Adalimumab biosimilar(Alvotech)

REYKJAVIK, ICELAND (June 16, 2026) — Alvotech (NASDAQ: ALVO; ALVO-SDB) (“Alvotech” or the “Company”), a global biotechnology company specializing in the development and manufacture of biosimilar medicines for patients worldwide, today announced the pricing of its previously announced underwritten public offering (the “Offering”) of 22,666,667 of its ordinary shares at an offering price of $3.75 per share. All ordinary shares to be sold in the Offering will be offered by Alvotech. The Offering is expected to close on or about June 17, 2026, subject to satisfaction of customary closing conditions. The Company has also granted the underwriters a 30-day option to purchase up to an additional 3,400,000 ordinary shares at the public offering price, less underwriting discounts and commissions. Before deducting the underwriting discounts and commissions and offering expenses, the Company expects to receive total gross proceeds of approximately $85 million from the Offering, or approximately $98 million if the underwriters exercise in full their option to purchase additional shares. Concurrent with the Offering, Alvotech has entered into Subscription Agreement(s) with certain investors that are professional clients or eligible counterparties in the European Economic Area falling within article 1(4) of Regulation (EU) 2017/1129, pursuant to which Alvotech will issue and sell 17,826,666 ordinary shares to such investors at a price of $3.75 per ordinary share, which represents the per share public offering price, in a private placement exempt from the registration requirements of the Securities Act of 1933, as amended. The gross proceeds from the concurrent private placement, before deducting any transaction-related expenses, are expected to be approximately $67 million. The concurrent private placement is expected to close on or about June 25, 2026, subject to the consummation of the Offering and other customary conditions. However, the consummation of the Offering is not contingent on the consummation of the concurrent private placement. The total gross proceeds from the Offering and the concurrent private placement are expected to be approximately $152 million, or approximately $165 million if the underwriters exercise in full their option to purchase additional shares, in each case before deducting underwriting discounts and commissions and estimated offering expenses payable. Alvotech intends to use the net proceeds from this Offering and the concurrent private placement to fund the continued development of its biosimilar assets, as well as working capital and general corporate purposes, which may include, among others, intellectual property protection and enforcement, commercial expenditures, capital expenditures, acquisitions or collaborations, pre-clinical and clinical development of its product candidates, research and development and product development, pre-commercialization activities and repayment or refinancing of indebtedness or other corporate borrowings. BofA Securities, Jefferies and Evercore ISI are acting as joint book-running managers for the Offering. The Offering is being made pursuant to a registration statement on Form F-3, including a base prospectus, that was previously filed with the U.S. Securities and Exchange Commission (“SEC”) on October 20, 2023, and declared effective on October 30, 2023. The ordinary shares referred to in this press release are being offered in the United States only by means of a prospectus supplement and the accompanying prospectus that forms a part of the registration statement. Copies of the final prospectus supplement and the accompanying prospectus related to this Offering may be obtained, when available, from: BofA Securities, Attention: Prospectus Department, 201 North Tryon Street, Charlotte, NC 28255-0001, or by email at dg.prospectus_requests@bofa.com; Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, New York, NY 10022, by telephone at (877) 821-7388, or by email at prospectus_department@jefferies.com; or Evercore Group L.L.C., Attention: Equity Capital Markets, 55 East 52nd Street, 35th Floor, New York, NY 10055, by telephone at (888) 474-0200, or by email at ecm.prospectus@evercore.com. Investors may also obtain these documents at no cost by visiting the SEC’s website at . 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. Important information This press release shall not constitute an offer to sell or the solicitation of an offer to buy these shares, nor shall there be any sale of these shares, in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. The distribution of this document may, in certain jurisdictions, be restricted by local legislations. Persons into whose possession this document comes are required to inform themselves about and to observe any such potential local restrictions. This press release is not a prospectus for the purposes of Regulation (EU) 2017/1129 of the European Parliament and of the Council of June 14, 2017 on the prospectus to be published when shares are offered to the public admitted to trading on a regulated market, as amended (the “Prospectus Regulation”) and has not been approved by any regulatory authority in any jurisdiction. The Company has not authorized any offer to the public of shares or other securities in any member state of the EEA and no prospectus has been or will be prepared in connection with the Offering. In any EEA Member State, this communication is only addressed to and is only directed at “qualified investors” in that Member State within the meaning of the Prospectus Regulation. With respect to the member States of the European Economic Area (a “Relevant Member State”), no action has been undertaken or will be undertaken to make an offer to the public of the shares referred to herein requiring a publication of a prospectus in any Relevant Member State. As a result, the shares may not and will not be offered in any Relevant Member State except in accordance with the exemptions set forth in Article 1(4) of the Prospectus Regulation or under any other circumstances which do not require the publication by the Company of a prospectus pursuant to Article 3 of the Prospectus Regulation and/or to applicable regulations of that Relevant Member State. In addition, in the United Kingdom, this announcement is directed at and for distribution only to Qualified Investors who are (i) persons who have professional experience in matters relating to investments falling within Article 19(5) of the Financial Services and Markets Act (Financial Promotion) Order 2005, as amended (the "Order"), or (ii) persons who are high net worth entities falling within Article 49(2)(a) to (d) of the Order, and (iii) other persons to whom this announcement may otherwise lawfully be communicated (all such persons together being referred to as "Relevant Persons"). The shares referred to herein are only available to, and any invitation, offer or agreement to subscribe, purchase or otherwise acquire such shares will be engaged in only with Relevant Persons. Any person who is not a Relevant Person should not act or rely on this communication or any of its contents. No announcement or information regarding this Offering may be disseminated to the public in jurisdictions where a prior registration or approval is required for such purpose. Other than the registration statement filed with the SEC, no steps have been taken, or will be taken, for the Offering of shares in any jurisdiction where such steps would be required. The issue or sale of shares, and the subscription for or purchase of shares, are subject to special legal or statutory restrictions in certain jurisdictions. This press release contains inside information within the meaning of MAR that Alvotech is legally obliged to publish. The information was released for publication, through the agency of the contact persons below, at the date and time indicated by the dateline of publication. 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, but are not limited to, Alvotech’s expectations regarding the completion and timing of the Offering and the concurrent private placement, the potential exercise of the underwriters’ option to purchase additional shares, and the expected use of proceeds. In some cases, you can identify forward-looking statements by terminology such as “may”, “should”, “expect”, “intend”, “will”, “estimate”, “anticipate”, “believe”, “predict”, “potential”, “aim” or “continue”, or the negatives of these terms or variations of them or similar terminology. 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: whether or not we will be able to consummate the Offering the final terms of the offering, the satisfaction of customary conditions precedent to close the proposed Offering and concurrent private placement, and other risks and uncertainties 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, including the final prospectus supplement and the accompanying prospectus related to this Offering and the Company’s most recent annual report on Form 20-F. 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 a representation, guarantee, assurance, prediction or definitive statement of a fact or probability. You should not place undue reliance on forward-looking statements, which speak only as of the date they are made. 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. Media Benedikt Stefansson Sarah MacLeod alvotech.media@alvotech.com Investors Dr. Balaji V Prasad Benedikt Stefansson alvotech.ir@alvotech.com

免疫介导的炎症性疾病（IMIDs），包括银屑病、狼疮、多发性硬化症和炎症性肠病，是以免疫失调和炎症细胞因子过度表达为特征的慢性疾病。生物疗法已改变了IMID的管理，生物类似药的引入通过降低成本和减轻医疗系统负担改善了治疗可及性。尽管获得监管批准并证明了与参照生物药的相似性，但由于互换性和外推方面存在不确定性、利益相关者之间沟通不足，以及影响患者和医生信心的反安慰剂效应（nocebo effect），生物类似药的采用仍然有限。虽然监管机构提供了详细指南和欧洲公共评估报告（European Public Assessment Reports, EPAR），但监管和认知障碍在临床实践中持续存在。本研究回顾了在IMIDs中从参照生物药转换为生物类似药的真实世界和临床试验数据，并证明了其安全性和有效性结果具有可比性。然而，患者的认知和沟通策略显著影响治疗成功。尽管已有证据，但患者和医疗专业人员中仍存在消极认知和信心不足。提升对生物类似药的理解和信心可增加其可及性和可用性，从而增强其广泛使用带来的益处。因此，解决教育、监管和临床实践方面的差距对于优化生物类似药在IMID管理中的整合至关重要。**1 Introduction** 免疫介导的炎症性疾病（IMIDs）是一组由免疫反应失调、持续性炎症和组织损伤驱动的异质性慢性疾病，包括类风湿关节炎（RA）、银屑病和银屑病关节炎（PsA）、炎症性肠病（IBD）等。尽管临床表型多样，但IMIDs共享遗传易感性和炎症通路，常伴有多病共存，导致生活质量下降、残疾和长期医疗资源使用。遗传学进展支持IMIDs共享风险结构的概念，流行病学显示其在个体和家庭中聚集。IMIDs影响3%-5%的人口，年发病率为80/100,000人年。患者常出现多病共存，并发症如心血管、代谢、骨骼疾病和认知缺陷导致焦虑和抑郁。环境风险因素如感染和创伤可诱发疾病，尤其对遗传易感者。细胞因子在免疫网络中介导细胞通讯、放大炎症并协调效应功能，其在诊断、分层和预后中具有临床意义。生物疗法通过靶向细胞因子、受体和免疫细胞迁移，改善了疾病控制和结局。然而，生物药的高成本限制了可及性，促生了生物类似药的发展。生物类似药高度类似于已授权的参照生物药，在质量、安全性和有效性上无临床有意义差异，其开发遵循严格的相似性比较方法。从参照生物药到生物类似药的转换是IMID管理的关键，但实施依赖于政策、临床医生和患者信心及共同决策。转换可能引发反安慰剂效应（nocebo effect），需谨慎沟通和随访。尽管有进展，各国和各机构间的采用率差异、医院采购差异、装置处理等问题仍存在挑战。本研究旨在总结生物类似药在IMID中应用的依据，并评估科学、监管和临床因素，尤其关注转换实践和真实世界实施。**2 Objectives and Methodology** 本研究旨在评估生物类似药的益处，识别其在IMID治疗中应用的障碍，并分析应对策略以最大化生物类似药利用。具体目标包括：(i) 分析欧盟（EU）和美国食品药品监督管理局（FDA）层面的监管策略以促进临床实践；(ii) 检查生物制药行业在生物类似药开发和市场可用性中的作用；(iii) 解决IMID中采用生物类似药的障碍并提出监管建议。由于本研究聚焦欧洲背景，政策分析主要基于欧洲药品管理局（EMA）的监管数据和指南，FDA信息仅用于比较分析。文献检索在PubMed、临床试验信息系统（CTIS）和Google Scholar中进行，时间范围为2019-2025年。主要检索词包括：(biosimilar) AND (IMID)等。纳入标准为原始研究、综述和临床试验，报告真实世界数据、转换结局、监管视角或实施策略，且以英文发表。排除标准包括仅关注肿瘤或非IMID适应症的文章等。初步检索后，最终纳入43篇文章。**3 IMIDs** IMIDs是以免疫反应失调和炎症细胞因子过表达为特征的复杂慢性疾病，包括中轴型脊柱关节炎（axSpA）、银屑病、PsA、IBD、克罗恩病、溃疡性结肠炎（UC）、多发性硬化症等。细胞因子由多种细胞分泌，分为肿瘤坏死因子（TNF）、白介素（IL）、干扰素（IFN）等家族。遗传易感性和环境触发因素导致免疫耐受丧失，引起慢性免疫激活，包括先天性和适应性免疫反应、T细胞失衡（Th1/Th17反应增强、调节性T细胞功能受损）、B细胞功能障碍及促炎细胞因子释放（如TNF-α、IL-6、IL-17）。这些机制通过自我放大循环维持慢性炎症和组织损伤。传统药物仅能控制炎症，而生物药能靶向免疫病理、预防组织损伤并实现长期缓解，但因高成本限制可及性。RA、银屑病、PsA和克罗恩病是受生物疗法影响最大的四种IMID。RA关键细胞因子为TNF-α、IL-1和IL-6；克罗恩病使用英夫利西单抗和阿达木单抗；银屑病和PsA需TNF-α抑制剂等。生物类似药通过降低成本和市场竞争扩大了患者对生物药的可及性。然而，治疗互换性仍是医疗专业人员和患者的犹豫点，缺乏教育和信息可导致反安慰剂效应（nocebo effect）。未来IMID治疗将基于分子方法，包括（表观）基因组学、转录组学、蛋白质组学和代谢组学，并整合激酶组分析、细胞疗法和多组学分析以识别精准靶向干预。**4 Development and Manufacture of Biological Medicines** 生物药含有源自生物来源的活性物质，通过单克隆抗体和重组DNA技术生产。其制造过程包括细胞系开发、细胞培养、大规模生产、产品分离、纯化、制剂和最终灌装。第一步是生产细胞系的基因开发，将编码目标蛋白的基因插入表达载体并导入宿主细胞（常用哺乳动物、细菌或酵母细胞），筛选稳定表达克隆并建立主细胞库（MCB）和工作细胞库（WCB）。从WCB的细胞在生物反应器中培养，优化温度、pH、氧合和营养供应。收获后经下游处理包括离心、过滤、病毒清除、去除宿主细胞蛋白等。纯化主要通过系列色谱步骤实现。最终制剂加入赋形剂以确保稳定性、生物活性和货架期。每个阶段受国际人用药品注册技术协调会（ICH）质量指南约束，包括Q5、Q6、Q7、Q8、Q9、Q10和Q11。关键质量属性（CQAs）应在开发中识别并在制造中监测，以确保药物特性、纯度、生物活性和稳定性。生物材料的固有微异质性对批次间质量和一致性构成挑战，需严格控制关键步骤的CQAs。**5 Regulation of Biological Medicines** 根据欧洲药品管理局（EMA）指南，生物类似药是“与已在欧盟（EU）批准的参照药高度相似的生物药”，但并非其仿制药。EMA通过集中程序评估生物类似药申请，拥有严格的评估框架。生物类似药与参照生物药采用相同的质量、安全和有效性标准，通过全面的比较研究（包括分析、功能、非临床和临床数据）证明相似性。比较研究包括比较质量研究、比较非临床研究和比较临床研究（药代动力学、药效学、有效性、安全性和免疫原性）。一旦证明相似性，可进行适应症外推。在EU，申请需包括风险管理计划（RMP），批准后需提交上市后安全性研究（PASS）和定期安全性更新报告（PSUR）。EMA的指南列出了截至2019年批准的生物类似药列表。**6 Role of Biosimilars in IMIDs: Economic and System-Level Impact** 生物类似药的出现通过增加可用性和降低成本重塑了生物疗法的可及性。参照药专利到期后，生物类似药的市场进入促进价格竞争，降低药品采购成本，减轻医疗系统财务负担。在IMID中，患者需长期或终身生物治疗，降低成本可促使更早治疗启动、扩大患者资格并重新分配医疗资源。临床证据表明生物类似药与参照药的安全性和有效性相当，且在IMID中采用治疗达标策略可改善患者生活质量。生物类似药不仅是低价替代品，还是治疗达标策略的推动者，支持持续疾病控制并降低住院、手术和残疾相关下游成本。**7 Clinical and Perceptual Barriers to Biosimilar Use** 尽管EMA有严格的批准流程，但医疗专业人员和患者仍对生物类似药存在担忧。主要问题包括互换性、数据外推和反安慰剂效应（nocebo effect）。生物类似药开发需通过I期临床研究证明药代动力学（PK）等效性，并至少一项III期随机对照试验（RCT）在敏感患者群体中确认有效性、安全性和免疫原性。其临床开发路径较参照药更为简化，基于整体证据方法。一旦证明等效性，可进行数据外推。EMA认为生物类似药在EU批准后可互换，但不规范实施方式，导致各国政策不一致。互换性可通过在处方医生控制下转换或在药房层面替代实现。监管责任划分导致欧洲各国在转换、替代和药师参与方面政策异质。此外，反安慰剂效应（nocebo effect）是主要认知障碍，即患者因负面预期而出现症状恶化。在IMID中，患者对生物类似药的劣势感知可导致依从性差、不良事件报告率升高和治疗中止。该效应可通过结构化教育和共同决策缓解。反安慰剂效应（nocebo effect）的决定因素包括患者、医生、医疗系统和社会影响，见表5（略）。**8 Clinical Equivalence—Real-World Data** 治疗达标方法在IMID中是革命性的，生物类似药使更早治疗成为可能。一项关于阿达木单抗和托珠单抗的研究显示，生物类似药采用率因国家而异，与缺乏教育和激励有关。本部分回顾了RA、IBD、银屑病和PsA四种常见IMID的临床试验结果。**8.1 RA** 研究1是一项随机双盲III期试验，将患者随机分配至生物类似药ADL-PF或参照药阿达木单抗（ADL, Humira）治疗，评估52-92周的疗效、安全性和免疫原性，未发现临床有意义差异。研究2评估从参照药利妥昔单抗转换至生物类似药CT-P10的疗效和安全性，72周内耐受良好，无差异。研究3从参照药ADL转换至生物类似药SDZ-ADL，患者报告结局和生命质量评分均有改善。研究4为从ADL转换至生物类似药FKB327的随机双盲试验，显示转换不影响疗效和免疫原性。**8.2 IBD** NOR-SWITCH试验（研究1）在IBD患者中比较稳定使用英夫利西单抗与转换至其生物类似药的结果，52周后无显著差异。研究2（VOLTAIRE-CD）在克罗恩病患者中比较ADL生物类似药ADL-adbm与参照药ADL的有效性和安全性，主要不良事件为注射部位反应。研究3在澳大利亚IBD患者中从英夫利西单抗转换至CT-P13，48周内安全，未增加不良事件。研究4为从ADL（Humira）转换至SB5，患者事先接受教育后75%在12个月后仍持续治疗。研究5在IBD和风湿病患者中从ADL转换至SB5，显示疗效和安全性与ADL相似。**8.3 Psoriasis and PsA** 研究1从乌司奴单抗转换至生物类似药AVT04，52周内显示等效性，安全性和疗效相似。研究2从ADL转换至AVT02，52周内安全性和免疫原性等效，改善患者生命质量。**8.4 Switching Studies Applicable to Multiple IMIDs** VOLTAIRE-X和REFLECTIONS B538-12试验从参照药ADL转换至生物类似药ADL-adbm和ADL-afzb，显示安全性和药代动力学等效。PLANETAS和PLANETRAS试验从英夫利西单抗转换至CT-P13，在axSpA和RA中证明等效。NOR-SWITCH试验在多种IMID患者中显示非劣效性。研究3在克罗恩病患者中证明英夫利西单抗与CT-P13等效。所有研究表明生物类似药与参照药在安全性、有效性和免疫原性上等效，但患者认知期望影响治疗持续性，教育干预可提高持续性。**9 Addressing Barriers to Biosimilar Adoption** 生物类似药采用常因医疗专业人员知识和信心不足、患者转换担忧、政策不一致和缺乏协调指南而不理想。医生犹豫源于对互换性、免疫原性和长期安全性的不确定性，患者感知和反安慰剂效应（nocebo effect）常导致治疗中断。医生可通过教育患者、分享知识、减少反安慰剂效应（nocebo effect）和采取共同决策来克服障碍。利益相关者（患者、药师、医生、制造商、医疗专业人员和系统）之间的协作至关重要。EMA建立了教育和监管框架，包括欧洲公共评估报告（EPAR），但其技术复杂性限制了临床使用。克服采用障碍的策略包括：医患沟通、多学科管理、社会观察学习和监测反安慰剂效应（nocebo effect）。共同决策可增强信任，多学科团队确保持续教育，社会观察学习通过同伴正面经历强化信心。使用验证工具识别高风险患者并实施干预，可改善结果。**10 Conclusion and Future Perspectives** 生物类似药是IMID治疗达标策略中的重大进步，提供生物药级有效性并降低成本，扩大早期可及性。广泛证据证实其与参照药在安全性、有效性和免疫原性上匹配，但最优使用仍受监管模糊性和利益相关者不确定性阻碍。需更清晰的欧洲监管指南，尤其是关于转换方案、互换性和反安慰剂效应（nocebo effect）预防策略，并改善EPAR和真实世界证据的可及性。政策和激励应与以患者为中心的护理一致，支持标准化沟通、共同决策和转换后结构化随访。信任、教育和透明沟通对成功采用生物类似药至关重要。多学科团队（包括临床药师）在提供一致证据指导中发挥关键作用。加强登记和药物警戒应追踪安全性、持续性和患者报告结局。最终，优化生物类似药使用需要监管、临床和患者参与领域的协调努力。通过解决反安慰剂效应（nocebo effect）、标准化转换实践并将共同决策嵌入常规护理，生物类似药可成为可持续高质量IMID管理中完全受信任的组成部分。