BNT-221

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CAR-T疗法开发最新进展       美国最大的癌症治疗和研究组织之一的 City of Hope 日前进行了一项开创性1期研究，针对CAR-T 细胞对胶质母细胞瘤的治疗。这项试验显示出了CAR-T针对无法治愈的脑肿瘤的巨大应用潜力。       这项研究是迄今为止报道过的规模最大的实体瘤 CAR-T 试验，评估CAR-T针对肿瘤相关抗原白细胞介素 13 受体 α 2 (IL13Rα2) 的活性。治疗脑癌的主要挑战之一是药物难以穿过血脑屏障。为了克服这一障碍，这项试验将 CAR T 细胞直接输送到脑肿瘤和脑脊液中，脑脊液是保护和包围大脑和脊髓的液体。       这项1期研究在 65 名复发性高级别胶质瘤患者中评估了靶向 IL-13Rα2的CAR-T 疗法，其中大多数是复发性胶质母细胞瘤 (rGBM)。50% (29/58) 的患者病情稳定或更好，在方案外额外的 CAR-T 周期后出现两次部分缓解、一次完全缓解和第二次完全缓解。对于复发性多形性胶质母细胞瘤，所有患者的中位总生存期为 7.7 个月。该试验最终对一组患者进行了治疗，这个患者组使用了优化的制造工艺，并将 CAR-T 细胞注射到肿瘤部位和脑脊液中。这些患者实现了10.2个月的中位总生存期，显著高于复发性胶质母细胞瘤患者 6 个月的预期生存率。这项研究结果发表在了最新一期的Nature Medicine上。       虽然CAR-T疗法开发方兴未艾，但涉及该疗法的安全性讨论却一直都是行业焦点。2024 年 1 月 23日 ，FDA 要求在目前获批的6 种 CAR-T 治疗产品中添加与继发性癌症风险相关的黑框警告。FDA 于 2024 年 1 月 19 日向各相关公司发出了单独的信函。这些 CAR-T 产品针对抗原 CD19 或 B 细胞成熟抗原 (BCMA)。FDA要求六款CAR-T产品的制造商添加黑框警告，指出“使用 BCMA 和 CD19 导向的转基因自体 T 细胞免疫疗法治疗后可能会导致 T 细胞恶性肿瘤”。       几乎与此同时，FDA 最终确定了CAR-T 治疗产品的指南，涵盖与癌症患者的开发和临床试验设计相关的因素。FDA的另一份最终指南涉及纳入人类基因组编辑的基因治疗产品，为研究性新药应用提供建议，包括产品设计、制造、非临床安全性评估和临床试验设计。       2. CAR-T疗法       嵌合受体雏形是由魏茨曼科学研究所的 Eshhar 小组于 1989 年开发的，到目前CAR-T 细胞已经快速发展了几代（图1B）。       图1. A: CAR-T细胞结构；B: 第一代CAR信号结构域仅具有CD3衍生的信号结构域。第二代 CAR 中加入了共刺激结构域。第三代CAR有两个共刺激域。第四代 CAR-T 细胞激活后可表达 IL-12 等趋化因子。第五代 CAR 具有独特的共刺激结构域，可激活特定的信号通路，例如 JAK/STAT3。（图片来源：Cancer Gene Ther）       CAR 由三个基本结构域组成：细胞外结构域、跨膜结构域和细胞内结构域 （图1A）。胞内结构域在 T 淋巴细胞信号传导中发挥着至关重要的作用，能够不依赖人类白细胞抗原 (HLA) 而杀死恶性细胞。胞外结构域由单链可变片段 (scFv，Single-chain variable fragment) 组成，它是抗体轻链和重链可变区构建的融合蛋白。这个胞外结构域通过间隔区与跨膜结构域连接，并进一步与细胞内信号传导结构域连接，导致癌细胞细胞溶解。胞外 scFv 帮助CAR-T 细胞附着到特定靶向细胞，胞内结构域则有助于 T 细胞激活。在胞内信号传导域上，存在初级刺激域和次级共刺激域（图1）。      CAR-T 疗法根据特定癌症类型和患者需求提供个性化治疗，彻底改变了癌症治疗。CAR-T疗法对患者自身 T 细胞进行基因改造，使其能够识别并结合肿瘤抗原。修饰后的 T 细胞经过增殖后，会被输回患者体内，以靶向并消灭癌细胞（图 2）。       图2. 自体 CAR-T 细胞的生产从患者的白细胞分离开始，然后进行 T 细胞富集和激活。为了促进 CAR 转基因的引入并永 久整合，需要转导活化的 T 细胞（例如使用慢病毒载体）。之后经过基因工程改造的 T 细胞在静态或动态培养物中生长、冷冻保存，然后重新引入患者体内。       3. FDA批准的CAR-T疗法       目前，FDA已批准了六种CAR-T细胞疗法：       Tisagenlecleucel（Kymriah）       图片来源：Clinical Trials Arena       •适应症：急性淋巴细胞白血病、B 细胞淋巴瘤、滤泡性淋巴瘤       •靶标：CD19       •开发商：诺华       •首次获批时间：2017年8月30日       Tisagenlecleucel（商品名Kymriah）用于治疗 B 细胞急性淋巴细胞白血病 (ALL)。       Tisagenlecleucel最初由宾夕法尼亚大学发明，诺华公司完成了开发，并于2017年8月30日首次获得 FDA 批准，成为美国第一个获得 FDA 批准的CAR-T疗法。       Axicabtagene Ciloleucel（Yescarta）       •适应症：B 细胞淋巴瘤、滤泡性淋巴瘤       •靶标：CD19       •开发商：Kite Pharma Inc.       •首次获批时间：2017年10月18日       Brexucabtagene Autoleucel（Tecartus）       •适应症：复发性或难治性 (r/r) B 细胞前体急性淋巴细胞白血病 (B-ALL)、复发/难治性套细胞淋巴瘤（r/r MCL）       •靶标：CD19       •开发商：Kite Pharma, Inc       •首次获批时间：2020年7月24日       Lisocabtagene Maraleucel（Breyanzi）       •适应症：大 B 细胞淋巴瘤 (LBCL)，包括弥漫性大 B 细胞淋巴瘤 (DLBCL)（包括惰性淋巴瘤引起的 DLBCL）、高级别 B 细胞淋巴瘤、原发性纵隔大 B 细胞淋巴瘤和3B 级滤泡性淋巴瘤       •靶标：CD19       •开发商：BMS       •首次获批时间：2021年2月5日       Idecabtagene Vicleucel（Abecma）       图片来源：Abecmahcp.com       •适应症：复发性或难治性多发性骨髓瘤 (经过四种或更多种既往疗法，包括免疫调节剂、蛋白酶体抑制剂和抗 CD38 单克隆抗体)。   •靶标：BCMA       •开发商：Celgene Corporation（隶属于BMS）       •首次获批时间：2021年3月26日       Ciltacabtagene autoleucel（Carvykti）       •适应症：多发性骨髓瘤       •靶标：BCMA       •开发商：Janssen Biotech, Inc       •获批时间：2022年2月28日       4. 2024年待批CAR-T疗法       Carvykti (ciltacabtagene autoleucel, cilta-cel)       •BLA属性：新适应症       •适应症：癌症-治疗已接受过至少一种既往疗法 (包括蛋白酶体抑制剂和免疫调节剂) 的复发性和lenalidomide难治性多发性骨髓瘤成人患者       •靶标：BCMA       •开发商：Janssen 和 Legend Biotech       •BLA类型：标准审评       •PDUFA时间：2024年4月5日       Breyanzi (lisocabtagene maraleucel)       •BLA属性：新适应症       •适应症：癌症 -治疗成人复发性或难治性滤泡性淋巴瘤 (FL)       •靶标：CD19       •开发商：BMS       •BLA类型：优先审评       •PDUFA时间：2024年5月23日       Breyanzi (lisocabtagene maraleucel)       •BLA属性：新适应症       •适应症：癌症 -治疗布鲁顿酪氨酸激酶抑制剂后复发或难治性套细胞淋巴瘤 (MCL) 成人患者       •靶标：CD19       •开发商：BMS       •BLA类型：优先审评       •PDUFA时间：2024年5月31日       Obecabtagene autoleucel (obe-cel)       •BLA属性：新疗法       •适应症：治疗复发性或难治性成人 B 细胞急性淋巴细胞白血病 (ALL)       •靶标：CD19       •开发商：Autolus Therapeutics       •BLA类型：标准审评       •PDUFA时间：2024年11月16日       5. 引领CAR-T开发的生物科技公司       随着CAR-T疗法不断被大型制药公司看重，专注于这种细胞疗法的生物科技公司也成为了行业的关注焦点。       Allogene Therapeutics       •总部：美国加州旧金山       •创立时间：2017年       •主要CAR-T资产：ALLO-501A（cema-cel，复发性或难治性非霍奇金淋巴瘤 ，2期）       图3. Allogene的CAR-T项目ALLO-501A作用机理示意图。（图片来源：Allogene）       Allogene的技术平通通过开发同种异体 CAR-T 细胞治疗产品来解决自体 CAR-T 疗法的局限性。同种异体疗法使用来自健康捐赠者的 T 细胞。其最 先进的项目是 cema-cel（ALLO-501A，图3），是一种抗CD19 CAR-T 疗法，目前处在复发性或难治性非霍奇金淋巴瘤的2期研究，也在一项1期研究中针对复发/难治性慢性淋巴细胞白血病。除此之外，Allogene还在两项 1 期试验中以 B 细胞成熟抗原 (BCMA) 为靶标，研究其治疗多发性骨髓瘤的 CAR-T 候选药物 ALLO-715 和 ALLO-6053。       Anixa Biosciences       •总部：美国加州圣荷西       •创立时间：1982年       •主要CAR-T资产：1项1期资产（卵巢瘤）       Anixa Biosciences 专注于癌症治疗，是一家从事 CAR-T 细胞治疗和癌症疫苗领域的公司。Anixa Biosciences的一项1期资产针对卵巢瘤开发。这项研究是Anixa Biosciences与Moffitt癌症中心合作进行的，靶标是卵巢上存在的卵泡刺激素受体（FSHR）。       Autolus Therapeutics       •总部：英国伦敦       •创立时间：2014年       •主要CAR-T资产：Obe-cel（obecabtagene autoleucel，AUTO1，复发/难治性 B-细胞急性淋巴细胞白血病，已提交BLA申请）       Autolus Therapeutics是CAR-T 疗法的领跑者，他们最 先进的CAR-T资产obe-cel已经递交了BLA申请。Obe-cel以 CD19 为靶点，针对当前 CD19 CAR-T 细胞疗法在临床活性和安全性方面的局限性。Obe-cel 具有快速与靶标结合并解离速率，最大 程度地减少工程化T细胞的过度激活，降低毒性和T 细胞耗竭，从而增强持久性，提高工程化T 细胞连续杀死目标癌细胞的能力。       Obe-cel 在成人急性淋巴细胞白血病的达到了终点并向CBER递交了BLA，它的PDUFA 日期定为 2024 年 11 月 16 日。       BioNTech       •总部：德国美因茨       •创立时间：2008年       •主要CAR-T资产：BNT211（实体瘤，1期），BNT221（难治性转移性黑色素瘤，1期）       德国生物技术公司 BioNTech 的主要开发重点是mRNA 癌症疫苗，但其管线中也拥有三款 CAR-T 资产。       BioNTech 的BNT211针对实体瘤，其晚期实体瘤的 1/2 期研究表现出了优良的抗肿瘤活性，总体缓解率为 59%，疾病控制率为 95%。BioNTech的另一款候选CAR-T资产BNT221 正在难治性转移性黑色素瘤患者中进行1期研究。       2024年2月， BioNTech向 Autolus Therapeutics 支付了 2.5 亿美元，使用后者在英国的生产和临床基地来进一步开发 BNT211。       Cartesian Therapeutics       •总部：美国麻省沃特敦       •创立时间：2007年       •主要CAR-T资产：Descartes-08（重症肌无力，2期；系统性红斑狼疮和其它自免疫疾病，1期）       Cartesian Therapeutics的特别之处在于他们的CAR-T资产针对的不是肿瘤学，而是自免疫疾病。他们开发了首 个针对自身免疫性疾病的 mRNA CAR-T 细胞疗法。       mRNA 细胞疗法是一种集传统mRNA 疗法与传统 DNA 工程细胞疗法之优势而创造出的新疗法。与传统的基于纳米颗粒的 RNA 疗法相比，mRNA 细胞疗法在重复给药时可能具有最小的免疫原性。它还可以用组织特异性归巢蛋白进行工程改造。       与传统昂贵的DNA细胞疗法相比，mRNA细胞疗法的设计不需要预处理化疗，具有可预测和可控的药代动力学，并避免基因组整合的风险。与 DNA 类似物相比，mRNA 细胞疗法可能更安全、更有效且更便宜，并且有可能在门诊环境中进行。此外，mRNA 细胞疗法旨在实现真正的联合治疗，无需受限于载体载荷。       Descartes-08正在针对重症肌无力进行II期研究。其IIa研究表明，这款候选药物是安全且耐受性良好的，并且能够引起持久的反应。2b 期研究已开始招募患者。Descartes-08还有一项I期研究针对系统性红斑狼疮和其它自免疫疾病。       2023年11 月，Cartesian Therapeutics与美国 Selecta Biosciences 合并，合并后的公司拥有超过 1.1 亿美元的资金支持 Descartes-08 进入临床第 3 阶段。       CARGO Therapeutics       •总部：美国加州圣马特奥       •创立时间：2019年       •主要CAR-T资产：CRG-22（接受CD19 CAR-T细胞疗法后患有复发/难治性大B细胞淋巴瘤的患者，2期；尚未接受 CAR-T 细胞治疗的大B细胞淋巴瘤，1期；儿童 B-细胞急性淋巴细胞白血病，1期）       CARGO Therapeutics 在首次公开募股中筹集了超过 2.8 亿美元资金，已开始对资产 CAR-T 细胞疗法候选药物 CRG-022 进行 2 期试验。该候选药物靶向 CD22，是一种 B 细胞特异性抗原，在超过 8% 的弥漫性 LBCL 病例中有表达（图4）。由于对 CD19 CAR-T 细胞疗法产生耐药性的患者在 CD19 抗原表达丧失（antigen escape）后，CD22 表达通常会保留，因此CRG-022被设计为在患者接受 CD19 靶向 CAR-T 疗法后使用。       图4. CARGO Therapeutics针对的抗原逃逸（Antigen Escape）问题。（图片来源：CARGO Therapeutics）       除此之外，Cargo 正在努力解决共刺激配体（T 细胞表达的分子，如 CD58）的丢失问题。它通过开发 CAR-T 细胞来实现这一目标，无论肿瘤细胞上潜在的 CD58 下调或缺失，CAR-T 细胞都能通过肿瘤抗原诱导 CD2 共刺激信号传导，通过这种方式解决免疫疗法的耐药性问题。Kite Pharma       •总部：美国洛杉矶       •创立时间：2009年（2017年被吉利德收购）       •主要CAR-T管线资产：Axicabtagene ciloleucel（2L+ 高危滤泡性淋巴瘤，3期；1L高危大B细胞淋巴瘤，3期）       从前文介绍的获批CAR-T疗法中就不难看出Kite Pharma在这个领域的地位。六款上市CAR-T疗法中他们开发了两款。其旗帜性产品是治疗 LBCL 的自体 CAR-T 药物 Yescarta ，早在2017 年就获得 FDA 批准，目前正在进行针对其它形式淋巴癌的临床测试。       2023年年底，Kite Pharma宣布将扩大与美国生物技术公司Arcellx的合作关系，推进后者针对BCMA的多发性骨髓瘤候选药物。       Ref.       Brown, C. E. et al. Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat Med (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41591-024-02875-1       KYMRIAH Patient Site. https://www.us.kymriah.com/       Cartesian Therapeutics website. https://www.cartesiantherapeutics.com/rna-cell-therapy/       Stansfield, N. FDA Finalizes Sets of Guidelines for Both CAR-T Products and Genome Editing Products. CGTLive. 12. 03. 2024.       FDA Activity Recap: January 2024 Features Major Approval, New Black Box Warnings, and Updated Guidance Documents. CGTLive. 05. 02. 2024.       Peter, R. M. Eight CAR-T cell therapy companies you should know about. Labiotech. 21. 03. 2024.【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

Positive clinical data updates across multiple drug classes including antibody-drug conjugate (ADC) candidates BNT323/DB-1303, BNT325/DB-1305, CAR-T candidate BNT211, T cell therapy candidate BNT221 and mRNA cancer vaccine candidate BNT116Progress across the oncology pipeline with multiple late-stage trials initiated since third quarter startNew and expanded strategic collaborations reflect BioNTech's commitment to delivering transformational therapies for oncology and infectious diseasesSuccessful launches of Omicron XBB.1.5-adapted monovalent COVID-19 vaccine in markets worldwide Updated 2023 COVID-19 vaccine revenue guidance of around €4 billion Guidance reduction of planned 2023 R&D expenses to €1.8-2.0 billion and SG&A expenses to €600-650 millionFirst nine months of 20231 revenues of €2.3 billion2, net profit of €472 million and diluted earnings per share of €1.94 ($2.113) Conference call and webcast scheduled for November 6, 2023, at 8:00 am ET (2:00 pm CET) MAINZ, Germany, November 6, 2023 (GLOBE NEWSWIRE) -- BioNTech SE (Nasdaq: BNTX, “BioNTech” or “the Company”) today reported financial results for the three and nine months ended September 30, 2023, and provided an update on its corporate progress. “Over the last quarter, we complemented our investigational pipeline with ADC candidates, initiated later-stage clinical trials and presented significant data across modalities including cancer vaccines, cell therapies, ADCs and immune checkpoint modulators. Our strategy focuses on assembling a diverse toolbox of complementary technologies to deliver novel therapies, aiming to improve the standard-of-care for cancer patients,” said Prof. Ugur Sahin, M.D., CEO and Co-Founder of BioNTech. “We combine our internal innovation engine with a high-performance partnership model to transform healthcare and improve patients' quality of life.” Financial Review for the Third Quarter and First Nine Months of 2023 in millions €, except per share data Third Quarter 2023 Third Quarter 2022 Nine Months 2023 Nine Months 2022 Total Revenues2 895.3 3,461.2 2,340.0 13,032.3 Net Profit 160.6 1,784.9 472.4 7,155.7 Diluted Earnings per Share 0.67 6.98 1.94 27.70 Total revenues reported were €895.3 million2 for the three months ended September 30, 2023, compared to €3,461.2 million for the comparative prior year period. For the nine months ended September 30, 2023, total revenues were €2,340.0 million2, compared to €13,032.3 million for the comparative prior year period. Inventory write-downs by BioNTech's collaboration partner Pfizer, Inc. ("Pfizer") reduced BioNTech's revenues by €507.9 million and €615.4 million for the three and nine months ended September 30, 2023, respectively. Cost of sales were €161.8 million for the three months ended September 30, 2023, compared to €752.8 million for the comparative prior year period. For the nine months ended September 30, 2023, cost of sales were €420.7 million, compared to €2,811.5 million for the comparative prior year period. The change was in line with decreasing COVID-19 vaccine revenues. Research and development (R&D) expenses were €497.9 million for the three months ended September 30, 2023, compared to €341.8 million for the comparative prior year period. For the nine months ended September 30, 2023, research and development expenses were €1,205.3 million, compared to €1,027.2 million for the comparative prior year period. Research and Development expenses are mainly influenced by progressing clinical studies for pipeline candidates, the development of variant adapted as well as next generation COVID-19 vaccines and expanding R&D headcount. General and administrative (G&A) expenses were €144.5 million for the three months ended September 30, 2023, compared to €141.0 million for the comparative prior year period. For the nine months ended September 30, 2023, G&A expenses were €386.6 million, compared to €361.8 million for the comparative prior year period. G&A expenses were mainly influenced by increased expenses for IT services as well as expanding the G&A headcount. Income taxes were accrued in an amount of €66.8 million for the three months ended September 30, 2023, compared to €659.2 million accrued for the comparative prior year period. For the nine months ended September 30, 2023, income taxes were accrued with an amount of €50.5 million, compared to €2,625.8 million accrued for the comparative prior year period. The derived annual effective income tax rate for the nine months ended September 30, 2023, was 9.7% which is expected to change over the 2023 financial year to be in line with the updated estimated annual cash effective income tax rate of somewhere around 21% for the BioNTech Group. Net profit was €160.6 million for the three months ended September 30, 2023, compared to €1,784.9 million for the comparative prior year period. For the nine months ended September 30, 2023, net profit was €472.4 million, compared to €7,155.7 million net profit for the comparative prior year period. Cash and cash equivalents as well as security investments were €16,967.6 million, comprising €13,495.8 million cash and cash equivalents and €3,471.8 million security investments, respectively, as of September 30, 2023. Subsequent to the end of the reporting period, as of October 16, 2023, a payment of €565.0 million was received from BioNTech's collaboration partner, settling BioNTech’s gross profit share for the second quarter of 2023 (as defined by the contract with Pfizer). Diluted earnings per share was €0.67 for the three months ended September 30, 2023, compared to a diluted earnings per share €6.98 for the comparative prior year period. For the nine months ended September 30, 2023, diluted earnings per share was €1.94, compared to €27.70 diluted earnings per share for the comparative prior year period. Shares outstanding as of September 30, 2023, were 237,715,500, excluding 10,836,700 shares in treasury. In March 2023, BioNTech initiated a new share repurchase program pursuant to which the Company was able to purchase American Depositary Shares, or ADSs, each representing one ordinary share of the Company, in the amount of up to $0.5 billion during the remainder of 2023. During the three months ended September 30, 2023, 3,114,280 ADSs were repurchased under the share repurchase program at an average price of €97.15 ($106.923), for total consideration of €302.5 million ($333.1 million3). The trading plan for BioNTech's 2023 program concluded on September 18, 2023. “In the third quarter, we continued to invest in our capabilities and our portfolio of innovative product candidates while strengthening the financial position of BioNTech. About €17 billion in cash and security investments provide strategic flexibility and is a major strength, especially in these days, where financial stability is key,” said Jens Holstein, CFO of BioNTech. “We updated our financial guidance for the full year 2023. In line with anticipated revenues of around €4 billion, we reduced relevant cost drivers for 2023 as we effectively manage our expenditures.” Outlook updated for the 2023 Financial YearThe Company updated its COVID-19 vaccine revenue guidance and updates its previous expense and capex guidance for the 2023 financial year: BioNTech COVID-19 Vaccine Revenues for the 2023 Financial Year: Initial Guidance Mar 2023 Updated GuidanceNov 2023 Estimated BioNTech COVID-19 vaccine revenues for the full 2023 financial year ~ €5 billion ~ €4 billion The revenues estimate reflects expected revenues related to BioNTech’s share of gross profit from COVID-19 vaccine sales in the collaboration partners’ territories, from direct COVID-19 vaccine sales to customers in BioNTech’s territory and expected revenues generated from products manufactured by BioNTech and sold to collaboration partners. Revenue guidance is based on various assumptions. These include, but are not limited to, expectations regarding: transitions in the purchasing environment; the timing and receipt of regulatory approvals and recommendations; the progress of vaccination campaigns; and seasonal variations in SARS-CoV-2 circulation and vaccination uptake. Several factors drive the Company’s adjusted revenue guidance. Such factors include BioNTech’s and Pfizer’s lower than previously forecast revenue expectations for the full 2023 financial year, which take into account delays in the expected timing of regulatory approvals, as well as the effects of Pfizer’s recently-announced write-downs and other charges. While fewer primary vaccinations and lower population-wide levels of boosting are anticipated overall compared to the same period in prior years, vaccine adaptation and seasonal trends are expected to lead to demand peaks in the autumn and winter compared to other seasons. As a result of later-than-anticipated regulatory approvals and their effect on national vaccination campaign timelines, expected sales have shifted to future periods. In general, the Company continues to remain largely dependent on revenues generated in its collaboration partner’s territories. In addition, BioNTech's revenues have been affected by the inventory write-downs and other charges related to COMIRNATY that were previously announced by the Company’s collaboration partner Pfizer. As a result of the Company’s continued assessment of these write-downs and other charges, the Company has determined that the charges originating on BioNTech’s end had largely already been reflected in the Company’s financial results for the 2022 financial year, and to a smaller extent, continued to be reflected during 2023. Ultimately, the initial estimate of “up to €0.9 billion” impact has been refined by the Company. The impact from the collaboration partner's charges onto the Company's revenues has been identified to be €0.6 billion for the nine months ended September 30, 2023 and €0.5 billion for the three months ended September 30, 2023, which is reflected in the revised revenues guidance. Planned 2023 Financial Year Expenses and Capex4: Initial Guidance Mar 2023 Updated GuidanceNov 2023 R&D expenses5 €2,400m - €2,600m €1,800m - €2,000m SG&A expenses €650m - €750m €600m - €650m Capital expenditures for operating activities6 €500m - €600m €200m - €300m Estimated 2023 Financial Year Tax Assumptions: Initial Guidance Mar 2023 Updated GuidanceNov 2023 BioNTech Group estimated annual cash effective income tax rate7 ~ 27% ~ 21% The full interim unaudited condensed consolidated financial statements can be found in BioNTech's Report on Form 6-K for the period ended September 30, 2023, filed today with the United States Securities and Exchange Commission ("SEC") and available at https://www.sec.gov/. Endnotes 1Financial information is prepared and presented in Euros and numbers are rounded to millions and billions of Euros in accordance with standard commercial practice. 2BioNTech’s profit share is estimated based on preliminary data shared between Pfizer and BioNTech as further described in the Annual Report. Any changes in the estimated share of the collaboration partner’s gross profit will be recognized prospectively. 3Calculated applying the average foreign exchange rate for the nine months ended September 30, 2023, as published by the German Central Bank (Deutsche Bundesbank). 4Numbers reflect current base case projections and are calculated based on constant currency rates. Excluding external risks that are not yet known and/or quantifiable, including, but not limited to, the effects of ongoing and/or future legal disputes or related activity. 5Numbers include effects identified from additional collaborations or potential M&A transactions to the extent disclosed and will be updated as needed. 6Numbers exclude potential effects caused by or driven from collaborations or M&A transactions. 7Numbers exclude potential effects caused by or driven from share-based payment settlements in the course of 2023. Operational Review and Pipeline Update for the Third Quarter 2023 and Key Post Period-End Events COVID-19 Vaccine Marketed Products In August, BioNTech and Pfizer received a positive opinion from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) recommending marketing authorization for the companies' Omicron XBB.1.5-adapted monovalent COVID-19 vaccine for individuals 6 months of age and older.In September, BioNTech and Pfizer received approval of their supplemental Biologics License Application by the U.S. Food and Drug Administration (FDA) for their Omicron XBB.1.5-adapted monovalent COVID-19 vaccine for individuals 12 years and older, and emergency use authorization for individuals 6 months through 11 years of age. Several other national healthcare regulatory bodies, including in the United Kingdom (UK), Japan, Canada and South Korea, have approved BioNTech and Pfizer's monovalent XBB.1.5-adapted vaccine.In October, BioNTech and Pfizer announced an agreement between the Japanese government and Pfizer Japan Co., Ltd. to supply an additional 9 million doses of the Omicron XBB.1.5-adapted COVID-19 vaccine for the special vaccination program in Japan which started this autumn. This follows an agreement between the Japanese government and Pfizer Inc. in July to supply 20 million doses and additional supplies as needed, and an agreement announced in September to provide additional 10 million doses of the companies’ Omicron XBB.1.5-adapted COVID-19 vaccine for the special vaccination program in Japan. Select Oncology Pipeline Highlights - Recent and upcoming trial starts and data readouts Antibody-Drug Conjugate (ADC) Pipeline BioNTech's pipeline comprises several ADCs that are based on a topoisomerase I inhibitor as payload. BNT323/DB-1303 is an HER2-targeted ADC candidate being developed in collaboration with Duality Biologics (Suzhou) Co. Ltd. (“DualityBio”). An open-label, multi-center, randomized Phase 3 clinical trial (NCT06018337) is planned to evaluate BNT323/DB-1303 versus investigator's choice of chemotherapy in advanced or metastatic Hormone Receptor (HR)+, HER2-low breast cancer subjects whose disease has progressed on at least two lines of prior endocrine therapy (ET) or within six months of first line ET plus CDK4/6 inhibitor in the metastatic setting, and no prior chemotherapy. The study aims to enroll approximately 532 patients.In September, clinical data from the ongoing Phase 1/2 clinical trial (NCT05150691) evaluating BNT323/DB-1303 in patients with advanced/unresectable, recurrent, or metastatic HER2-expressing solid tumors were presented at the 2023 European Congress on Gynaecological Oncology Annual Meeting. BNT323/DB-1303 showed a manageable safety profile and no new safety signals were observed. BNT323/DB-1303 demonstrated encouraging antitumor activity in patients (n=17) with advanced, recurrent or metastatic HER2-expressing endometrial cancer with an objective response rate (“ORR”; confirmed and unconfirmed) of 58.8% and disease control rate (“DCR”) of 94.1%. BNT324/DB-1311 is an ADC candidate being developed in collaboration with DualityBio. In September, the first patient was dosed in a first-in-human, open-label Phase 1/2 clinical trial (NCT05914116) evaluating BNT324/DB-1311 in multiple advanced solid tumors. BNT325/DB-1305 is a TROP-2-targeted ADC candidate being developed in collaboration with DualityBio. In October, clinical data from the ongoing Phase 1/2 clinical trial (NCT05438329) in patients with advanced solid tumors were presented at the 2023 European Society of Medical Oncology (ESMO) Annual Meeting suggesting a manageable safety profile at lower dose levels. Encouraging preliminary activity of BNT325/DB-1305 was observed with an ORR of 30.4% (7/23), and DCR of 87.0% (20/23) (both unconfirmed) across overall study population. Encouraging efficacy signals were observed in non-small cell lung cancer (NSCLC) patients with an ORR of 46.2% (6/13) and an DCR of 92.3% (12/13) (both unconfirmed). BNT326/YL202 is a HER3-targeted ADC candidate being developed in collaboration with MediLink Therapeutics (Suzhou) Co., Ltd. (“MediLink”). A multicenter, open-label, first-in-human Phase 1 clinical trial (NCT05653752) evaluating YL202 as a later-line treatment in patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated NSCLC or HR-positive and HER2-negative breast cancer is ongoing. Next-Generation Immune Checkpoint Immunomodulator Pipeline BNT316/ONC-392 (gotistobart) is an anti-CTLA-4 monoclonal antibody candidate being developed in collaboration with OncoC4, Inc. (“OncoC4”). BNT316/ONC-392 (gotistobart) is designed to offer a differentiated safety profile that may allow for higher dosing and longer duration of treatment both as monotherapy and in combination with other therapies. In November, clinical data were presented at the 2023 Society for Immunotherapy of Cancer (SITC) Annual Meeting from the ongoing Phase 1/2 trial (NCT04140526) showing that BNT316/ONC-392 (gotistobart) monotherapy has a manageable safety profile. Early readout of the expansion cohort showed encouraging clinical activity in patients with immunotherapy-resistant NSCLC. A Phase 3 trial evaluating BNT316/ONC-392 (gotistobart) monotherapy in this patient population is ongoing.A Phase 2 clinical trial (NCT05682443) is planned to evaluate the safety and efficacy of BNT316/ONC-392 in combination with lutetium Lu-177 vipivotide tetraxetan in metastatic castration resistant prostate cancer patients who have disease progressed on androgen receptor pathway inhibition. BNT312/GEN1042 is a bispecific antibody candidate based on Genmab A/S (“Genmab”)'s DuoBody technology and designed to induce conditional immune activation by crosslinking CD40 and 4-1BB positive cells. In November, preclinical data demonstrating in vivo antitumor activity and peripheral immune modulation of a chimeric variant of BNT312/GEN1042 were presented at the 2023 SITC Annual Meeting. These data support ongoing Phase 1/2 clinical studies evaluating the combination of BNT312/GEN1042 with pembrolizumab and chemotherapy in patients with advanced solid tumors (NCT04083599, NCT05491317). BNT314/GEN1059 is a bispecific antibody candidate designed to boost antitumor immune responses through EpCAM-dependent 4-1BB agonistic activity. This is the fifth drug candidate under BioNTech's collaboration with Genmab where the development costs and potential future profits will be shared equally. In October, preclinical data characterizing the mechanism of action of BNT314/GEN1059 were presented at the 2023 ESMO Annual Meeting. A first-in-human trial sponsored by BioNTech is planned to investigate the clinical safety and preliminary antitumor activity of BNT314/GEN1059 in patients with solid tumors. Cancer Vaccines Pipeline BNT116 is based on BioNTech’s FixVac platform, and is a wholly owned, systemically administered, off-the-shelf mRNA-based cancer vaccine candidate. This candidate is being evaluated for the treatment of advanced NSCLC. In July, BioNTech and Regeneron Pharmaceuticals Inc. (“Regeneron”) initiated a randomized, controlled Phase 2 clinical trial (NCT05557591) to evaluate BNT116 in combination with cemiplimab (Regeneron’s Libtayo) and cemiplimab alone as first-line treatment in patients with advanced NSCLC whose tumors express PD-L1 in ≥ 50% of tumor cells.In November, clinical data from the ongoing Phase 1 clinical trial (NCT05142189) evaluating the safety, tolerability and preliminary efficacy of BNT116 alone and in combination with cemiplimab (Regeneron’s Libtayo) or chemotherapy across various cohorts of patients were presented at the 2023 SITC Annual Meeting. BNT116 was generally well tolerated with an expected safety profile as monotherapy and in combination with cemiplimab. In heavily pretreated NSCLC patients, treatment with BNT116 with cemiplimab from cycle 3 onwards showed early clinical activity. BNT122 (Autogene cevumeran) is an mRNA cancer vaccine candidate based on an individualized neoantigen-specific immunotherapy (iNeST) approach being developed in collaboration with Genentech, Inc. (“Genentech”), a member of the Roche Group (“Roche”). In October, the first patient was dosed in a randomized Phase 2 clinical trial (NCT05968326) evaluating the safety and efficacy of BNT122 in combination with atezolizumab (Roche’s Tecentriq) followed by adjuvant standard-of-care chemotherapy (mFOLFIRINOX) in patients with resected pancreatic ductal adenocarcinoma (PDAC) compared to chemotherapy alone. The Phase 2 study is expected to enroll 260 patients with resected PDAC, who have not received prior systemic anti-cancer treatment and showed no evidence of disease after surgery. Cell Therapy Pipeline BNT211 is an autologous Claudin-6 (CLDN6)-targeting chimeric antigen receptor (CAR) T cell therapy candidate that is being tested alone and in combination with a CAR-T cell Amplifying RNA Vaccine (“CARVac”), encoding CLDN6. In October, clinical data from the ongoing Phase 1/2 clinical trial (NCT04503278) were presented at the 2023 ESMO Annual Meeting detailing the new dose escalation of CLDN6 CAR-T cells with and without a CLDN6-encoding mRNA vaccine for the treatment of CLDN6-positive relapsed/refractory solid tumors using an automated manufacturing process. CLDN6 CAR-T cells ± CLDN6 CARVac demonstrated encouraging signs of clinical activity. In several patients treated with CARVac, an increased persistence of cancer-specific CAR-T cells was observed. The rate of treatment-dependent adverse events was dose-dependent. After determination of the recommended Phase 2 dose, BioNTech plans to initiate a pivotal trial in germ cell tumors. BNT221 is an autologous, fully personalized, polyspecific T-cell therapy candidate directed against selected sets of individual neoantigens. BNT221 is based on expanded neoantigen-specific memory T cells and induced naive T cells. In October and November, first monotherapy clinical data from the ongoing first-in-human Phase 1 dose escalation clinical trial (NCT04625205) in patients with checkpoint inhibitor unresponsive or refractory metastatic melanoma were presented at the 2023 ESMO and SITC Annual Meetings. These initial results showed a manageable safety profile and encouraging activity signs of tumor regression in several patients with anti-PD-1/anti-CTLA-4 pretreated advanced or metastatic melanoma. Select Infectious Pipeline Highlights - Recent trial starts and data readouts COVID-19-Influenza Combination mRNA Vaccine Program – BNT162b2 + BNT161 In October, BioNTech and Pfizer announced top-line results from a Phase 1/2 clinical trial (NCT05596734) evaluating the safety, tolerability and immunogenicity of mRNA-based combination vaccine candidates for influenza and COVID-19 in healthy adults 18 to 64 years of age. In the clinical trial, the vaccine candidates were compared to licensed influenza vaccines and the Pfizer-BioNTech COVID-19 Omicron BA.4/BA.5 adapted bivalent vaccine given separately at the same visit. The data from the trial demonstrated robust immune responses to influenza A, influenza B, and SARS-CoV-2 strains, as well as a safety profile consistent with the safety profile of the companies’ COVID-19 vaccine. A pivotal Phase 3 trial is expected to be initiated in the coming months. Mpox Program - BNT166 The BNT166 vaccine candidates encode surface antigens that are expressed in the two infectious forms of the mpox virus (MPXV) with the aim to efficiently fight virus replication and infectivity. In partnership with the Coalition for Epidemic Preparedness Innovations (CEPI), BNT166 is part of BioNTech’s infectious disease vaccine programs aiming to help provide equitable access to effective and well-tolerated vaccines for high medical need indications. In October, the first patient was dosed in a Phase 1/2 clinical trial (NCT05988203) evaluating the safety, tolerability, reactogenicity and immunogenicity of two mRNA-based multivalent vaccine candidates against mpox. The trial aims to enroll 96 healthy participants with and without prior history of known or suspected smallpox vaccination. Corporate Update for the Third Quarter 2023 and Key Post Period-End Events In July, BioNTech successfully completed its previously announced acquisition of InstaDeep Ltd. (“InstaDeep”), following the satisfaction of all customary closing conditions. The acquisition supports the Company’s strategy to build world-leading capabilities in Artificial Intelligence (“AI”)-driven drug discovery and development. InstaDeep will operate as a UK-based global subsidiary of BioNTech. The transaction adds approximately 290 highly skilled professionals to BioNTech’s existing bioinformatics and data science workforce, including teams in AI, machine learning, bioengineering, data science, and software development.In September, BioNTech and CEPI announced a strategic partnership to advance mRNA-based vaccine candidates with the development of BNT166 for the prevention of mpox, an infectious disease that can lead to severe, life-threatening complications. The strategic partnership aims to contribute to CEPI’s 100 Days Mission, a goal to accelerate development of well-tolerated and effective vaccines against a potential future pandemic virus so that a vaccine can be ready for regulatory authorization and manufacturing at scale within 100 days of recognition of a pandemic pathogen. This mission is spearheaded by CEPI and embraced by the G7, G20, and industry leaders. The partnership between BioNTech and CEPI could help accelerate responses to future outbreaks caused by viruses of the Orthopoxvirus viral family. CEPI will provide funding of up to $90 million to support the development of mRNA-based vaccine candidates.Post period-end, in October, BioNTech and MediLink entered into a strategic research collaboration and worldwide license agreement to develop a next-generation ADC candidate against Human Epidermal Growth Factor Receptor 3 (HER3). Under the terms of the agreement, MediLink will grant BioNTech exclusive global rights, excluding Mainland China, Hong Kong Special Administrative Region, and Macau Special Administrative Region, for the development, manufacturing, and commercialization of one of MediLink's ADC assets. In exchange, BioNTech will provide MediLink with an upfront payment totaling of $70 million and additional development, regulatory and commercial milestone payments potentially totaling over $1 billion. The completion of the agreement is subject to customary closing conditions.Also, post period-end in November, BioNTech and Biotheus Inc. (“Biotheus”), announced an exclusive license and collaboration agreement under which BioNTech will have the rights to develop, manufacture and commercialize PM8002, a bispecific antibody candidate targeting PD-L1 and VEGF, globally except in Greater China, where Biotheus retains the rights to PM8002. PM8002 is currently being tested in a Phase 2/3 study in China to evaluate the efficacy and safety of the candidate as a monotherapy or in combination with chemotherapy in patients with NSCLC. Upcoming Investor and Analyst Events BioNTech’s Innovation Series Day will take place tomorrow, Tuesday, November 7, 2023, from 9.00 a.m. ET (3.00 p.m. CET) in Boston, USA. The event will provide an update on BioNTech’s clinical progress across its pipeline and provide a deep dive into scientific and technological innovations from its research engine. The slide presentation and audio of the webcast will be available via this link.BioNTech's fourth quarter and full year 2023 financial results and corporate update are scheduled for Wednesday, March 20, 2024. Conference Call and Webcast Information BioNTech invites investors and the general public to join a conference call and webcast with investment analysts today, November 6, 2023, at 8.00 a.m. ET (2.00 p.m. CET) to report its financial results and provide a corporate update for the third quarter of 2023. To access the live conference call via telephone, please register via this link. Once registered, dial-in numbers and a pin number will be provided. The slide presentation and audio of the webcast will be available via this link. Participants may also access the slides and the webcast of the conference call via the “Events & Presentations” page of the Investor Relations section of the Company’s website at https://biontech.com. A replay of the webcast will be available shortly after the conclusion of the call and archived on the Company’s website for 30 days following the call. About BioNTechBiopharmaceutical New Technologies (BioNTech) is a next generation immunotherapy company pioneering novel therapies for cancer and other serious diseases. The Company exploits a wide array of computational discovery and therapeutic drug platforms for the rapid development of novel biopharmaceuticals. Its broad portfolio of oncology product candidates includes individualized and off-the-shelf mRNA-based therapies, innovative chimeric antigen receptor (CAR) T cells, several protein-based therapeutics, including bispecific immune checkpoint modulators, targeted cancer antibodies and antibody-drug conjugate (ADC) therapeutics, as well as small molecules. Based on its deep expertise in mRNA vaccine development and in-house manufacturing capabilities, BioNTech and its collaborators are developing multiple mRNA vaccine candidates for a range of infectious diseases alongside its diverse oncology pipeline. BioNTech has established a broad set of relationships with multiple global pharmaceutical collaborators, including Duality Biologics, Fosun Pharma, Genentech, a member of the Roche Group, Genevant, Genmab, OncoC4, Regeneron, Sanofi and Pfizer. For more information, please visit www.BioNTech.com. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: BioNTech's expected revenues and net profit related to sales of BioNTech's COVID-19 vaccine, referred to as COMIRNATY where approved for use under full or conditional marketing authorization, in territories controlled by BioNTech's collaboration partners, particularly for those figures that are derived from preliminary estimates provided by BioNTech's partners; the rate and degree of market acceptance of BioNTech's COVID-19 vaccine and, if approved, BioNTech's investigational medicines; expectations regarding anticipated changes in COVID-19 vaccine demand, including changes to the ordering environment and expected regulatory recommendations to adapt vaccines to address new variants or sublineages; the initiation, timing, progress, results, and cost of BioNTech's research and development programs, including those relating to additional formulations of BioNTech's COVID-19 vaccine, and BioNTech's current and future preclinical studies and clinical trials, including statements regarding the timing of initiation and completion of studies or trials and related preparatory work and the availability of results; our expectations with respect to our intellectual property; the impact of the Company’s acquisition of InstaDeep Ltd. and the Company's collaboration and licensing agreements; the development of sustainable vaccine production and supply solutions, and the nature and feasibility of these solutions; and BioNTech's estimates of commercial and other revenues, cost of sales, research and development expenses, sales and marketing expenses, general and administrative expenses, capital expenditures, income taxes, net profit, cash, cash equivalents and security investments, shares outstanding and cash outflows and share consideration. In some cases, forward-looking statements can be identified by terminology such as “will,” “may,” “should,” “expects,” “intends,” “plans,” “aims,” “anticipates,” “believes,” “estimates,” “predicts,” “potential,” “continue,” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this press release are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond BioNTech’s control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks and uncertainties include, but are not limited to: BioNTech's pricing and coverage negotiations with governmental authorities, private health insurers and other third-party payors after BioNTech's initial sales to national governments; the future commercial demand and medical need for initial or booster doses of a COVID-19 vaccine; competition from other COVID-19 vaccines or related to BioNTech's other product candidates, including those with different mechanisms of action and different manufacturing and distribution constraints, on the basis of, among other things, efficacy, cost, convenience of storage and distribution, breadth of approved use, side-effect profile and durability of immune response; the timing of and BioNTech's ability to obtain and maintain regulatory approval for BioNTech's product candidates; the ability of BioNTech’s COVID-19 vaccines to prevent COVID-19 caused by emerging virus variants; BioNTech's and its counterparties’ ability to manage and source necessary energy resources; BioNTech's ability to identify research opportunities and discover and develop investigational medicines; the ability and willingness of BioNTech's third-party collaborators to continue research and development activities relating to BioNTech's development candidates and investigational medicines; the impact of the COVID-19 pandemic on BioNTech's development programs, supply chain, collaborators and financial performance; unforeseen safety issues and potential claims that are alleged to arise from the use of BioNTech's COVID-19 vaccine and other products and product candidates developed or manufactured by BioNTech; BioNTech's and its collaborators’ ability to commercialize and market BioNTech's COVID-19 vaccine and, if approved, its product candidates; BioNTech's ability to manage its development and expansion; regulatory developments in the United States and other countries; BioNTech's ability to effectively scale BioNTech's production capabilities and manufacture BioNTech's products, including BioNTech's target COVID-19 vaccine production levels, and BioNTech's product candidates; risks relating to the global financial system and markets; and other factors not known to BioNTech at this time. You should review the risks and uncertainties described under the heading “Risk Factors” in BioNTech's Report on Form 6-K for the period ended September 30, 2023 and in subsequent filings made by BioNTech with the SEC, which are available on the SEC’s website at https://www.sec.gov/. Except as required by law, BioNTech disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release in the event of new information, future developments or otherwise. These forward-looking statements are based on BioNTech’s current expectations and speak only as of the date hereof. CONTACTS Investor RelationsVictoria Meissner, M.D.+1 617 528 8293Investors@biontech.de Media Relations Jasmina Alatovic +49 (0)6131 9084 1513 Media@biontech.de Interim Consolidated Statements of Profit or Loss Three months ended September 30, Nine months ended September 30, 2023 2022 2023 2022 (in millions €, except per share data) (unaudited) (unaudited) (unaudited) (unaudited) Revenues Commercial revenues 893.7 3,394.8 2,336.6 12,923.3 Research & development revenues 1.6 66.4 3.4 109.0 Total revenues 895.3 3,461.2 2,340.0 13,032.3 Cost of sales (161.8) (752.8) (420.7) (2,811.5) Research and development expenses (497.9) (341.8) (1,205.3) (1,027.2) Sales and marketing expenses (14.4) (12.8) (44.7) (44.9) General and administrative expenses (144.5) (141.0) (386.6) (361.8) Other operating expenses (31.4) (285.1) (223.7) (594.6) Other operating income 27.8 459.8 105.2 1,157.5 Operating income 73.1 2,387.5 164.2 9,349.8 Finance income 156.3 60.9 363.2 448.5 Finance expenses (2.0) (4.3) (4.5) (16.8) Profit before tax 227.4 2,444.1 522.9 9,781.5 Income taxes (66.8) (659.2) (50.5) (2,625.8) Profit for the period 160.6 1,784.9 472.4 7,155.7 Earnings per share Basic earnings for the period per share 0.67 7.43 1.96 29.47 Diluted earnings for the period per share 0.67 6.98 1.94 27.70 Interim Consolidated Statements of Financial Position September 30, December 31, (in millions €) 2023 2022 Assets (unaudited) Non-current assets Intangible assets 665.5 158.5 Goodwill 365.6 61.2 Property, plant and equipment 728.9 609.2 Right-of-use assets 197.0 211.9 Other financial assets 1,292.7 80.2 Other non-financial assets 0.3 6.5 Deferred tax assets 208.1 229.6 Total non-current assets 3,458.1 1,357.1 Current assets Inventories 415.7 439.6 Trade and other receivables 2,002.0 7,145.6 Contract assets 6.8 — Other financial assets 2,253.3 189.4 Other non-financial assets 286.2 271.9 Income tax assets 289.3 0.4 Cash and cash equivalents 13,495.8 13,875.1 Total current assets 18,749.1 21,922.0 Total assets 22,207.2 23,279.1 Equity and liabilities Equity Share capital 248.6 248.6 Capital reserve 1,228.4 1,828.2 Treasury shares (10.8) (5.3) Retained earnings 19,305.4 18,833.0 Other reserves (904.8) (848.9) Total equity 19,866.8 20,055.6 Non-current liabilities Lease liabilities, loans and borrowings 161.9 176.2 Other financial liabilities 38.5 6.1 Income tax liabilities — 10.4 Provisions 8.6 8.6 Contract liabilities 268.0 48.4 Other non-financial liabilities 13.1 17.0 Deferred tax liabilities 43.1 6.2 Total non-current liabilities 533.2 272.9 Current liabilities Lease liabilities, loans and borrowings 40.0 36.0 Trade payables and other payables 222.7 204.1 Other financial liabilities 321.6 785.1 Refund liabilities — 24.4 Income tax liabilities 545.2 595.9 Provisions 318.0 367.2 Contract liabilities 167.1 77.1 Other non-financial liabilities 192.6 860.8 Total current liabilities 1,807.2 2,950.6 Total liabilities 2,340.4 3,223.5 Total equity and liabilities 22,207.2 23,279.1 Interim Consolidated Statements of Cash Flows Three months ended September 30, Nine months ended September 30, 2023 2022 2023 2022 (in millions €) (unaudited) (unaudited) (unaudited) (unaudited) Operating activities Profit for the period 160.6 1,784.9 472.4 7,155.7 Income taxes 66.8 659.2 50.5 2,625.8 Profit before tax 227.4 2,444.1 522.9 9,781.5 Adjustments to reconcile profit before tax to net cash flows: Depreciation and amortization of property, plant, equipment, intangible assets and right-of-use assets 41.3 33.5 104.6 94.3 Share-based payment expenses 15.5 61.4 37.2 86.4 Net foreign exchange differences (20.4) 116.2 (364.3) (222.3) Loss on disposal of property, plant and equipment 3.3 0.2 3.6 0.4 Finance income excluding foreign exchange differences (148.5) (7.7) (357.4) (226.5) Finance expense excluding foreign exchange differences 2.0 4.3 4.5 16.8 Movements in government grants — — (3.0) — Unrealized net (gain) / loss on derivative instruments at fair value through profit or loss (3.5) (2.3) 84.7 82.3 Working capital adjustments: Decrease in trade and other receivables, contract assets and other assets 631.2 2,245.4 6,648.6 5,016.7 Decrease in inventories 33.2 72.9 23.9 207.7 (Decrease) / increase in trade payables, other financial liabilities, other liabilities, contract liabilities, refund liabilities and provisions (25.0) 565.9 (293.9) 760.3 Interest received 70.3 4.3 166.4 6.5 Interest paid (1.2) (4.3) (3.7) (16.5) Income tax paid (10.2) (753.3) (1,292.4) (2,834.7) Share-based payments (4.2) (1.7) (761.2) (4.7) Net cash flows from operating activities 811.2 4,778.9 4,520.5 12,748.2 Investing activities Purchase of property, plant and equipment (53.2) (77.9) (165.6) (192.6) Proceeds from sale of property, plant and equipment (0.8) 0.4 (0.8) 0.4 Purchase of intangible assets and right-of-use assets (97.2) (4.7) (348.9) (26.2) Acquisition of subsidiaries and businesses, net of cash acquired (336.9) — (336.9) — Investment in other financial assets (744.1) (1.1) (3,407.2) (31.1) Proceeds from maturity of other financial assets — — — 375.2 Net cash flows from / (used in) investing activities (1,232.2) (83.3) (4,259.4) 125.7 Financing activities Proceeds from issuance of share capital and treasury shares, net of costs — — — 110.5 Proceeds from loans and borrowings 0.1 0.4 0.1 0.6 Repayment of loans and borrowings (0.1) — (0.1) (18.8) Payments related to lease liabilities (9.3) (10.0) (28.0) (31.9) Share repurchase program (301.7) (643.8) (737.7) (930.7) Dividends — — — (484.3) Net cash flows used in financing activities (311.0) (653.4) (765.7) (1,354.6) Net increase / (decrease) in cash and cash equivalents (732.0) 4,042.2 (504.6) 11,519.3 Change in cash and cash equivalents resulting from exchange rate differences and other valuation effects 61.2 46.7 125.3 211.7 Cash and cash equivalents at the beginning of the period 14,166.6 9,334.8 13,875.1 1,692.7 Cash and cash equivalents as of September 30 13,495.8 13,423.7 13,495.8 13,423.7