GEN-1042

On March 6th, the journal Nature Reviews Drug Discovery published a review article discussing the latest advances and applications of bispecific antibodies (bsAbs) in cancer treatment.  Bispecific antibodies (bsAbs) offer a unique advantage due to their ability to target two different antigens simultaneously, which helps to enhance the immune system's recognition and killing of tumor cells. As of the end of 2023, 14 bsAbs have been approved: 11 for cancer treatment and 3 for non-oncological indications. BsAbs come in various structural formats, target different antigens, and mediate antitumor functions through different molecular mechanisms. In the study, the authors outlined recent advances in the application of bsAbs in the field of cancer therapy, focusing on bsAbs that are either approved or in clinical development stage. This includes but is not limited to: bispecific antibody-mediated dual signaling pathway modulators, tumor-targeted receptor agonists, bsAb-drug conjugates, bispecific T cells, natural killer cells, and innate immune cell activators, as well as bispecific checkpoint inhibitors and co-stimulators. Furthermore, the authors also envisioned next-generation bsAbs that are in early development stages, which include trispecific antibodies, bsAb prodrugs, bsAbs that induce tumor-target degradation, and bsAbs that mimic cytokine functions. These novel bsAbs hold the promise to further expand the range and strategies of cancer treatment, providing more precise and efficient therapeutic options. Current Status of Bispecific Antibody ResearchOver the past decade, bispecific antibodies (bsAbs) have garnered significant attention due to their unique multimodal mechanisms of action. Between 2021 and 2023, nine bsAbs have been approved for cancer treatment, reflecting the development trajectory of such antibodies as novel therapeutic agents. The success of bsAbs lies in their ability to surpass the therapeutic effects of natural monospecific antibodies, for instance by recruiting immune effector cells to cancer cells, or by targeting different signaling pathways simultaneously with one molecule. According to statistics, there are currently over 200 bsAbs in clinical development. Among these, 50% have entered Phase II or Phase III clinical trials, and some have already been approved for marketing. Approximately three-quarters of bsAbs are being developed for the treatment of solid tumors, and within the realm of solid tumor therapy, T cell engagers (TCEs, accounting for 32.9%) as well as bsAbs with checkpoint inhibition and/or immunomodulatory mechanisms (accounting for 45.1%) hold a dominant position. In contrast, bsAbs targeting hematological malignancies are primarily composed of TCEs (accounting for 75%) and other mechanisms of immune activation (accounting for 21.9%). These mechanisms usually achieve checkpoint inhibition and/or immunomodulatory effects on natural killer cells and other immune cells through the exploitation of highly tumor-selective or lineage-specific antigens. Notably, around 10% of bsAbs for the treatment of solid tumors have adopted a dual signal inhibition strategy. Below is an overview of the 11 bispecific antibodies approved for cancer treatment: Catumaxomab (Removab): The first approved bispecific antibody (bsAb), developed in collaboration by Trion Pharma and Fresenius, targets EpCAM and CD3ε, and was used for the treatment of malignant ascites (such as that associated with ovarian cancer), but was withdrawn from the EU market in 2013. Blinatumomab (Blincyto): Developed by Amgen, this bispecific T cell engager (TCE) targets CD19 and CD3ε with a BiTE 1+1 format. It was approved in 2014 in the United States, European Union, and Japan for the treatment of acute lymphoblastic leukemia (ALL). Amivantamab (Rybrevant): Developed by J&J, this agent targets both EGFR and MET. Its mechanism of action includes signal transduction inhibition and antibody-dependent cellular cytotoxicity (ADCC) effects, using a Duobody 1+1 format. It was approved in the United States and European Union in 2021 for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. Tebentafusp (KIMMTRAK): Produced by Immunocore, this agent targets the gp100-HLA-A*02 complex and CD3ε. It is a TCE in the form of an scFv-TCR fusion protein. It was approved in 2022 in the United States and European Union for the treatment of uveal melanoma. Mosunetuzumab (Lunsumio): Developed by Roche, this is a bispecific TCE that targets CD20 and CD3ε, using a KiH 1+1 IgG format. It was approved in 2022 in the United States and European Union for the treatment of relapsed/refractory follicular lymphoma. Cadonilimab (Kaitanni): Developed by Akeso, a Chinese biopharmaceutical company, this agent targets PD1 and CTLA4 and is classified as a dual immune checkpoint inhibitor. It has an IgG-scFv tetrabody 2+2 structure and was approved in China in 2022 for the treatment of hepatocellular carcinoma. Teclistamab: Also introduced by J&J, teclistamab is a bispecific T-cell engager (TCE) targeting BCMA and CD3ε. Utilizing a Duobody 1+1 structure, it was approved in 2022 in the United States and the European Union for the treatment of relapsed/refractory multiple myeloma. Glofitamab (Columvi): Originating from the Roche Group, glofitamab is a CD20 and CD3ε bispecific TCE using a CrossMAb 2+1 structure. It received approval in 2023 in the United States and the European Union for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Epcoritamab (T)Epkinly: Jointly developed by Genmab and AbbVie, epcoritamab is also a TCE targeting CD20 and CD3ε. It features a Duobody 1+1 structure and was approved in 2023 in the United States, the European Union, and Japan for the treatment of relapsed/refractory DLBCL. Talquetamab: Another product from J&J, talquetamab targets GPRC5D and CD3ε, and is also a TCE type. Using a Duobody 1+11 structure, it was approved in 2023 in the United States and the European Union for the treatment of relapsed/refractory multiple myeloma. Elranatamab (Elrexfio): Developed by Pfizer, elranatamab targets BCMA and CD3ε as a TCE. With a bsAb (bispecific antibody) 1+1 structure, it was approved in 2023 in the United States and the European Union for the treatment of relapsed/refractory multiple myeloma. The discovery of new bsAbs is primarily driven by the underlying biological principles, and it is necessary to match them with optimal bsAb designs in order to select the correct structural forms, affinity ranges, and epitopes. Characteristics such as target selection, epitope positioning, affinity, valency, distance between binding sites, molecular size, flexibility, and the presence of an Fc region and its mediated effector functions have profound impacts on the functional attributes and developmental feasibility. Based on whether they engage T-cells, the marketed bsAbs can be categorized into T-cell engaging and non-T-cell engaging types. T cell engager (TCE) category of bsAbs: The primary purpose of designing this class of antibodies is to connect T cells and tumor cells via specific antigen-binding sites, thereby activating the cytotoxic activity of T cells against tumor cells. Among the 11 approved bsAbs, 6 have structures similar to IgG, consisting of two heavy chains (with the constant region depicted in dark grey, VH domains in dark blue or dark red) and two light chains (constant region in light grey, VL domains in light blue or light red). Most of these bsAbs adopt a 1+1 ratio, meaning each antigen has one binding site; additionally, there is one TCE that utilizes a 2+1 ratio model by fusing an extra Fab fragment onto one heavy chain, allowing it to bind two different antigens simultaneously. Non-T cell engager category of bispecific antibodies: These bsAbs include different types of constructions. For example, blinatumomab is an Fc-fragment lacking fusion protein composed of two single-chain variable fragments (scFv) stitched together; tebentafusp is a product where an scFv fragment is fused with a T cell receptor (TCR) fragment. There are also IgG-scFv fusion proteins with a 2+2 ratio mode, meaning they contain two full IgG domains and two scFv domains, capable of binding simultaneously to two different antigens. Representative monoclonal antibodies in clinical research: The mechanism of action of bsAbsBispecific antibodies (bsAbs) exhibit immense potential in cancer therapy due to their unique design and diverse mechanisms of action. The following is a brief overview of the different mechanisms of bispecific antibodies and their underlying principles: Dual receptor inhibitor bispecific antibodies: Bispecific antibodies with dual receptor-blocking capabilities can simultaneously target two different cell surface receptors, such as EGFR, HER2, and VEGF. For instance, Amivantamab (JNJ-61186372) is a bispecific antibody designed to concurrently bind to the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor (MET). These receptors play key roles in the pathogenesis of non-small cell lung cancer (NSCLC), promoting the proliferation and survival of tumor cells. Traditional monospecific therapies may lead to resistance as tumor cells exploit alternative compensatory signaling pathways. However, as the first approved bispecific antibody targeting both receptor tyrosine kinases, Amivantamab can more effectively inhibit the progression of NSCLC. By simultaneously blocking both the EGFR and MET signaling pathways, it can reduce or overcome resistance due to redundancy associated with single-drug treatments. The design purpose of zenocutuzumab (MCLA-128) is to simultaneously bind to both the HER2 and HER3 receptors. This dual-targeting strategy utilizes the biological characteristic of the interactions between members of the HER family: HER2 and HER3 are capable not only of forming homodimers but can also create heterodimers with other HER family members (including EGFR), activating downstream signaling pathways that promote tumor cell growth, survival, and metastasis. In clinical studies, zenocutuzumab has been found to have therapeutic potential in patients with solid tumors harboring NRG1 gene fusions. NRG1 is a ligand for HER3, and its binding to HER3 induces the formation of the HER2/HER3 heterodimer complex, thereby driving cancer cell proliferation. By simultaneously blocking HER2 and HER3, zenocutuzumab is anticipated to prevent the activation of this pro-tumorigenic signaling pathway, thereby inhibiting the progression of this specific type of tumor. Ligand-Receptor Inhibitory bsAbs: Ligand-receptor inhibitory bispecific antibodies (bsAbs) block signal transduction by interfering with the binding of ligands to their receptors or by inhibiting receptor homodimerization. For example, bispecific antibodies targeting VEGF and ANG2 can simultaneously blockade the VEGFR and TIE2 pathways, both of which promote angiogenesis, thereby suppressing tumor growth and metastasis. Vanucizumab is one such bsAb that concurrently inhibits the biological activities of two different biomolecules, VEGF-A and angiopoietin-2 (ANG2). VEGF and ANG2 are cytokines that play key roles in the genesis and progression of tumors by activating their respective receptor pathways to stimulate tumor neovascularization, which in turn supports tumor growth, invasion, and metastasis. In preclinical model studies, vanucizumab has demonstrated significant anti-tumor, anti-angiogenic, and anti-metastatic activities. Similarly, BI836880 is a trispecific nanobody-based fusion protein comprising three distinct nanobodies that respectively target VEGF (Vascular Endothelial Growth Factor), ANG2 (Angiopoietin-2), and HSA (Human Serum Albumin). The design of this drug aims to inhibit tumor growth and spread by simultaneously blocking VEGF and ANG2, two key signaling pathways involved in tumor angiogenesis. The portion that binds to HSA is intended to extend the drug's half-life in the human body, ensuring a more prolonged therapeutic effect. Receptor-Activated bsAbs: Activating bi-specific antibodies (bsAbs) function by promoting the formation of effective clusters of specific receptors to activate their downstream signaling pathways, such as targeting the members of the TNFRSF family and their receptors. For example, RO6874813 (also known as RG7386) is a tetravalent bi-specific antibody designed to target cancer-associated fibroblasts (CAFs) surface Fibroblast Activation Protein-alpha (FAPα) and Death Receptor 5 (DR5). FAPα is highly expressed in the Tumor MicroEnvironment (TME), particularly on CAFs associated with tumor progression and metastasis. DR5, a member of the TNF superfamily, can initiate apoptosis in cancer cells when activated by a specific ligand like TRAIL. RO6874813, by binding to both FAPα and DR5, can efficiently direct pro-apoptotic signals to tumor cells and enhances the selectivity and potency toward DR5 by avoiding degradation or inactivation caused by endogenous or exogenous decoy receptors. In experimental studies, this drug has demonstrated strong selectivity and in vivo antitumor activity, effectively killing tumor cells in FAPα-positive mouse models, and therefore it has great potential as a novel anti-cancer therapy. BsAbs for Directed Payload Delivery: BsAbs designed for targeted payload delivery typically employ two strategies: one is pretargeted therapy, which initially uses one binding site to deliver the drug to the tumor site, followed by the capture of a radiolabeled payload or drug complex with another site; the other involves directly linking toxins or radioactive isotopes to the bsAb to selectively kill cancer cells. For example, a bsAb targeting CEACAM5 or HER2 can carry a radioactive isotope, delivering it precisely to the tumor tissue. For instance, zanidatamab zovodotin (ZW49) is a bispecific antibody-drug conjugate (bsADC) that combines a bispecific antibody targeting the HER2 receptor with a cytotoxic payload derived from Auristatin. Zanidatamab is the core component of this ADC, capable of binding different epitopes on the HER2 receptor concurrently. This biparatopic (dual-epitope targeting) mechanism helps to enhance the affinity for HER2-positive tumor cells and to form more stable and functionally potent HER2 complexes. ZW49 leverages this bispecific structure to precisely target cancers that express or amplify HER2, especially because once the auristatin-derived cytotoxin is conjugated, it can release its cytotoxic payload inside tumor cells upon entry, thereby exerting a cytotoxic effect and killing cancer cells. Other Bispecific Antibodies (bsAbs) for Cancer Treatment: The mechanisms of action of most bispecific antibodies (bsAbs) used in cancer immunotherapy can be broadly classified into two categories. One category works by enhancing the natural or endogenous immune response driven by T cells, for example, by amplifying existing anti-tumor responses or overcoming immune checkpoint inhibition. The other category functions by providing synthetic immunity, such as through bsAb-mediated recruitment, activation, and interaction of immune cells. The article also overviews the most prominent mechanisms of action of bsAbs and multispecific antibodies, covering a variety of molecular design strategies including immune checkpoint inhibitors (CPIs), effector cell engagers, and co-stimulatory bsAbs. Dual Checkpoint Inhibitors (Dual CPIs): In cancer immunotherapy, bispecific antibodies are used to block two different immune checkpoint proteins simultaneously, to more effectively relieve the suppression of T cell activity by tumors. For instance, designed bsAbs can target checkpoints like PD-L1 and CTLA4 at the same time. Effector Cell Engagers: These bsAbs are designed to directly connect tumor cells to immune effector cells, such as natural killer cells (NK cells), macrophages, and dendritic cells (DCs), to promote the recognition and elimination of tumor cells by effector cells. For example, some bsAbs can bind to receptors such as NKp46 or NKp30 alongside tumor-associated antigens, thereby enhancing the NK cells' cytotoxic action against tumors; others operate by targeting CD3 molecules to engage T cells with tumor cells expressing specific antigens, like BiTEs and T-cell engagers. Co-stimulatory bsAbs: These bispecific antibodies are designed to simultaneously activate two co-stimulatory receptors in the immune system to enhance the immune response. For instance, FS120 is a tetravalent bsAb targeting 4-1BB and OX40, which can effectively activate T cells and generate anti-tumor activity, while avoiding the hepatic toxicity issues possibly caused by agonistic 4-1BB monoclonal antibodies alone. Additionally, there is a bivalent bsAb targeting 4-1BB and CD40 (tecaginlimab), which not only activates T cells but also induces a robust CD8+ T cell-mediated immune response by activating dendritic cells (DCs). MDCs and Dendritic Cell-Activating bsAbs: Some bsAbs are designed to specifically bind to markers on the surface of myeloid dendritic cells (MDCs) or DCs, such as Clec12a, for the precise delivery of immune activation signals. They activate DCs and improve their antigen-presenting capabilities, thereby triggering a potent CD8+ T cell immune response. Tumor-Targeting Co-stimulatory bsAbs: These antibodies are engineered to target specific antigens on tumor cells while activating co-stimulatory receptors of the immune system. For instance, bsAbs against CD47 can block the "don't eat me" signal, making tumor cells more susceptible to recognition and clearance by phagocytic cells. In addition, they can recruit other effector cells through the Fc region, increasing the aggressiveness towards the tumor. Innate Immune Cell Engagers and T Cell Engagers: These bispecific antibodies (bsAbs) are designed to activate and direct natural killer (NK) cells and T cells to tumor cells. Some of these bsAbs retain or enhance the binding ability to FcγRIII to ensure the effective participation of NK cells; while others incorporate cytokines such as IL-2 or IL-15 into the bsAb structure to expand and activate the innate immune cell population. PROTAC bispecific antibodies (bsAbs): This is a molecular drug that combines the technology of proteasome-mediated protein degradation with traditional bispecific antibody design strategies. These antibodies promote the tagging of target tumor-associated proteins with ubiquitin by simultaneously binding to E3 ubiquitin ligases or other factors capable of triggering internalization and subsequent degradation processes (such as membrane-accessible E3 ubiquitin ligases or transferrin receptors), leading to their degradation in the proteasome. Compared to traditional antibody therapies that only block signaling pathways to inhibit tumor cell growth, PROTAC bsAbs achieve a more thorough intervention by degrading target proteins, effectively addressing treatment failure due to drug resistance. Although this field is still in the early stages of development and no PROTAC bsAb has entered the clinical research phase, their design concept is compatible with the development of "standard" bispecific antibodies and provides a unique possibility for exploring new anti-cancer approaches. In the future, with further research and technological development, PROTAC bsAbs are expected to become a potent, highly selective, and targeted cancer treatment method. Moreover, the article provides a detailed description of the design features of different bispecific antibody (bsAb) structures, such as using an IgG-like structure and ensuring the correct assembly of heavy chains and light chains through techniques like the "knobs-into-holes" technology and Fab-arm exchange (cFAE). It also discusses engineering modifications to the Fc region to attenuate or eliminate the binding to Fcγ receptors and complement, hence reducing nonspecific effects. The article also introduces the use of bsAbs to stimulate members of the TNFRSF family (e.g., DR4 and DR5) as potent and tumor-selective agonists. By designing bispecific antibodies that target tumor-associated antigens and TNFRSF members, efficient anti-tumor effects are achieved. It is noted that this mechanism is also applicable to costimulatory molecules that depend on receptor clustering for activation, such as 4-1BB, OX40, and CD40.

Expanded and advanced oncology pipeline to 20 programs in 24 ongoing clinical trials including five ongoing randomized Phase 2 clinical trials; multiple trials with registrational potential expected to be initiated in 2023 and 2024 Announced licensing agreement with OncoC4 to complement the Company’s oncology portfolio with clinical stage next-generation immune checkpoint modulator; a randomized Phase 3 trial planned to start in 2023 Initiated Phase 1 trials for four mRNA vaccine candidates in the infectious disease field Approximately 2 billion doses of COMIRNATY® invoiced in 2022, including approximately 550 million doses of Omicron-adapted bivalent COVID-19 vaccines Fourth quarter and full year revenues of €4.3 billion1 and €17.3 billion1, respectively Full year net profit of €9.4 billion and fully diluted earnings per share of €37.77 ($39.77²) Strong liquidity of €13.9 billion cash and cash equivalents; €1.8 billion gross profit share settlement was received in cash as of January 12, 2023 Expect to authorize a share repurchase program of up to $0.5 billion during the remainder of 2023 Conference call and webcast scheduled for March 27 at 8:00 am ET (2:00 pm CET) MAINZ, Germany, March 27, 2023 (GLOBE NEWSWIRE) -- BioNTech SE(Nasdaq: BNTX, “BioNTech” or the ”Company”) today reported financial results for the three months and full year ended December 31, 2022, and provided an update on its corporate progress. “We made significant progress in 2022 by advancing our pipeline and launching the world’s first Omicron BA.4/BA.5 adapted bivalent COVID-19 vaccine. In addition, multiple new modalities achieved encouraging clinical data and we progressed nine new programs into clinical trials,” said Prof. Ugur Sahin, M.D., CEO and Co-Founder of BioNTech. “As we look to 2023 and beyond, we plan to continue investing in our transformation with a focus on building commercial capabilities in oncology and working towards registrational trials. Our mid-term goal is to seek approval for multiple oncology products in cancer indications with high unmet medical need.” Financial Review for the Fourth Quarter and Full Year 2022 Financial Results in millions, except per share data Fourth Quarter 2022 Fourth Quarter 2021 Full Year 2022 Full Year 2021 Total Revenues1 €4,278.3 €5,532.5 €17,310.6 €18,976.7 Net Profit €2,278.7 €3,166.2 €9,434.4 €10,292.5 Diluted Earnings per Share €9.26 €12.18 €37.77 €39.63 Total revenues reported were €4,278.3 million1 for the three months ended December 31, 2022, compared to €5,532.5 million1 for the comparative prior year period. For the year ended December 31, 2022, total revenues were €17,310.6 million1, compared to €18,976.7 million1 for the comparative prior year period. The change corresponds with the demand for COVID-19 vaccines. Cost of sales were €183.5 million for the three months ended December 31, 2022, compared to €583.2 million for the comparative prior year period. For the year ended December 31, 2022, cost of sales were €2,995.0 million, compared to €2,911.5 million for the comparative prior year period. Cost of sales were impacted by expenses arising from inventory write-offs and expenses for production capacities derived from agreements with contract manufacturing organizations that became redundant. In addition, during the three months ended December 31, 2022, cost of sales were impacted by the release of provisions. Research and development expenses were €509.8 million for the three months ended December 31, 2022, compared to €271.5 million for the comparative prior year period. For the year ended December 31, 2022, research and development expenses were €1,537.0 million, compared to €949.2 million for the comparative prior year period. The increase was mainly due to expenses in connection with the development and production of BioNTech’s and Pfizer’s Omicron-adapted bivalent COVID-19 vaccines and from progressing the clinical studies for BioNTech’s pipeline candidates. The increase was further driven by a higher headcount in the R&D area and expenses incurred under BioNTech’s share-based-payment arrangements. General and administrative expenses were €122.9 million for the three months ended December 31, 2022, compared to €130.9 million for the comparative prior year period. For the year ended December 31, 2022, general and administrative expenses were €484.7 million, compared to €285.8 million for the comparative prior year period. The increase was mainly due to increased expenses for IT and purchased external services as well as an increase in headcount. Income taxes were accrued in an amount of €893.9 million of tax expenses for the three months ended December 31, 2022, compared to €1,547.7 million of tax expenses for the comparative prior year period. For the year ended December 31, 2022, income taxes accrued were €3,519.7 million of tax expenses, compared to €4,753.9 million of tax expenses for the comparative prior year period. The derived annual effective income tax rate for the year ended December 31, 2022, was 27.2%. Net profit was €2,278.7 million for the three months ended December 31, 2022, compared to €3,166.2 million for the comparative prior year period. For the year ended December 31, 2022, net profit was €9,434.4 million, compared to €10,292.5 million for the comparative prior year period. Cash and cash equivalents were €13,875.1 million as of December 31, 2022. Subsequent to the end of the reporting period, the payment settling BioNTech’s gross profit share for the third quarter of 2022 (as defined by the contract) in the amount of €1,816.5 million was received from our collaboration partner as of January 12, 2023. The contractual settlement of the gross profit share under the COVID-19 collaboration with Pfizer has a temporal offset of more than one calendar quarter. As Pfizer’s fiscal quarter for subsidiaries outside the United States differs from BioNTech’s financial reporting cycle, it creates an additional time lag between the recognition of revenues and the payment receipt. Shares Outstanding: Shares outstanding as of December 31, 2022, were 243,215,169. “Our COVID-19 vaccine revenues, driven by the delivery of our Omicron-adapted bivalent vaccines, have ensured another strong financial performance in 2022,” said Jens Holstein, CFO of BioNTech. “We believe that the Company’s financial success in 2022 will provide a springboard to accelerate and build upon our diversified clinical pipeline and fuel our research and development in the coming years. The announced acquisition of InstaDeep and the recent license and collaboration agreement with OncoC4, which adds a clinical program to our existing portfolio aim to create future value for BioNTech mid- to long-term. We anticipate our COVID-19 franchise will further support our already existing financial strength in the years to come. As a science and innovation driven company, we plan to continue to invest heavily in R&D and are willing to invest in mergers and acquisitions as well as collaborations to create future growth for the Company.” Outlook for the 2023 Financial Year: The Company’s outlook contains the following components: BioNTech COVID-19 Vaccine Revenues for the 2023 Financial Year: Estimated BioNTech COVID-19 vaccine revenues for the 2023 financial year ~ €5 billion This revenue estimate reflects expected revenues related to BioNTech’s share of gross profit from COVID-19 vaccine sales in the collaboration partner’s territories, from direct COVID-19 vaccine sales to customers in BioNTech’s territory and expected revenues from sales to collaboration partners which may be influenced by costs like inventory write-offs once materialized and shared with the collaboration partner Pfizer. Revenue guidance is based on various assumptions including but not limited to the expected transition from an advanced purchase agreement environment to commercial market ordering starting in 2023 and a regulatory recommendation to adapt the COVID-19 vaccines to address newly circulating variants or sublineages of SARS-CoV-2. The estimated BioNTech COVID-19 vaccine revenues reflect expected deliveries under existing or committed supply contracts and anticipated sales through traditional commercial orders. A re-negotiation of the existing supply contract with the European Commission is ongoing, with the potential for a rephasing of deliveries of doses across multiple years and/or a volume reduction. While a vaccine adaptation is expected to lead to an increased demand, fewer primary vaccinations and lowered population-wide levels of boosting are anticipated. Seasonal demand is assumed, moving expected revenue generation significantly to the second half of the year 2023. Planned 2023 Financial Year Expenses and Capex: R&D expenses €2,400 million - €2,600 million SG&A expenses €650 million - €750 million Capital expenditures €500 million - €600 million Estimated 2023 Financial Year Tax Assumptions: BioNTech Group estimated annual cash effective income tax rate ~27% Numbers reflect current base case projections, include potential effects caused or driven by additional collaborations or potential M&A transactions to the extent they have been disclosed and are calculated based on constant currency rates. Operational Review of the Fourth Quarter and Key Post Period-End Events COVID-19 Vaccine Programs – BNT162 (COMIRNATY) Commercial updates In December 2022, BioNTech and Pfizer announced that approximately 2 billion doses of COMIRNATY were invoiced globally in 2022 between the two companies, including approximately 550 million doses of the Original/Omicron BA.4-5-adapted bivalent COVID-19 vaccine, as of mid-December 2022. In January 2023, BioNTech and Pfizer announced that negotiations were ongoing for the re-phasing of delivery timelines for the COMIRNATY supply agreement with the European Commission (EC). The agreement with the EC was signed in May 2021 and a rephasing agreement was previously reached in May 2022. As part of BioNTech’s and Pfizer's 2-billion-doses-pledge to support equitable access to medicines, the companies have delivered approximately 1.7 billion doses of COMIRNATY to low- and middle-income countries in line with demand. The deliveries include both the Original/Omicron BA.4-5-adapted bivalent COVID-19 vaccine and the original COVID-19 vaccine. Clinical development and regulatory updates Original COVID-19 vaccine In October 2022, BioNTech and Pfizer received EC approval for the conversion of the conditional Marketing Authorization (CMA) to full Marketing Authorization (MA). The conversion applies to all existing indications and formulations of the COMIRNATY product group authorized in the European Union, including Original/Omicron BA.1- and BA.4-5-adapted bivalent COVID-19 vaccines as booster doses for individuals aged 12 years and older. In October 2022, BioNTech and Pfizer received EC approval for full MA for a 3-µg dose of the original COVID-19 vaccine as a three-dose series for children aged six months through four years. In October 2022, BioNTech and Pfizer received EC approval for a fourth dose booster of the original COVID-19 vaccine in individuals 12 years of age and older at an interval of at least three months between the administration of the original COVID-19 vaccine and the last prior dose of a COVID-19 vaccine. Original/Omicron BA.4-5-adapted bivalent COVID-19 vaccine booster In the second half of 2022, BioNTech and Pfizer received approval or authorization of a 30-µg booster dose of the Original/Omicron BA.4-5-adapted bivalent COVID-19 vaccine for individuals aged 12 years and older, granted by the U.S. Food and Drug Administration (FDA) (August), European Commission (EC) (September), Health Canada (October), and Health Bureau of the Hong Kong Special Administrative Region of the People's Republic of China (November). The Original/Omicron BA.4-5-adapted bivalent COVID-19 vaccine was approved or authorized for use in more than 65 countries and regions in 2022. Authorization of a 10-µg booster dose of Original/Omicron BA.4-5-adapted bivalent COVID-19 vaccine in children five through 11 years of age was granted by U.S. FDA (EUA) (October) and EC (November). In November 2022, BioNTech and Pfizer reported updated 30-day clinical data from the randomized Phase 2/3 clinical trial evaluating the safety, tolerability and immunogenicity of the companies’ Original/Omicron BA.4-5-adapted bivalent COVID-19 vaccine, given as a 30-µg booster dose. The data demonstrated a robust and broadly neutralizing immune response one month after a 30-µg booster dose. There was a substantially higher increase in Omicron BA.4/BA.5-neutralizing antibody titers compared to pre-booster levels for those who received the bivalent vaccine compared to the original COVID-19 vaccine, with similar favorable safety and tolerability pro between both vaccines. In November 2022, BioNTech and Pfizer announced results from an analysis examining the immune response induced by the Original/Omicron BA.4-5-adapted bivalent COVID-19 vaccine against newer Omicron sublineages with enhanced escape mechanisms, including BA.4.6, BA.2.75.2, BQ.1.1 and XBB.1. The published data (Zou et al. Neutralization of BA.4–BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent Vaccine; N Engl J Med 2023; 388:854-857) indicated that the bivalent vaccine elicits a greater increase in neutralizing antibody titers than the original COVID-19 vaccine against these emerging Omicron sublineages. In December 2022, BioNTech and Pfizer received U.S. FDA EUA for their Original/Omicron BA.4-5-adapted bivalent COVID-19 vaccine as the third 3-µg dose in the three-dose primary series for children six months through four years of age. Next-generation COVID-19 vaccine In November 2022, BioNTech and Pfizer initiated a Phase 1 clinical trial to evaluate the safety, tolerability and immunogenicity of BNT162b4, a next-generation COVID-19 vaccine candidate that aims to enhance SARS-CoV-2 T cell responses and potentially broaden protection against upcoming variants and increase durability of protection. COVID-19 – Influenza Combination mRNA Vaccine Program (BNT162b2 + BNT161) In October 2022, BioNTech and Pfizer initiated a Phase 1 open-label, dose-finding clinical trial to evaluate the safety, tolerability and immunogenicity of a combination of the COVID-19 and influenza mRNA vaccines to help protect individuals against influenza and COVID-19 with a single injection. A data update from this trial is expected in 2023. In December, BioNTech and Pfizer received Fast Track Designation from the U.S. FDA for their mRNA-based combination vaccine candidate. Fourth Quarter 2022 Infectious Disease Pipeline Update and Outlook HSV-2 Vaccine Program – BNT163 In December 2022, BioNTech initiated a Phase 1 clinical trial of BNT163, a herpes simplex virus (HSV) vaccine candidate for the prevention of genital lesions caused by HSV-2 and potentially HSV-1. The trial will evaluate the safety, tolerability and immunogenicity of BNT163. A data update is expected in 2H 2023. Malaria Vaccine Program – BNT165 In December 2022, BioNTech initiated a Phase 1 clinical trial of BNT165b1, the first candidate from the Company’s BNT165 program to develop a multi-antigen malaria vaccine candidate. This first clinical trial (NCT05581641) will evaluate the safety, tolerability and exploratory immunogenicity of the vaccine candidate. A data update is expected in 2H 2023. Shingles Vaccine Program – BNT167 In February 2023, BioNTech and Pfizer initiated a randomized controlled, dose-selection Phase 1/2 clinical trial of BNT167, the companies’ mRNA vaccine candidates against shingles (also known as herpes zoster). The clinical trial (NCT05703607) will evaluate the safety, tolerability, and immunogenicity of mRNA vaccine candidates against shingles. A data update is expected in 2023. Fourth Quarter 2022 Oncology Pipeline Update and Outlook In 2022, BioNTech started five first-in-human clinical trials: BNT116, a FixVac program for non-small cell lung cancer (NSCLC), BNT141 and BNT142, two RiboMabs for CLDN18.2-positive and CLDN6-positive solid tumors and BNT313, a HexaBody targeting CD27, and BNT322 (undisclosed target), two new antibody candidates from its collaboration with Genmab being evaluated in solid tumors. BNT113, a candidate based on BioNTech’s FixVac off-the-shelf mRNA-based cancer immunotherapy approach, is being developed as a first-line treatment for patients with unresectable recurrent or metastatic HPV16+ head and neck squamous cell carcinoma, or HNSCC, expressing PD-L1. BNT113 has not previously been combined with anti-PD1 therapy. In December 2022, BioNTech presented preliminary safety data from the run-in portion (Part A) of the ongoing Phase 2 trial designed to demonstrate the safety of the combination of BNT113 and pembrolizumab at the annual European Society for Medical Oncology (ESMO) Immuno-Oncology Congress. As of July 5, 2022, of 15 treated patients, 12 had completed the safety run-in (pembrolizumab + four BNT113 doses). Data showed safety was acceptable and in line with the safety pro BNT113 and pembrolizumab as single agents; no new safety signals were observed for the combination. The randomized Part B is ongoing. Autogene cevumeran (BNT122) is a candidate based on an individualized neoantigen-specific immunotherapy (iNeST) approach developed for the treatment of adjuvant and metastatic cancers in collaboration with Genentech, a member of the Roche Group. Each autogene cevumeran dose includes up to 20 different neoantigens selected on a patient-by-patient basis. In 2023, BioNTech and Genentech are expecting a data update from an ongoing open-label Phase 2 trial evaluating the efficacy and safety of autogene cevumeran in combination with pembrolizumab versus pembrolizumab alone in patients with previously untreated advanced melanoma. A Phase 2 clinical trial of autogene cevumeran in the adjuvant setting in patients with pancreatic ductal adenocarcinoma (PDAC) is planned to open in 2023. BNT211 is a chimeric antigen receptor (CAR) directing T cells against the novel target CLDN6 that is tested alone and in combination with a CAR-T cell Amplifying RNA Vaccine, or CARVac, encoding CLDN6. CARVac is intended to drive in vivo expansion of transferred CAR-T cells to increase their persistence and efficacy. In 2023, BioNTech expects to provide a data update on the ongoing Phase 1/2 dose escalation and expansion, evaluating CLDN6 CAR-T cells with or without CLDN6 CARVac in patients with CLDN6-positive relapsed or refractory advanced solid tumors. In September 2022, BioNTech provided a data update from the ongoing study at the ESMO Congress, which demonstrated signs of anti-tumor activity and a manageable safety pro both dose levels. An efficacy assessment of 21 evaluable patients showed an overall response rate, or ORR, of 33% and a disease control rate, or DCR, of 67% with one complete response, six partial responses and seven patients with stable disease. Particularly encouraging clinical responses were seen in patients with testicular cancer treated with dose level 2 after lymphodepletion (n=7), where one complete response, three partial responses and two stable diseases were observed, representing an ORR of 57% and a DCR of 85%. The Company expects a Phase 2 study of BNT211 in patients with 2L+ platinum resistant testicular cancer to start in 2024. BNT312 (GEN1042) is a first-in-class bispecific antibody candidate designed to induce conditional immune activation by crosslinking CD40 and 4-1BB positive cells. In December 2022, BioNTech and Genmab presented updated data from the safety run-in and expansion cohorts of the Phase 1/2 study of BNT312 combination therapy at the ESMO Immuno-Oncology Annual Congress. The data demonstrated that BNT312 + pembrolizumab (PEM) ± chemotherapy (CTx) was well tolerated with no reported dose-limiting toxicity. Most adverse events were grade 1/2 and manageable. BNT312 (GEN1042) + PEM + CTx showed encouraging early activity in patients with advanced/metastatic HNSCC, with responses observed in 4/4 evaluable patients. The observed immune activity mediated by BNT312 retained with combination therapy. Enrollment in this trial is ongoing in all cohorts (NSCLC, pancreatic ductal adenocarcinoma, and HNSCC). BNT313 (GEN1053) is a monospecific antibody candidate targeting CD27 to address malignant solid tumors. It is based on Genmab's HexaBody technology and is engineered to induce clustering of CD27 on the plasma membrane of T cells with the aim of enhancing T cell activation, proliferation and differentiation without depleting T cells. In November 2022, the Company initiated a Phase 1 clinical trial to evaluate the safety, tolerability and preliminary efficacy of BNT313 for the treatment of malignant solid tumors. Preclinical data characterizing the mechanism of action of BNT313 were presented at the 37th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in November 2022. In the in vitro experiments, BNT313 exhibited CD27 agonist activity independently of Fc gamma receptor-mediated crosslinking. BNT313 enhanced activation, proliferation and proinflammatory cytokine secretion of human CD4+ and CD8+ T cells as well as CD8+ T cell mediated cytotoxic activity towards tumor cells in vitro. In mice expressing human CD27 protein, it enhanced expansion and IFN-γ secretion of antigen-specific CD8+ T cells in vivo. Overall, the data supported a mechanism of action that distinguishes BNT313 from benchmark monoclonal antibodies targeting CD27. Fourth Quarter 2022 and Subsequent Corporate Updates In November 2022, BioNTech’s affiliate BioNTech Pharmaceuticals Asia Pacific Pte. Ltd. announced the signing of an agreement to acquire a GMP-certified manufacturing facility in Singapore which is planned to also serve as BioNTech’s Regional Headquarters. In November 2022, BioNTech entered a multi-target research collaboration with Ryvu Therapeutics S.A. to develop and commercialize immunomodulatory small molecule candidates as well as standalone small molecules from Ryvu’s STING agonist portfolio. In November 2022, the second tranche of BioNTech’s share repurchase program of American Depositary Shares (ADSs) was authorized, with a value of up to $0.5 billion, commencing on December 7, 2022 and ending on March 17, 2023. In total, under both tranches of the share repurchase program, 9,166,684 ADSs were repurchased at an average price of $142.04, for a total consideration of approximately $1.3 billion (€1,268.4 million). As of December 31, 2022, BioNTech had share capital registered in the commercial register (“Handelsregister”) in the amount of €248,552,200, which was divided into 248,552,200 registered shares (“Namensaktien”), including an amount of €5,337,031 relating to 1,548,439 ordinary shares held in the form of ADSs and 3,788,592 ordinary shares, each held in treasury. In December 2022, BioNTech announced that the first six ISO-sized shipping containers for the BioNTainer have been completed in Europe, underwent quality checks by BioNTech experts and were being prepared for shipment to Kigali. The containers subsequently arrived in March 2023. In January 2023, BioNTech announced that it had entered into an agreement to acquire its long-standing strategic collaboration partner InstaDeep Ltd., enabling the creation of a fully integrated, enterprise-wide capability that leverages artificial intelligence (AI) and machine learning (ML) technologies across BioNTech’s therapeutic platforms and operations. The transaction is expected to add approximately 240 highly skilled professionals to BioNTech’s workforce, including teams in AI, ML, bioengineering, data science, and software development. In February 2023, BioNTech completed the construction of its first proprietary plasmid DNA manufacturing facility in Marburg. In March 2023, BioNTech entered into an exclusive worldwide licensing agreement with OncoC4, Inc. to co-develop and commercialize ONC-392, an anti-CTLA-4 monoclonal antibody as monotherapy or combination therapy in various cancer indications. The companies plan to start a Phase 3 trial (NCT05671510) of ONC-392 as monotherapy treatment in NSCLC patients who progress after PD-1/PD-L1 treatment in 2023. The transaction is expected to close in the first half of 2023, subject to customary closing conditions and regulatory clearance. Environmental, Social, and Governance (ESG) overview BioNTech published its ESG report (Sustainability Report 2022) on March 27, 2023. The report can be found in the Investor Relations section of BioNTech’s website. Upcoming investor and analyst events The Annual General Meeting is scheduled for May 25, 2023. BioNTech expects to host an Innovation Series Day on November 7, 2023. Endnotes The full audited consolidated financial statements can be found in BioNTech’s Annual Report on Form 20-F for the year ended December 31, 2022, filed with the SEC and available at (the “Annual Report”). 1 BioNTech’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. ² Calculated applying the average foreign exchange rate for the year ended December 31, 2022 as published by the German Central Bank (Deutsche Bundesbank). Conference Call and Webcast Information BioNTech invites investors and the general public to join a conference call and webcast with investment analysts on March 27, 2023 at 8.00 a.m. EDT (2.00 p.m. CEST) to report its financial results and provide a corporate update for the fourth quarter and financial year 2022. 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 . 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 BioNTech Biopharmaceutical 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 T cells, bispecific immune checkpoint modulators, targeted cancer antibodies and 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 Genmab, Sanofi, Genentech, a member of the Roche Group, Regeneron, Genevant, Fosun Pharma and Pfizer. For more information, please visit Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, 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; 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; the timing and expected impact of the Company’s planned acquisition of InstaDeep Ltd. and collaboration and licensing agreements with OncoC4, Inc. and others; the development of sustainable vaccine production and supply solutions, including BioNTainers, 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, and shares outstanding. 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 pro 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 vaccine 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 claims for potential personal injury or death arising 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 foreign 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 Annual Report on Form 20-F for the year ended December 31, 2022 and in subsequent filings made by BioNTech with the SEC, which are available on the SEC’s website at . 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. BioNTech Contacts Investor Relations Michael Horowicz +1 (617) 955 7420 Investors@biontech.de Media Relations Jasmina Alatovic +49 (0)6131 9084 1513 Media@biontech.de Statements of Profit or Loss Three months ended December 31, Years ended December 31, 2022 2021 2022 2021 2020 (in millions, except per share data) (unaudited) (unaudited) Revenues Commercial revenues €4,271.3 €5,525.9 €17,194.6 €18,874.0 €303.5 Research & development revenues 7.0 6.6 116.0 102.7 178.8 Total revenues €4,278.3 €5,532.5 €17,310.6 €18,976.7 €482.3 Cost of sales (183.5) (583.2) (2,995.0) (2,911.5) (59.3) Research and development expenses (509.8) (271.5) (1,537.0) (949.2) (645.0) Sales and marketing expenses (14.6) (17.9) (59.5) (50.4) (14.5) General and administrative expenses (122.9) (130.9) (484.7) (285.8) (94.0) Other operating expenses (376.2) (67.1) (407.0) (94.4) (2.4) Other operating income 221.6 237.8 815.3 598.4 250.5 Operating income / (loss) €3,292.9 €4,699.7 €12,642.7 €15,283.8 €(82.4) Finance income 38.8 16.3 330.3 67.7 1.6 Finance expenses (159.1) (2.1) (18.9) (305.1) (65.0) Profit / (loss) before tax €3,172.6 €4,713.9 €12,954.1 €15,046.4 €(145.8) Income taxes (893.9) (1,547.7) (3,519.7) (4,753.9) 161.0 Profit for the period €2,278.7 €3,166.2 €9,434.4 €10,292.5 €15.2 Earnings per share Basic profit for the period per share €9.38 €12.96 €38.78 €42.18 €0.06 Diluted profit for the period per share €9.26 €12.18 €37.77 €39.63 €0.06 Statements of Financial Position December 31, December 31, (in millions) 2022 2021 Assets Non-current assets Intangible assets €219.7 €202.4 Property, plant and equipment 609.2 322.5 Right-of-use assets 211.9 197.9 Other financial assets 80.2 21.3 Other non-financial assets 6.5 14.4 Deferred tax assets 229.6 — Total non-current assets €1,357.1 €758.5 Current assets Inventories 439.6 502.5 Trade and other receivables 7,145.6 12,381.7 Other financial assets 189.4 381.6 Other non-financial assets 271.9 113.4 Income tax assets 0.4 0.4 Cash and cash equivalents 13,875.1 1,692.7 Total current assets €21,922.0 €15,072.3 Total assets €23,279.1 €15,830.8 Equity and liabilities Equity Share capital 248.6 246.3 Capital reserve 1,828.2 1,674.4 Treasury shares (5.3) (3.8) Retained earnings 18,833.0 9,882.9 Other reserves (848.9) 93.9 Total equity €20,055.6 €11,893.7 Non-current liabilities Lease liabilities, loans and borrowings 176.2 171.6 Other financial liabilities 6.1 6.1 Income tax liabilities 10.4 4.4 Provisions 8.6 184.9 Contract liabilities 48.4 9.0 Other non-financial liabilities 17.0 12.8 Deferred tax liabilities 6.2 66.7 Total non-current liabilities €272.9 €455.5 Current liabilities Lease liabilities, loans and borrowings 36.0 129.9 Trade payables 204.1 160.0 Other financial liabilities 785.1 1,190.4 Refund liabilities 24.4 90.0 Income tax liabilities 595.9 1,568.9 Provisions 367.2 110.2 Contract liabilities 77.1 186.1 Other non-financial liabilities 860.8 46.1 Total current liabilities €2,950.6 €3,481.6 Total liabilities €3,223.5 €3,937.1 Total equity and liabilities €23,279.1 €15,830.8 Statements of Cash Flows Three months ended December 31, Years ended December 31, 2022 2021 2022 2021 2020 (in millions) (unaudited) (unaudited) Operating activities Profit for the period €2,278.7 €3,166.2 €9,434.4 €10,292.5 €15.2 Income taxes 893.9 1,547.7 3,519.7 4,753.9 (161.0) Profit before tax €3,172.6 €4,713.9 €12,954.1 €15,046.4 €(145.8) Adjustments to reconcile profit before tax to net cash flows: Depreciation and amortization of property, plant, equipment, intangible assets and right-of-use assets 29.0 26.0 123.3 75.2 38.7 Share-based payment expenses 19.4 20.5 108.6 93.9 32.1 Net foreign exchange differences 847.8 (92.0) 625.5 (387.5) 41.3 Loss on disposal of property, plant and equipment 0.2 4.2 0.6 4.6 0.6 Finance income excluding foreign exchange differences (38.8) (0.3) (265.3) (1.5) (1.6) Finance expense excluding foreign exchange differences 2.1 2.2 18.9 305.2 22.3 Movements in government grants 0.3 20.6 0.3 (89.0) 92.0 Other non-cash income / (loss) — (2.2) — (2.2) 1.7 Unrealized net (gain) / loss on derivative instruments at fair value through profit or loss (323.3) 32.4 (241.0) 57.3 — Working capital adjustments: Decrease / (increase) in trade and other receivables, contract assets and other assets (646.8) (1,712.7) 4,369.9 (11,808.1) (247.9) Decrease / (increase) in inventories (144.8) (109.1) 62.9 (438.4) (49.8) Increase in trade payables, other financial liabilities, other liabilities, contract liabilities, refund liabilities and provisions (674.6) 362.2 85.7 1,516.1 204.6 Interest received 22.8 0.2 29.3 1.2 1.4 Interest paid (5.0) (6.1) (21.5) (12.2) (3.6) Income tax received / (paid), net (1,387.4) (3,456.9) (4,222.1) (3,457.9) 0.5 Share-based payments (44.3) (2.4) (51.8) (13.4) — Net cash flows from / (used in) operating activities €829.2 €(199.5) €13,577.4 €889.7 €(13.5) Investing activities Purchase of property, plant and equipment (136.6) (39.4) (329.2) (127.5) (66.0) Proceeds from sale of property, plant and equipment 0.2 2.0 0.6 3.4 1.2 Purchase of intangible assets and right-of-use assets (7.9) (14.0) (34.1) (26.5) (19.4) Acquisition of subsidiaries and businesses, net of cash acquired — (20.8) — (20.8) (60.6) Purchase of financial instruments (16.7) (19.5) (47.8) (19.5) — (Investment) / proceeds from maturity of other financial assets — (8.2) 375.2 (375.2) — Net cash flows used in investing activities €(161.0) €(99.9) €(35.3) €(566.1) €(144.8) Financing activities Proceeds from issuance of share capital and treasury shares, net of costs — — 110.5 160.9 753.0 Proceeds from loans and borrowings 0.2 — 0.8 — 156.0 Repayment of loans and borrowings — (50.7) (18.8) (52.6) (1.6) Payments related to lease liabilities (9.2) 1.8 (41.1) (14.1) (12.7) Share repurchase program (55.7) — (986.4) — — Dividends — — (484.3) — — Net cash flows from / (used in) financing activities €(64.7) €(48.9) €(1,419.3) €94.2 €894.7 Net increase in cash and cash equivalents 603.5 (348.3) 12,122.8 417.8 736.4 Change in cash and cash equivalents resulting from exchange rate differences (152.1) 15.3 59.6 64.7 (45.3) Cash and cash equivalents at the beginning of the period 13,423.7 2,025.7 1,692.7 1,210.2 519.1 Cash and cash equivalents at December 31 €13,875.1 €1,692.7 €13,875.1 €1,692.7 €1,210.2