全景：从传统药物到先进治疗 完成分层后，临床面对的是一个远比十年前丰富的“治疗名单”（图2）：基石治疗是5-ASA与诱导用激素（布地奈德MMX/系统激素），其上则是抗TNF、抗整合素、抗IL-12/23与IL-23、JAK抑制剂、S1P受体调节剂等多类机制各异的先进治疗。 近两年多项里程碑式III期RCT充实了这一名单：古塞奇尤单抗的QUASAR研究、乌帕替尼的U-ACTIVATE长期扩展研究，以及尤其值得关注的依曲莫德ENLIGHT东亚III期研究——后者发表于Lancet Gastroenterol Hepatol，由空军军医大学西京医院吴开春教授牵头、浙江大学医学院附属邵逸夫医院曹倩教授等共同参与，覆盖中国内地和台湾地区及韩国52家医院，是少有的以中国研究者为主导的国际III期RCT，诱导期12周临床缓解率25.0% vs. 安慰剂5.4%。 需要特别说明的是，上述AT的III期缓解率均来自“中-重度活动性”、且多为既往常规治疗、生物制剂或JAK抑制剂应答不足或不耐受的难治人群，其分母与一线、轻-中度人群完全不同。因此这些数字既不宜彼此简单横比（各试验入组标准与终点定义不一），更不能与5-ASA在轻-中度人群中的缓解率直接相提并论。 图2  中度UC的治疗选择全景（按机制分类）。先进治疗均获批用于中-重度UC；治疗目标已从临床缓解逐步演进至内镜愈合、组织学缓解乃至疾病清除(disease clearance)。 值得注意的是，英国利兹大学Ford团队2025年发表于Aliment Pharmacol Ther的维持期网络Meta分析（纳入28项RCT）提示，不同药物在不同终点上各擅胜场，并无单一“最优解”——这正是治疗需要个体化权衡的根源。 三、序贯之辩：Step-up，还是早期升级？ 有了分层与选择，下一个核心问题是：先用什么、何时升级、失败后如何换。这正是当前争论最集中的地带。 一方面，多部指南开始推荐对中-重度活动性UC在5-ASA失败后更早升级到AT。德国基尔大学Schreiber团队2026年发表于United European Gastroenterol J、覆盖五国的离散选择实验（DCE）显示，患者与消化科医生在升级到一线AT时，最看重“1年缓解概率”（相对重要性约45%~49%），其次才是5年肿瘤风险等安全性维度，且双方都愿为更高缓解概率承担一定风险。这反映出在偏重的患者中，对疗效的诉求正在推动决策前移。具体到中度人群，奥扎莫德长期治疗用于5-ASA失败后的中度活动性UC也显示出可观的持续缓解（Yarur等2026），说明对优化传统治疗后仍未达标者，及时升级AT是一条有循证支撑、且针对该人群专门验证过的路径。 另一方面，对偏轻的中度UC，并无证据支持跳过5-ASA优化而直接早期升级。即便需要升级，时点的把握仍应循证——参照STRIDE-II达标治疗原则，优化治疗4周无显著改善或2周完全无改善时再考虑升级，避免在交界区无谓拖延或过度治疗。 巴西坎皮纳斯大学Imbrizi等2025年发表于World J Gastroenterol的定位/序贯综述给出了实用的决策框架：在分子标志物尚不能可靠预测疗效之前，初始与后续治疗的选择应基于疾病严重度、表型、并发症风险、合并症、肠外表现，以及疗效·安全·便利·可及性之间的平衡。需要补充的是，“尚不能可靠预测疗效”这一局限是双向的——既难以事先判定谁会对某种AT应答，也难以预知谁能仅靠5-ASA优化达标；因此“按时点评估、未达标即调整”的策略，对两个方向上的治疗同等适用。 四、夯实基础：传统治疗的优化空间与边界 第三节已指出，对偏轻的中度UC，跳过传统药物优化而直接升级缺乏证据支持。那么“优化”究竟意味着什么、它的边界又在哪里？这是决策链中承上启下的一环。就证据现状而言，四大主流指南（ECCO、DGVS、ACG、BSG）仍一致推荐5-ASA为任何病变范围轻-中度UC的一线治疗。其优化可从三个维度展开——但每个维度也都有相应的边界。 优化维度一：用足剂量——疗效常被低估。 美沙拉嗪疗效具有明确剂量依赖性（图3）。Nguyen 2018网络Meta显示中度病例宜起始即用更高剂量（可至4.8 g/d）；Barberio 2021纳入11,733例的网络Meta证实≥3.3 g/d显著优于低剂量诱导缓解。关键在于，提高剂量并不增加不良反应，使“用足剂量”成为低风险、高回报的优化杠杆。临床上“5-ASA失败”常被过早宣判——而剂量、剂型、疗程往往尚未真正到位。 图3  美沙拉嗪的剂量依赖性（左）与起效·评估时间窗（右）。剂量-效应为基于Nguyen 2018与Barberio 2021网络Meta结论的示意性图示，非真实效应量。 优化维度二：安全性接近安慰剂，但疗效存在上限。 发表于ECCO 2026大会的系统综述摘要（P0733, Landeira等）显示，口服与直肠5-ASA的随机效应汇总缓解率分别为54.8%与65.4%（图4），而严重不良事件率仅2.3%/1.2%、停药率3.4%/1.1%（图5）。安全性高是5-ASA的突出特点；但疗效存在“天花板”，对偏重或难治的患者往往力有不逮。5-ASA与AT两者各擅其场，需按患者所处的疾病状态权衡取舍，而非以一方否定另一方。 图4  ECCO 2026系统综述(P0733, Landeira等)中口服与直肠5-ASA的随机效应汇总缓解率。注：数据来自轻-中度混合人群，不应直接等同于“中度UC”单独缓解率。 图5  口服与直肠5-ASA的安全性（ECCO 2026系统综述汇总数据）。TRAE=治疗相关不良事件；SAE=严重不良事件。 五、联合之道：从5-ASA到与先进治疗的叠加 治疗决策不只是“单选”，也包括联合。在中度UC中，联合策略贯穿三个层面。 1. 5-ASA口服+直肠联合：对病变范围超过直肠的左半结肠型或广泛型UC，口服联合直肠给药优于口服单药。这一优势既有机制基础——直肠途径可在远端结肠形成更高的黏膜药物浓度，ECCO 2026系统综述中直肠途径的汇总缓解率（65.4%）亦高于口服（54.8%）；也有量化的整体获益：Louis等2022年的决策树模型（10,000例模拟）显示，采用“优化”策略（联合口服+直肠并最大化剂量）后，诱导期无需系统激素或生物制剂即达缓解的患者较标准治疗增加39%（6565 vs. 4725），并相应避免了若干静脉血栓栓塞与严重感染；维持期复发减少21%（1830 vs. 2311），每例患者一年净节省约£272。一项覆盖66国、222名医生的全球调查（D'Amico等2024）亦印证，口服（≥4 g/d）联合直肠5-ASA是临床优化治疗时的首选方案。这是最基础、却最常被低估的联合。 2. 5-ASA基础上加用布地奈德MMX：一项欧洲与加拿大的真实世界研究显示，在优化5-ASA基础上加用布地奈德MMX，临床获益率（>60%）显著高于布地奈德MMX单药（33%）；且在5-ASA优化至少2周后再加用，三项终点的达标比例更高。 3. 升级到AT后是否保留5-ASA：这是争议最大、也是临床最常面对的联合抉择。当患者从5-ASA升级到生物制剂或小分子时，5-ASA究竟应作为“可叠加的基础”继续，还是就此停用？近年的真实世界证据给出了方向并不一致的信号，且迄今缺乏随机对照试验的直接验证。决策时应综合既往5-ASA应答情况、患者偏好、潜在的结直肠癌化学预防价值，做个体化权衡。 现有较高质量证据多未显示"升级后继续叠加 5-ASA"带来额外获益。Singh等汇总英夫利西单抗与戈利木单抗RCT的个体患者数据（IPD）分析发现，升级到抗 TNF 后，无论诱导还是维持，合用5-ASA对临床缓解、临床应答、黏膜愈合与生化缓解均无改善；Ma等针对维得利珠单抗的真实世界队列得出同样结论（Clin Gastroenterol Hepatol 2019）；另一项英夫利西单抗真实世界队列（University of Alberta，Dig Dis Sci 2021）、以及 ECCO 2024 一项中-重度 UC 研究（Tomasic 等，P667）也一致提示"无额外获益"。 与之相对，部分真实世界数据提示联用可能与更高黏膜愈合相关（如图6的 meta 回归，高使用率组45.0% vs. 低使用率组29.0%，r=0.503, P=0.067），但此类关联为观察性、易受适应证混杂影响（病情更复杂者往往保留更多基础用药），证据级别有限。安全性方面，停用并不增加风险——Ungaro等基于美国与丹麦两个全国性队列（n=3,589）显示，启动抗TNF后停用5-ASA并未增加激素、住院或手术风险（Gut 2019）。 图6  2026年ECCO: UC维持期，ADT治疗的患者继续5-ASA治疗可提高黏膜愈合率。 尽管疗效证据有限，真实世界中升级后"顺势保留 5-ASA"却相当普遍。Ma等的系统综述/meta分析显示，升级到免疫抑制剂或生物/小分子治疗的UC患者中，仍合用5-ASA者的汇总比例高达80.7%（Aliment Pharmacol Ther 2019）。这种"惯性保留"背后既有合理考量（患者偏好、医保报销规则、对结直肠癌化学预防价值的顾虑，以及5-ASA本身良好的安全性），也有主动减停意识尚未普及的因素——2025年已出现专门探讨"联用先进治疗时如何减停5-ASA"的质性研究，提示减停往往需要医患共同的风险评估与沟通才能推进（Patient Prefer Adherence 2025）。亚洲的处方现状同样印证了高保留倾向：覆盖8个亚洲地区的医生调查显示，5-ASA的延续使用常出于患者偏好与报销因素，而非已证实的叠加疗效（图7）。 图7 一项医生调查，以了解溃疡性结肠炎管理的实践和偏好，重点是5-ASA的使用和与指南建议的一致性。 German综述的系统检索结论是：尚无RCT证实升级后继续5-ASA有短期临床获益，但亦无证据显示有害。因此合理立场是结合患者偏好、既往5-ASA应答及潜在结直肠癌化学预防作用，个体化决定是否保留，而非一刀切。 六、整合：中度UC的治疗决策路径 将上述分层、选择、序贯与联合整合为一条可操作的路径，其内核可概括为： 1. 精准分层：多维度判定，明确是偏轻的“中度”还是接近“中-重度”。 2. 夯实基石：优化5-ASA（口服+直肠，4~4.8 g/d，疗程≥6个月），必要时联用激素。 3. 达标评估：参照STRIDE-II于2~4周评估，避免过早宣判失败或无谓拖延。 4. 序贯/选择：升级时按患者特征匹配机制，权衡疗效·安全·给药方式·合并症·可及性。 5. 联合与长期管理：升级后个体化可保留5-ASA，长期监测，瞄准内镜/组织学愈合乃至疾病清除。 专家结语 近些年的循证更新，把中度UC的临床命题从“用什么药”推向了“如何决策”——分层、优化、升级、联合，环环相扣。在这一图景中，新型生物制剂与小分子拓展了疗效能力的上限，传统治疗则守住了安全与可及的下限；二者并非取代关系，而是同一条决策链上、面向不同患者与不同时点的不同选项。 对偏轻的中度UC，用足、用对传统药物并设定清晰的升级时点，常可避免不必要的过度治疗；对偏重或传统药物失败的患者，及时升级、并在升级后个体化评估，则更可能带来深度而持久的获益。真正的临床决策，不在于偏爱某一类药物，而在于：选对方向、把握时点。 主要参考文献 1. Imbrizi M, Azevedo MFC, Baima JP, et al. Positioning and sequencing of advanced therapies in inflammatory bowel disease: a guide for clinical practice. World J Gastroenterol. 2025;31(29):107745. 2. Caron B, Jairath V, D'Amico F, et al. Definition of mild to moderate ulcerative colitis in clinical trials: a systematic literature review. United European Gastroenterol J. 2022;10(8):854-867. 3. Khan N, Wong E, Narula N. Patients with ulcerative colitis that have endoscopic Mayo score 1 and active histologic inflammation have similar outcomes to mild-moderate patients with Mayo score 2: a post hoc analysis of the VARSITY trial. 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Stopping 5-aminosalicylates in patients with ulcerative colitis starting biologic therapy does not increase the risk of adverse clinical outcomes: analysis of two nationwide population-based cohorts. Gut. 2019;68(6):977-984. 23. Ma C, Guizzetti L, Cipriano LE, et al. Systematic review with meta-analysis: high prevalence and cost of continued aminosalicylate use in patients with ulcerative colitis escalated to immunosuppressive and biological therapies. Aliment Pharmacol Ther. 2019;49(4):364-374. 24. Cruchelow KR, Bonnet KR, Zuckerman AD, Schlundt DG, Horst SN. Deprescribing 5-aminosalicylates in patients with ulcerative colitis on concomitant advanced therapy: a qualitative analysis. Patient Prefer Adherence. 2025;19:1351-1364. 25. Limsrivilai J, Lai AY, Li STH, et al. Role of 5-aminosalicylic acid in ulcerative colitis management in 8 Asian territories: a physician survey. Intest Res. 2025;23(2):117-128. 26. ·  Schnoy E, Dignass A, Gaskins M, Kucharzik T. From guidelines to evidence-based practice — a German perspective on mesalazine as first-line therapy for mild-to-moderate UC. Z Gastroenterol. 2025 (corrected 2026). 欢迎投稿！ tougao@medvoices.cn 稿件类型：研究速递，综述译稿，指南/共识，病例分享。 版权属《消化医声》所有。欢迎个人转发分享。其他任何媒体、网站如需转载或引用本网版权所有之内容，须经本网授权同意（加小编微信：GI-2022）。

REYKJAVIK, Iceland, June 08, 2026 (GLOBE NEWSWIRE) -- Alvotech (NASDAQ: ALVO; ALVO-SDB), a global biotechnology company specializing in the development and manufacture of biosimilar medicines for patients worldwide, today announced that the U.S. Food and Drug Administration (FDA) has accepted for review a Biologics License Application (BLA) for AVT16, a proposed interchangeable biosimilar to Entyvio ® (vedolizumab) lyophilized vial for intravenous administration. Under a partnership with Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA), Alvotech is responsible for development and manufacturing of AVT16, while Teva is responsible for commercialization. “FDA acceptance of the BLA for AVT16 is another important step in advancing our mission to increase access to biologic medicines for patients worldwide,” said Joseph McClellan, Chief Operating Officer of Alvotech. “Our proposed interchangeable biosimilar to Entyvio builds on our experience in immunology and reflects the strength of our fully integrated development and manufacturing platform.” Entyvio is a biologic medicine approved for the treatment of adults with moderately to severely active ulcerative colitis and Crohn’s disease. AVT16 is among Alvotech’s disclosed biosimilar candidates in immunology and form part of the company’s broader pipeline of biosimilar candidates aimed at expanding access to biologic medicines in major therapeutic areas. The BLA submission is supported by a comprehensive data package, including analytical, pharmacokinetic, and immunogenicity data generated to support the demonstration of biosimilarity between AVT16 and the reference product. AVT16 has been submitted as a proposed interchangeable biosimilar. In the United States, an interchangeable biosimilar may be substituted for the reference product at the pharmacy without the intervention of the prescriber, subject to applicable laws. If approved, AVT16 would add to the range of biosimilar options available to patients and healthcare providers in the United States. In February 2026, Alvotech announced positive results from a pivotal pharmacokinetic study for AVT80, a proposed biosimilar to Entyvio for subcutaneous administration. The randomized, double-blind, single-dose, parallel-group, three-arm study compared AVT80 to Entyvio in healthy adult participants and met all its primary endpoints. Based on regulatory advice, the clinical study is considered pivotal to support the demonstration of clinical similarity for both AVT16 and AVT80. About AVT16 AVT16 is a proposed interchangeable biosimilar candidate to Entyvio ® (vedolizumab), a humanized monoclonal antibody. AVT16 is being developed as a lyophilized vial for intravenous administration. In the European Union, the European Medicines Agency has validated a Marketing Authorization Application covering both AVT16 (lyophilized vial) and AVT80 (pre-filled syringe and auto-injector). AVT16 and AVT80 are investigational products and have not received regulatory approval in any markets. Biosimilarity and interchangeability have not been established by regulatory authorities and are not claimed. About Entyvio ® Entyvio ® (vedolizumab) is an integrin receptor antagonist indicated for the treatment of adults with moderately to severely active ulcerative colitis and Crohn’s disease. Vedolizumab targets and binds specifically to the alpha-4-beta-7 integrin, which is involved in the migration of certain white blood cells into gastrointestinal tissue. Use of trademarks Entyvio ® is a registered trademark of Millennium Pharmaceuticals, Inc. The use of this trademark is solely for the purpose of identifying the reference product. Alvotech and Teva do not claim any rights to the trademark. For further information, contact: Media Benedikt Stefansson Sarah MacLeod alvotech.media@alvotech.com Investors Dr. Balaji V Prasad Benedikt Stefansson alvotech.ir@alvotech.com About Alvotech Alvotech is a biotechnology company, founded by Robert Wessman, focused solely on the development and manufacture of biosimilar medicines for patients worldwide. Alvotech seeks to be a global leader in biosimilars by delivering high-quality, cost-effective products and services, enabled by a fully integrated approach and broad in-house capabilities. Five biosimilars are already approved and marketed in multiple global markets, including biosimilars to Humira ® (adalimumab), Stelara ® (ustekinumab), Simponi ® (golimumab), Eylea ® (aflibercept) and Prolia ® /Xgeva ® (denosumab). The current development pipeline includes nine disclosed biosimilar candidates aimed at treating autoimmune disorders, eye disorders, osteoporosis, respiratory disease, and cancer. Alvotech has formed a network of strategic commercial partnerships to provide global reach and leverage local expertise in markets that include the United States, Europe, Japan, China, and other Asian countries and large parts of South America, Africa and the Middle East. For more information, please visit . None of the information on the Alvotech website shall be deemed part of this press release. For more information, please visit our investor portal , and our website or follow us on social media on LinkedIn , Facebook , Instagram and YouTube . Alvotech Forward Looking Statements Certain statements in this communication may be considered “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements include, for example, Alvotech’s expectations regarding competitive advantages, business prospects and opportunities including pipeline product development, future plans and intentions, regulatory submissions, review and interactions, the potential approval and commercial launch of its product candidates, the timing of regulatory approval, market launches and financial projections. Such forward-looking statements are subject to risks, uncertainties, and other factors which could cause actual results to differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are based upon estimates and assumptions that, while considered reasonable by Alvotech and its management, are inherently uncertain and are inherently subject to risks, variability, and contingencies, many of which are beyond Alvotech’s control. Factors that may cause actual results to differ materially from current expectations include, but are not limited to factors set forth in the sections entitled “Risk Factors” and “Cautionary Note Regarding Forward-Looking Statements” in documents that Alvotech may from time-to-time furnish with the SEC. There may be additional risks that Alvotech does not presently know or that Alvotech currently believes are immaterial that could also cause actual results to differ from those contained in the forward-looking statements. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on by an investor as, a guarantee, assurance, prediction or definitive statement of a fact or probability. Alvotech does not undertake any duty to update these forward-looking statements or to inform the recipient of any matters of which any of them becomes aware of which may affect any matter referred to in this communication. Alvotech disclaims any and all liability for any loss or damage (whether foreseeable or not) suffered or incurred by any person or entity as a result of anything contained or omitted from this communication and such liability is expressly disclaimed.