424B5
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Filed pursuant to Rule 424(b)(5)
Registration No. 333-239970

5,500,000 American Depositary Shares

 

 

LOGO

Representing 5,500,000 Ordinary Shares

 

 

We are offering 5,500,000 American Depositary Shares, or the ADSs, with each ADS representing one ordinary share, or the Underwritten Offering. The Selling Shareholder identified in this prospectus is offering 825,000 ADSs if and to the extent that the underwriters exercise their option to purchase additional ADSs described below. We will not receive any of the proceeds from the sale of ADS by the Selling Shareholder. ADSs representing our ordinary shares are listed on the Nasdaq Global Select Market under the symbol “BNTX.” On July 21, 2020, the last reported sale price of the ADSs on the Nasdaq Global Select Market was $91.60 per ADS.

 

 

This offering is part of a Global Offering consisting of a rights offering and this Underwritten Offering, covering, in the aggregate, up to 7,505,596 ordinary shares (including ordinary shares represented by ADSs), as described further in this prospectus. The ADSs being offered by this prospectus are being so offered based upon irrevocable, binding agreements under German law from certain holders of our ordinary shares, representing 74.83% of our outstanding ordinary shares (including ordinary shares represented by ADSs), not to transfer or exercise rights to subscribe for our new ordinary shares that we intend to grant in a rights offering we intend to conduct. This offering together with the rights offering constitute the Global Offering.

Investing in the ADSs representing our ordinary shares involves a high degree of risk. See “Risk Factors” beginning on page 22 of this prospectus.

We are an “emerging growth company” and a “foreign private issuer” as defined under the U.S. federal securities laws and, as such, are eligible for reduced public company disclosure requirements. See “Prospectus Summary—Implications of Being an Emerging Growth Company and a Foreign Private Issuer” for additional information.

Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or determined if this prospectus is truthful or complete. Any representation to the contrary is a criminal offense.

 

     PER ADS      TOTAL  

Public offering price

   $ 93.00000    $ 511,500,000

Underwriting discounts and commissions(1)

   $ 5.29161      $ 29,103,855  

Proceeds to us before expenses

   $ 87.70839      $ 482,396,145  

 

(1)

See “Underwriting” for details concerning underwriter compensation and expense reimbursement arrangements.

The underwriters have the option for a period of 30 days from the date of this prospectus to purchase an additional 825,000 ADSs from the Selling Shareholder.

Delivery of the ADSs is expected to be made on or about July 27, 2020.

 

 

 

J.P. Morgan   BofA Securities   Berenberg
UBS Investment Bank     Canaccord Genuity
COMMERZBANK   Wolfe Capital Markets and Advisory   Bryan, Garnier & Co.

Prospectus dated July 22, 2020


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TABLE OF CONTENTS

 

ABOUT THIS PROSPECTUS

     i  

ABOUT THE GLOBAL OFFERING

     i  

PRESENTATION OF FINANCIAL INFORMATION

     i  

TRADEMARKS, SERVICE MARKS AND TRADE NAMES

     ii  

MARKET AND INDUSTRY DATA

     ii  

PROSPECTUS SUMMARY

     1  

RISK FACTORS

     22  

CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS

     30  

USE OF PROCEEDS

     32  

DIVIDEND POLICY

     34  

CAPITALIZATION

     35  

DILUTION

     37  

SELECTED CONSOLIDATED FINANCIAL DATA

     39  

UNAUDITED PRO FORMA CONDENSED COMBINED FINANCIAL INFORMATION

     41  

BUSINESS

     49  

PRINCIPAL AND SELLING SHAREHOLDERS

     187  

DESCRIPTION OF SHARE CAPITAL AND ARTICLES OF ASSOCIATION (SATZUNG)

     190  

DESCRIPTION OF AMERICAN DEPOSITARY SHARES

     205  

SHARES AND ADSs ELIGIBLE FOR FUTURE SALE

     213  

TAXATION

     215  

UNDERWRITING

     226  

EXPENSES OF THE GLOBAL OFFERING

     235  

LEGAL MATTERS

     236  

EXPERTS

     236  

SERVICE OF PROCESS AND ENFORCEMENT OF LIABILITIES

     236  

WHERE YOU CAN FIND MORE INFORMATION

     238  

INCORPORATION OF CERTAIN INFORMATION BY REFERENCE

     239  

Neither we, the Selling Shareholder, nor any of the underwriters have authorized anyone to provide you with information that is different from that contained in this prospectus, any amendment or supplement to this prospectus, or any free writing prospectus we may authorize to be delivered or made available to you. Neither we, the Selling Shareholder, nor any of the underwriters take responsibility for, or provide assurance as to the reliability of, any other information that others may give you. We and the underwriters are offering to sell ADSs and seeking offers to purchase ADSs only in jurisdictions where offers and sales are permitted. The information contained in this prospectus is accurate only as of the date on the cover page of this prospectus, regardless of the time of delivery of this prospectus or the sale of any ADSs. Our business, financial condition, results of operations and prospects may have changed since the date on the cover page of this prospectus.

For investors outside the United States: Neither we, the Selling Shareholder, nor the underwriters have taken any action that would permit this offering or possession or distribution of this prospectus in any jurisdiction where action for that purpose is required, other than in the United States. Persons outside the United States who come into possession of this prospectus must inform themselves about, and observe any restrictions relating to, the offering of the ADSs representing our ordinary shares and the distribution of this prospectus outside of the United States.

The prospectus summary beginning on page 1 herein highlights information contained elsewhere in this prospectus and does not contain all of the information that you should consider in making your investment decision. Before deciding to invest in the ADSs representing our ordinary shares, you should read this entire prospectus carefully, including the sections titled “Risk Factors” and “Business” in this prospectus and the sections titled “Risk Factors,” “Business” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and our consolidated financial statements and related notes in our Forms 20-F and 6-K incorporated by reference herein. You should also read the other documents incorporated by reference into the registration statement of which this prospectus forms a part. See “Where You Can Find More Information.”


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ABOUT THIS PROSPECTUS

Unless otherwise indicated or the context otherwise requires, all references in this prospectus to the terms “BioNTech,” the “Company,” “we,” “us” and “our” refer to BioNTech SE and our wholly owned subsidiaries.

ABOUT THE GLOBAL OFFERING

This prospectus relates to a firm commitment underwritten offering of our ordinary shares to be represented by American Depositary Shares, or ADSs, which we refer to as the Underwritten Offering. The Underwritten Offering is part of a Global Offering that consists of (i) a rights offering to be extended to our ordinary shareholders and ADS holders, or the Rights Offering, and (ii) the Underwritten Offering. Under German law, where a company obtains binding, irrevocable agreements from certain existing shareholders not to transfer or exercise rights to be granted in a future rights offering, the company is permitted to attempt to sell the shares represented by such rights either before or after the rights offering. Based on binding irrevocable agreements not to transfer or exercise rights that we have obtained from certain holders of our ordinary shares, representing 74.83% of our outstanding ordinary shares (including ordinary shares represented by ADSs), we are conducting the Underwritten Offering pursuant to this prospectus prior to the commencement of the Rights Offering.

The Rights Offering is being conducted pursuant to a separate registration statement and prospectus. The price to public that is set in the Underwritten Offering will be the subscription price for the Rights Offering. Shareholders and ADS holders as of the respective record dates for our ordinary shares and the ADSs representing our ordinary shares who have not agreed to forego exercising their rights will have the opportunity in the Rights Offering to subscribe for up to 1,889,189 new ordinary shares or new ADSs (representing approximately 0.81% of our outstanding ordinary shares) at the subscription price. ADSs PURCHASED IN THE UNDERWRITTEN OFFERING ARE NOT ENTITLED TO RECEIVE RIGHTS TO SUBSCRIBE FOR NEW ORDINARY SHARES OR NEW ADSs IN THE RIGHTS OFFERING. Accordingly, a total of up to 7,389,189 ordinary shares (including ordinary shares represented by ADSs) may be sold by us in the Global Offering.

PRESENTATION OF FINANCIAL INFORMATION

This prospectus includes financial information derived from our audited consolidated financial statements as of December 31, 2019 and 2018 and for the years ended December 31, 2019, 2018 and 2017, which have been prepared in accordance with International Financial Reporting Standards, or IFRS, as issued by the International Accounting Standards Board, or IASB, which differ in certain significant respects from U.S. generally accepted accounting principles, or U.S. GAAP, and are incorporated by reference herein. It also includes financial information derived from our unaudited interim condensed consolidated financial statements as of March 31, 2020 and for the three months ended March 31, 2020 and 2019 that have been prepared on the same basis as the audited financial statements and are incorporated by reference herein.

Our financial information is presented in Euros. For the convenience of the reader, we have translated some of our financial information into U.S. dollars. Unless otherwise indicated, these translations were made at the rate of €1.00 to $1.1107, the noon buying rate of the Federal Reserve Bank of New York on May 29, 2020. Such U.S. dollar amounts are not necessarily indicative of the amounts of U.S. dollars that could actually have been purchased upon exchange of Euros at the dates indicated. All references in this prospectus to “$” mean U.S. dollars and all references to “€” mean Euros and all references in this prospectus to “k$” and “k€” refer to thousands of U.S. dollars and thousands of Euros, respectively.

 

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We have made rounding adjustments to some of the figures contained in this prospectus. Accordingly, numerical figures shown as totals in some tables may not be exact arithmetic aggregations of the figures that preceded them.

TRADEMARKS, SERVICE MARKS AND TRADE NAMES

The BioNTech SE logo, FixVac®, RiboMab®, RiboCytokine®, MammaTyper®, RECON® and NEO-STIM and other trademarks or service marks of BioNTech appearing in this prospectus are the property of the Company. Solely for convenience, some of the trademarks, service marks, logos and trade names referred to in this prospectus are presented without the ® and symbols, but such references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensors to these trademarks, service marks and trade names. This prospectus contains additional trademarks, service marks and trade names of others. All trademarks, service marks and trade names appearing in this prospectus are, to our knowledge, the property of their respective owners. We do not intend our use or display of other companies’ trademarks, service marks, copyrights or trade names to imply a relationship with, or endorsement or sponsorship of us by, any other companies.

MARKET AND INDUSTRY DATA

This prospectus contains industry, market and competitive position data that are based on industry publications and studies conducted by third parties as well as our own internal estimates and research. These industry publications and third-party studies generally state that the information they contain has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. While we believe that each of these publications and third-party studies is reliable, we have not independently verified the market and industry data obtained from these third-party sources. Forecasts and other forward-looking information obtained from these sources are subject to the same qualifications and uncertainties as the other forward-looking statements contained in this prospectus. These forecasts and forward-looking information are subject to uncertainty and risk due to a variety of factors, including those described in “Risk Factors.” These and other factors could cause results to differ materially from those expressed in our forecasts or estimates or those of independent third parties. While we believe our internal research is reliable and the definitions of our market and industry are appropriate, neither such research nor these definitions have been verified by any independent source.

 

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PROSPECTUS SUMMARY

This summary highlights selected information contained elsewhere in this prospectus and in the documents we incorporate by reference herein. This summary does not contain all of the information you should consider before making an investment decision. You should read this entire prospectus carefully, especially the risks of investing in the ADSs representing our ordinary shares discussed under “Risk Factors” beginning on page 22 of this prospectus, along with our consolidated financial statements and notes to those consolidated financial statements and the other information incorporated by reference in this prospectus.

Overview

BioNTech was founded in 2008 on the understanding that every cancer patient’s tumor is unique and that in order to effectively address this challenge, we must create individualized treatments for each patient. To realize this vision, we combine decades of groundbreaking research in immunology, cutting-edge therapeutic platforms and a suite of patient profiling and bioinformatic tools to develop immunotherapies for cancer and other diseases. We leverage powerful new therapeutic mechanisms and exploit a diverse array of biological targets to harness the power of each patient’s immune system to address the unique molecular signature of each patient’s underlying disease. The breadth of our immunotherapy technologies and expertise has also enabled us to develop therapies to address a range of rare and infectious diseases, and we have recently rapidly mobilized these with the aim of addressing the COVID-19 pandemic. We believe we are uniquely positioned to develop and commercialize the next generation of immunotherapies with the potential to significantly improve clinical outcomes for patients and usher in a new era of individualized medicine.

Our approach to therapeutic development in oncology is based on the key drivers of cancer heterogeneity. The interaction between cancer and the immune system is shaped by various host, tumor and environmental factors. The complex interplay of these sources of interpatient heterogeneity both affects the course of disease and determines the most appropriate choice of treatment.



 

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LOGO

Leveraging our expertise in the field of immunology, we and our collaborators have advanced a development pipeline of over 20 product candidates, of which 12 have entered into 13 ongoing clinical trials. Our most advanced programs are focused on oncology, where we have treated over 500 patients across 17 tumor types to date. In our Phase 1 trials, we have observed single-agent antigen-specific immune responses in over 90% of advanced melanoma patients treated with BNT111, our wholly owned lead off-the-shelf immunotherapy product candidate from our FixVac platform. In addition, we have observed single-agent antigen-specific immune responses in patients treated with BNT121, the precursor to RO7198457 (BNT122), our lead individualized neoantigen specific immunotherapy product candidate from our iNeST platform, which we are co-developing with Genentech, Inc., or Genentech. For both product candidates, we have also observed durable reduction in tumor volume, including objective responses, in both the monotherapy and checkpoint-combination settings.

We believe our technology and expertise is broadly applicable across a number of therapeutic areas, such as infectious diseases and rare diseases. In April 2020, we initiated a first-in-human clinical trial program for our BNT162 vaccine program to prevent COVID-19, which includes four vaccine candidate variants based on three distinct mRNA formats. We are co-developing BNT162 with Pfizer Inc., or Pfizer, worldwide (ex-China) and with



 

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Shanghai Fosun Pharmaceutical (Group) Co., Ltd, or Fosun Pharma, in China. We initiated the BNT162 program in late January 2020 in response to the global COVID-19 pandemic, and initiated human testing following preclinical studies and within approximately three months of initiating the research program. Our ability to rapidly design and test multiple vaccine variants leveraged our deep experience with mRNA vaccines and our prior preclinical work in the infectious disease field.

Our immunotherapy product candidates span four distinct drug classes:

 

   

mRNA Therapeutics. We have developed multiple proprietary formats and formulations of messenger ribonucleic acid, or mRNA, to deliver genetic information to cells, where it is used to express proteins for therapeutic effect.

 

   

Cell Therapies. We are developing a range of cell therapies, including CAR-T cells, neoantigen-based T cell therapies and TCR therapies, in which the patient’s T cells are modified or primed to target cancer-specific antigens.

 

   

Antibodies. We are developing next-generation antibodies, including bispecifics, that are designed to target immune checkpoints and novel cancer antigens.

 

   

Small Molecule Immunomodulators. We use small molecules to augment the activity of other drug classes by inducing specific and discrete patterns of immunomodulation.

Our Approach

In oncology, we are focused on delivering on the promise of individualized immunotherapy for cancer patients. We believe that we can accomplish this by applying the following principles:

 

   

Harnessing the full potential of the immune system by exploiting multiple drug classes and addressing multiple complementary immune pathways.

 

   

Broadening the universe of patients benefiting from cancer immunotherapy.

 

   

Improving the success rate of treatment by developing and engineering highly potent, precise and target-specific drug candidates either as off-the-shelf or individualized immunotherapies.

 

   

Focusing on curative approaches by addressing interindividual variability and cancer heterogeneity.

Similarly, in infectious disease, we are deploying our full suite of technologies and immunotherapeutic understanding to develop mRNA vaccines against emerging infectious diseases, such as COVID-19, in a manner that is designed to be faster and more easily scalable, and with more flexible constructs, than traditional vaccine development.



 

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Our patient-centric approach starts with profiling and diagnostics by utilizing a target identification engine. This engine combines next generation sequencing, genomics, bioinformatics, machine learning and artificial intelligence to (a) identify gene targets of interest, (b) characterize the functional relevance of these targets (i.e., the ability to raise an immune response to or through a target) and (c) demonstrate their drugability. From our founding onwards, we have been developing the novel technologies needed to match the identified targets to the optimal individualized treatment approach. Our patient-centric model is illustrated below.

 

 

LOGO



 

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Our Pipeline

We are advancing a deep and broad portfolio of product candidates derived from our four drug classes.

 

LOGO



 

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We believe the breadth of our technology positions us to combine modes of action in a coordinated, potentially synergistic way to treat cancer in a more efficacious manner than current existing therapies. For example, we have capitalized on synergies in our portfolio by combining our CAR-T cell development with a CARVac primer based on our FixVac platform. We further believe that our patient-centric approach and our broad, potentially synergistic portfolio of drug platforms place us at the forefront of a paradigm shift toward individualized immunotherapies in oncology and allow us to potentially address a larger share of cancer patients, as illustrated below:

 

 

LOGO

We have established relationships with seven pharmaceutical collaborators, which comprise Genentech, Sanofi S.A., or Sanofi, Genmab A/S, or Genmab, Genevant Sciences GmbH, or Genevant, Bayer AG, or Bayer, Pfizer Inc., or Pfizer, and Shanghai Fosun Pharmaceutical (Group) Co., Ltd, or Fosun Pharma, in order to advance our science and development capabilities and provide capital, most of which has been non-dilutive. In addition, we have established research collaborations with the University of Pennsylvania and Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz (Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg Universität Mainz gemeinnützige GmbH), or TRON. We either wholly own or retain significant rights to all of our clinical stage programs, either in the form of a global share of profit and co-commercialization rights with our collaborators in certain markets or significant royalties and milestones.

Our ability to develop, control and optimize the manufacturing of our product candidates is a core strategic pillar and competitive advantage, especially for our individualized mRNA product candidates. We operate three Good Manufacturing Practice, or GMP, certified manufacturing facilities in Germany, where we manufacture mRNA therapeutics and engineered cell therapies for our own pipeline and for external customers. We operate a fourth manufacturing facility in Germany where we manufacture custom peptides to support our extensive immunomonitoring activities, which are critical to our development programs. Additionally, we have collaborated with Siemens AG to develop efficient, semi-automated processes to produce our individualized mRNA immunotherapies on demand.

Our team is comprised of pioneers and entrepreneurs in the fields of immunology and oncology, with experience in pioneering cutting-edge technologies for new, forward-looking therapeutic applications in order to capture new opportunities. Our scientific founders each have over 25 years of experience characterizing the



 

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molecular signatures of cancer and discovering potent high-precision immunotherapies. They are translating this combined knowledge into the development of highly individualized treatments to target patients’ specific cancers and other diseases. Our co-founders, Chief Executive Officer Prof. Ugur Sahin, M.D., and Supervisory Board member Prof. Christoph Huber, M.D., along with our Chief Medical Officer Özlem Türeci, M.D., have been published widely in the field of immunology and oncology and are recognized as thought leaders in their disciplines.

Recent Developments

June 30, 2020 Preliminary Financial Results

As of June 30, 2020, we maintained cash and cash equivalents of €573.0 million ($636.4 million). Cash and cash equivalents as of June 30, 2020 is preliminary, unaudited and subject to completion and may differ from what will be reflected in our unaudited interim financial statements as of and for the three months ended June 30, 2020. Our unaudited interim condensed consolidated financial statements as of and for the three and six months ended June 30, 2020 will not be available to you prior to investing in the Underwritten Offering.

In addition to €573.0 million ($636.4 million) in cash and cash equivalents at June 30, 2020, we expect to receive €223.9 million ($251.0 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) as proceeds from the June 2020 Private Placement described below, which is expected to settle in August 2020.

Pfizer COVID-19 Collaboration

On April 9, 2020, we announced that we and Pfizer had entered into a collaboration agreement to co-develop our potential first-in-class COVID-19 mRNA vaccine program, BNT162, aimed at preventing COVID-19. Under the terms of the agreement, Pfizer agreed to pay us $185 million in upfront payments, including an equity investment of €103.9 million ($113 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)), which was received in late April 2020, and a cash payment of €65.5 million ($72 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)), which was received in May 2020. The issuance of 2,377,446 ordinary shares with the nominal amount of €2,377,446 was registered within the commercial register (Handelsregister) as of May 5, 2020. We are eligible to receive future milestone payments of up to $563 million for potential aggregate consideration of $748 million. Pfizer and we will share development costs equally. Initially, Pfizer will fund 100% of the development costs, and we will repay Pfizer our 50% share of these costs if success-based milestones are reached, or with proceeds generated from the commercialization of the vaccine, if approved. If the vaccine program is not successful or does not generate sufficient proceeds, we will not be required to pay back our 50% share of the development costs incurred.

We and Pfizer are jointly conducting clinical trials for four COVID-19 vaccine candidate variants initially in the United States and Europe across multiple sites. In late April 2020, we and Pfizer announced that the German regulatory authority, the Paul-Ehrlich-Institut, approved the Phase 1/2 clinical trial and the first patients in the first cohort of our Phase 1/2 clinical trial were dosed shortly thereafter. In early May 2020, Pfizer and we initiated a clinical trial for BNT162 in the United States and the first participants were dosed shortly thereafter. On July 13, 2020, we and Pfizer announced that our BNT162b1 and BNT162b2 vaccine candidate variants were granted Fast Track designation by the FDA. During the clinical development stage, we and our partners will provide clinical supply of the vaccine from our GMP-certified mRNA manufacturing facilities in Europe. We and Pfizer are working together to scale-up manufacturing capacity at risk to provide worldwide supply in response to the pandemic. If the vaccine candidate is approved, we and Pfizer would also work jointly to commercialize the vaccine worldwide (excluding China which is covered by our collaboration with Fosun Pharma). If the vaccine candidate is approved, we and Pfizer expect to manufacture up to 100 million doses by the end of 2020 and potentially more than 1.3 billion doses by the end of 2021.



 

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On July 20, 2020, we announced that we and Pfizer entered into a binding term sheet for a supply agreement with the United Kingdom. Pursuant to the term sheet, we and Pfizer expect to supply 30 million doses of BNT162, if approved, to the United Kingdom. Under the terms of the binding term sheet, we and Pfizer are eligible to receive a fully refundable advance payment per dose upon signing of a definitive supply agreement. The advance payment will be treated as a prepayment towards the total cost of the contracted number of doses of BNT162, with the remainder of the contracted price per dose to be paid upon delivery of the contracted doses.

On July 22, 2020, we announced that the United States government has agreed to purchase an initial order of 100 million doses of BNT162 and has the option to acquire up to 500 million additional doses from us and Pfizer. The U.S. government will pay $1.95 billion upon the receipt of the first 100 million doses, following FDA authorization or approval.

We are also in late-stage discussions with other governments and governmental bodies related to the establishment of supply agreements for BNT162, if approved. We expect that we and Pfizer will enter into further binding and non-binding agreements to supply additional doses of BNT162 as early as 2020 and 2021. Certain of the agreements may also provide an option to purchase additional doses, under specified circumstances.

July 2020 BNT162 Data Announcements

On July 1, 2020, we and Pfizer announced preliminary data from our ongoing U.S. Phase 1/2 trial of BNT162b1. The initial part of this randomized, placebo-controlled, observer-blinded study is evaluating the safety, tolerability and immunogenicity of escalating dose levels of BNT162b1, one of four vaccine candidate variants in development as part of our BNT162 program, in 45 healthy adults between 18 and 55 years of age.

The participants received two doses, 21 days apart, of placebo, 10µg or 30µg of BNT162b1, or received a single dose of 100µg of the vaccine candidate. Because of a strong vaccine booster effect, the highest neutralizing titers were observed seven days after the second dose of 10µg or 30µg on day 28 after vaccination. The neutralizing GMTs were 168 and 267 for the 10µg and 30µg dose levels, respectively, corresponding to 1.8- and 2.8-times the neutralizing GMT of 94 observed in a panel of 38 sera from subjects who had contracted SARS-CoV-2.

In all 24 subjects who received 2 vaccinations at 10µg and 30µg dose levels of BNT162b1, elevation of RBD-binding IgG concentrations was observed after the second injection with respective GMCs of 4,813 and 27,872 units/ml at day 28, seven days after immunization. These concentrations are 8- and 46.3-times the GMC of 602 units/ml in a panel of 38 sera from subjects who had contracted SARS-CoV-2.

At day 21 after a single injection, the 12 subjects who received 100µg of BNT162b1 had an RBD-binding IgG GMC of 1,778 units/ml and a SARS-CoV neutralizing GMT of 33, which are 3-times and 0.35-times, respectively, the GMC and GMT of the convalescent serum panel.

At the 10µg or 30µg dose levels, adverse reactions, including low grade fever, were more common after the second dose than the first dose. Following dose 2, 8.3% of participants who received 10µg and 75.0% of participants who received 30µg BNT162b1 reported fever ³ 38.0 °C. Local reactions and systemic events after injection with 10µg and 30µg of BNT162b1 were dose-dependent, generally mild to moderate, and transient. The most commonly reported local reaction was injection site pain, which was mild to moderate, except in one of 12 subjects who received a 100µg dose, which was severe. No serious adverse events were reported. Given higher numbers of subjects experiencing local reactions and systemic events after a single 100µg dose with no significant increases in immunogenicity compared to the 30µg dose level, the 12 participants in the 100µg group were not administered a second dose.

On July 20, 2020, we and Pfizer announced preliminary data from our ongoing German Phase 1/2 trial of BNT162b1. The initial part of this open-label, non-randomized, non-placebo-controlled study is evaluating the safety, tolerability and immunogenicity of escalating dose levels of BNT162b1, one of four vaccine candidate variants in development as part of our BNT162 program, in 60 healthy adults, between 18 and 55 years of age.



 

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The preliminary data we reported was from 12 subjects each who received two doses of 1µg, 10µg, 30µg and 50µg (except for one individual each in the 10µg and 50µg who discontinued due to non-study drug related reasons) and 12 subjects who received a single dose of 60µg. The two doses received by the participants were given 21 days apart.

In 34 of the 36 subjects who received two vaccinations at 10µg, 30µg, or 50µg dose levels of BNT162b1, RBD-specific CD4+ T cell responses were observed. All subjects but the two exceptions at the lowest dose level had cytokine profiling of the RBD-specific CD4+ T cells that demonstrated a TH1-dominant profile for these cells. While the magnitude varied between individuals, participants with the strongest CD4+ T cell responses to RBD had more than 10-fold of the memory responses observed in the same participants when stimulated with cytomegalovirus (CMV), Epstein Barr virus (EBV), influenza virus and tetanus toxoid-derived immuno- dominant peptide panels. The strength of RBD-specific CD4+ T cell responses correlated positively with both RBD-binding IgG and with SARS-CoV-2 neutralizing antibody titers. Among vaccine-induced CD8+ T cell responses, which were observed in 29 of 36 participants, strong responses were mounted by the majority of participants and were comparable with memory responses against CMV, EBV, influenza virus and tetanus toxoid in the same participants. The strength of RBD-specific CD8+ T cell responses correlated positively with vaccine-induced CD4+ T cell responses, but did not significantly correlate with SARS-CoV-2 neutralizing antibody titers. Additionally, although at 1µg the immunogenicity rate was lower (6 of 8 responding participants), the magnitude of vaccine-induced CD4+ and CD8+ T cells in some participants was almost as high as with 50µg BNT162b1.

Elevation of SARS-CoV-2 RBD-binding IgG concentrations was observed, with respective GMCs ranging from 265 units/ml to 1,672 units/ml at day 21. At day 29, seven days after the second dose, RBD-binding IgG GMCs ranged from 2,015 units/ml to 25,006 units/ml. At day 43, RBD-binding IgG GMCs ranged from 3,920 units/ml to 18,289 units/ml. These concentrations are 6.5- to 30.4-times the GMC of 602 units/ml in a panel of sera from 38 subjects who had contracted SARS-CoV-2. At day 29, the SARS-CoV-2 neutralizing GMTs reached 36 (1µg dose), 158 (10µg dose), 308 (30µg dose) and 578 (50µg dose) compared to neutralizing GMT of 94 observed in the convalescent serum panel. At day 43, SARS-CoV-2 neutralizing GMTs reached .7-fold (1µg dose) to 3.2-fold (50µg dose) compared to those of a panel of SARS-CoV-2 infection convalescent human sera. Furthermore, sera of vaccinated subjects displayed broadly neutralizing activity in pseudovirus neutralization assays across a panel of sixteen SARS-CoV-2 RBD variants represented in publicly available SARS-CoV-2 sequences and against the newly dominant D614G strain. In summary, antibody responses elicited by BNT162b1 in our German clinical trial largely mirrored those observed in our U.S. clinical trial.

At the 10µg, 30µg and 50µg dose levels, certain adverse reactions, including low grade fever, were more common after the second dose than the first dose. Following the second dose, 25.0%, 25.0% and 33.3% of participants who received the 10µg, 30µg and 50µg doses, respectively reported fever of at least 38.0 degrees Celsius. Local reactions and systemic events after injection with 10µg, 30µg and 50µg of BNT162b1 were dose- dependent, generally mild to moderate and transient, with occasional severe events (grade 3) of flu-like symptoms and injection site reactions. The most commonly reported local reaction was injection site pain, which was mild to moderate, except in one of 12 subjects who received a 60µg dose, which was severe. No serious adverse events were reported, and there were no withdrawals due to adverse events related to the vaccine. Based on the adverse reactions reported after the 50µg boost dose, a second 60µg dose was not administered to participants who had received an initial 60µg dose.

For additional information on these preliminary results, please review our reports on Form 6-K filed with the SEC on July 1, 2020 and July 20, 2020 and incorporated by reference herein.

Based on preclinical and clinical data observed to-date, we and Pfizer have decided to progress our BNT162 development program into a Phase 2b/3 trial, which is anticipated to commence in late July 2020, subject to input and approval from the appropriate regulatory bodies. For the initial Phase 2b/3 trial, we intend to select either BNT162b1 or BNT162b2. Both the BNT162b1 and the BNT162b2 vaccine candidates have received Fast Track



 

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status from the FDA. Since clinical evaluation of the BNT162b2 candidate started several weeks later than BNT162b1, only preliminary clinical data are currently available for the BNT162b2 candidate. A set of data obtained for a cohort of subjects 18-55 years of age immunized with 10µg of BNT162b2 indicates that BNT162b2 induces similar virus neutralizing antibody responses as observed for BNT162b1. The preliminary observations are subject to further data collection and analysis. Assessment of dose dependent immune response and safety profile as well as analysis of T cell responses is currently pending. On the basis of additional data expected to be collected and analyzed for BNT162b1 and BNT162b2 in the coming days, along with input from the FDA, we intend to select a lead candidate to take into a Phase 2b/3 trial. We and Pfizer currently expect to inform the FDA of our selection of the BNT162 candidate variant before the closing of this offering. Based on clinical data from our ongoing Phase 1/2 trials of BNT162b1 in the United States and Germany, BNT162b1 appears to be a viable variant to advance into a Phase 2b/3 trial. However, given that additional information relating to BNT162b2 is becoming available over the next few days, we and Pfizer plan to make the ultimate decision on the final candidate based on multiple factors, including the overall observed safety, tolerability and immunogenicity profiles for each vaccine candidate at different dose levels, a full immunogenicity data set and feedback from the FDA on the data collected for each candidate. If we ultimately move forward with the BNT162b2 variant, it will be due to the fact that based on our scientific judgment in light of the totality of preclinical data and clinical data available to us at the time of selection and the other factors described above, the BNT162b2 variant has better potential for clinical and commercial success. We do not plan to disclose which BNT162 variant has been selected until we receive FDA approval to commence the Phase 2b/3 clinical trial, and we likely will not publish any data with respect to the BNT162b2 variant before we make our selection.

June 2020 iNeST Data Update

In June 2020, we presented data from a monotherapy dose-finding cohort of our RO7198457 (BNT122) Phase 1 trial in multiple solid tumors in which RO7198457 (BNT122) was observed to have a manageable safety profile and induced strong neoantigen-specific immune responses in patients with low and intermediate mutational load tumors types. This data related to 31 patients enrolled in cohorts with doses ranging from 25-100µg. The most common tumor types were HR+/HER2+ breast, prostate, and ovarian cancer with a median of 5 lines of prior therapies (range 1-17). Most patients enrolled had a low level of PD-L1 expression in the tumor as determined by immunohistochemistry (97% patients with <5% PD-L1 expression on tumor cells (TC) and 93% patients with <5% expression on immune cell (IC)). The majority of adverse events were Grade 1 or Grade 2 and those occurring in more than 20% of patients included infusion related reaction (IRR), fatigue, cytokine release syndrome (CRS), nausea, and diarrhea. IRR and CRS were transient and reversible and presented primarily as Grade 1 or Grade 2 chills and fever. A single dose limiting toxicity of Grade 3 CRS occurred at the 100µg dose level. None of the patients discontinued RO7198457 (BNT122) due to AEs. RO1798457 (BNT122) induced pulsatile release of pro-inflammatory cytokines with each dose, consistent with TLR agonist activity of RNA. Ex vivo T cell responses were detected in approximately 86% of patients treated with RO7198457 (BNT122) as a monotherapy. Analysis of MHC multimers showed the induction of up to 5.3% neo-epitope specific CD8 T-cells with effector memory phenotype in the peripheral blood. RO7198457 (BNT122) induced T cells against multiple neoantigens were detected in post-treatment tumor biopsies. Of 26 patients that underwent at least one tumor assessment, one patient with gastric cancer and metastatic liver lesions had a durable best response of confirmed complete response and remains on study after 1.5 years (3.8%) and 12 patients had stable disease (46.2%).

Also in June 2020, we presented data from 132 patients enrolled in cohorts with doses ranging from 15µg to 50µg of RO7198457 (BNT122) in combination with 1200mg atezolizumab. The most common tumor types enrolled were non-small cell lung cancer, or NSCLC, triple-negative breast cancer, or TNBC, melanoma and colon cancer with a median of three lines of prior therapies (range 1-11). Most patients enrolled had low levels of PD-L1 expression in the tumor as determined by immunohistochemistry (93% patients with <5% PD-L1 expression on tumor cells (TC0/1) and 79% patients with <5% PD-L1 expression on immune cell (IC0/1)). The



 

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majority of adverse events were Grade 1 or Grade 2 and those occurring in more than 15% of patients included infusion related reaction (IRR), fatigue, nausea, cytokine release syndrome (CRS) and diarrhea. IRR and CRS were transient and reversible and presented primarily as Grade 1 or Grade 2 chills and fever. There were no dose

limiting toxicities. Eight patients (5.6%) discontinued due to AEs related to study drugs. RO1798457 (BNT122) induced a self-limiting increase of pro-inflammatory cytokines with each dose, consistent with the TLR agonist activity of RNA. Ex vivo T cell responses were observed in peripheral blood in 46 out of 63 (73%) patients. Induction of up to 5.7% MHC multimer-stained CD8+ T-cells with effector memory phenotype was observed in the peripheral blood. RO7198457 (BNT122) induced T cells against multiple neoantigens were detected in post-treatment tumor biopsies. Of 108 patients that underwent at least one tumor assessment, 1 patient had a complete response as their best response (0.9%), 8 patients had partial responses (7.4%), and 53 patients had stable disease (49.1%).

Based on data from our study of BNT121 as an adjunct to surgery in patients with metastatic melanoma, we believe that RO7198457 (BNT122) is potentially well suited to control metastatic relapses in patients with a lower tumor burden. Additionally, RO7198457 (BNT122) as a monotherapy and in combination with atezolizumab has been observed to have a manageable safety profile to date and to induce significant levels of neoantigen-specific immune responses, even in late-stage, heavily pre-treated patients. Accordingly, we and our collaborator, Genentech, intend to initiate two additional randomized Phase 2 trials in the second half of 2020 in early and adjuvant stage NSCLC and colorectal cancer, where we believe the mechanism of action of RO7198457 (BNT122) is best suited. We also continue to investigate RO7198457 (BNT122) in our ongoing Phase 2 trial in first line melanoma in combination with pembrolizumab.

June 2020 Private Placement

On June 29, 2020, we announced the signing of a private investment by a fund associated with Temasek Capital Management Pte. Ltd., or Temasek, and another accredited investor, which investment we refer to as the June 2020 Private Placement. The June 2020 Private Placement consisted of approximately €123.9 million ($138.9 million, using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) in ordinary shares and a €100.0 million ($112.1 million, using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) four-year mandatory convertible note. Upon the closing of the June 2020 Private Placement, which is expected to occur in August 2020, subject to customary closing conditions, the investors will receive an aggregate of 2,595,996 of our ordinary shares and will be subject to a 180-day lock-up period. The four-year mandatory convertible note will have a coupon of 4.5% per annum and a conversion premium of 20% above the reference price.

Acquisition of Neon Therapeutics, Inc.

On May 6, 2020, we announced the closing of our acquisition of Neon Therapeutics, Inc., or Neon, a biotechnology company developing novel neoantigen-based T cell therapies, through a stock transaction and including de minimis cash consideration, or the Merger. The Merger was first announced on January 16, 2020. Neon, now BioNTech US Inc., or BioNTech US, is operated as our wholly owned subsidiary. The transaction combines two organizations with a common culture of pioneering translational science and a shared vision for the future of cancer immunotherapy. Through the acquisition, we leverage Neon’s deep expertise in the development of neoantigen therapies, with both vaccine and T-cell capabilities. Our most advanced program acquired in the Merger is NEO-PTC-01, a personalized neoantigen-targeted T cell therapy candidate consisting of multiple T cell populations targeting the most therapeutically relevant neoantigens from each patient’s tumor. We also acquired a precision T cell therapy program targeting shared neoantigens in genetically defined patient populations. The lead program from this approach, NEO-STC-01, is a T cell therapy candidate targeting shared RAS neoantigens. In addition, Neon had assembled libraries of high-quality TCRs against various shared neoantigens across common HLAs. This pipeline is underpinned by Neon’s platform technologies including RECON®, its machine-learning bioinformatics platform, and NEO-STIM, its proprietary process to directly prime, activate and expand neoantigen-targeting T cells ex vivo.



 

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Based on the acquisition date share price, the implied aggregate value of the Merger consideration was approximately €89.9 million ($97.1 million) financed by issuing new ordinary shares as a stock transaction and

including a de minimis cash consideration which was paid to settle Neon’s outstanding stock options. The new subsidiary is based in Cambridge, Massachusetts and serves as our U.S. headquarters.

Impacts of COVID-19

On March 11, 2020, the World Health Organization declared the outbreak of COVID-19 as a pandemic, which continues to spread throughout the United States, the European Union and around the world. As we advance our clinical programs, we are in close contact with our principal investigators and clinical sites, which are located in jurisdictions affected by the COVID-19 pandemic, and are assessing the impact of the COVID-19 pandemic on our clinical trials, expected timelines and costs on an ongoing basis. In light of recent developments relating to the COVID-19 pandemic, the primary focus of healthcare providers and hospitals is currently on fighting the novel coronavirus. In addition, in response to the spread of COVID-19, we have modified our business practices, including restricting employee travel, developing social distancing plans for our employees and cancelling physical participation in meetings, events and conferences. In addition, for certain of our earlier-stage programs, including BNT141 and BNT142 (RiboMabs), BNT151 and BNT152/153 (RiboCytokines), BNT161 (Influenza), BNT171 (Rare Disease) and BNT411 (TLR7), we have delayed commencement of trials, experienced slowed patient enrollment or experienced other delays as a result of the COVID-19 pandemic. This partial disruption, even temporary, may severely impact our operations and overall business by delaying the progress of our clinical trials and preclinical studies. All anticipated milestones set forth in this prospectus are subject to further future adjustment as a result of the COVID-19 pandemic. See “Risk Factors.”

Risks Associated with Our Business

Our business is subject to a number of risks of which you should be aware before making an investment decision. These risks are discussed more fully in the section of this prospectus titled “Risk Factors” immediately following this prospectus summary and in the section titled “Risk Factors” in our Annual Report on Form 20-F for the year ended December 31, 2019, incorporated by reference herein. These risks include, but are not limited to, the following:

 

   

Data from our COVID-19 vaccine development program is not predictive of the safety or efficacy of any vaccine candidate. Even if a COVID-19 vaccine is approved for use, we will need to devote significant resources to scale-up our manufacturing and distribution capabilities, which would divert resources away from our other clinical and preclinical programs. Even if a COVID-19 vaccine is approved for use, there can be no assurance that it would ever become profitable, due to, among other things, government interest, public perception regarding a vaccine and competing treatments being developed.

 

   

We are a clinical-stage biopharmaceutical company with no pharmaceutical products approved for commercial sale. We have incurred significant losses since our inception and we anticipate that we will continue to incur significant losses for the foreseeable future, which makes it difficult to assess our future viability.

 

   

We will require substantial additional financing to achieve our goals, and a failure to obtain this capital on acceptable terms, or at all, could force us to delay, limit, reduce or terminate our product development programs, commercialization efforts or other operations.

 

   

We will need to develop and expand our company, and we may encounter difficulties in managing this development and expansion, which could disrupt our operations.

 

   

No mRNA immunotherapy has been approved, and none may ever be approved. mRNA drug development has substantial clinical development and regulatory risks due to the novel and unprecedented nature of this new category of therapeutics.



 

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Our product candidates may not work as intended, may cause undesirable side effects or may have other properties that could delay or prevent their regulatory approval, limit the commercial profile of an approved label, or result in significant negative consequences following marketing approval, if any.

 

   

Clinical development involves a lengthy and expensive process with an uncertain outcome, and delays can occur for a variety of reasons outside of our control. Clinical trials of our product candidates may be delayed, and certain programs may never advance in the clinic or may be more costly to conduct than we anticipate, any of which can affect our ability to fund our company and would have a material adverse impact on our business.

 

   

Interim top-line and preliminary data from studies or trials that we announce or publish from time to time may change as more data become available and are subject to audit and verification procedures that could result in material changes in the final data.

 

   

We face risks related to health epidemics, such as the current COVID-19 outbreak, that could adversely affect our operations.

 

   

Our planned clinical trials or those of our collaborators may reveal significant adverse events not seen in our preclinical or nonclinical studies and may result in a safety profile that could delay or terminate clinical trials, or delay or prevent regulatory approval or market acceptance of any of our product candidates.

 

   

Some of our product candidates are classified as gene therapies by the FDA and the EMA, and the FDA has indicated that our product candidates will be reviewed within its Center for Biologics Evaluation and Research, or CBER. Even though our mRNA product candidates are designed to have a different mechanism of action from gene therapies, the association of our product candidates with gene therapies could result in increased regulatory burdens, impair the reputation of our product candidates, or negatively impact our platform or our business.

 

   

We may be unable to obtain regulatory approval for our product candidates under applicable international regulatory requirements. The denial or delay of such approval would delay commercialization of our product candidates and adversely impact our potential to generate revenue, our business and our results of operations.

 

   

We face significant competition in an environment of rapid technological and scientific change, and our failure to effectively compete would prevent us from achieving significant market penetration. Most of our competitors have significantly greater resources than we do and we may not be able to compete successfully.

 

   

Even if we obtain regulatory approval for our product candidates, the products may not gain the market acceptance among physicians, patients, hospitals, cancer treatment centers and others in the medical community necessary for commercial success.

 

   

Our mRNA product candidates are based on novel technologies and any product candidates we develop may be complex and difficult to manufacture. We may encounter difficulties in manufacturing, product release, shelf life, testing, storage, supply chain management or shipping. If we or any of the third-party manufacturers we work with encounter such difficulties, our ability to supply materials for clinical trials or any approved product could be delayed or stopped.

 

   

Certain of our product candidates are uniquely manufactured for each patient and we may encounter difficulties in production, particularly with respect to scaling our manufacturing capabilities. If we or any of the third-party manufacturers with whom we contract encounter these types of difficulties, our ability to provide our product candidates for clinical trials or our products for patients, if approved, could be delayed or stopped, or we may be unable to maintain a commercially viable cost structure.

 

   

We have entered into several arrangements with a related party for the performance of nonclinical research programs, and these arrangements present potential conflicts of interest.



 

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Our existing collaborations, or any future collaboration arrangements that we may enter into, may not be successful, which could significantly limit the likelihood of receiving the potential economic benefits of the collaboration and adversely affect our ability to develop and commercialize our product candidates.

 

   

If our efforts to obtain, maintain, protect, defend and/or enforce the intellectual property related to our product candidates and technologies are not adequate, we may not be able to compete effectively in our market.

 

   

We may not fully realize the anticipated benefits of the Neon acquisition or realize such benefits within the timing anticipated.

 

   

The price of the ADSs may be volatile and fluctuate substantially, which could result in substantial losses for purchasers of the ADSs.

Corporate Information

We were incorporated on June 2, 2008 as Petersberg 91, V V AG, a German stock corporation (Aktiengesellschaft). We changed our name to BioNTech AG on December 11, 2008. On March 8, 2019, we converted to a European stock corporation (Societas Europaea, or SE) under the laws of Germany and the European Union called BioNTech SE. We completed our initial public offering in October 2019. ADSs representing our ordinary shares are currently listed on the Nasdaq Global Select Market under the symbol “BNTX.”

Our principal executive offices are located at An der Goldgrube 12, D-55131 Mainz, Germany. Our telephone number is +49 6131-9084-0. Our website address is http://www.biontech.de. The information contained on, or that can be accessed through, our website is not incorporated by reference into this prospectus. We have included our website address as an inactive textual reference only.

Implications of Being an Emerging Growth Company and a Foreign Private Issuer

Emerging Growth Company

As a company with less than $1.07 billion in revenue during our last fiscal year, we are an “emerging growth company” as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act. As such, we may take advantage of certain exemptions from various reporting requirements that are applicable to publicly traded entities that are not emerging growth companies. These exemptions include:

 

   

the ability to include only two years of audited financial statements and only two years of related Management’s Discussion and Analysis of Financial Condition and Results of Operations disclosure;

 

   

an exemption from the auditor attestation requirement in the assessment of our internal control over financial reporting pursuant to the Sarbanes-Oxley Act of 2002, as amended;

 

   

to the extent that we no longer qualify as a foreign private issuer, (i) reduced disclosure obligations regarding executive compensation in our periodic reports and proxy statements and (ii) exemptions from the requirement to hold a non-binding advisory vote on executive compensation, including golden parachute compensation; and

 

   

an exemption from compliance with the requirement that the Public Company Accounting Oversight Board has adopted regarding a supplement to the auditor’s report providing additional information about the audit and the financial statements.

As a result, the information contained in this prospectus may be different from the information you receive from other public companies in which you hold shares.



 

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Section 107 of the JOBS Act also provides that an emerging growth company can take advantage of an extended transition period for complying with new or revised accounting standards applicable to public companies. This provision allows an emerging growth company to delay the adoption of certain accounting standards until those standards would otherwise apply to private companies. This transition period is only applicable under U.S. GAAP. As a result, we will adopt new or revised accounting standards on the relevant dates on which adoption of such standards is required or permitted by the IASB.

We may take advantage of these provisions for up to five years from the completion of our initial public offering or until such earlier time that we are no longer an emerging growth company. We would cease to be an emerging growth company upon the earliest to occur of: (i) the last day of the first fiscal year in which our annual gross revenues exceed $1.07 billion, (ii) the date on which we have issued more than $1 billion in non-convertible debt securities during the previous three years and (iii) the first day of the year following the first year in which, as of the last business day of our most recently completed second fiscal quarter, the market value of our common equity held by non-affiliates exceeds $700 million. As of June 30, 2020, which was the last business day of our most recently completed second fiscal quarter, the market value of our common equity held by non-affiliates exceeded $700 million. Consequently, we expect that we will cease to be an emerging growth company no later than December 31, 2020, and we expect to qualify as a large accelerated filer as of that date. As a result, we expect that, as of December 31, 2020, we will be required to adhere to, among other things, the auditor attestation requirement in the assessment of internal control over financial reporting and compliance with the requirement that the Public Company Accounting Oversight Board has adopted regarding a supplement to the auditor’s report providing additional information about the audit and the financial statements. For additional information, please see “Risk Factors” in our Annual Report on Form 20-F for the year ended December 31, 2019, incorporated by reference herein.

Foreign Private Issuer

We report under the Securities Exchange Act of 1934, as amended, or the Exchange Act, as a non-U.S. company with foreign private issuer status. Even after we no longer qualify as an emerging growth company, as long as we continue to qualify as a foreign private issuer under the Exchange Act, we are exempt from certain provisions of the Exchange Act that are applicable to U.S. domestic public companies, including:

 

   

the rules under the Exchange Act requiring domestic filers to issue financial statements prepared under U.S. GAAP;

 

   

the sections of the Exchange Act regulating the solicitation of proxies, consents or authorizations in respect of a security registered under the Exchange Act;

 

   

the sections of the Exchange Act requiring insiders to file public reports of their share ownership and trading activities and liability for insiders who profit from trades made in a short period of time; and

 

   

the rules under the Exchange Act requiring the filing with the Securities and Exchange Commission, or the SEC, of quarterly reports on Form 10-Q containing unaudited financial statements and other specified information, and current reports on Form 8-K upon the occurrence of specified significant events.

Notwithstanding these exemptions, we will file with the SEC, within four months after the end of each fiscal year, or such applicable time as required by the SEC, an annual report on Form 20-F containing financial statements audited by an independent registered public accounting firm.

We may take advantage of these exemptions until such time as we are no longer a foreign private issuer. We would cease to be a foreign private issuer at such time as more than 50% of our outstanding voting securities are held by U.S. residents and any of the following three circumstances applies: (i) the majority of our executive



 

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officers or directors are U.S. citizens or residents, (ii) more than 50% of our assets are located in the United States or (iii) our business is administered principally in the United States.

Both foreign private issuers and emerging growth companies also are exempt from certain more stringent executive compensation disclosure rules. Thus, as long as we remain a foreign private issuer, even after we no longer qualify as an emerging growth company, we will continue to be exempt from the more stringent compensation disclosures required of companies that are neither an emerging growth company nor a foreign private issuer.



 

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THE UNDERWRITTEN OFFERING

 

Public offering price

$93.00 per ADS.

 

ADSs offered by us

5,500,000 ADSs, each representing one ordinary share

 

The Selling Shareholder

MIG Verwaltungs AG, through MIG GmbH & Co. Fonds 7 KG, MIG GmbH & Co. Fonds 8 KG and MIG GmbH & Co. Fonds 9 KG

 

Ordinary shares to be outstanding immediately after the Underwritten Offering

238,173,455 ordinary shares, including ordinary shares represented by ADSs

 

Option to purchase additional ADSs

The underwriters have an option, exercisable for a period of 30 days after the date of this prospectus, to purchase an aggregate of up to 825,000 additional ADSs from the Selling Shareholder.

 

American Depositary Shares

The underwriters will deliver American Depositary Shares, or the ADSs. Each ADS represents one of our ordinary shares, no par value per share.

 

  As an ADS holder, you will not be treated as one of our shareholders and you will not have shareholder rights. The depositary, The Bank of New York Mellon, will be the holder of the ordinary shares underlying the ADSs. You will have the rights of an ADS holder as provided in the deposit agreement among us, the depositary and holders and beneficial owners of ADSs from time to time. To better understand the terms of the ADSs, see “Description of American Depositary Shares.” We also encourage you to read the deposit agreement, the form of which is incorporated by reference as an exhibit to the registration statement of which this prospectus forms a part.

 

Depositary

The Bank of New York Mellon

 

Risk factors

See “Risk Factors” beginning on page 22 as well as the risk factors contained in our Annual Report on Form 20-F for the year ended December 31, 2019 and the other information contained in this prospectus or incorporated by reference herein for a discussion of factors you should consider before deciding to invest in the ADSs.

 

Use of proceeds

We estimate that the net proceeds to us from the Underwritten Offering will be approximately $478.0 million (€430.4 million), after deducting underwriting discounts and commissions and estimated offering expenses payable by us. We will not receive any proceeds from the potential sale of ADSs in this Underwritten Offering by the Selling Shareholder, pursuant to the underwriters’ option to purchase additional ADSs from the Selling Shareholder. We intend to use the



 

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net proceeds from the Underwritten Offering and the net proceeds, if any, from the Rights Offering, to:

 

   

advance our iNeST program candidate RO7198457 (BNT122) into late-stage trials;

 

   

advance our ongoing and currently planned clinical trials for our FixVac product candidates, BNT111, BNT112, BNT113, BNT114, BNT115 and our targeted cancer antibody, MVT-5873 (BNT321), as well as fund our portion of the research and development expenses for SAR441000 (BNT131), which is being developed in collaboration with Sanofi, GEN1046 (BNT311) and GEN1042 (BNT312), which are being developed in collaboration with Genmab and advance the development of BNT162, our COVID-19 vaccine candidate, which is being developed in collaboration with Pfizer;

 

   

initiate clinical trials for additional product candidates, including product candidates from our CAR T, RiboMabs, RiboCytokines and TCR platforms in oncology;

 

   

further accelerate and expand our infectious disease immunotherapy programs;

 

   

advance our rare disease protein replacement therapy platforms outside of oncology;

 

   

advance additional preclinical product candidates, develop additional product candidates leveraging our therapeutic platforms and fund the further development of our core technologies; and

 

   

fund the further expansion of our manufacturing and laboratory capacity, the continued development of our infrastructure and investment in preparation for commercialization for launch of BNT162, if approved.

 

  We expect to use the remainder of any net proceeds from the Global Offering, as well as our existing cash and cash equivalents, for general corporate purposes. We may also use a portion of the net proceeds to in-license or acquire or invest in complementary technologies, products, businesses or assets, either alone or together with a collaborator. However, we have no current commitments or obligations to do so.

 

  See “Use of Proceeds” for a more complete description of the intended use of proceeds from the Global Offering.

 

Nasdaq Global Select Market symbol

ADSs representing our ordinary shares are listed on the Nasdaq Global Select Market under the symbol “BNTX.”

As required by German law, following the setting of the price to public for this underwritten offering, which we refer to as the Underwritten Offering, we intend to commence a rights offering, or the Rights Offering, to holders of our ordinary shares and ADSs representing our ordinary shares. The Underwritten Offering and the Rights Offering are part of a single, global offering which we refer to in this prospectus as the “Global Offering.”



 

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We have obtained irrevocable, binding agreements from certain holders of our ordinary shares, representing 74.83% of our outstanding ordinary shares (including ordinary shares represented by ADSs), not to transfer or exercise their rights to subscribe for new ordinary shares in the Rights Offering. Under German law, the law of our jurisdiction of organization, we are permitted to offer new ordinary shares and ADSs, in an amount equal to the percentage of securities represented by the irrevocable agreements not to transfer or exercise rights, to new investors in advance of the Rights Offering. We intend to accomplish this through the Underwritten Offering described above. Following the Underwritten Offering, our shareholders and ADS holders as of the respective record dates who have not agreed to forego exercising rights have the opportunity in the Rights Offering to subscribe for up to 1,889,189 new ordinary shares or new ADSs (representing approximately 0.81% of our outstanding ordinary shares) at a subscription price equal to the price to public in the Underwritten Offering. ADSs purchased in the Underwritten Offering are not entitled to receive rights to subscribe for new ordinary shares or new ADSs in the Rights Offering. Accordingly, a total of up to 7,389,189 ordinary shares (including ordinary shares represented by ADSs) may be sold by us in the Global Offering. If all of the shares and ADSs in the Rights Offering are subscribed for (excluding those attributable to holders that have irrevocably agreed not to transfer or exercise rights), we will offer 7,389,189 ordinary shares (including ordinary shares represented by ADSs) in the Global Offering and will have 240,062,644 ordinary shares outstanding immediately after the Global Offering.

Unless otherwise indicated, the number of our ordinary shares to be outstanding after the Underwritten Offering is based on 226,779,744 ordinary shares outstanding as of March 31, 2020 and excludes:

 

   

16,338,305 ordinary shares available for issuance upon the exercise of options outstanding as of March 31, 2020;

 

   

254,065 ordinary shares available for issuance upon the exercise of options expected to be granted in 2021 and 2022 under our long-term incentive program as of March 31, 2020;

 

   

5,282,436 ordinary shares available for future issuance under our Employee Stock Ownership Plan or any future share option plan as of March 31, 2020 (after taking into account the issuance of options expected to be granted in 2021 and 2022);

 

   

1,580,777 ordinary shares issued to Fosun Pharma in connection with our collaboration with Fosun Pharma;

 

   

2,377,446 ordinary shares issued to Pfizer in connection with our collaboration with Pfizer;

 

   

1,935,488 ADSs representing our ordinary shares issued to former stockholders of Neon in the Merger; and

 

   

5,524,506 ordinary shares held in treasury.

Unless otherwise indicated, all information contained in this prospectus:

 

   

excludes the 2,595,996 ordinary shares to be issued in the June 2020 Private Placement, which is expected to close in August 2020;

 

   

assumes no exercise of the outstanding options described above;

 

   

assumes no exercise of the option granted to the underwriters to purchase up to 825,000 additional ADSs from the Selling Shareholder in the Underwritten Offering; and

 

   

excludes the effects of our acquisition of Neon; for more information, see “Unaudited Pro Forma Condensed Combined Financial Information.”



 

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SUMMARY CONSOLIDATED FINANCIAL DATA

The following tables set forth a summary of our historical consolidated financial data for the years ended December 31, 2019, 2018 and 2017, as of March 31, 2020 and for the three months ended March 31, 2020 and 2019. We derived the summary of our results for the years ended December 31, 2019, 2018 and 2017 from our audited consolidated financial statements incorporated by reference herein. The summary consolidated financial data as of March 31, 2020 and for the three months ended March 31, 2020 and 2019 have been derived from our unaudited interim condensed consolidated financial statements incorporated by reference herein and have been prepared on the same basis as the audited financial statements. In the opinion of management, the unaudited interim data reflects all adjustments necessary for a fair presentation of the financial information in those statements. We present our consolidated financial statements in Euros and in accordance with IFRS as issued by the IASB.

The summary consolidated financial data below should be read together with our consolidated financial statements and related notes, and our unaudited interim condensed consolidated financial statements included elsewhere in this prospectus, as well as the section of this prospectus titled “Selected Consolidated Financial Data” and the section titled “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in our Forms 20-F and 6-K incorporated by reference herein. Our historical results for any prior period are not necessarily indicative of results to be expected in any future period, and the results for the three months ended March 31, 2020 are not necessarily indicative of the results to be expected for the full year ended December 31, 2020.

 

     For the
Three Months Ended
March 31,
    For the Years Ended
December 31,
 
     2020     2019     2019     2018     2017  
(in thousands except per share data)    (unaudited)                    

Consolidated statements of operations:

          

Revenues from contracts with customers

   27,663     26,154     108,589     127,575     61,598  

Cost of sales

     (5,842     (3,205     (17,361     (13,690     (9,318
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Gross profit

   21,821     22,949     91,228     113,885     52,280  
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Research and development expenses

     (65,122     (57,241     (226,466     (143,040     (85,496

Sales and marketing expenses

     (486     (560     (2,718     (3,041     (6,603

General and administrative expenses

     (15,815     (9,276     (45,547     (26,334     (23,520

Other operating income

     425       331       2,724       5,396       2,349  

Other operating expenses

     (100     (38     (739     (720     (288
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Operating loss

   (59,277   (43,835   (181,518   (53,854   (61,277
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Finance income

     6,417       3,578       4,122       8,046       2,133  

Finance expenses

     (103     (74     (326     (48     (26,007

Interest expenses related to lease liability

     (415     (425     (1,718     (1,721     (676

Share of loss of equity method investees

     —         —         —         (84     (78
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Loss before tax

   (53,378   (40,756   (179,440   (47,662   (85,905
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Income taxes

     (8     (6     268       (600     (45

Loss for the period

   (53,386   (40,762   (179,172   (48,262   (85,950
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Loss attributable to equity holders of the parent

     (53,386     (40,646     (179,056     (48,019     (85,653
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Loss attributable to non-controlling interests

     —         (116     (116     (243     (297
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Basic and diluted loss per share

   (0.24   (0.20   (0.85   (0.25   (0.51
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 


 

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The following table presents our summary consolidated statement of financial position as of March 31, 2020 (i) on an actual basis, (ii) on a pro forma basis to give effect to (a) the issuance of 1,935,488 ADSs representing our ordinary shares in our acquisition of Neon, (b) the issuance of 1,580,777 of our ordinary shares in a private placement to Fosun Pharma for proceeds of €45.6 million ($50.0 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) and (c) the issuance of 2,377,446 of our ordinary shares in a private placement to Pfizer for proceeds of €103.9 million ($113.0 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) and (iii) on a pro forma as adjusted basis to give further effect to the sale of up to 5,500,000 ADSs representing ordinary shares by us in the Underwritten Offering at the public offering price of $93.00 per ADS, and after deducting underwriting discounts and commissions and estimated offering expenses payable by us.

 

     As of March 31, 2020  
     Actual     Pro Forma(1)     Pro Forma
As adjusted(1)(2)
 
(in thousands)    (unaudited)  

Consolidated statements of financial position:

      

Cash and cash equivalents

   451,597     601,055     1,031,411  

Total assets

     732,208       971,214       1,401,570  

Total liabilities

     284,078       284,078       284,078  

Share capital

     232,304       238,198       243,698  

Capital reserve

     686,714       919,826       1,344,682  

Accumulated losses

     (478,213     (478,213     (478,213

Total equity

     448,130       687,136       1,117,492  

 

(1)

Does not reflect the issuance of 2,595,996 ordinary shares and a four-year mandatory convertible note for anticipated gross proceeds of €223.9 million ($251.0 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) in the June 2020 Private Placement, expected to close in August 2020.

(2)

If the Rights Offering is fully subscribed (excluding ordinary shares underlying rights offered to holders that have irrevocably agreed not to transfer or exercise their rights), our cash and cash equivalents, total assets and total equity would each increase by €150.0 million and our share capital would increase by €1.9 million.



 

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RISK FACTORS

Investing in the ADSs representing our ordinary shares involves a high degree of risk. You should carefully consider the following risks, together with all of the other information contained in this prospectus and in our filings with the Securities and Exchange Commission, or the SEC, that we have incorporated by reference in this prospectus. If any of the following risks actually occur, our business, prospects, operating results and financial condition could suffer materially. In such event, the trading price of the ADSs representing our ordinary shares could decline and you might lose all or part of your investment.

Risks Related to Our COVID-19 Vaccine Development Program and Our Intellectual Property

We may experience significant volatility in the market price of the ADSs representing our ordinary shares following announcements and data releases regarding our ongoing development of BNT162 as a potential COVID-19 vaccine.

Biopharmaceutical companies that are developing potential therapeutics and vaccines to combat COVID-19 and SARS-CoV-2, including BioNTech SE, have experienced significant volatility in the price of their securities upon publication of preclinical and clinical data as well as news about their development programs. For example, following the announcement of our collaborations with Pfizer and Fosun Pharma relating to the development of BNT162, our vaccine candidate program for the prevention of COVID-19, the last reported sales price of the ADSs representing our ordinary shares on the Nasdaq Global Select Market increased from $30.93 on March 13, 2020, the day before the announcement, to $92.00 on March 18, 2020, before decreasing to $46.50 on March 20, 2020. In addition to the preclinical and clinical data we and Pfizer have already disclosed in connection with our BNT162 development program, we and Pfizer intend over the coming months to make public several additional COVID-19 vaccine data readouts and clinical updates. We also expect to announce data, in due course, for the other three vaccine candidate variants that we are currently testing for the prevention of COVID-19 as part of our BNT162 program. On July 20, 2020, we announced that we and Pfizer have entered into a binding term sheet for a supply agreement with the United Kingdom and on July 22, 2020, we announced that the U.S. government has agreed to purchase doses of BNT162 from us and Pfizer. In addition, we are in late-stage discussions with other governments and governmental bodies related to the establishment of supply agreements for BNT162, if approved. We cannot predict public reaction or the impact on the market price of the ADSs representing our ordinary shares once the terms of any or all of these supply arrangements are announced. We also cannot guarantee that the ultimate supply agreements we enter into, if any, will be for the number of doses we currently estimate and that aggregate consideration to be received under any such supply agreements will ultimately be what we currently expect. Given the attention being paid to the COVID-19 pandemic and the public scrutiny of COVID-19 development announcements and data releases to date, we expect that the public announcements we and Pfizer intend to make in the coming months regarding the ongoing development of BNT162 will attract significant attention and scrutiny and that, as a result, the price of the ADSs representing our ordinary shares may be particularly volatile during this time.

We are currently developing multiple candidate variants in our BNT162 program, which rely on different mechanisms of action, and the efficacy or safety of one variant is not indicative or predictive of the efficacy or safety of another variant.

We are currently developing four vaccine candidate variants for the prevention of COVID-19 as part of our BNT162 program. The first, which is the variant for which we and Pfizer announced Phase 1/2 data on July 1 and July 20, 2020, is BNT162b1, which utilizes nucleoside-modified mRNA (modRNA) and encodes the receptor binding domain antigen. Two of our four vaccine candidate variants, including BNT162b1, include a modRNA, one includes a uridine containing mRNA (uRNA), and the fourth variant utilizes self-amplifying mRNA (saRNA). Each mRNA format is combined with a lipid nanoparticle (LNP) formulation. The larger spike sequence is included in two of the vaccine candidate variants and the smaller optimized receptor binding domain from the spike protein is included in the other two candidate variants. Each variant has a distinct mechanism of action, and, as a result, clinical activity or safety results observed from one variant may not be indicative or

 

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predictive of the efficacy or safety profile or results observed of another variant. For example, the data we recently announced for our BNT162b1 variant may differ in material respects from the safety or efficacy profile of the other vaccine candidate variants and should not be considered predictive of the safety or efficacy of our other vaccine candidate variants.

We cannot guarantee that the BNT162 variant we choose to advance into late stage clinical development will perform better than any of the variants we do not choose to advance. Further, even if we demonstrate a sufficient safety profile for BNT162 we may not be able to demonstrate sufficient efficacy in subsequent trials to obtain regulatory approval.

Based on preclinical and clinical data observed to-date, we and Pfizer have decided to progress our BNT162 development program into a Phase 2b/3 trial, which we plan to commence in late July 2020, subject to input and approval the from the appropriate regulatory bodies. For the initial Phase 2b/3 trial, we intend to select either the vaccine candidate variant for which we have already released data publicly, BNT162b1, or our modRNA vaccine candidate variant targeting the 2P-mutated full spike protein, BNT162b2. Both the BNT162b1 and the BNT162b2 vaccine candidates have received Fast Track status from the FDA. Since clinical evaluation of the BNT162b2 candidate started several weeks later than BNT162b1, only preliminary clinical data are currently available for the BNT162b2 candidate. A set of data obtained for a cohort of subjects aged to 18-55 years immunized with 10µg of BNT162b2 indicates that BNT162b2 may induce strong virus neutralizing antibody responses with titers in a similar range as observed for BNT162b1. The preliminary observations are subject to further data collection and analysis. Assessment of dose dependent immune response and safety profile as well as analysis of T cell responses is currently pending. On the basis of additional data expected to be collected and analyzed for BNT162b1 and BNT162b2 in the coming days, along with input from the FDA, we intend to select a lead candidate to take into a Phase 2b/3 trial. We and Pfizer currently expect to inform the FDA of our selection of the BNT162 candidate variant before the closing of this offering. Based on clinical data from our ongoing Phase 1/2 trials of BNT162b1 in the United States and Germany, BNT162b1 appears to be a suitable variant to advance into a Phase 2b/3 trial. If we and Pfizer ultimately determine to advance the BNT162b2 variant, we intend to base this decision on multiple factors, including the overall observed safety, tolerability and immunogenicity profiles for each vaccine candidate at different dose levels, as well as feedback from the FDA on the data collected for each candidate. If we ultimately move forward with the BNT162b2 variant, it will be due to the fact that based on our scientific judgment in light of the totality of preclinical data and clinical data available to us at the time of selection and the other factors described above, the BNT162b2 variant has better potential for clinical and commercial success. We do not plan to disclose which BNT162 variant has been selected until we receive FDA approval to commence the Phase 2b/3 clinical trial, and we do not plan to publish any data with respect to the BNT162b2 variant before we make our selection.

We cannot guarantee that the candidate variant that we select will ultimately prove to be the optimal variant. We and Pfizer intend to choose the variant to advance based on our scientific judgment in light of the preclinical and clinical data available to us at the time as to which variant has the best chance for success. It is possible that subsequent data regarding the variant we choose could prove to be less favorable or subsequent data from a variant that is not advanced could prove to be more favorable. In addition, it is possible that public perception of subsequently released data on the variant we choose to advance could be negative and could cause our stock price to decrease regardless of the progress of the Phase 2b/3 trial. It is also possible that the FDA may disagree with or have questions about our variant selection, which could delay the start of our Phase 2b/3 trial.

Regardless of the variant we select for Phase 2b/3, we cannot guarantee that the results from subsequent data analyses and announcements will be in line with the data that we have previously published. In addition, the total number of patients evaluated in Phase 1 is small relative to the number we intend to evaluate in Phase 2b/3 and may not be indicative of the safety or immunogenicity of BNT162 in a larger and more diverse patient population. Similarly, the samples of convalescent sera, or blood samples from people who have recovered from

COVID-19, used to benchmark the level of antibodies produced by subjects receiving BNT162 in clinical studies, have been taken from a small number of people and may not be representative of the antibody levels in a

 

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broader population of people who have recovered from COVID-19. Future results in clinical trials of BNT162 may not be as positive when compared to the antibody levels in other samples of convalescent sera.

Furthermore, because the assays being used to measure and analyze the effectiveness of COVID-19 vaccines have only recently been developed and are continuing to evolve, indications of immunogenicity and the duration of immunity observed in our Phase 1/2 trials may not be predictive of the achievement of clinically relevant endpoints.

In addition, by definition our Phase 1/2 clinical trials are designed to evaluate only safety and not efficacy. Positive results from these Phase 1/2 trials do not guarantee we will be able to demonstrate in our Phase 2b/3 trial that BNT162 is efficacious. More specifically, we do not yet know the levels of immunity required to prevent COVID-19 infection, and have not yet tested the ability of our vaccine candidates to prevent infection in humans. Failure to adequately demonstrate safety or to eventually demonstrate sufficient efficacy of BNT162 could delay or prevent us from receiving regulatory approval of BNT162 and there can be no assurance that BNT162 will be approved in a timely manner, if at all.

The development of our BNT162 program may divert resources from the clinical development of our other product candidates and we may not recoup our investments in the program.

Although we believe that our BNT162 program could result in an effective COVID-19 vaccine, clinical trials involve a lengthy and expensive process with an uncertain outcome. Given the severity and urgency of the COVID-19 pandemic, we have committed significant capital and resources to fund and supply the development of BNT162. However, the development of BNT162 will require us to expend financial, personnel and other resources and may cause delays in or otherwise negatively impact our other development programs, despite uncertainties surrounding the longevity and extent of COVID-19 as a global health concern. Furthermore, our business could be negatively impacted by our allocation of significant resources to a global health threat that is unpredictable and could rapidly dissipate or against which our vaccine, if developed, may not be partially or fully effective.

If we are successful in producing a vaccine against COVID-19, we may need to devote significant resources to its scale-up and development.

If any clinical trials for BNT162 are perceived to be successful, we may need to work toward the large scale technical development, manufacturing scale-up and larger scale deployment of this vaccine candidate through a variety of government mechanisms such as an Emergency Use Authorization program in the United States. We may also need to access facilities capable of rapidly manufacturing BNT162 in the volumes necessary to support large-scale clinical trials or commercial sales. If we are unable to conduct production and manufacturing activities or if our vaccine requires more doses to achieve sufficient efficacy than we expect, we may not complete our product development or commercialization efforts in a timely manner. In addition, during a global health crisis, such as the COVID-19 pandemic, where the spread of a disease needs to be controlled, closed or heavily regulated national borders will create challenges and potential delays in our development and production activities and may necessitate that we pursue strategies to develop and produce our vaccine candidate variants within self-contained national or international borders, at potentially much greater expense and with longer timeframes for public distribution.

There can be no assurance that BNT162, even if approved, would ever become profitable, due to government interest and public perception regarding a vaccine.

As a result of the emergency situations in many countries, there is a heightened risk that a COVID-19 vaccine may be subject to adverse governmental actions in certain countries, including intellectual property expropriation, compulsory licenses, strict price controls or other actions. Additionally, we may need to, or we may be required by governmental or non-governmental authorities to, set aside specific quantities of doses of BNT162 for designated purposes or geographic areas. We are likely to face challenges related to the allocation of

 

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supply of BNT162, particularly with respect to geographic distribution. Thus, even if BNT162 is approved, such governmental actions may limit our ability to recoup our current and future expenses.

Furthermore, public sentiment regarding commercialization of a COVID-19 vaccine may limit or negate our ability to generate revenues from sales of BNT162. Given that COVID-19 has been designated as a pandemic and represents an urgent public health crisis, we are likely to face significant public attention and scrutiny over any future business models and pricing decisions with respect to BNT162. If we are unable to successfully manage these risks, we could face significant reputational harm, which could negatively affect the price of the ADSs representing our ordinary shares.

The regulatory pathway for BNT162 is highly dynamic and continues to evolve and may result in unexpected or unforeseen challenges.

To date, BNT162 has moved rapidly through the regulatory review process of the FDA and foreign regulatory authorities. The speed at which all parties are acting to create and test many therapeutics and vaccines for SARS-CoV-2 and COVID-19 is unusual, and evolving or changing plans or priorities within the FDA and foreign regulatory authorities, including changes based on new knowledge of COVID-19 and how the disease affects the human body, may significantly affect the regulatory timeline for BNT162. Results from clinical testing may raise new questions and require us to redesign proposed clinical trials, including revising proposed endpoints or adding new clinical trial sites or cohorts of subjects.

For example, the FDA on June 30, 2020 adopted guidance outlining the FDA’s current recommendations regarding the data needed to facilitate clinical development and licensure of vaccines to prevent COVID-19. In particular, the June 30, 2020 guidance suggests that the primary efficacy endpoint estimate for a placebo-controlled efficacy trial should be at least 50%. The guidance also includes discussion of chemical, manufacturing and controls and safety concerns. Although we intend to design any future clinical trials for BNT162 in accordance with this guidance, we cannot be certain that, as the regulatory pathway continues to evolve, we will be able to complete a clinical trial in accordance with the FDA’s guidance and regulations then in effect. A failure to complete a clinical trial in accordance with guidance and regulations then in effect could impair our ability to obtain approval for BNT162, which may adversely affect our operating results, reputation and ability to raise capital and enter into or maintain collaborations to advance our other product candidates.

Additionally, the FDA has the authority to grant an Emergency Use Authorization to allow unapproved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions when there are no adequate, approved, and available alternatives. If we are granted an Emergency Use Authorization for BNT162, we would be able to commercialize BNT162 prior to FDA approval. However, the FDA may revoke an Emergency Use Authorization where it is determined that the underlying health emergency no longer exists or warrants such authorization, and we cannot predict how long, if ever, an Emergency Use Authorization would remain in place. Such revocation could adversely impact our business in a variety of ways, including if BNT162 is not yet approved by the FDA and if we and our manufacturing partners have invested in the supply chain to provide BNT162 under an Emergency Use Authorization.

Even if regulatory approval is received for a BNT162 vaccine candidate, the later discovery of previously unknown problems associated with BNT162 may result in restrictions, including withdrawal of the product from the market, and lead to significant liabilities and reputational damage.

Because the path to marketing approval of any vaccine against COVID-19 is unclear, we may have a widely used vaccine in circulation in the United States or another country prior to our receipt of marketing approval. Unexpected safety issues, including any that we have not yet observed in our Phase 1/2 clinical trials for BNT162, could lead to significant reputational damage for BioNTech and our technology platforms going forward and other issues, including delays in our other programs, the need for re-design of our clinical trials and the need for significant additional financial resources.

 

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We also may be restricted or prohibited from marketing or manufacturing a BNT162 vaccine, even after obtaining product approval, if previously unknown problems with the product or its manufacture are subsequently discovered. We cannot provide assurance that newly discovered or developed safety issues will not arise following regulatory approval. With the use of any vaccine by a wide patient population, serious adverse events may occur from time to time that did not arise in the clinical trials of the product or that initially appeared to be unrelated to the vaccine itself and only with the collection of subsequent information were found to be causally related to the product. Any such safety issues could cause us to suspend or cease marketing of our approved products, possibly subject us to substantial liabilities, and adversely affect our ability to generate revenue and our financial condition.

We may be unable to produce a successful COVID-19 vaccine and establish a competitive market share for our vaccine before a competitor or before the COVID-19 outbreak is effectively contained or the risk of coronavirus infection is significantly diminished.

A large number of vaccine manufacturers, academic institutions and other organizations currently have programs to develop COVID-19 vaccine candidates. While we are not aware of all of our competitors’ efforts, we believe that the University of Oxford/AstraZeneca plc, CanSino Biologics Inc., Sanofi/GlaxoSmithKline plc Inovio Pharmaceuticals, Inc., China National Pharmaceutical Group (Sinopharm)/Beijing Institute of Biological Products and Wuhan Institute of Biological Products, Moderna, Inc., Johnson & Johnson, Novavax, Inc. and other companies are all in the early stages of developing vaccine candidates against COVID-19. Our competitors pursuing vaccine candidates may have greater financial, product candidate development, manufacturing and marketing resources than we do. Larger pharmaceutical and biotechnology companies have extensive experience in clinical testing and obtaining regulatory approval for their products, and may have the resources to heavily invest to accelerate discovery and development of their vaccine candidates.

Our efforts to develop BNT162 for regulatory approval and commercialization may fail if competitors develop and commercialize one or more COVID-19 vaccines before we are able to do so, or if they develop and commercialize one or more COVID-19 vaccines that are safer, more effective, produce longer immunity against COVID-19, require fewer administrations, have fewer or less severe side effects, have broader market acceptance, are more convenient or are less expensive than any vaccine candidate that we may develop.

Other companies or organizations may challenge our intellectual property rights or may assert intellectual property rights that prevent us from developing and commercializing our product candidates and other technologies.

We practice in new and evolving scientific fields, the continued development and potential use of which has resulted in many different patents and patent applications from organizations and individuals seeking to obtain intellectual property protection in the fields. We own and in-license patent applications and issued patents that describe and/or claim certain technologies, including products, reagents, formulations and methods including uses and manufacturing methods, or features or aspects of any of these. These issued patents and pending patent applications claim certain compositions of matter and methods relating to the discovery, development, manufacture and commercialization of therapeutic modalities and our delivery technologies, including LNPs. If we, our co-owners or our licensors are unable to obtain, maintain, protect, defend or enforce patent protection with respect to our product candidates and other technology and any product candidates and technology we develop, our business, financial condition, results of operations and prospects could be materially harmed.

As the scientific fields mature, our known competitors and other third parties have filed, and will continue to file, patent applications claiming inventions in the field in the United States and abroad. There is uncertainty about which patents will issue, and, if they do, as to when, to whom and with what claims. With respect to both in-licensed and owned intellectual property, we cannot predict whether the patent applications we and our licensors are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient protection from competitors.

 

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We, our co-owners or our licensors may in the future become a party to patent proceedings or priority disputes in the United States, Europe or other jurisdictions. The Leahy-Smith America Invents Act, or the America Invents Act, enacted in September 2011, included a number of significant changes that affect the way patent applications will be prosecuted and also may affect patent litigation. These include allowing third-party submission of prior art to the USPTO during patent prosecution and additional procedures to attack the validity of a patent through USPTO-administered post-grant proceedings, including post-grant review, inter partes review and derivation proceedings. We expect that our competitors and other third parties will institute litigation and other proceedings, such as interference, reexamination and opposition proceedings, as well as inter partes and post-grant review proceedings against us and the patents and patent applications that we own and in-license. For example, various third parties have filed opposition papers challenging our issued EP patent 2714071 which relates to our iNeST product candidates, and whose claims recite steps relating to neoantigen selection.

We expect that we will be subject to similar proceedings or priority disputes, including oppositions, in Europe or other foreign jurisdictions relating to patents and patent applications in our portfolio.

If we, our co-owners or our licensors are unsuccessful in any interference proceedings or other priority or validity disputes, including any derivations, post-grant review, inter partes review or oppositions, to which we or they are subject, we may lose valuable intellectual property rights through the narrowing or loss of one or more patents owned or in-licensed, or our owned or in-licensed patent claims may be narrowed, invalidated or held unenforceable. In many cases, the possibility of appeal exists for either us or our opponents, and it may be years before final, unappealable rulings are made with respect to these patents in certain jurisdictions. The timing and outcome of these and other proceedings is uncertain and may adversely affect our business if we are not successful in defending the patentability and scope of our pending and issued patent claims. In addition, third parties may attempt to invalidate our intellectual property rights. Even if our rights are not directly challenged, disputes could lead to the weakening of our intellectual property rights. Our defense against any attempt by third parties to circumvent or invalidate our intellectual property rights could be costly to us, could require significant time and attention of our management and could have a material adverse impact on our business and our ability to successfully compete against our current and future competitors.

There are many issued and pending patent filings that claim aspects of technologies that we may need for our mRNA product candidates or other product candidates, including patent filings that relate to relevant delivery technologies. There are also many issued patents that claim targeting genes or portions of genes that may be relevant for immunotherapies we wish to develop. In addition, there may be issued and pending patent applications that may be asserted against us in a court proceeding or otherwise based upon the asserting party’s belief that we may need such patents for the development, manufacturing and commercialization of our product candidates. Thus, it is possible that one or more organizations, ranging from our competitors to non-practicing entities or patent assertion entities, has or will hold patent rights to which we may need a license, or hold patent rights which could be asserted against us. Such licenses may not be available on commercially reasonable terms or at all, or may be non-exclusive. If those organizations refuse to grant us a license to such patent rights on reasonable terms or a court rules that we need such patent rights that have been asserted against us and we are not able to obtain a license on reasonable terms or at all, we may be unable to perform research and development or other activities or market products covered by such patents, and we may need to cease the development, manufacture and commercialization of one or more of the product candidates we may develop. Any of the foregoing could result in a material adverse effect on our business, financial condition, results of operations or prospects.

 

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Risks Related to Ownership of the ADSs and the Underwritten Offering

A significant portion of our total outstanding ordinary shares after the Underwritten Offering will be restricted from immediate resale but may be sold in the near future. The large number of shares eligible for sale or subject to rights requiring us to register them for sale could cause the market price of the ADSs to drop significantly, even if our business is performing well.

Sales of a substantial number of ordinary shares or the ADSs could occur at any time, subject to certain restrictions described below. These sales, or the perception in the market that holders of a large number of shares intend to sell shares, could reduce the market price of the ADSs. Based on the number of our ordinary shares outstanding as of July 22, 2020, we will have 238,173,455 ordinary shares outstanding after the Underwritten Offering. Additionally, if the Rights Offering is fully subscribed (excluding new ordinary shares underlying rights offered to holders that have irrevocably agreed not to transfer or exercise their rights), we will have 240,062,644 shares outstanding.

In connection with the Underwritten Offering, we, all of our directors and officers and certain significant shareholders have entered into lock-up agreements with the underwriters under which we and they agreed, subject to specific exceptions, not to sell any of our shares for at least 90 days following the date of this prospectus. The remaining ordinary shares will be available for sale after the Underwritten Offering since they are not subject to contractual and legal restrictions on resale. Any or all of the shares subject to lock-up agreements may be released prior to the expiration of the lock-up period at the discretion of the lead underwriters for the Underwritten Offering. To the extent shares are released before the expiration of the lock-up period and these shares are sold into the market, the market price of the ADSs could decline.

We intend to file one or more registration statements on Form S-8 under the Securities Act of 1933, as amended, or the Securities Act, to register all ordinary shares issued or issuable under our equity plans. Any such Form S-8 registration statements will automatically become effective upon filing. Accordingly, shares registered under such registration statements will be available for sale in the open market following the expiration of the applicable lock-up period. See “Shares and ADSs Eligible for Future Sale” appearing elsewhere in this prospectus for a more detailed description of the restrictions on selling shares.

Sales of ADSs or our ordinary shares as restrictions end or pursuant to registration rights may make it more difficult for us to finance our operations through the sale of equity securities in the future at a time and at a price that we deem appropriate. These sales also could cause the trading price of the ADSs to fall and make it more difficult for you to sell the ADSs.

If you purchase ADSs in the Underwritten Offering, you will incur immediate and substantial dilution in the book value of your investment.

You will suffer immediate and substantial dilution in the net tangible book value of the ADSs if you purchase ADSs in the Underwritten Offering. Based on the public offering price of $93.00 per ADS, after giving effect to the Underwritten Offering, purchasers of ADSs in the Underwritten Offering will experience immediate dilution in net tangible book value of $88.23 per ADS. In addition, after giving effect to the Underwritten Offering, investors purchasing ADSs in the Underwritten Offering will contribute 28.32% of the total amount invested by shareholders since inception but will only own 2.31% of the ordinary shares outstanding. See “Dilution” for a more detailed description of the dilution to new investors in the Underwritten Offering.

Holders of the ADSs may not be able to participate in any future preemptive subscription rights issues or elect to receive dividends in shares, which may cause additional dilution to their holdings. For example, purchasers who acquire ADSs in the Underwritten Offering will not receive rights to participate in the concurrent Rights Offering.

Under German law, the existing shareholders of a company generally have a preemptive right in proportion to the amount of shares they hold in connection with any issuance of ordinary shares, convertible bonds, bonds

 

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with warrants, profit participation rights and participating bonds. However, our shareholders in a shareholders’ meeting may vote, by a majority representing at least three-quarters of the share capital represented at the meeting, to waive this preemptive right provided that, from the company’s perspective, there exists good and objective cause for such waiver.

The deposit agreement provides that the depositary need not make rights available to you unless the distribution to ADS holders of both the rights and any related securities are either registered under the Securities Act or exempted from registration under the Securities Act. We are under no obligation to file a registration statement with respect to any such rights or securities or to endeavor to cause such a registration statement to be declared effective. Moreover, we may not be able to establish an exemption from registration under the Securities Act. Accordingly, ADS holders may be unable to participate in our future rights offerings and may experience dilution in their holdings. In addition, if the depositary is unable to sell rights that are not exercised or not distributed or if the sale is not lawful or reasonably practicable, it will allow the rights to lapse, in which case you will receive no value for these rights. Purchasers who acquire ADSs in the Underwritten Offering will not receive rights to participate in the concurrent Rights Offering.

Our principal shareholders and management own a significant percentage of our ordinary shares and will be able to exert significant control over matters subject to shareholder approval.

Our executive officers, directors, five percent shareholders, and their affiliates beneficially own approximately 69.99% of our ordinary shares (including ordinary shares represented by ADSs) and, upon closing of the Underwritten Offering, that same group will beneficially own approximately 68.37% of our outstanding ordinary shares (including ordinary shares represented by ADSs), assuming no exercise of the underwriters’ option to purchase additional ADSs from the Selling Shareholder. If the underwriters exercise in full their option to purchase additional ADSs from the Selling Shareholder, that same group will beneficially own approximately 68.37% of our outstanding ordinary shares (including ordinary shares represented by ADSs). Therefore, even after the Underwritten Offering, these shareholders will have the ability to influence us through their ownership positions. For example, these shareholders, acting together, may be able to exert significant influence over matters such as elections of directors, amendments of our organizational documents, or approval of any merger, sale of assets or other major corporate transaction. This may prevent or discourage unsolicited acquisition proposals or offers for our ordinary shares that you may believe are in your best interest as one of our shareholders.

We have broad discretion in the use of our cash, cash equivalents and investments, including the net proceeds from the Underwritten Offering, and we may not use them effectively.

Our management will have broad discretion in the application of our cash, cash equivalents and investments, including the net proceeds from the Global Offering, and could spend the proceeds in ways that do not improve our results of operations or enhance the value of our ordinary shares. The failure by our management to apply these funds effectively could result in financial losses that could have a material adverse impact on our business, cause the price of the ADSs to decline, and delay the development of our product candidates. Pending their use, we may invest our cash, cash equivalents and investments, including the net proceeds from the Global Offering, in a manner that does not produce income or that loses value. See “Use of Proceeds” for more information.

 

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CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS

This prospectus contains forward-looking statements concerning our business, operations and financial performance and condition, as well as our plans, objectives and expectations for our business operations and financial performance and condition. Many of the forward-looking statements contained in this prospectus can be identified by the use of forward-looking words such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “potential,” “should,” “target,” “would” and other similar expressions that are predictions of or indicate future events and future trends, although not all forward-looking statements contain these identifying words.

Forward-looking statements are based on our management’s beliefs and assumptions and on information currently available to our management. Such statements are subject to risks and uncertainties, and actual results may differ materially from those expressed or implied in the forward-looking statements due to a variety of factors, including, but not limited to, those identified in the section titled “Risk Factors” in this prospectus and in our Annual Report on Form 20-F for the year ended December 31, 2019, incorporated by reference herein. These risks and uncertainties include factors relating to:

 

   

the initiation, timing, progress, results, and cost of our research and development programs and our 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, the period during which the results of the trials will become available and our research and development programs;

 

   

the timing of and our ability to obtain and maintain regulatory approval for our product candidates;

 

   

our COVID-19 vaccine development program, including the timing thereof (including as it relates to the selection of a candidate variant and the FDA’s acceptance of our candidate variant to advance into a Phase 2b/3 trial), the data therefrom, and our ability to successfully commercialize any approved vaccine;

 

   

our ability to supply the quantities of BNT162 to support clinical development and, if approved, market demand, including our production estimates for 2020 and 2021;

 

   

the potential to supply the United States government with up to 500 million additional doses of BNT162 pursuant to its option to purchase additional doses from us and Pfizer;

 

   

our expectations around the timing of entry, number of potential doses covered and amount of consideration under potential agreements for the supply of BNT162, our COVID-19 vaccine candidate, if approved;

 

   

the impact of the evolving COVID-19 pandemic, and the global response thereto;

 

   

our ability to identify research opportunities and discover and develop investigational medicines;

 

   

the ability and willingness of our third-party collaborators to continue research and development activities relating to our development candidates and investigational medicines;

 

   

our expectations regarding the size of the patient populations for our product candidates, if approved for commercial use;

 

   

our estimates of our expenses, ongoing losses, future revenue and capital requirements and our needs for or ability to obtain additional financing;

 

   

our ability to identify, recruit and retain key personnel;

 

   

our and our collaborators’ ability to protect and enforce our intellectual property protection for our proprietary and collaborative product candidates, and the scope of such protection;

 

   

the development of and projections relating to our competitors or our industry;

 

   

our ability to commercialize our product candidates, if approved;

 

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the pricing and reimbursement of our investigational medicines, if approved;

 

   

the rate and degree of market acceptance of our investigational medicines;

 

   

the amount of and our ability to use net operating losses and research and development credits to offset future taxable income;

 

   

our ability to manage our development and expansion;

 

   

regulatory developments in the United States and foreign countries;

 

   

our ability to manufacture our product candidates with advantages in turnaround times or manufacturing cost;

 

   

our ability to implement, maintain and improve effective internal controls;

 

   

the ability to realize the anticipated benefits of transactions related to our acquisition of Neon and other acquisitions, restructuring activities, including in connection with our acquisition of Neon, or other initiatives in a timely manner or at all;

 

   

the extent to which the Rights Offering is subscribed;

 

   

our use of the proceeds from the Global Offering; and

 

   

our expectations regarding the time during which we will be a foreign private issuer.

The preceding list is not intended to be an exhaustive list of all of our forward-looking statements. The forward-looking statements contained in this prospectus speak only as of the date of this prospectus, and unless otherwise required by law, we do not undertake any obligation to update them in light of new information or future developments or to release publicly any revisions to these statements in order to reflect later events or circumstances or to reflect the occurrence of unanticipated events.

 

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USE OF PROCEEDS

We estimate that the net proceeds to us from the Underwritten Offering will be approximately $478.0 million (€430.4 million), based on the public offering price of $93.00 per ADS, and after deducting underwriting discounts and commissions and estimated offering expenses payable by us. We will not receive any proceeds from the potential sale of ADSs in this Underwritten Offering by the Selling Shareholder, pursuant to the underwriters’ option to purchase additional ADSs from the Selling Shareholder.

If the Rights Offering is fully subscribed (excluding ordinary shares underlying rights offered to holders that have irrevocably agreed not to transfer or exercise their rights), we estimate that the additional net proceeds to us in the Global Offering will be approximately $166.6 million (€150.0 million), based on the subscription price of $93.00 per ordinary share or ADS, and after deducting fees and estimated offering expenses payable by us.

We currently intend to use the net proceeds from the Global Offering to:

 

   

advance our iNeST program candidate RO7198457 (BNT122) into late-stage trials;

 

   

advance our ongoing and currently planned clinical trials for our FixVac product candidates, BNT111, BNT112, BNT113, BNT114, BNT115 and our targeted cancer antibody, MVT-5873 (BNT321), as well as fund our portion of the research and development expenses for SAR441000 (BNT131), which is being developed in collaboration with Sanofi, GEN1046 (BNT311) and GEN1042 (BNT312), which are being developed in collaboration with Genmab and advance the development of BNT162, our COVID-19 vaccine candidate, which is being developed in collaboration with Pfizer;

 

   

initiate clinical trials for additional product candidates, including product candidates from our CAR-T, RiboMabs, RiboCytokines and TCR platforms in oncology;

 

   

further accelerate and expand our infectious disease immunotherapy programs;

 

   

advance our rare disease protein replacement therapy platforms outside of oncology;

 

   

advance additional preclinical product candidates, develop additional product candidates leveraging our therapeutic platforms and fund the further development of our core technologies; and

 

   

fund the further expansion of our manufacturing and laboratory capacity, the continued development of our infrastructure and investment in preparation for commercialization for launch of BNT162, if approved.

We expect to use the remainder of any net proceeds from the Global Offering, as well as our existing cash and cash equivalents, for general corporate purposes. We may also use a portion of the net proceeds to in-license or acquire or invest in complementary technologies, products, businesses or assets, either alone or together with a collaborator. However, we have no current plans, commitments or obligations to do so.

Our expected use of net proceeds from the Global Offering represents our current intentions based on our present plans and business condition, which could change as our plans and business conditions evolve. The amounts and timing of our actual use of net proceeds will vary depending on numerous factors, including the progress of our clinical development of our product candidates, including our ongoing clinical trials. As a result, we cannot predict with certainty all of the particular uses for the net proceeds to be received upon the closings of

the Global Offering or the amounts that we will actually spend on the uses set forth above. Our management will have broad discretion in the application of the net proceeds from the Global Offering.

We expect that we will need to raise significant additional funds beyond the Global Offering in order to continue to advance our pipeline. In particular, we will need additional funds in order to advance our product

 

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candidates through Phase 3 clinical trials and to potential commercialization. We may seek to raise capital through public or private equity or debt financing, government or other third-party grants or funding, sales of assets, marketing and distribution arrangements, other collaborations or a combination of these approaches.

Based on our planned use of the net proceeds of the Global Offering and our existing cash and cash equivalents, we estimate that such funds will be sufficient to enable us to fund our operating expenses and capital expenditure requirements through at least the next 18 months. We have based this estimate on assumptions that may prove to be incorrect, and we could use our available capital resources sooner than we currently expect.

Pending our use of the net proceeds from the Global Offering, we plan to invest the net proceeds in short- and intermediate-term interest-bearing financial instruments.

 

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DIVIDEND POLICY

We have never paid or declared any cash dividends on our ordinary shares, and we do not anticipate paying any cash dividends on our ordinary shares in the foreseeable future. We intend to retain all available funds and any future earnings to fund the development and expansion of our business. In addition, our ability to pay cash dividends is also limited in certain circumstances under the terms of an agreement we have entered into with the Bill & Melinda Gates Foundation. All of the shares represented by the ADSs offered by this prospectus will generally have the same dividend rights as all of our other outstanding shares.

Under German law, we may pay dividends only from the distributable profit (Bilanzgewinn) reflected in our unconsolidated financial statements (as opposed to the consolidated financial statements for us and our subsidiaries) prepared in accordance with the principles set forth in the German Commercial Code (Handelsgesetzbuch) and adopted by our management board (Vorstand) and the supervisory board (Aufsichtsrat), or, as the case may be, by our shareholders in a shareholders’ meeting. See “Description of Share Capital and Articles of Association (Satzung),” which explains in more detail the procedures we must follow and the German law provisions that determine whether we are entitled to declare a dividend.

 

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CAPITALIZATION

The table below sets forth our cash and cash equivalents and our total capitalization as of March 31, 2020:

 

   

on an actual basis;

 

   

on a pro forma basis to give effect to (i) the issuance of 1,935,488 ADSs representing our ordinary shares in our acquisition of Neon, (ii) the issuance of 1,580,777 of our ordinary shares in a private placement to Fosun Pharma for proceeds of €45.6 million ($50.0 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) and (iii) the issuance of 2,377,446 of our ordinary shares in a private placement to Pfizer for proceeds of €103.9 million ($113.0 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)); and

 

   

on a pro forma as adjusted basis to give further effect to the sale of up to 5,500,000 ordinary shares (including ADSs representing ordinary shares) by us in the Underwritten Offering at the public offering price of $93.00 per ADS, and after deducting underwriting discounts and commissions and estimated offering expenses payable by us.

The table below does not reflect the effects of the issuance of the 2,595,996 ordinary shares and a mandatory convertible note to be issued in the June 2020 Private Placement, which is expected to close in August 2020, and our receipt of proceeds of €223.9 million ($251.0 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) therefrom.

Our capitalization following the Underwritten Offering will be adjusted based on the actual public offering price and other terms of the Underwritten Offering determined at pricing, including the amount by which actual offering expenses are higher or lower than estimated. You should read this table in conjunction with our consolidated financial statements and related notes included in this prospectus as well as the sections in this prospectus titled “Use of Proceeds” and “Selected Consolidated Financial Data” and the section titled “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in our Forms 20-F and 6-K incorporated by reference herein.

 

     As of March 31, 2020  
     Actual     Pro Forma     Pro Forma
As Adjusted(1)
 
     (unaudited)  
(in thousands except share data)             

Cash and cash equivalents

   451,597     601,055     1,031,411  
  

 

 

   

 

 

   

 

 

 

Total debt

     19,548       19,548       19,548  

Equity

      

Ordinary shares, no par value per share: 232,304,250 shares, actual; 238,197,961 shares, pro forma; 243,697,961 shares, pro forma as adjusted

      

Share capital

     232,304       238,198       243,698  

Capital reserve

     686,714       919,826       1,344,682  

Treasury shares

     (5,525     (5,525     (5,525

Accumulated losses

     (478,213     (478,213     (478,213

Other reserves

     12,850       12,850       12,850  
  

 

 

   

 

 

   

 

 

 

Total equity

     448,130       687,136       1,117,492  
  

 

 

   

 

 

   

 

 

 

Total capitalization

   467,678     706,684     1,137,040  
  

 

 

   

 

 

   

 

 

 

 

(1)

If the Rights Offering is fully subscribed (excluding ordinary shares underlying rights offered to holders that have irrevocably agreed not to transfer or exercise their rights), our cash and cash equivalents and total equity would each increase by €150.0 million, our share capital would increase by €1.9 million and our capital reserve would increase by €148.1 million.

 

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The number of our ordinary shares issued and outstanding actual is based on 232,304,250 ordinary shares outstanding (including 5,524,506 shares held in treasury) as of March 31, 2020 and excludes:

 

   

16,338,305 ordinary shares available for issuance upon the exercise of options outstanding as of March 31, 2020;

 

   

254,065 ordinary shares available for issuance upon the exercise of options expected to be granted in 2021 and 2022 under our long-term incentive program as of March 31, 2020; and

 

   

5,282,436 ordinary shares available for future issuance under our Employee Stock Ownership Plan or any future share option plan as of March 31, 2020 (after taking into account the issuance of options expected to be granted in 2021 and 2022).

 

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DILUTION

If you invest in the ADSs in the Underwritten Offering, your interest will be diluted immediately to the extent of the difference between the public offering price per ADS and our as adjusted net tangible book value per ADS after completion of the Underwritten Offering. The discussion in this section does not reflect the effects of the issuance of the 2,595,996 ordinary shares and a mandatory convertible note to be issued in the June 2020 Private Placement, which is expected to close in August 2020, and our receipt of proceeds of €223.9 million ($251.0 million, translated using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) therefrom.

Net tangible book value per ADS represents the amount of our total assets less our total liabilities, excluding intangible assets, divided by the number of our ordinary shares outstanding as of March 31, 2020. As of March 31, 2020, we had a historical net tangible book value of €354.2 million ($393.4 million), corresponding to a net tangible book value per ordinary share of €1.56 ($1.73) (equivalent to $1.73 per ADS). Our pro forma net tangible book value as of March 31, 2020 was €593.2 million ($658.9 million), corresponding to a pro forma net tangible book value per ordinary share of €2.55 ($2.83) (equivalent to $2.83 per ADS), based on the total number of shares of our common stock outstanding as of March 31, 2020, and after giving effect to (i) the issuance of 1,935,488 ADSs representing our ordinary shares in connection with our acquisition of Neon, (ii) the issuance of 1,580,777 of our ordinary shares in a private placement to Fosun Pharma for proceeds of €45.6 million ($50.0 million, using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) and (iii) the issuance of 2,377,446 of our ordinary shares in a private placement to Pfizer for proceeds of €103.9 million ($113.0 million, using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)).

After giving effect to the issuance and sale of 5,500,000 ADSs in the Underwritten Offering at the public offering price of $93.00 per ADS, which was the last reported sale price of the ADSs on the Nasdaq Global Select Market on July 21, 2020, our pro forma as adjusted net tangible book value as of March 31, 2020 would have been €1,023.6 million ($1,136.9 million), corresponding to a net tangible book value per ordinary share of €4.29 ($4.77) (equivalent to $4.77 per ADS). This represents an immediate increase in net tangible book value of €1.74 ($1.94) per ordinary share (equivalent to $1.94 per ADS) to existing shareholders and immediate dilution of $88.23 per ADS to new investors purchasing ADSs in the Underwritten Offering. Dilution per ADS to new investors is determined by subtracting our pro forma as adjusted net tangible book value per ADS from the public offering price per ADS paid by new investors.

The following table illustrates this dilution on a per-ADS basis:

 

Public offering price per ADS

      $ 93.00  

Historical net tangible book value per ADS as of March 31, 2020

   $ 1.73     

Pro forma net tangible book value per ADS as of March 31, 2020

   $ 2.83     

Increase in net tangible book value per ADS attributable to the Underwritten Offering

   $ 1.94     

Pro forma as adjusted net tangible book value per ADS after the Underwritten Offering

      $ 4.77  

Dilution per ADS to new investors participating in the Underwritten Offering

      $ 88.23  

 

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If the Rights Offering is fully subscribed (excluding ordinary shares underlying rights offered to holders that have irrevocably agreed not to transfer or exercise their rights), our pro forma as adjusted net tangible book value per ordinary share would be €4.89 ($5.43) (equivalent to $5.43 per ADS), representing an immediate increase in pro forma as adjusted net tangible book value to existing shareholders of €2.34 ($2.60) (equivalent to $2.60 per ADS) per ordinary share and immediate dilution of $87.57 per ADS to new investors, after deducting underwriting discounts and commissions, fees and estimated offering expenses payable by us.

The following table sets forth, on a pro forma as adjusted basis as of March 31, 2020, after giving effect to (i) the issuance of 1,935,488 ADSs representing our ordinary shares in connection with our acquisition of Neon, (ii) the issuance of 1,580,777 of our ordinary shares in a private placement to Fosun Pharma for proceeds of €45.6 million ($50.0 million, using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)) and (iii) the issuance of 2,377,446 of our ordinary shares in a private placement to Pfizer for proceeds of €103.9 million ($113.0 million, using the exchange rate then in effect as published by the German Central Bank (Deutsche Bundesbank)), the number of ordinary shares owned by existing shareholders and to be owned by new investors purchasing ADSs in the Underwritten Offering, the total consideration paid by existing shareholders and new investors purchasing ADSs in the Underwritten Offering, the average price per ordinary share paid by our existing shareholders and the average price per ADS to be paid by new investors purchasing ADSs in the Underwritten Offering. The calculation below is based on the public offering price of $93.00, before deducting underwriting discounts and commissions and estimated offering expenses payable by us:

 

    Ordinary Shares
Purchased
    Total Consideration     Average
Price
Per Share
    Average Price
Per ADS
 
    Number     Percent     Amount     Percent  

Existing shareholders

    232,673,455       97.69   $ 1,294,746,948       71.68   $ 5.56     $ 5.56  

Investors participating in the Underwritten Offering

    5,500,000       2.31   $ 511,500,000       28.32     93.00       93.00  
 

 

 

   

 

 

   

 

 

   

 

 

     

Total

    238,173,455       100   $ 1,806,246,948       100   $ 7.58     $ 7.58  

The number of our ordinary shares issued and outstanding actual, is based on 226,779,744 ordinary shares outstanding as of March 31, 2020 and excludes:

 

   

16,338,305 ordinary shares available for issuance upon the exercise of options outstanding as of March 31, 2020;

 

   

254,065 ordinary shares available for issuance upon the exercise of options expected to be granted in 2021 and 2022 under our long-term incentive program as of March 31, 2020;

 

   

5,282,436 ordinary shares available for future issuance under our Employee Stock Ownership Plan or any future share option plan as of March 31, 2020 (after taking into account the issuance of options expected to be granted in 2021 and 2022); and

 

   

5,524,506 ordinary shares held in treasury.

We may choose to raise additional capital due to market conditions or strategic considerations even if we believe we have sufficient funds for our current or future operating plans. To the extent that additional capital is raised through the sale of equity or convertible debt securities, the issuance of such securities may result in further dilution to our shareholders.

 

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SELECTED CONSOLIDATED FINANCIAL DATA

The following tables present selected consolidated financial data as of December 31, 2019, for the years ended December 31, 2019, 2018 and 2017, as of March 31, 2020 and for the three months ended March 31, 2020 and 2019. We derived the selected consolidated statements of operations for the years ended December 31, 2019, 2018 and 2017 and the selected consolidated statement of financial position data as of December 31, 2019 from our audited consolidated financial statements incorporated by reference herein. The selected consolidated statements of operations data for the three months ended March 31, 2020 and 2019 and the selected consolidated statement of financial position data as of March 31, 2020 have been derived from our unaudited interim condensed consolidated financial statements incorporated by reference herein and have been prepared on the same basis as the audited financial statements. In the opinion of management, the unaudited interim data reflects all adjustments necessary for a fair presentation of the financial information in those statements. We present our consolidated financial statements in Euros and in accordance with IFRS as issued by the IASB.

The selected consolidated financial data below should be read together with our consolidated financial statements and related notes, our unaudited interim condensed consolidated financial statements and the section titled “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in our Forms 20-F and 6-K incorporated by reference herein, as well as the section of this prospectus titled “Capitalization.” Our historical results for any prior period are not necessarily indicative of results to be expected in any future period, and the results for the three months ended March 31, 2020 are not necessarily indicative of the results to be expected for the full year ended December 31, 2020.

 

     For the
Three Months Ended
March 31,
    For the Years Ended
December 31,
 
     2020     2019     2019     2018     2017  
(in thousands except per share data)    (unaudited)                    

Consolidated statements of operations:

          

Revenues from contracts with customers

   27,663     26,154     108,589     127,575     61,598  

Cost of sales

     (5,842     (3,205     (17,361     (13,690     (9,318
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Gross profit

   21,821     22,949     91,228     113,885     52,280  
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Research and development expenses

     (65,122     (57,241     (226,466     (143,040     (85,496

Sales and marketing expenses

     (486     (560     (2,718     (3,041     (6,603

General and administrative expenses

     (15,815     (9,276     (45,547     (26,334     (23,520

Other operating income

     425       331       2,724       5,396       2,349  

Other operating expenses

     (100     (38     (739     (720     (288
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Operating loss

   (59,277   (43,835   (181,518   (53,854   (61,277
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Finance income

     6,417       3,578       4,122       8,046       2,133  

Finance expenses

     (103     (74     (326     (48     (26,007

Interest expenses related to lease liability

     (415     (425     (1,718     (1,721     (676

Share of loss of equity method investees

     —         —         —         (84     (78
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Loss before tax

   (53,378   (40,756   (179,440   (47,662   (85,905
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Income taxes

     (8     (6     268       (600     (45

Loss for the period

   (53,386   (40,762   (179,172   (48,262   (85,950
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Loss attributable to equity holders of the parent

     (53,386     (40,646     (179,056     (48,019     (85,653
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Loss attributable to non-controlling interests

     —         (116     (116     (243     (297
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Basic and diluted loss per share

   (0.24   (0.20   (0.85   (0.25   (0.51
  

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

 

39


Table of Contents
     As of  
     March 31,
2020
     December 31,
2019
 
(in thousands)    (unaudited)         

Consolidated statement of financial position:

     

Cash and cash equivalents

   451,597      519,149  

Total assets

     732,208        797,647  

Total liabilities

     284,078        304,155  

Share capital

     232,304        232,304  

Accumulated losses

     (478,213      (424,827

Total equity

   448,130      493,492  

 

40


Table of Contents

UNAUDITED PRO FORMA CONDENSED COMBINED FINANCIAL INFORMATION

On May 6, 2020, BioNTech SE, or BioNTech, announced the closing of the Neon Therapeutics, Inc., or Neon, acquisition. The merger agreement was first announced on January 16, 2020. Based on the acquisition date share price, the implied aggregate value of the merger consideration was approximately $97.1 million (€89.9 million using the exchange rate as of closing) financed by issuing new ordinary shares as a stock transaction and including de minimis cash consideration which was paid to settle Neon’s outstanding stock options.

The following unaudited pro forma condensed combined financial information are based on BioNTech’s historical consolidated financial statements prepared in accordance with International Financial Reporting Standards as issued by the IASB, or IFRS, and Neon’s historical consolidated financial statements as adjusted to give effect to our acquisition of Neon. As Neon prepared its financial statements in accordance with U.S. generally accepted accounting principles, or U.S. GAAP, and applied U.S. dollars as its reporting currency, adjustments have been made to convert Neon’s financial statements to IFRS and its reporting currency to Euros. Please see Notes 2 and 3 to the unaudited pro forma condensed combined financial information for a discussion of the adjustments made to convert Neon’s financial information from U.S. GAAP to IFRS.

The unaudited pro forma condensed combined statement of operations for the year ended December 31, 2019 and the three months ended March 31, 2020 gives effect to this transaction as if it had occurred on January 1, 2019. The unaudited pro forma condensed combined statement of financial position as of March 31, 2020 gives effect to this transaction as if it had occurred on March 31, 2020.

The unaudited pro forma condensed combined financial information includes the latest estimates of the fair value of Neon’s assets to be acquired and liabilities to be assumed and the related allocations of the purchase price using the factual circumstances as of the time of closing. These figures are applied to the unaudited condensed combined statement of financial position as of March 31, 2020. As the detailed valuation studies are still ongoing, these estimates and assumptions are subject to change.

As indicated in Note 5 to the unaudited pro forma condensed combined financial information, BioNTech has made certain adjustments to adjust the historical book values of the assets and liabilities of Neon to reflect preliminary estimates of the fair values necessary to prepare the unaudited pro forma condensed combined financial information, with the excess of the estimated purchase price over the net assets of Neon, as adjusted to reflect estimated fair values, recorded as goodwill.

Additionally, as indicated in Note 2 to the unaudited pro forma condensed combined financial information, estimated effects related to the application of IFRS have been based on preliminary assessments and as indicated in Note 3 to the unaudited pro forma condensed combined financial information, the reporting currency has been applied based on a simplified method. Actual results are expected to differ from this unaudited pro forma condensed combined financial information once BioNTech has completed the valuation studies necessary to finalize the required purchase price allocation and finalized conforming accounting changes for Neon. Such differences may be material.

The assumptions and estimates underlying the unaudited adjustments to the pro forma condensed combined financial information are described in the accompanying notes, which should be read together with the pro forma condensed combined financial information. The unaudited pro forma condensed combined financial information should be read together with:

 

   

BioNTech’s audited consolidated financial statements and related notes incorporated by reference in this registration statement as of December 31, 2019 and 2018 and for the years ended December 31, 2019, 2018 and 2017;

 

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Table of Contents
   

BioNTech’s unaudited interim condensed consolidated financial statements and related notes incorporated by reference in this registration statement as of and for the three months ended March 31, 2020 and for the three months ended March 31, 2019;

 

   

Neon’s audited consolidated financial statements and related notes as of December 31, 2019 and 2018 and for the years then ended incorporated by reference in this registration statement; and

 

   

Neon’s unaudited interim condensed consolidated financial statements and related notes as of March 31, 2020 and for the three months ended March 31, 2020 and 2019 incorporated by reference in this registration statement.

The unaudited pro forma condensed combined financial information does not include the realization of any future cost savings or restructuring or integration charges that are expected to result from the Merger.

The unaudited pro forma condensed combined financial information is not intended to represent or be indicative of the consolidated results of operations and financial condition of the consolidated company that would have been reported had the acquisition been completed as of the dates presented, and should not be taken as being representative of the future consolidated results of operations or financial condition of the consolidated company.

 

42


Table of Contents

Unaudited Pro Forma Condensed Combined Statement of Financial Position

as of March 31, 2020

(in thousands)

 

    BioNTech
SE
Historical
IFRS
EUR
    Neon
Therapeutics,
Inc.
Historical
US GAAP
USD
    Neon
Therapeutics,
Inc.
Historical
US GAAP
EUR1
    Neon
Therapeutics,
Inc.
IFRS
Adjustments
EUR1
    Pro Forma
Adjustments
EUR1
    Notes     Pro Forma
Combined
EUR1
 

Intangible assets

    93,932       —         —         —         83,618       5 a), 5 e)       177,550  

Property, plant and equipment

    96,290       6,694       6,110       —         (482     5 e)       101,918  

Right-of-use assets

    49,131       7,228       6,597       290       —         2 a)       56,018  

Other non-current assets

    —         471       430       —         —           430  
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Total non-current assets

    239,353       14,393       13,137       290       83,136         335,916  

Inventories

    9,629       —         —         —         —           9,629  

Trade receivables

    10,310       —         —         —         —           10,310  

Deferred expenses and other current assets

    21,319       1,962       1,791       —         —           23,110  

Cash and cash equivalents

    451,597       15,047       13,734       —         —           465,331  
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Total assets

    732,208       31,402       28,662       290       83,136         844,296  
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Total shareholders’ equity

    448,130       14,431       13,172       290       74,868       2 a), 5 a), 5 d)       536,460  

Contract liabilities

    75,187       —         —         —         —           75,187  

Deferred tax liabilities

    —         —         —         —         7,931       5 b)       7,931  

Other non-current liabilities

    66,848       6,204 2      5,663       —         —           72,511  
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Total non-current liabilities

    142,035       6,204       5,663       —         7,931         155,629  

Trade payables

    19,417       3,043       2,777       —         —           22,194  

Contract liabilities

    94,824       —         —         —         —           94,824  

Other current liabilities

    27,802       7,724 3      7,050       —         337       5 c)       35,189  
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Total liabilities

    284,078       16,971       15,490       —         8,268         307,836  
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

Total liabilities and equity

    732,208       31,402       28,662       290       83,136         844,296  
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

   

 

 

   

 

 

 

 

(1)

Please see Note 3 to the unaudited pro forma condensed combined financial information.

(2)

Consists of operating lease liabilities of $6,200 and other liabilities of $4.

(3)

Consists of accrued expenses of $6,437 and operating lease liabilities of $1,287.

 

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Table of Contents

Unaudited Pro Forma Condensed Combined Statement of Operations

For the year ended December 31, 2019

(in thousands, except for per share information)

 

    BioNTech
SE
Historical
IFRS
EUR
    Neon
Therapeutics,
Inc.
Historical
US GAAP
USD
    Neon
Therapeutics,
Inc.
Historical
US GAAP
EUR1
    Neon
Therapeutics,
Inc.
IFRS
Adjustments
EUR1
    Pro Forma
Adjustments
EUR1
    Notes     Pro Forma
Combined
EUR1
 

Revenue

    108,589       —         —         —         —           108,589  

Cost of sales

    (17,361     —         —         —         —           (17,361

Research and development expenses

    (226,466     (59,718     (53,768     (226     (1,117     2 a), 2 b)       (281,577

Sales and marketing expenses

    (2,718     —         —         —         —           (2,718

General and administrative expense

    (45,547     (21,420     (19,286     (715     —         2 a), 2 b)       (65,548

Other operating income

    2,724       —         —         —         —           2,724  

Other operating expenses

    (739     —         —         —         —           (739
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Operating loss

    (181,518     (81,138     (73,054     (941     (1,117       (256,630

Finance income, net

    2,078       1,401       1,261       (660     —         2 a     2,679  

Other expenses

    —         (39     (35     —         —           (35
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Loss before tax

    (179,440     (79,776     (71,828     (1,601     (1,117       (253,986

Income taxes

    268       —         —         —         —           268  
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Loss for the period

    (179,172     (79,776     (71,828     (1,601     (1,117       (253,718

Loss for the period attributable to non-controlling interests

    (116     —         —         —         —           (116

Net loss attributable to common stockholders

    (179,056     (79,776     (71,828     (1,601     (1,117       (253,602
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Basic and diluted loss per share

    (0.85               (1.19
 

 

 

             

 

 

 

Weighted-average shares

    211,499             1,935         213,434  

 

(1)

Please see Note 3 to the unaudited pro forma condensed combined financial information.

 

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Table of Contents

Unaudited Pro Forma Condensed Combined Statement of Operations

For the three months ended March 31, 2020 (in thousands, except for per share information)

 

    BioNTech
SE
Historical
IFRS
EUR
    Neon
Therapeutics,
Inc.
Historical
US GAAP
USD
    Neon
Therapeutics,
Inc.
Historical
US GAAP
EUR1
    Neon
Therapeutics,
Inc.
IFRS
Adjustments
EUR1
    Pro Forma
Adjustments
EUR1
    Notes     Pro Forma
Combined
EUR1
 

Revenue

    27,663       —         —         —         —           27,663  

Cost of sales

    (5,842     —         —         —         —           (5,842

Research and development expenses

    (65,122     (9,446     (8,566     407       (279     2 a), 2 b)       (73,560

Sales and marketing expenses

    (486     —         —         —         —           (486

General and administrative expense

    (15,815     (7,220     (6,548     518       —         2 a), 2 b)       (21,845

Other operating income

    425       —         —         —         —           425  

Other operating expenses

    (100     —         —         —         —           (100
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Operating (loss) income

    (59,277     (16,666     (15,114     925       (279       (73,745

Finance income, net

    5,899       68       62       (167     —         2 a     5,794  

Other expenses

    —         —         —         —         —           —    
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

(Loss) income before tax

    (53,378     (16,598     (15,052     758       (279       (67,951

Income taxes

    (8     —         —         —         —           (8
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Net (loss) income attributable to common stockholders

    (53,386     (16,598     (15,052     758       (279       (67,959
 

 

 

   

 

 

   

 

 

   

 

 

   

 

 

     

 

 

 

Basic and diluted loss per share

    (0.24               (0.30
 

 

 

             

 

 

 

Weighted-average shares

    226,779             1,935         228,714  

 

(1)

Please see Note 3 to the unaudited pro forma condensed combined financial information.

Notes to Unaudited Pro Forma Condensed Combined Financial Information

 

1

Basis of preparation

The historical consolidated financial statements of BioNTech and Neon have been adjusted in the unaudited pro forma condensed combined financial information to give effect to pro forma events that are (1) directly attributable to the business combination, (2) factually supportable and (3) with respect to the unaudited pro forma condensed combined statements of operations, expected to have a continuing impact on the combined results following the business combination. The business combination was accounted for under the acquisition method of accounting in accordance with IFRS 3, Business Combinations. As the acquirer for accounting purposes, BioNTech has performed preliminary estimates of the fair value of Neon’s assets acquired and liabilities assumed and performed a preliminary conversion to conform the U.S. GAAP accounting policies of Neon to its own accounting policies under IFRS.

 

2

Accounting policy conformity changes

The historical financial information of Neon was prepared in accordance with U.S. GAAP. The following preliminary adjustments convert Neon’s financial information from U.S. GAAP to IFRS and align Neon’s accounting policies to those applied by BioNTech.

 

45


Table of Contents
  a)

Neon adopted ASC 842 as of January 1, 2019 for lease accounting. For the year ended December 31, 2019 and the three months ended March 31, 2020, BioNTech applied IFRS 16 for lease accounting. The following adjustments reflect as if Neon had adopted IFRS 16 as of January 1, 2019:

 

   

Decrease in research and development expenses of k€349 and decrease of general and administrative expenses of k€78 and increase of finance expense of k€660 the year ended December 31, 2019, respectively, due to increased depreciation and reclassification of operating lease interest expense into finance expense.

 

   

Decrease in research and development expenses of k€99 and decrease of general and administrative expenses of k€22 and increase of finance expense of k€167 the three months ended March 31, 2020, respectively, due to increased depreciation and reclassification of operating lease interest expense into finance expense.

 

   

Increase in right-of-use assets and total shareholder’s equity of k€290 as of March 31, 2020.

 

  b)

The following adjustments reflect the change from straight-line method to the accelerated method of recognizing stock compensation expense per IFRS 2 and the reversal of mark-to-market expense for stock options granted to non-employees:

 

   

Increase in research and development expenses of k€575 and increase in general and administrative expenses of k€793 for the year ended December 31, 2019.

 

   

Decrease in research and development expenses of k€308 and decrease in general and administrative expenses of k€496 for the three months ended March 31, 2020.

 

3

Foreign currency adjustments

The historical consolidated financial statements of Neon were presented in U.S. dollars. The historical financial information was translated from U.S. dollars to Euro using the following historical exchange rates:

 

     $ / €  

Average exchange rate for the year ended December 31, 2019

     1.11  

Average exchange rate for the three months ended March 31, 2020

     1.10  

Period end exchange rate as of March 31, 2020

     1.10  

Exchange rate as of closing

     1.08  

 

4

Business combination

Financing transaction

BioNTech completed the acquisition of Neon for 0.063 new ADSs representing new ordinary shares of BioNTech in exchange for each outstanding share of Neon common stock and settled Neon’s outstanding stock options in cash.

Preliminary purchase price allocation

BioNTech has performed a preliminary valuation analysis of the fair market value of Neon’s assets and liabilities. The following table summarizes the preliminary purchase price allocation as of March 31, 2020 including the consideration based on factual circumstances as of closing date (in thousands). The total consideration was calculated based on the new shares issued as of closing, and included the acquisition date share price as well as a cash consideration which will be made to settle Neon’s outstanding stock options. The USD consideration is translated into Euro as of March 31, 2020 using the period end exchange rate as of March 31, 2020.

 

46


Table of Contents

Total consideration

   88,667  

Intangible assets

   482  

Property, plant and equipment

   5,628  

Right-of-use assets

   6,887  

In-process research and development

   29,032  

Prepaid expenses and other assets

   2,221  

Cash and cash equivalents

   13,734  

Long-term liabilities

   (5,663

Accounts payable

   (2,777

Other liabilities

   (7,050

Deferred tax liabilities, net

   (7,931
  

 

 

 

Goodwill

   54,104  
  

 

 

 

This preliminary purchase price allocation has been used to prepare pro forma adjustments in the unaudited pro forma condensed combined statement of financial position and statement of operations. The final purchase price allocation will be determined when BioNTech has completed the detailed valuations and necessary calculations. The final allocation could differ materially from the preliminary allocation used in the pro forma adjustments. The final allocation may include material changes in allocations to intangible assets such as licenses, technology and customer relationships as well as goodwill and other changes to assets and liabilities.

 

5

Pro forma adjustments

The pro forma adjustments are based on BioNTech’s preliminary estimates and assumptions that are subject to change. The following adjustments have been reflected in the unaudited pro forma condensed combined financial information:

 

  a)

Reflects the adjustment of intangible assets acquired by BioNTech to their estimated fair values. As part of the preliminary valuation analysis, BioNTech identified intangible assets in form of in-process research and development projects. The fair value of identifiable intangible assets is determined primarily using the income method approach. Since all information required to perform a detailed valuation analysis of Neon’s intangible assets could not be obtained as of the date of this filing, for purposes of these unaudited pro forma condensed combined financial information, BioNTech used certain assumptions based on publicly available data for the industry. Amortization for the in-process research and development in the amounts of k€1,117 for the year ended December 31, 2019 and k€279 for the three months ended March 31, 2020 has been reflected in the unaudited pro forma condensed combined statements of operations. These preliminary estimates of fair value will likely differ from final amounts BioNTech will calculate after completing a detailed valuation analysis, and the difference could have a material impact on the accompanying unaudited pro forma condensed combined financial information. A change in the valuation of intangible assets would correspond to an increase or decrease in the balance of goodwill.

 

  b)

Adjusts the deferred tax liabilities resulting from the acquisition. The estimated increase in deferred tax liabilities to k€7,931 stems primarily from the fair value adjustments for non-deductible intangible assets based on an estimated tax rate of 27.32%. This estimate of deferred income tax balances is preliminary and subject to change based on management’s final determination of the fair value of assets acquired and liabilities assumed by jurisdiction.

 

  c)

Represents the cash consideration which will be made to settle Neon’s outstanding stock options.

 

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Table of Contents
  d)

Represents the elimination of the historical equity of Neon and the issuance of ordinary shares to finance the acquisition, as follows (in thousands):

 

Net equity proceeds from issuance of 0.063 American Depositary Shares of the Company per share of Neon and cash settlement of Neon’s outstanding stock options

   88,330  

Less: historical Neon shareholders’ equity converted into Euro and IFRS adjusted as of March 31, 2020

   (13,462
  

 

 

 

Pro forma adjustment to shareholders’ equity

   74,868  
  

 

 

 

 

  e)

The adjustment reclassifies software assets of k€482 from property, plant and equipment to intangibles to conform the presentation of the balance of BioNTech’s presentation.

 

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BUSINESS

 

I.

Overview

BioNTech was founded in 2008 on the understanding that every cancer patient’s tumor is unique and that in order to effectively address this challenge, we must create individualized treatments for each patient. To realize this vision, we combine decades of groundbreaking research in immunology, cutting-edge therapeutic platforms and a suite of patient profiling and bioinformatic tools to develop immunotherapies for cancer and other diseases. We leverage powerful new therapeutic mechanisms and exploit a diverse array of biological targets to harness the power of each patient’s immune system to address the unique molecular signature of each patient’s underlying disease. The breadth of our immunotherapy technologies and expertise has also enabled us to develop therapies to address a range of rare and infectious diseases, and we have recently rapidly mobilized these with the aim of addressing the COVID-19 pandemic. We believe we are uniquely positioned to develop and commercialize the next generation of immunotherapies with the potential to significantly improve clinical outcomes for patients and usher in a new era of individualized medicine.

We and our collaborators have advanced a development pipeline of over 20 product candidates, of which 12 have entered into 13 ongoing clinical trials. While we believe our approach is broadly applicable across a number of therapeutic areas, our most advanced programs are focused on oncology, where we have treated over 500 patients across 17 tumor types to date. Our immunotherapy drug classes consist of messenger ribonucleic acid, or mRNA, therapeutics, cell therapies, antibodies and small molecule immunomodulators. Our product candidates span oncology, infectious diseases and rare diseases.

We have assembled an exceptional team of over 1,400 employees and have established relationships with seven pharmaceutical collaborators, including Genentech, Inc., or Genentech, Sanofi S.A., or Sanofi, Genmab A/S, or Genmab, Genevant Sciences GmbH, or Genevant, Bayer AG, or Bayer, Pfizer Inc., or Pfizer, and Shanghai Fosun Pharmaceutical (Group) Co., Ltd., or Fosun Pharma. We have built out comprehensive, highly automated, on-demand in-house manufacturing capabilities that complement the development of our individualized immunotherapies.

Our immunotherapy product candidates span the following four distinct drug classes:

 

   

mRNA Therapeutics. We are utilizing messenger ribonucleic acid, or mRNA, to deliver genetic information to cells, where it is used to express proteins for therapeutic effect. We are developing a portfolio of immunotherapies that utilize four different mRNA formats and three different formulations to derive five distinct platforms for the treatment of cancer. Three of these platforms are currently in human testing: (i) our off-the-shelf shared antigen immunotherapy, or FixVac; (ii) our individualized neoantigen specific immunotherapy, or iNeST, in collaboration with Genentech; and (iii) our intratumoral immunotherapy, in collaboration with Sanofi. In addition, we are developing two platforms in which we use mRNA to express directly in the patient either (a) particular antibodies, or RiboMabs, or (b) specific cytokines, or RiboCytokines. In collaboration with Pfizer, the University of Pennsylvania, Genevant and Fosun Pharma we are also leveraging our mRNA technology beyond oncology to address COVID-19, influenza, other infectious diseases and rare diseases.

 

   

Cell Therapies. We are developing a range of cell therapies, including chimeric antigen receptor, or CAR, T cells, neoantigen-based T cell therapies and T cell receptor, or TCR, therapies, in which the patient’s T cells are modified or primed to target cancer-specific antigens We are also combining our mRNA FixVac platform with our first CAR-T product candidates, using “CARVac” immune boosters to enhance the persistence of CAR-T cells in vivo.

 

   

Antibodies. We are developing, in collaboration with Genmab, next-generation bispecific antibodies that are designed to target immune checkpoints that modulate the patient’s immune response to cancer. We are also exploring additional targeted cancer antibody approaches utilizing our in-house and recently acquired antibody capabilities.

 

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Small Molecule Immunomodulators. We use small molecules to augment the activity of other drug classes by inducing specific and discrete patterns of immunomodulation. We are developing a small molecule toll-like receptor 7, or TLR7, immunomodulator for the treatment of solid tumors.

We have leveraged these four drug classes to build a robust pipeline of product candidates. Our pipeline includes 12 product candidates in 13 ongoing clinical trials. Our most advanced programs are focused on oncology, where we have to-date treated over 500 patients across 17 solid tumor types. We also are developing more than 10 additional preclinical programs and expect to initiate clinical testing with several of them in the near future. We are targeting the advancement of up to three product candidates into the clinic in 2020, with clinical data updates for up to four additional programs expected by the end of 2020. In our Phase 1 trials, we have observed antigen-specific immune responses in over 90% of advanced melanoma patients treated with BNT111, our lead FixVac off-the-shelf product candidate, as a single agent. In addition, we have observed single-agent antigen-specific immune responses in patients treated with BNT121, the precursor to RO7198457 (BNT122), our lead iNeST product candidate. In both trials, we have observed durable objective responses (reduction in tumor volume) in both the monotherapy and checkpoint-combination settings.

We believe our technology and expertise is broadly applicable across a number of therapeutic areas, such as infectious diseases and rare diseases. In April 2020, we initiated a first-in-human clinical trial program for our BNT162 vaccine program to prevent COVID-19, which includes four vaccine candidate variants based on three distinct mRNA formats. We are co-developing BNT162 with Pfizer worldwide (ex-China) and with Fosun Pharma in China. We initiated the BNT162 program in late January 2020 in response to the global COVID-19 pandemic, and initiated human testing following preclinical studies and within approximately three months of initiating the research program. On July 1 and July 20, 2020, we and Pfizer announced preliminary data from our Phase 1/2 clinical trials of BNT162. Our ability to rapidly design and test multiple vaccine variants leveraged our deep experience with mRNA vaccines and our prior preclinical work in the infectious disease field.

We have established multiple collaborations to advance our science and development capabilities and provide capital, most of which has been non-dilutive. We have entered into selective collaborations with leading pharmaceutical companies where a collaborator may bring incremental expertise or resources that we currently do not possess in-house. To date, we have formed relationships with seven pharmaceutical companies, which comprise Genentech, Sanofi, Genmab, Genevant, Bayer, Pfizer and Fosun Pharma. We have entered into some of these collaborations in order to advance our technologies and business outside of our initial focus on cancer. We are collaborating with Pfizer to develop an influenza vaccine and with Pfizer and Fosun Pharma to develop a COVID-19 vaccine, each utilizing our mRNA-based immunotherapy technology. We also have a collaboration with Genevant to develop protein replacement therapies in up to five rare disease indications. Furthermore, we are collaborating with the University of Pennsylvania, or Penn, to develop mRNA-based vaccines in up to 10 additional infectious disease indications. We have a relationship with Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz (Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg Universität Mainz gemeinnützige GmbH), or TRON, to further our immunotherapy research. We either wholly own or retain significant rights to all of our clinical stage programs, either in the form of a global share of profit and co-commercialization rights with our collaborators in certain markets or significant royalties and milestones.

Our ability to develop, control and optimize the manufacturing process is a core strategic pillar and competitive advantage across our portfolio, in particular for our individualized product candidates. We operate three Good Manufacturing Practice, or GMP, certified manufacturing facilities in Germany, where we manufacture mRNA therapeutics and cell therapies for our own pipeline and for external customers. We operate a fourth manufacturing facility in Germany where we manufacture custom peptides to support our extensive immunomonitoring activities within our development programs. We have collaborated with Siemens AG, or Siemens, to develop efficient, semi-automated processes to produce our individualized mRNA immunotherapies on demand.

 

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Our Team

Our team combines proven biotechnology entrepreneurs, world-renowned immunologists and sophisticated biopharma investors. We were founded in 2008 by our scientific founders, Prof. Ugur Sahin, M.D., Prof. Christoph Huber, M.D. and Özlem Türeci, M.D., with a seed investment of €150 million from the Strüngmann family, through its investment vehicle AT Impf, and MIG Fonds, or MIG. Andreas and Thomas Strüngmann are serial entrepreneurs, having co-founded Hexal AG, a German pharmaceutical firm, which they built and sold to Novartis, along with their majority stake in Eon Labs, Inc., a U.S. public pharmaceutical firm, for a combined €5.6 billion (at the time, $8.3 billion). After selling Hexal, they founded a family office focused on healthcare. The Strüngmann family office and MIG have invested in, helped build and sold, either on their own or together, a number of biotechnology and healthcare companies, such as SuppreMol, Ganymed AG, or Ganymed, CorImmun, Sivantos (former Siemens hearing aid business), Press Ganey (surgery survey company) and Apceth (cell therapy manufacturing company). Helmut Jeggle and Michael Motschmann, on behalf of the Strüngmann family and MIG, respectively, along with Dr. Huber, were founding members of our Supervisory Board.

BioNTech has been supported since its inception by Prof. Rolf Zinkernagel, M.D., Ph.D. and Prof. Hans Hengartner, Ph.D., who serve on our Scientific Advisory Board. Dr. Zinkernagel is a Professor Emeritus at the University of Zurich, University Hospital, and former head of the Institute of Experimental Immunology in Zurich. Prof. Zinkernagel was awarded the Nobel Prize in 1996 for the discovery of how the immune system recognizes virus-infected cells. Prof. Hengartner is a world-renowned immunologist and Professor Emeritus at the Federal Institute of Technology ETH Zurich and the University of Zurich.

At the time of BioNTech’s founding, Dr. Sahin and Dr. Türeci were the Chief Scientific Officer and the Chief Medical Officer, respectively, of Ganymed, a private biotechnology company that was founded in 2001 and was focused on developing a monoclonal antibody targeting CLDN18.2 (zolbetuximab). The Strüngmann family office and MIG were majority investors in Ganymed. When Dr. Sahin became Chief Executive Officer of BioNTech, he stepped down from the management board of Ganymed and became the chair of its Scientific Advisory Board. Dr. Türeci continued to lead Ganymed as its Chief Executive Officer until it was sold to Astellas Pharma Inc. in 2016 for up to $1.4 billion.

Our initial group of scientific founders have been joined by experienced pharmaceutical executives, immunologists and biotechnology specialty investors. Sean Marett, our Chief Business Officer and Chief Commercial Officer, led the business development teams at Evotec, and previously was an executive at GlaxoSmithKline in the United States. Dr. Sierk Poetting, our Chief Financial Officer and Chief Operating Officer, joined us from Sandoz, where he served as the Chief Financial Officer in North America. Ryan Richardson, our Chief Strategy Officer, joined BioNTech from J.P. Morgan Securities LLC, where he served as Executive Director, Healthcare Investment Banking. We have also attracted talented scientists such as Katalin Karikó, our Senior Vice President & Head of RNA Protein Replacement, who has more than 30 years of experience working with RNA, has published more than 70 peer-reviewed papers and is co-inventor on mRNA-related patents, including a foundational patent relating to modified mRNA.

 

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Our Pipeline of Product Candidates

We are advancing a deep and broad portfolio of product candidates derived from our four drug classes focused on the treatment of cancer, infectious and rare diseases:

 

LOGO

 

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1.    Oncology

FixVac. Our FixVac product candidates contain selected combinations of pharmacologically optimized uridine mRNA encoding known cancer-specific shared antigens. They feature our proprietary immunogenic mRNA backbone and proprietary RNA-lipoplex, or RNA-LPX, delivery formulation, designed to enhance stability and translation, target dendritic cells and trigger both innate and adaptive immune responses. We and investigators are currently evaluating five FixVac product candidates in clinical trials, including BNT111 in a Phase 1 trial in advanced melanoma, BNT112 in a Phase 1/2 trial in prostate cancer, BNT113 in a Phase 1 trial in HPV+ head and neck cancers, BNT114 in a Phase 1 trial in triple negative breast cancer and BNT115 in a Phase 1 trial in ovarian cancer.

As of the July 2019 interim cut-off, 95 patients with metastatic melanoma had been dosed at least once in our Phase 1 clinical trial of BNT111. Forty-two of these patients had macroscopic tumor lesions at the time they were enrolled, and these patients were evaluated for preliminary clinical activity, with 25 receiving BNT111 as a monotherapy and 17 receiving BNT in combination with a checkpoint inhibitor. Three of the 25 patients who received BNT111 as a monotherapy demonstrated a partial response, one patient had a metabolic complete response as measured by FGD-PET imaging and seven had stable disease following treatment. Six of the 17 patients who received BNT111 in combination with a checkpoint inhibitor demonstrated a partial response and two had stable disease following treatment. We intend to publish a peer-reviewed article with additional data from our ongoing trial of BNT111 in melanoma in 2020.

We expect to initiate a Phase 2 trial with registrational potential for BNT111 in metastatic melanoma in the second half of 2020. We enrolled the first patient in a Phase 1/2 trial for BNT112, our FixVac product candidate targeting prostate cancer, in the second half of 2019. In addition, we are planning to initiate a Phase 2 trial with registrational potential for BNT113 in HPV+ head and neck cancers by the end of 2020.

Individualized neoantigen specific immunotherapy (iNeST). Our iNeST immunotherapies contain unmodified, pharmacologically optimized mRNA encoding up to 20 patient-specific neoantigens and also feature our proprietary RNA-LPX formulation. We are conducting, in collaboration with Genentech, multiple clinical trials of our iNeST product candidate, RO7198457 (BNT122). The iNeST Phase 1a (monotherapy)/1b (in combination with atezolizumab) trial is a non-registrational, signal seeking study recruiting mostly patients with late stage advanced cancers, including patients that failed multiple lines of prior treatment. We believe that iNeST is particularly well suited for patients with a lower tumor burden. This positioning is supported by clinical activity shown in our previously reported Phase 1 trial, in which BNT121 was administered intranodally in 13 patients with metastatic melanoma. In this trial, as of October 2019 we have observed stable, progression-free survival in nine patients for up to 60 months following surgery and treatment with BNT121. In addition, three out of five patients had an objective response, two patients received iNeST alone and the third patient also received checkpoint immunotherapy. We also observed a significant decrease in the cumulative recurrence rate post-treatment as compared to pre-treatment. Based on these findings, we, in collaboration with Genentech, initiated a randomized iNeST Phase 2 trial in first-line metastatic melanoma in combination with pembrolizumab. In June 2020, we reported data from a monotherapy dose-finding cohort of our RO7198457 (BNT122) Phase 1 trial in multiple solid tumors, which showed that ex vivo T cell responses were detected in approximately 86% of patients treated with RO7198457 (BNT122) as a monotherapy and later in June 2020 we provided a data update for an additional cohort in combination with atezolizumab. We and Genentech expect to provide an enrollment update from our RO7198457 (BNT122) Phase 2 trial in first-line melanoma in the second half of 2020. We expect this enrollment update to include an update on the ongoing study, including patient enrollment numbers, with efficacy and safety data expected in an interim update in the second half of 2021. We and Genentech plan to initiate two additional clinical trials for RO7198457 (BNT122) in 2020 in adjuvant NSCLC and adjuvant colorectal cancer.

mRNA intratumoral immunotherapy. In collaboration with Sanofi, we are conducting a Phase 1 trial of SAR441000 (BNT131), our first mRNA-based intratumoral immunotherapy, as a monotherapy and in combination with cemiplimab in patients with solid tumors. SAR441000 (BNT131) consists of a modified mRNA that encodes

 

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the IL-12sc, IL-15sushi, GM-CSF and IFN-a cytokines. SAR441000 (BNT131) is designed to be administered directly into the tumor in order to alter the tumor microenvironment and enhance the immune system’s ability to recognize and fight cancer within the tumor (proximal) as well as in other untreated locations (distal).

CLDN6 CAR-T cell immunotherapy. We are developing a proprietary chimeric antigen receptor T cell, or CAR-T, product candidate, BNT211, targeting Claudin-6, or CLDN6, a novel solid tumor-specific antigen. We developed BNT211 utilizing our target discovery engine, and we plan to administer it along with a CARVac “primer” to boost the immune response and promote CAR-T cell persistence. We expect to initiate a Phase 1/2 clinical trial for BNT211 in patients with advanced CLDN6 + solid tumors in the second half of 2020.

Neoantigen-based T cell therapies. We recently acquired a neoantigen-based T cell platform. Our lead product candidate under this platform, NEO-PTC-01 (BNT221), is a personalized neoantigen-targeted adoptive T cell therapy candidate consisting of multiple T cell populations targeting the most therapeutically relevant neoantigens from each patient’s tumor. We expect to initiate a Phase 1 clinical trial in NEO-PTC-01 (BNT221) in metastatic melanoma in the second half of 2020.

Next-generation checkpoint immunomodulators. We are developing, in collaboration with Genmab, novel next-generation bispecific antibodies that are designed for conditional activation of immunostimulatory checkpoint molecules. Our first bispecific candidates are GEN1046 (BNT311), which targets PD-L1 in conjunction with 4-1BB, and GEN1042 (BNT312), which targets CD40 in conjunction with 4-1BB. While 4-1BB is a known immune checkpoint target that is expressed on T cells and natural killer, or NK, cells, prior attempts to target 4-1BB with monoclonal antibodies have been severely limited by liver toxicities. Our 4-1BB targeting product candidates are designed to avoid toxicities by conditionally activating a 4-1BB receptor only together with the binding of either PD-L1 or CD40. We have initiated Phase 1/2a trials of GEN1046 (BNT311) and GEN1042 (BNT312) in solid tumors. We expect to report interim data on GEN1046 (BNT311) in 2H 2020.

Targeted Cancer Antibodies. In May 2019, we acquired an antibody with a novel mode of action, MVT-5873 (BNT321). BNT321 is a fully human IgG1 monoclonal antibody targeting sialyl Lewis A (sLea), a novel epitope expressed specifically in pancreatic and other solid tumors. MVT-5873 (BNT321) is currently in Phase 1 clinical development in pancreatic cancer, which we resumed in December 2019 upon the enrollment of the first patient. Positive interim data were announced in February 2018.

In addition, we have several other cancer immunotherapy programs in development, including:

 

   

RiboMabs: novel classes of mRNA-based therapeutics that are designed to encode antibodies directly in the patient’s body. We expect to initiate Phase 1 clinical trials for our first two RiboMab product candidates, BNT141 and BNT142, in the first half of 2021.

 

   

RiboCytokines: novel classes of mRNA-based therapeutics that are designed to encode cytokines directly in the patient’s body. We expect to initiate Phase 1 clinical trials for our first RiboCytokine product candidates, BNT151 and BNT152/BNT153 (combination), in the first half of 2021.

 

   

TCR therapy: T cells with engineered TCRs that are designed to specifically target cancer cells.

 

   

Precision T cell therapy: Autologous, non-engineered T cells targeting shared RAS neoantigens prevalent across many solid tumors.

 

   

Small molecule immunomodulators: novel intratumoral agents that trigger inflammation and improvement of antigen presentation by antigen-presenting cells. We filed an IND for our first small molecule immunomodulator product candidate, BNT411, in the fourth quarter of 2019 and dosed the first patient in our Phase 1 clinical trial for BNT411 in solid tumors in July 2020.

 

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2.    Infectious Disease Immunotherapies

We have collaborated with third parties to exploit the immunotherapeutic properties of our mRNA drug class for the treatment and prevention of infectious diseases. Notably, we have recently started development of four vaccine candidate variants for the prevention of COVID-19. We expect to advance our flu vaccine into the clinic by the end of 2021, and our first programs under our Penn collaboration into the clinic by the first half of 2021.

 

   

COVID-19 vaccine: In response to the COVID-19 pandemic, we are developing a vaccine candidate based on mRNA technology to induce immunity and prevent COVID-19 in response to the growing global health threat posed by the disease. Building on our existing collaboration with Pfizer, in April 2020, we announced that we and Pfizer had entered into a collaboration agreement to co-develop our potential first-in-class COVID-19 mRNA vaccine program, BNT162, aimed at preventing COVID-19. We and Pfizer are jointly conducting clinical trials for four COVID-19 vaccine candidate variants initially in the United States and Europe across multiple sites. If a vaccine candidate is approved, we and Pfizer will also work jointly to commercialize the vaccine worldwide (excluding China which is covered by a collaboration with Fosun Pharma). If the vaccine candidate is approved, we and Pfizer expect to manufacture up to 100 million doses by the end of 2020 and potentially more than 1.3 billion doses by the end of 2021. In March 2020, we entered into a strategic alliance with Fosun Pharma to co-develop a COVID-19 vaccine in China. Upon regulatory approval, Fosun Pharma will commercialize the vaccine in China, while we retained the full rights to develop and commercialize the vaccine in the rest of the world (jointly with Pfizer). On July 1 and July 20, 2020, we and Pfizer announced preliminary data from our Phase 1/2 clinical trials of BNT162.

 

   

Flu vaccine: In August 2018, we entered into a collaboration with Pfizer to develop mRNA-based immunotherapies for the prevention of influenza, product candidate BNT161.

 

   

Infectious diseases: In October 2018, we entered into a research collaboration with Penn, under which we have the exclusive option to develop and commercialize mRNA immunotherapies for the treatment of up to 10 infectious disease indications. In August 2019, we entered into a letter agreement and investment agreement with the Bill & Melinda Gates Foundation to advance the development of immunotherapies for the prevention and/or treatment of HIV and tuberculosis and up to three additional infectious diseases.

3.    Rare Disease Protein Replacement Therapies

We are collaborating with Genevant in order to capitalize on opportunities for our mRNA technology in rare disease indications potentially featuring expedited paths to market. We are combining our mRNA technology with Genevant’s lipid nanoparticle, or LNP, delivery technology to create up to five mRNA protein replacement therapies for the treatment of rare diseases with high unmet medical needs. We expect our first compound to enter the clinic in the second half of 2021.

II. Our Strengths

We are developing a broad portfolio of technologies and product candidates that we believe position us at the forefront of the next generation of targeted, specific immunotherapies. Our key strengths include:

We are a next-generation immunotherapy powerhouse pioneering individualized immunotherapies to address the shortcomings of existing treatments for cancer and other indications with significant unmet need.

 

   

We have established leadership and expertise in immunology and oncology. Through 11 years of rigorous scientific investigation and clinical translation, we have developed a portfolio of disruptive immunotherapy technologies designed to address the challenges of disease heterogeneity and patient variability.

 

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Our team has consistently been first-movers and has published over 150 scientific papers in leading peer-reviewed journals. We were the first to develop an intravenously delivered mRNA-based human therapeutic, the first to advance an individualized mRNA-based cancer immunotherapy into clinical trials, and the first to establish scaled in-house manufacturing for such a product candidate.

 

   

Since our founding in 2008, we have advanced four of our therapeutic platforms into human clinical trials, generated promising early evidence of clinical activity in several cancer types, raised $1.6 billion of capital from renowned global biopharmaceutical investors, formed collaborations with seven leading pharmaceutical companies, and acquired complementary assets ranging from research and manufacturing units to clinical programs.

 

   

Our efforts are driven by a group of over 1,400 employees including over 600 in research and development, overseen by our founders who are internationally recognized thought leaders in their disciplines.

We are developing product candidates addressing highly specific immuno-oncology targets, employing a technology-agnostic approach.

 

   

Our portfolio includes four drug classes, spanning mRNA therapeutics, cell therapies, antibodies and small molecule immunomodulators, which can be used alone or in combination to enhance therapeutic effect and produce potentially synergistic effects, as demonstrated in our combination of our BNT211 CAR-T product candidate with a CARVac immune primer.

 

   

Our oncology pipeline includes 11 product candidates in 12 ongoing clinical trials, and more than 10 preclinical programs.

 

   

We have developed significant expertise in the selection of optimal combinations of targets for the specific and individualized treatment of particular cancers. We have assembled libraries of more than 200 proprietary or known shared antigens and have developed predictive algorithms capable of efficiently identifying multiple neoantigens on an individualized basis for any patient. We further enhanced these capabilities with our acquisition of Neon.

 

   

Our approach enables real-time monitoring of therapeutic effect on the immune system in a feedback loop of biological surveillance that we believe has the potential to further enhance the success of individualized immunotherapy approaches.

We have tested our lead mRNA candidates in over 500 patients and have already demonstrated signs of single-agent clinical activity in our two lead programs.

 

   

Our most advanced programs are focused on oncology where we have to-date dosed over 500 patients across 17 solid tumor types.

 

   

In our Phase 1 trials, we observed single-agent antigen specific immune responses in over 90% of advanced melanoma patients treated with BNT111, our lead off-the-shelf immunotherapy product candidate leveraging our wholly owned FixVac platform. In addition, we observed single-agent antigen-specific immune responses in patients treated with BNT121, the precursor to our lead individualized neoantigen specific immunotherapy product candidate derived from our iNeST platform. In June 2020, we reported data from a monotherapy dose-finding cohort of our RO7198457 (BNT122) Phase 1 trial in multiple solid tumors, which showed that ex vivo T cell responses were detected in approximately 86% of patients treated with RO7198457 (BNT122) as a monotherapy and later in June 2020 we provided a data update for an additional cohort in combination with atezolizumab. For both candidates, we have observed durable objective responses in both the monotherapy and checkpoint combination settings.

 

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We have developed a very broad and advanced mRNA therapeutic portfolio for the treatment of cancer.

 

   

We have over a decade of experience pioneering the use of mRNA as a drug class, yielding five distinct mRNA platforms in oncology, each with the potential to generate multiple first-in-class product candidates.

 

   

We have developed four distinct mRNA formats, each tailored to specific therapeutic applications. We have also developed and optimized multiple delivery formulations for our mRNA product candidates, including our proprietary non-viral RNA-LPX, to deliver our mRNA systemically and target it to relevant organs in the body.

 

   

The combination of these platforms, formats and delivery formulations is designed to address a wide range of disease targets, and tailor drug products for systemic or intratumoral delivery, as well as directly encode mAbs or cytokines in vivo.

 

   

This broad mRNA expertise is a core strategic asset of our company. It is protected by a global patent portfolio and our proprietary technical knowledge and trade secrets.

We have a deep, diversified pipeline and expect data updates for up to four oncology programs and one in infectious disease by the end of 2020.

 

   

We have already advanced our portfolio to a critical stage of maturity with multiple programs progressing in parallel. We expect numerous near-term product candidate development updates, including:

 

   

data updates in up to five clinical programs by the end of 2020; and

 

   

advancement of up to three product candidates into the clinic in 2020.

 

   

Our preclinical oncology pipeline is progressing rapidly. We initiated clinical trials for both of our lead checkpoint immunomodulator antibody product candidates in 2019, and enrolled the first patients in clinical trials of BNT112 and BNT321 (MVT-5873). We initiated clinical trials for BNT162 for COVID-19 in the first half of 2020 and for our small molecule product candidate, BNT411, in July 2020. We expect to initiate clinical trials for our lead CAR-T product candidate, BNT211, and our recently acquired adoptive T cell therapy product candidate, NEO-PTC-01 (BNT221) in the second half of 2020. We also expect to initiate clinical trials for our RiboMab and RiboCytokine product candidates in the first half of 2021.

 

   

We initiated clinical trials for BNT162 for COVID-19 in the first half of 2020. We expect to report our target indications and first product candidates for our infectious and rare disease platforms in 2020.

We have formed multiple collaborations with leading pharmaceutical companies and have retained significant development, commercial and financial rights across our portfolio.

 

   

We have chosen to form collaborations in oncology to rapidly advance our science and enhance our development capabilities, bring our potentially disruptive therapies to patients more quickly and provide capital, most of which has been non-dilutive.

 

   

We are currently collaborating with three pharmaceutical companies with expertise in oncology, Genentech, Sanofi and Genmab, and have retained significant rights in each of our collaborations.

 

   

In addition, we have formed collaborations with leading pharmaceutical companies to broaden our footprint beyond oncology. We have collaborations with Pfizer focused on influenza and COVID-19, and Fosun Pharma for COVID-19. We are collaborating with Penn to develop mRNA-based immunotherapies for up to 10 additional infectious disease indications. We have also formed a collaboration with Genevant for up to five rare disease indications.

 

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We have retained worldwide rights to all product candidates under our FixVac, RiboMabs, RiboCytokines and CAR-T platforms.

We have created a vertically integrated business with comprehensive in-house manufacturing capabilities.

 

   

We believe that to successfully bring individualized immunotherapies to patients, it is critical to control the manufacturing and supply processes. We therefore have chosen to invest early in scaling our in-house capabilities.

 

   

We currently operate four manufacturing facilities in Germany spanning mRNA and peptide production, viral vectors and engineered T cells, and we continue to invest significant human and financial capital into these activities.

 

   

In collaboration with Siemens, we are optimizing our iNeST production process, reducing turnaround time from over three months to less than six weeks currently, with the goal of delivering on-demand commercial supply.

Our Company’s scientific DNA, which is the foundation of the BioNTech approach, has attracted a talented team from over 50 countries around the world.

 

   

Prof. Ugur Sahin, M.D., our co-founder and Chief Executive Officer, and Özlem Türeci, M.D., our Chief Medical Officer, are physicians, scientists and innovators. They have made groundbreaking scientific and technological contributions in the field of personalized cancer immunotherapy and are co-inventors on more than 100 patents. Their daily work is motivated by their experience as researchers and cancer physicians aiming to exploit scientific insights and drive technological progress to develop commercially viable products that could help individual patients, an attitude and culture that has become the DNA of BioNTech.

 

   

Our DNA, with a deep culture of intellectual curiosity and innovation, has made us a destination of choice for scientific pioneers. This culture has attracted an exceptionally talented team from over 50 countries around the world.

 

   

We have participated in nearly 300 scientific publications, of which over 100 are in leading peer-reviewed journals.

III. Our Strategy

Our vision is to harness the power of the human immune system to develop truly individualized and patient-centric therapies for cancer and other serious diseases. We aim to rapidly develop, manufacture and, if approved, commercialize a portfolio of novel immunotherapies, including both off-the-shelf drugs and individualized treatments. The key elements of our strategy to achieve this vision are as follows:

Rapidly advance our potential first-in-class product candidates derived from our FixVac and iNeST platforms toward market approvals in oncology, either on our own or with our collaborators.

 

   

We and investigators are conducting five Phase 1 clinical trials with our wholly owned off-the-shelf FixVac mRNA immunotherapy. Our most advanced current FixVac product candidate, BNT111, is currently being evaluated in 115 patients with advanced melanoma, and we expect to initiate a Phase 2 trial with registrational potential in the second half of 2020.

 

   

We are also advancing, in collaboration with Genentech, our iNeST individualized neoantigen specific mRNA immunotherapy in two clinical trials, targeting more than eight tumor types, and have two additional clinical trials planned for 2020. Our most advanced iNeST program is a Phase 2 trial of our product candidate, RO7198457 (BNT122), in 132 patients with metastatic melanoma, evaluating iNeST in combination with pembrolizumab as a first-line therapy.

 

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We believe both FixVac and iNeST have therapeutic potential in a wide variety of solid tumors. We have identified significant market opportunities in additional indications and plan to pursue potentially expedited routes to market approval.

Progress additional product candidates through clinical development, leveraging our multiple drug classes and the synergies between them in order to expand our oncology pipeline.

 

   

In addition to FixVac and iNeST, we are also conducting a Phase 1 clinical trial of our intratumoral immunotherapy product candidate SAR441000 (BNT131) in collaboration with Sanofi, as a monotherapy in patients with advanced melanoma and as a combination therapy with an anti-PD-1/PD-L1 checkpoint inhibitor in patients with certain solid tumors.

 

   

Beyond mRNA, we plan to rapidly advance other product candidates from our immunotherapy drug classes into clinical proof-of-concept studies in solid tumor indications.

 

   

In collaboration with Genmab, we have initiated Phase 1/2a clinical trials for our product candidates GEN1046 (BNT311) and GEN1042 (BNT312) in solid tumors. These product candidates are based on our novel checkpoint immunomodulator bispecific monoclonal antibodies, which we believe have potential in a broad range of cancers.

 

   

We have also initiated a Phase 1 clinical trial for our small molecule product candidate, BNT411, in solid tumors and plan to initiate a Phase 1/2 clinical trial for our wholly owned CAR-T product candidate, BNT211, in multiple solid tumors, targeting a novel solid-tumor specific antigen, CLDN6, and a Phase 1 clinical trial for our recently acquired adoptive T cell therapy product candidate, NEO-PTC-01 (BNT221) in the second half of 2020.

Maximize the potential and leverage the broad applicability of our mRNA drug class in additional therapeutic areas beyond cancer, including through selective collaborations.

 

   

Beyond oncology, we intend to leverage our mRNA technology to direct the immune system to fight a range of infectious diseases and address missing or defective proteins in certain rare diseases.

 

   

Our collaborations with Pfizer in influenza and COVID-19, Fosun Pharma in COVID-19 and with Genevant in rare diseases underscore the potential of our approach. We intend to continue to seek value-adding collaborations with leading industry players who contribute their competencies and know-how to complement our powerful suite of technologies to address challenging diseases outside of our core therapeutic focus on oncology.

Strengthen our position as a leader in the highly automated, on-demand manufacturing of individualized therapies with the goal of delivering our therapies globally.

 

   

We will continue to invest to reduce cycle times and increase the automation of our processes, and to expand our manufacturing capacity across all platforms to support the efficient progression of our product candidates into late-stage clinical trials and commercialization.

 

   

We will continue to invest in and scale up our advanced, in-house GMP manufacturing capabilities and capacity across mRNA and cell therapy production.

Establish a commercial organization to bring our portfolio of cancer and infectious disease immunotherapies to patients.

 

   

We believe that developing our own commercial infrastructure will be key to maximizing the value of our programs. We intend to jointly participate in the commercialization of our collaborative programs where we retain significant commercial rights.

 

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We have expanded our footprint in the United States, and continued to do so with the acquisition of Neon, creating a U.S. research and development hub.

Expand our current technology suite by continuing to develop existing and new drug classes and platforms, and selectively in-licensing technologies that are complementary to our existing pipeline.

 

   

As our understanding of immunology and oncology evolves, we plan to continue developing existing as well as new drug classes and platforms that are consistent with our strategy, with particular focus on those that can benefit from our in-house expertise.

 

   

As evidenced by our recent acquisition of Neon, we also continuously assess the external environment for novel drug classes, platforms and product candidates that can further expand and improve our pipeline of innovative immunotherapeutics, and help us to execute our strategy.

Maintain our culture of scientific excellence to continue to drive future innovation.

 

   

We are committed to maintaining close ties to the scientific and academic community by fostering our many long-standing university relationships.

 

   

We also intend to continue our leadership in the Association for Cancer Immunotherapy, or CIMT, which provides us potential new sources of innovation and academic collaboration opportunities.

IV. Immunotherapy in Cancer

The immune system has evolved over hundreds of millions of years to identify and eradicate what is foreign to the body with a high level of efficiency. The immune system’s efficacy is attributable to approximately one trillion highly diversified immune cells that constantly travel throughout the body and interact in a coordinated manner. They are able to detect and eliminate diseased cells and pathogens with high precision by relying on a broad range of immune recognition receptors. Their powerful mechanisms both synergize and regulate each other.

The goal of immunotherapy in the field of oncology is to harness the power of the immune system to recognize malignant cells as “foreign,” overcome immune evasion mechanisms employed by cancers, eradicate cancer cells and thereby eliminate tumors.

Immunotherapy approaches in cancer have a long history. Recent years have seen an acceleration of scientific advancements and clinical breakthroughs in this field. The introduction over the last decade of checkpoint inhibitors such as Yervoy, Opdivo, Keytruda and Tecentriq, and CAR-T therapies such as Yescarta and Kymriah has demonstrated that even leveraging one single mechanism to harness the immune system may result in unprecedented, significantly improved clinical outcomes for a subset of patients.

While these first-generation immunotherapies have ignited the paradigm shift toward immuno-oncology, they also have limitations. For example, less than 40% of patients respond to checkpoint inhibitors, while CAR-T therapies have been primarily limited to blood cancers in subsets of patients, and have been hampered by toxicities.

Realizing the full potential of immunotherapy is the objective of the next generation of immuno-oncology drugs to be developed.

V. Challenges and Opportunities of Cancer Therapies

Cancer results from an accumulation of abnormalities, known as somatic mutations, in the genome of cells over time leading to malignant transformation, combined with a failure by the immune system to detect and eradicate such transformed cells. Due to their random nature, the vast majority of these aberrations are unique to the individual patient.

 

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As a consequence, heterogeneity is an intrinsic hallmark of cancer, posing a key challenge for cancer therapy:

 

   

Interindividual tumor heterogeneity. Tumors, even within the same cancer type, differ at the molecular level. For example, two patients with the same type of cancer usually share less than five percent of their mutations. As a result, patients often respond very differently to the same drug.

 

   

Intratumor heterogeneity. Within the same patient, cancer also evolves over time so that different tumor cell clones co-exist, in a manner known as clonal evolution. As a result, a patient’s cancer may be intra-tumorally as well as inter-tumorally heterogeneous. Therapies might target only a subfraction of tumor cell clones. This can lead to immune escape and therapy failure.

 

   

Cancer evolution and immune escapes. Cancer cells can adapt to therapeutic pressure, which results in treatment resistance. During immunotherapy, tumor cell clones may evolve that no longer express T cell recognized antigens or have defects in their antigen presentation machinery.

 

   

Tumor microenvironment. Tumors induce various forms of immunosuppressive microenvironments that prevent T cells from proliferating and executing their anti-tumor effector function.

 

   

Host, environment and immune system. The functional state of each patient’s immune system is dependent on the patient’s age, genetic makeup and environmental exposures. For example, the HLA haplotype, or the genetic makeup that encodes the major histocompatibility complex, is highly individual and decisive for which epitopes of an antigen are presented to T cells. Whereas a given tumor antigen might be a good target in one patient, a second patient might not be able to respond to it at all.

 

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The graphic below depicts the interaction between three key factors influencing the patient unique tumor profile:

 

 

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Interindividual heterogeneity of patients. The interaction between cancer and immune system is shaped by various host, tumor and environmental factors. The complex interplay of these sources of interpatient heterogeneity affects both the course of disease and the efficacy of immunotherapy.

Together, these factors make cancer an extremely complex and heterogeneous disease. As a consequence, in the majority of cancer types, less than 40% of treated individuals benefit from highly potent approved therapies, and responses are often not durable. While these hallmarks of cancer are a challenge for cancer therapy, they also present opportunities for immunotherapy. These interconnected layers of complexity and variability require a deep understanding of an individual cancer and call for a patient-centric approach in order to find an optimal treatment.

Transformation of Cancer Therapies

We believe the recent convergence of breakthrough technologies in life sciences has enabled innovative concepts to address the immunobiology of cancer at its core. One of these breakthroughs has been the establishment of cancer immunotherapy in the armamentarium of cancer treatments. Another has been the emerging progress towards individualized medicine. Technologies such as next-generation sequencing, or NGS, have confirmed beyond doubt the problematic diversity of tumors on the inter-patient level. At the same time, NGS enables fast, cost-efficient and precise high-resolution mapping of each patient’s individual disease. We believe the application of these breakthrough technologies has the potential to change drug development and profoundly alter the oncology treatment landscape.

 

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The ability to translate a comprehensive molecular map of an individual tumor into treatment decisions, and make individually tailored therapeutics available, have become the focus of the next generation of cancer therapy. The technology necessary for leapfrog advancements in oncology now exists, but to realize its potential, a radical paradigm shift is required in drug development.

VI. The BioNTech Approach

In oncology, we are focused on bringing cancer immunotherapy into the next generation. We believe that we can accomplish this by applying the following principles:

 

   

Exploiting the full potential of the immune system. Our broad pipeline includes mRNA-based immune activators, antigen-targeting T cells and antibodies, and defined immunomodulators of various immune cell mechanisms. This portfolio is designed to mirror the evolution of the immune system to rely on multiple complementary pathways.

 

   

Broadening the universe of patients benefiting from cancer immunotherapy. We discover and exploit novel targets and target combinations. Our aim is to extend the utility of immunotherapy to patient populations that are not currently amenable or do not benefit from the targets of current immunotherapies. One example is patients with low mutational load tumors, such as pancreatic and prostate cancer, which we address with tumor-associated antigens.

 

   

Improving the success rate. We engineer and develop highly potent drug candidates designed to achieve precision for the specific target. We further augment activity and counteract resistance mechanisms by combining compounds with non-overlapping, synergistic mechanisms of action, such as combining our FixVac immunotherapy (CARVac) with our novel CAR-T therapies.

 

   

Focusing on curative approaches. The root cause of recurrence or for lack of tumor eradication is interindividual variability and cancer heterogeneity. Addressing this biological reality is one of the mandatory design aspects of the product candidates we develop. For example, each of our cancer immunotherapies incorporates multiple targets in order to account for this variability.

We have applied these four guiding principles to a broad suite of therapeutic platforms optimized for a distinct mode of action, high precision targeting, high potency and efficacy. We expect each platform to yield a pipeline of drug candidates for further development.

We believe this technology-agnostic range of platforms and product candidates positions us to remain at the forefront of the shift toward an individually tailored, patient-centric therapeutic approach in oncology.

Similarly, in infectious disease, we are deploying our full suite of technologies and immunotherapeutic understanding to develop mRNA vaccines against emerging infectious diseases, such as COVID-19, in a manner that is designed to be faster and more easily scalable, and with more flexible constructs, than traditional vaccine development.

Patient-Centric Approach

We believe the next generation of cancer immunotherapy will start from the perspective of the molecular changes that have occurred in an individual patient, and then will provide a specific therapy for that patient. We believe that BioNTech is ideally positioned to drive this transformation.

Our patient-centric approach starts with profiling and diagnostics by utilizing a target identification engine. This engine combines next generation sequencing, genomics, bioinformatics, machine learning and artificial intelligence to (a) identify gene targets of interest, (b) characterize the functional relevance of these targets (i.e. the ability to raise an immune response to or through a target) and (c) demonstrate their drugability. From our very beginning onwards, we have been developing the novel technologies needed to match the identified targets to the optimal individualized treatment approach.

 

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Our patient-centric approach is illustrated and described below:

 

 

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Our patient-centric approach. Utilizing patient profiling, diagnostics and bioinformatics, we select from our suite of drug classes to provide optimal individualized treatment. Our treatments include off-the-shelf drugs as well as highly tailored immunotherapies that are produced on-demand for the individual patient.

Utilizing this approach:

 

1.

We develop and leverage our competencies in target discovery, biomarker science and computational medicine to thoroughly profile a patient’s tumor sample and immune cells for the selection of suitable targets and treatments. Combined with our deep domain expertise in immuno-oncology and product vision, we are able to use this data to develop next-generation product candidates.

 

2.

We have developed and are iteratively optimizing next-generation therapeutic platforms leveraging four drug classes. Each therapeutic platform bundles innovations designed to deliver a distinct mode of action with high-precision targeting, high potency and efficacy. Each platform is being developed to provide a pipeline of drug candidates with complementary and potentially synergistic modes of action.

 

3.

Our drug platforms are highly versatile and support the fast development of scalable manufacturing processes. We develop and establish highly digitalized and automated manufacturing technologies and quality controlled processes enabling fast delivery of customized therapies comprising off-the-shelf drugs, on-demand immunotherapies, and combinations thereof.

 

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We invest in innovation whenever we encounter technology barriers which may constrain clinical success. We are technology-agnostic and we seek to utilize the technology that is most suited for the respective purpose. By focusing on the three pillars discussed above over the last decade, we have integrated all of the building blocks of immunotherapy under one roof, enabling an approach with the potential to optimize patient outcomes.

Broad and Potentially Synergistic Suite of Platforms

We believe the depth and breadth of our understanding of immune system and cancer biology allows us to create an extensive pipeline of specific and potentially efficacious product candidates. We are exploiting a comprehensive repertoire of known and proprietary therapeutically relevant immuno-oncology targets and are developing a diverse spectrum of immunotherapeutic approaches, as shown in the chart below.

 

 

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We believe that harnessing complementary, potentially synergistic modes of action increases the likelihood of therapeutic success, reduces the risk of emergence of secondary resistance mechanisms, and also unlocks a larger potential market. Critically, this approach allows us to pursue a technology agnostic approach, providing the most appropriate therapeutic platform or a combination thereof for the intended patient and purpose.

For example, we believe our neoantigen immunotherapies are particularly well-suited to treat high mutation load cancers in the adjuvant setting to prevent the tumor from spreading or recurring following initial treatment such as surgery. In this setting, tumor volumes tend to be low and there remains the potential for strong T cell responses since the patient’s immune system has not been weakened by prior lines of treatment, and checkpoint inhibition alone often offers a poor risk-benefit profile or low response rate. Similarly, we believe our FixVac, CAR-T, neoantigen-targeted T cell and next-generation checkpoint immunomodulator platforms may have especially strong potential in lower mutation burden tumors such as ovarian or prostate cancers, which comprise a significant proportion of tumors and often also have a poor response to checkpoint inhibition. Likewise, we believe that monoclonal targeted cancer antibodies and CAR-T cell therapies are particularly well-suited for tumors that have defects in their antigen-presentation machinery.

 

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We believe our breadth of our technology positions us to combine modes of action in a coordinated way to treat cancer in a more efficacious manner than current existing therapies. We further believe that our patient-centric approach and our broad, potentially synergistic portfolio of drug platforms place us at the forefront of the paradigm shift toward individualized immunotherapies.

 

 

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Diversity of cancer patient populations, challenges and our therapeutic strategies. We believe our diversified portfolio allows us to potentially address a large share of cancer patients. Abbreviations: B2M, beta-2 microglobulin, a component of MHC.

VII. Selection of Therapeutic Targets and Therapies

Immunotherapy targets can be categorized as antigens for targeted immunotherapy with antibody- or T cell-based effector mechanisms and immunomodulatory targets to be exploited to improve the anti-tumoral function of immune cells.

A. Targeting Cancer Antigens

In order to address the broadest possible number of patients, our therapeutically targeted cancer antigen library comprises tumor associated antigens, viral neoantigens and mutant neoantigens:

1. Tumor Associated Antigens

Tumor associated antigens, or TAAs, are cancer selective targets that typically have a highly restricted expression pattern in normal tissues but are frequently expressed in a wide range of human cancers. Over the last 15 years, we have built up a database of approximately 200 cancer-selective antigens, including proprietary disease targets that could be used as targets for immunotherapy-based approaches.

 

   

Cancer-Germline and Cancer-Embryo-Fetal Antigens, which are normally expressed during embryonal development and silenced after birth or restricted to germline cells. These antigens are aberrantly expressed in a variety of human malignancies and are generally not expressed in healthy tissue, making them particularly suitable for our FixVac-, antibody- and CAR-T cell-based therapeutic approaches.

 

   

Differentiation antigens, which are normally expressed in a highly tissue-specific manner in normal tissues (e.g., on melanocytes or on prostate cells) but are also present in a high proportion of tumors derived from these tissues, are well-suited for therapeutic targeting with FixVac and antibody approaches.

 

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Tumor-associated carbohydrate antigens are carbohydrate-based cell surface tumor antigens generated by cancer cell-specific aberrant glycosylation that enable the development of antibody and CAR-T cell therapies.

2. Viral Neoantigens

Viral oncoproteins, or viral neoantigens, are virus-derived proteins that drive the oncogenic transformation of infected cells by viruses that can cause cancer. Examples are the E6 and E7 oncoproteins from human papilloma virus, or HPV. Viral oncoproteins are commonly acknowledged as safe and promising targets for immunotherapy as they are (i) absent from any non-infected tissue, (ii) highly immunogenic since they are not prone to central tolerance mechanisms and (iii) not subject to immune escape by gene silencing as they are crucial to maintaining the transformed state of the tumor cells. We leverage viral neoantigens as targets for our BNT113 FixVac program in HPV16+ head and neck cancer.

3. Mutant Neoantigens

Somatic mutations, or mutations of non-germline cells, are a hallmark of cancer. Driver mutations promote the oncogenic process, whereas passenger mutations are considered as functionally irrelevant. Both types of mutations, however, can alter the sequence of proteins and create new epitopes which are processed and presented on specialized major histocompatibility complex, or MHC, molecules. Mutated epitopes that are recognized by T cells are called neoepitopes and the sequence-altered proteins they are derived from are neoantigens. They are promising targets for cancer immunotherapy as (i) activation of the immune system against such antigens is highly specific (they are only expressed on cancer cells) and (ii) mutant neoantigens are exempt from central tolerance and thus T cell affinity for neoantigens may be significantly superior. We utilize individualized mutant neoantigens as targets for our iNeST product candidates.

B. Immunomodulatory Targets

The activity of immune cells can be controlled or manipulated by the targeting of receptors that control key biological processes in these cells, known as immunomodulation. Immunomodulatory targeting strategies include:

1. Checkpoint Inhibition

Checkpoint inhibition is a therapeutic approach by which T cell function is stimulated with mAbs that block their inhibitory receptors, which can be exploited by cancer cells to shut down T cell activity. Examples of checkpoint targets are PD-1, PD-L1, CTLA-4, TIGIT, LAG3 and many others. The concept is known as “releasing the brakes” and has been shown to be therapeutically effective in tumors with strong pre-existing immune cell infiltration. Our GEN1046 (BNT311) product candidate is a next-generation bispecific checkpoint immunomodulator, with one arm targeting PD-L1.

2. Immunostimulation

Immunostimulatory approaches are directed against receptors known to directly activate immune cells. Examples of these targets include co-stimulatory molecules such as CD40 and 4-1BB or cytokine receptors such as IL-2R, IL-7R and IL-12R. Immunostimulatory approaches provide a powerful opportunity to enhance immune activation, even in types of cancer that are not responsive to checkpoint inhibition due to lack of immune cell infiltration. However, this approach is often limited by a narrow therapeutic window associated with dose-limiting toxicity.

We believe that both concepts can be combined in a potentially synergistic and safe fashion by developing precisely engineered molecules, such as our BNT151 RiboCytokine program or GEN1042 (BNT312), our next-generation bispecific checkpoint immunomodulator targeting both CD40 and 4-1BB.

 

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C. Our Computational Approach to Individualized Immunotherapy

Bioinformatics are critical in the production of individualized therapies. We have accumulated a high level of experience in bioinformatic approaches to mutation detection, cancer genomics and immunotherapy through our ongoing research and preclinical studies and clinical trials.

Our validated patient-centric bioinformatic process, as illustrated below, allows the application of complex algorithms to the patient’s data in the context of drug manufacturing. Our bioinformatics processes are robust and scalable, incorporating our experience handling genomic data in a high-throughput environment, as we target making on-demand production of individualized immunotherapies commercially viable.

 

 

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From Patient to Analysis. Our bioinformatic process for the selection of neoepitopes.

1. Sequencing

We sequence the patient’s tumor and healthy tissue samples using NGS technology. Comparison of the patient’s sequenced tumor and healthy samples provides us with the data from which we can identify targets for the design of individualized cancer immunotherapies. This is a multi-step process in which mutation detection and neoantigen prediction are particularly important.

2. Mutation Detection

Mutation detection, which defines which tumor-specific mutations are present in any cancer, is the starting point for defining targets for individualized immunotherapy. Determining mutations from NGS data with high precision and sensitivity is challenging because numerous factors can lead to false positives, which can mask mutations. Despite advances in the field, commonly used mutation detection algorithms still exhibit high false positive mutation detections. In order to address these challenges, we have exclusively licensed a technology from TRON that combines tumor modeling with mutation detection, called MyMUT. MyMUT is a next-generation mutation detection system, which we believe has the following key characteristics:

 

   

High specificity and robustness. By combining tumor modeling, sophisticated statistical and genomic filters, and replicate sampling, MyMUT achieves clinical precision in detecting mutations with comparable sensitivity to state-of-the-art mutation detection systems. Higher specificity translates to potentially more effective immunotherapies, with faster and cheaper production. MyMUT is designed to deliver uniform performance for all patients regardless of tumor complexity, mutation burden or sample purity. MyMUT’s performance with low mutation tumors also allows us to offer individualized immunotherapies to patients with low tumor mutation burdens.

 

   

Intratumor heterogeneity. By performing tumor modeling, MyMUT can also identify clonal and subclonal mutations with high precision, allowing us to prioritize the former in neoantigen-directed immunotherapies and address intratumoral heterogeneity by targeting mutations that are common in a higher proportion of cancer cells within a tumor.

 

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Quality control (QC). By analyzing the genomic properties of sequenced samples, MyMUT can detect errors that pass standard sequencing QC, ensuring the quality and safety of individualized immunotherapies.

3. Neoepitope Selection

Only a portion of mutated peptides (neoepitopes) are suitable for raising an immune response in vivo. Our approach focuses on evoking responses involving both CD8+ T cells and CD4+ T cells. We do this by discerning the likelihood of presentation of the neoepitope to the T cell receptor as an MHC peptide complex using data from mRNA expression levels and MHC binding affinity predictions, among other factors. For example, in our first individualized neoepitope immunotherapy clinical study, all 13 stage III and IV melanoma patients selected for treatment developed a CD4+ and/or CD8+ T cell response, achieving an overall 60% immune response rate to predicted neoepitopes.

Presentation of a neoepitope on an MHC molecule does not, however, guarantee recognition by T cells, and an integrated view combining several properties impacting immunogenicity is necessary. Our algorithms are continuously being improved and extended with data collections from various sources such as our past and current clinical studies as well as HLA data. By using machine learning approaches applied to these large datasets we aim to further improve prediction of overall presentation of neoepitopes tailored to patients’ specific HLA types. With our acquisition of Neon, we further bolstered our neoepitope selection capabilities with the addition of Neon’s RECON bioinformatics engine. RECON uses a number of inputs from each patient, including DNA sequences from samples of tumor and normal tissue, RNA sequences from tumor samples, and the patient’s specific MHC allele profile. RECON processes data from these inputs using a proprietary combination of algorithms in order to produce a prioritized list of neoantigen-targeting peptides that can be manufactured for use in our product candidates.

VIII. Our mRNA Drug Class

 

At a glance: mRNA as a Therapeutic Drug Class

 

   

Natural molecule found universally within cells, with well-characterized properties.

 

   

Suitable to encode for antibodies, antigens, cytokines and any other type of protein.

 

   

Transient, with adaptable activity and half-life. Avoids genomic integration problems sometimes seen in gene therapy, potentially resulting in a better safety profile.

 

   

Can be designed and optimized pharmacologically and immunologically, making it suitable for a broad range of applications.

 

   

Fast manufacturability, making it a cost-effective and flexible therapeutic to produce.

In the last decade mRNA has progressed into a promising new class of medicine, with the potential to treat a wide variety of diseases with high unmet medical needs. mRNA is a long, polymeric molecule, composed of four different building blocks called nucleotides. In mRNA, hundreds or thousands of these nucleotides are linked in a unique order to convey genetic information to cells, where it is used to express proteins with biological effects.

Considering that all mRNA is generated with four different building blocks, but with unique sequence order, all therapeutic mRNAs have highly similar compositions, while having the capacity to encode a variety of different proteins. These characteristics allow for rapid development of mRNA therapeutics that are broadly applicable for treatment of many diseases, including cancer, infectious diseases and rare diseases. Our mRNA pipeline addresses all of these therapeutic areas.

 

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A. General Principles of mRNA Pharmacology

As a drug, manufactured mRNA provides instructions to a target cell to produce a desired therapeutic protein. The mRNA drug will temporarily change the status of the target cell where these instructions are translated into proteins. Based on the information encoded by the mRNA, the proteins will be either secreted or remain intracellular. The mRNA drug will eventually be degraded and eliminated from the body.

Our mRNA drugs are synthesized from a DNA template. With the exception of the 5’ cap, the template determines all structural elements of the mRNA. The mRNA molecule comprises:

 

   

an open reading frame, or ORF, which encodes for the protein of interest;

 

   

untranslated regions, or UTRs, which flank the ORF; and

 

   

the cap and the poly(A) tail, which are the two terminal structures of the linear mRNA, and are responsible for increased stability and translational efficiency of mRNA.

The mRNA drug needs to be appropriately formulated in order to protect it from breakdown by extracellular RNAses. The formulation is selected based on the intended application and route of delivery. After uptake into the target cell, the mRNA molecules are loaded into ribosomes, where translation into protein takes place. Subsequently, the mRNA is degraded by cellular mechanisms. In case of an immunotherapy application, the protein is degraded into immunogenic epitopes. These are loaded onto specialized molecules, namely MHC I or MHC II. These molecules present the epitopes to immune cells to provoke the desired immune response. In the case of other mRNA applications, the mRNA encodes proteins that are secreted from the cells, such as antibodies, and function extracellularly.

 

 

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General principles of mRNA pharmacology. Step 1: mRNA is either delivered in a buffered solution as naked molecules or formulated as nano-particles to protect degradation by extracellular enzymes and is taken up by cells. Step 2: Subsequently, mRNA is released from endosomes into the cytoplasm. Step 3: mRNA is translated by the protein synthesis machinery of host cells. Step 4: Termination of translation

 

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by degradation of mRNA. Step 5: The translated protein product acts in the cell in which it has been generated. Step 6: Alternatively, the protein product is secreted and may act via autocrine, paracrine or systemic, body-wide mechanisms. Steps 7 and 8: For vaccine activity, mRNA encoded antigens are degraded into shorter fragments and loaded onto MHC class I and class II molecules. Step 9: Protein-derived epitopes can then be presented on the cell surface by both MHC class I and MHC class II molecules, enabling stimulation of CD8+ and CD4+ T cells.

The structural elements of the mRNA have an impact on its performance. This includes potential immunogenicity, efficacy of translation and stability of the molecule. We leverage our extensive experience to design, synthesize, manufacture and formulate our therapeutic mRNA, and adapt its composition to suit the desired application.

 

 

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Our strategy for optimizing mRNA potency. The pharmacological properties of mRNA can be improved by biochemical optimization of the molecule for either (i) increasing the half-life of the mRNA, i.e., the mRNA is translated for a longer period of time before it is degraded, which results in sustained protein production after mRNA delivery, or for (ii) increasing the mRNA translation efficiency, i.e., the peak protein production is increased. Our optimization approach relies on combining both strategies in order to maximize the mRNA therapeutic effect.

 

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B. Our mRNA Backbone Concepts and Technologies

Our mRNAs all contain basic structural elements, including the 5’ cap, the untranslated regions and the poly(A) tail, in addition to a coding sequence, that are all encoded by our DNA template.

 

 

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The cap is added to the 5’ end of the mRNA during its synthesis. Our studies have demonstrated that incorporation of a unique cap analogue into the mRNA helps to achieve superior translational performance by stabilizing the mRNA molecule and directing the immune response. This unique cap analogue is extremely useful for our immunotherapy approaches.

 

   

The composition and structure of the 5’ and 3’ untranslated regions of the mRNA molecule are important determinants of the intracellular stability of mRNA. As a result of rigorous screening of different mRNA sequences, we identified specific UTRs that promote increased protein translation for long duration.

 

   

We have performed extensive research on the structure of the poly(A) tail and the translational performance of mRNA and customized our template design accordingly.

 

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The translational performance of mRNA can be increased by removing contaminating double-stranded RNA from the mRNA. We have extensive expertise in different mRNA purification procedures. We have also invented a novel mRNA purification method that greatly impacts translatability of our mRNA. Depending on the protein characteristics needed for treatment of a disease, we optimize the DNA template through a proprietary codon optimization process, changing the nucleotide sequence of the template without altering the amino acid composition of the encoded protein. We make further adjustments during mRNA production. We believe these fine tunings of the respective molecules are essential for the purpose-adapted performance of our mRNA.

 

 

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Our mRNA formats. As shown above, we have developed four mRNA formats, each optimized for different therapeutic applications. Abbreviations: y, 1-methylpseudouridine; UTR, untranslated region.

Our mRNA formats include:

1. Optimized Uridine mRNA (uRNA)

The nucleotide sequence of mRNA determines the amino acid sequence of the protein. In addition, the nature of nucleosides used for production of mRNA drugs can also influence recognition of the molecule by the immune system. Presence of naturally occurring uridine (U) in our optimized uridine mRNA makes it immunogenic by activating immune sensors. We have further optimized our uridine mRNA for immunogenicity (augmented antigen presentation on MHC I and MHC II) and pharmacological activity (enhanced stability and translational efficiency). Immunogenicity of the mRNA is an added benefit when mRNA is used for

 

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immunotherapy applications, by acting as an immunotherapy adjuvant. This makes our therapeutics for iNeST and FixVac even more potent, and we are additionally using this mRNA format in one of our COVID-19 vaccine candidate variants.

2. Nucleoside-modified mRNA (modRNA)

Immunogenic reaction against mRNA drugs needs to be avoided in applications where therapeutic proteins are produced, such as in our RiboMab and RiboCytokine platforms. We have profound expertise in incorporating naturally-occurring modified nucleosides into our therapeutic mRNAs. We have demonstrated that the presence of a variety of modified nucleosides in the manufactured mRNA suppresses its intrinsic immune activation, while leading to superior protein production for long duration. Deimmunizing mRNA by incorporating modified nucleosides helps to avoid production of anti-drug antibodies and broaden the therapeutic application of these types of mRNA drugs. We believe this customization has resulted in therapeutic mRNA that is both potent and well tolerated. We are also testing this mRNA format in multiple COVID-19 vaccine candidate variants, including BNT162b1, the vaccine candidate variant for which we and Pfizer announced preliminary data from our Phase 1/2 clinical trials on July 1 and July 20, 2020, and BNT162b2.

3. Self-amplifying mRNA (saRNA)

Our self-amplifying mRNA, or saRNA, drugs use the concept of viral replication, while not being an infectious, disease-causing agent itself. saRNA resembles conventional mRNA encoding the protein of interest, but also encoding a polymerase, called replicase, that multiplies part of the mRNA within the target cell. During self-amplification inside the cell, a double-stranded RNA intermediate is generated, which is recognized by intracellular immune sensors. This makes saRNA a very potent activator of the immune system and therefore an excellent category of immunotherapy. As we have demonstrated, our saRNA ensures high levels of sustained antigen production with a small amount of initial mRNA input. Our scientific team has designed this mRNA technology to act as a potent tool for prophylactic vaccination, with the potential application in infectious diseases with high medical needs. Accordingly, we are testing this mRNA format in one of our COVID-19 vaccine candidate variants.

4. Trans-amplifying mRNA (taRNA)

We have also expanded on our self-amplifying mRNA capabilities, developing a novel mRNA amplification technology by separating the target mRNA to be amplified and the replicase encoding mRNA. This advancement broadens the spectrum of applications by making the development of therapeutic mRNAs even more flexible, as the replicase can amplify mRNA encoding of not only one protein, but several different ones. In the case of vaccines, this allows us to produce the replicase in advance for use with different vaccines. Our trans-amplifying mRNA is a proprietary mRNA format that is particularly well-suited for prophylactic vaccines to prevent infectious diseases.

 

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C. Our mRNA Delivery Formulation Technologies

We have deep and broad expertise in the targeted delivery of mRNA therapeutics. We are convinced that our development of suitable delivery formulations in conjunction with our own therapeutic mRNAs is a key competitive advantage.

 

 

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Our mRNA delivery formulation technologies. We utilize a range of mRNA delivery formulations for different therapeutic needs.

We employ multiple mRNA delivery formulations, each designed for different functions and optimized for therapeutic product needs:

 

   

Lipoplex: Our lipoplex formulation, or LPX, embeds the mRNA between a lipid bilayer, which is used for our FixVac and iNeST platforms. We use a proprietary size- and charge-based non-viral mRNA lipoplex that was developed to deliver mRNA to dendritic cells in lymphoid compartments such as the spleen for optimal antigen presentation and immune response activation.

 

   

LNPs: For other applications, we encapsulate our mRNA in lipid nanoparticles, or LNPs. These formulations are suitable for our RiboMab, RiboCytokine and rare disease protein replacement platforms. Our LNP formulations can be adjusted according to our needs for delivery to particular target tissues, such as the liver in the case of our rare disease protein replacement platform.

 

   

Polyplexes: Our portfolio also comprises polyplexes, which are being utilized in certain of our discovery programs, in which the mRNA is bound to a polymer and then forms nanoparticles.

 

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As shown in the graphic below, our mRNA platforms utilize our wide range of mRNA formats, mRNA delivery formulations and mRNA delivery routes to optimize and tailor treatments.

 

 

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Our therapeutic mRNA technology toolbox. Our product candidates utilize multiple mRNA formats, a broad spectrum of delivery formulations and applications using various delivery routes.

D. Our mRNA Platforms

We are developing multiple mRNA-based therapeutic platforms. These include FixVac, iNeST, mRNA-based intratumoral immunotherapy, RiboMabs and RiboCytokines in the oncology space. In addition, we have implemented mRNA platforms for the development of infectious disease vaccines and protein replacement therapies for rare diseases.

 

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Importantly, each of these platforms enables the development of multiple pharmaceutical product candidates or programs.

 

 

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Our mRNA Platforms. We have multiple mRNA-based platforms utilizing different mRNA formats and delivery formulations, directed at a range of biological targets in oncology and infectious and rare diseases.

1. Cancer Immunotherapies

Our goal is to develop safe, potent, efficacious and cost-effective cancer immunotherapies which stimulate and potently expand tumor cell specific CD4+ and CD8+ T cells in cancer patients. Our cancer immunotherapy development integrates our competencies in mRNA backbone optimization, formulation development and immunological research.

We have developed novel immunotherapy approaches to replicate the highly potent and effective natural activation of the immune system in response to a viral infection. Our first generation mRNA cancer immunotherapies were delivered as naked mRNA by ultrasound guided injection into a patient’s lymph node and induced T cell responses and antitumoral activity when targeting mutant neoantigens in advanced melanoma patients. To further improve this potency and antigen specificity we have developed a nano-particulate mRNA lipoplex immunotherapy for intravenous delivery.

RNA-LPX Technology

 

At a glance: RNA-LPX Cancer Immunotherapy Technology

 

   

Potential first-in-class clinical intravenous nano-particulate mRNA immunotherapy, allowing systemic delivery.

 

   

Strong potency by systemic targeting to dendritic cells in lymphoid tissues.

 

   

Universally applicable for all cancer antigens.

 

   

Opportunity to deliver multiple antigens in parallel, enabling the induction of poly-specific T cell responses.

 

   

Synchronized adjuvant effect mediated by toll-like receptor 7 (TLR7)-triggering and type-I interferon-driven innate and adaptive immune stimulation.

 

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Preclinical anti-tumoral activity demonstrated against multiple tumors.

 

   

Unprecedented clinical immune responses against shared TAAs.

 

   

Beneficial clinical activity demonstrated in advanced melanoma patients.

To advance from local to systemic dendritic cell, or DC, targeting, we developed an innovative liposome-based RNA-lipoplex formulation, RNA-LPX, that allows for intravenous administration of our mRNA cancer immunotherapies. We have demonstrated in the clinic that systemic DC targeting by mRNA cancer immunotherapies can result in potent activity at very low doses. Consequently, less material is required for treating high patient numbers, making manufacturing more cost-effective.

 

 

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Our RNA-LPX technology. Our proprietary RNA-LPX formulation is designed to deliver vaccine mRNA precisely into DCs and macrophages in the spleen and other lymphoid compartments. The RNA-LPX has an inherent adjuvant function stimulating the release of cytokines such as IFN-a thereby promoting the activation of DCs and the induction of strong T cell responses. Abbreviations: BM, bone marrow; LN, lymph node; DC, dendritic cell; pDC, plasmacytoid dendritic cell; Mø, macrophage; IFN-a, interferon alpha.

 

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RNA-LPX protects mRNA from degradation outside of the cell and mediates its efficient uptake and expression of encoded antigens in various dendritic cell populations. Our RNA-LPX technology is designed to target a wide variety of antigens and address cancer patients with all possible HLA haplotypes. Utilizing RNA-LPX, we can target fixed groups of known shared antigens with our FixVac platform and a whole new class of patient-specific neoantigen targets with our iNeST platform.

 

 

LOGO

 

  a)

FixVac

 

At a glance: Our FixVac Platform

 

   

Concept: Cancer immunotherapies targeting shared antigens that we have identified to be frequently expressed across patients with a specific cancer type.

 

   

mRNA Format: Optimized uridine mRNA providing superior immunogenicity.

 

   

mRNA Delivery Formulation: Proprietary size- and charge-based RNA-LPX targeting DCs.

 

   

Development Approach: Worldwide rights; wholly owned.

 

   

Lead Candidate: BNT111 for metastatic melanoma.

 

   

Data Highlights: Three partial responses, one complete response and seven stable diseases in 25 patients with metastatic lesions at enrollment, following BNT111 monotherapy.

 

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Our FixVac approach involves off-the-shelf mRNA immunotherapies targeting cancer cell-specific shared tumor associated antigens for selected patient populations. Our FixVac product candidates target TAAs which are commonly expressed by a significant portion of patients in a given cancer type. We have developed a sophisticated target selection process which enables us to produce poly-specific FixVac immunotherapies that cover up to 95% of patients with a given cancer type. The use of off-the-shelf FixVac immunotherapies allows for large-batch manufacturing and prompt supply to patients with ready-to-use medication, ensuring a straight-forward cost- and time-efficient manufacturing process with favorable logistics.

Besides targeting commonly expressed TAAs, our target selection strategy facilitates the identification of suitable viral oncoproteins for the treatment of virus-induced cancers like HPV+ head and neck cancer. Patient stratification, if needed, can easily be performed at the clinical site or a central lab using standard biotechnological methods, thereby reducing treatment costs. As the viral genome is comparatively small, encoding only for a few proteins, we believe our FixVac approach is ideally suited for the treatment of virus-induced cancers.

Our FixVac Development Plan

We currently have six FixVac programs in development, with five in human trials, including our ongoing Phase 1 trial in advanced melanoma, a Phase 1 trial in HPV+ head and neck cancer and a Phase 1 trial in triple negative breast cancer. We expect to progress our advanced melanoma program into Phase 2 clinical trials with registrational potential in the second half of 2020. We enrolled the first patient in a Phase 1/2 trial in prostate cancer and the first patient was dosed in a Phase 1 ovarian cancer trial in the second half of 2019. In addition, we are planning to initiate a Phase 2 study with registrational potential for FixVac in HPV+ cancers by the end of 2020.

 

Candidate

  

Antigens

  

Development Phase

  

Next Potential Milestone

BNT111    Melanoma-specific antigens: NY-ESO-1, tyrosinase, MAGE-A3 and TPTE    Phase 1: Advanced melanoma    Report Phase 1 data: publication upcoming; initiate Phase 2 trial with registrational potential in 2H 2020
BNT112    Five prostate cancer-specific antigens, including PAP and three internally identified antigens    Phase 1/2: Prostate cancer    —  
BNT113    HPV E6 and E7 oncoproteins    Phase 1: HPV+ head and neck cancer (IST)    Initiate Phase 2 trial with registrational potential by end of 2020
BNT114    Selected breast cancer-specific antigens    Phase 1: TNBC    Report data update in 2H 2020
BNT115    Selected ovarian cancer-specific antigens    Phase 1    —  
BNT116    Non-small cell lung cancer    Preclinical    —  

 

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b)     Individualized Neoantigen Specific Immunotherapy (iNeST)

 

At a glance: Our iNeST Platform

 

   

Concept: Individualized cancer immunotherapy targeting neoantigens identified on a patient by patient basis and selected for immunogenicity.

 

   

mRNA Format: Optimized uridine mRNA providing superior immunogenicity.

 

   

mRNA Delivery Formulation: Proprietary size- and charge-based RNA-LPX targeting DCs.

 

   

Development Approach: 50:50 cost share with Genentech.

 

   

Lead Indication: RO7198457 (BNT122) as a first-line melanoma therapy in combination with pembrolizumab.

 

   

Data Highlights: In a previous Phase 1 trial of BNT121, we observed first-in-human data in 13 patients with metastatic melanoma demonstrating stable progression-free survival in nine patients for up to 60 months, and additional objective responses in three of five patients with metastatic disease at time of treatment with iNeST, including one patient receiving combination therapy. We also observed a significant decrease in the cumulative recurrence rate post-treatment as compared to pre-treatment. In June 2020, we reported data from a monotherapy dose-finding cohort of our RO7198457 (BNT122) Phase 1 trial in multiple solid tumors, which showed that ex vivo T cell responses were detected in approximately 86% of patients treated with RO7198457 (BNT122) as a monotherapy and later in June 2020 we provided a data update for an additional cohort in combination with atezolizumab.

We are a pioneer and global leader in developing fully individualized cancer immunotherapies. We have developed a first of its kind, on-demand manufacturing process to treat each individual patient based on the mutation profile of the patient’s tumor. We are investigating this treatment approach in the clinic in collaboration with Genentech.

 

 

LOGO

Our iNeST process. The figure above depicts our iNeST process for the on-demand production of individualized mRNA cancer immunotherapies.

Our iNeST process is summarized below:

 

   

A blood sample and tumor biopsy is taken from the patient to obtain healthy cells and tumor tissue. We extract healthy cells from the patient’s blood sample and tumor cells from the tumor sample. We use NGS to analyze genetic material (DNA and RNA) of these cells to identify which mutations are present in the cancer cells compared to healthy cells.

 

   

We apply proprietary bioinformatic algorithms to identify tumor-specific mutations. The mutations within a cancer cell differ widely from patient to patient and form a unique signature for each tumor. This genomic information can be further utilized to analyze tumor heterogeneity and microenvironment as well as individual aspects of the immune system like the HLA type.

 

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Based on these bioinformatic algorithms, we then select mutations that are the most promising therapeutic targets. The specific traits of the patient’s immune system, including HLA type, are key to the selection of the most appropriate targets. Picking multiple mutations increases the chance to induce potent T cell responses and reduces the risk that the tumor evades T cell attack over time. We account for heterogeneity of each tumor by preferentially selecting mutations that are expressed on all tumor cells. Importantly, the selected mutations are intended to ensure both CD4+ and CD8+ T cell induction.

 

   

Following mutation selection, we design the structure for the iNeST product. The chosen mutations have to be arranged in a certain order and the DNA sequence of the mutations has to be optimized. This is important to ensure a robust production of the starting material, or DNA matrix, for the GMP manufacturing of the iNeST product.

 

   

Next we produce the patient-specific iNeST product under GMP conditions and the iNeST product undergoes numerous different quality control tests.

 

   

The iNeST product is transferred to the hospital and injected into the same patient by the physician.

 

   

This process has been designed for the on-demand delivery of our iNeST products, and currently takes approximately six weeks.

Our iNeST Development Plan

We are currently developing iNeST therapeutics for the treatment of metastatic melanoma and multiple solid tumors. We are conducting two clinical trials of iNeST in collaboration with Genentech, including one randomized Phase 2 trial in first-line melanoma in combination with pembrolizumab and a Phase 1a/1b trial in patients with locally advanced or metastatic tumors (including in melanoma, non-small cell lung cancer, bladder cancer and other solid tumors) as a monotherapy and in combination with atezolizumab. In June 2020, we presented data from a monotherapy dose-finding cohort of our RO7198457 (BNT122) Phase 1a/1b trial in multiple solid tumors, and later in June 2020 we provided a data update for an additional cohort in combination with atezolizumab. Further, we expect to provide an enrollment update from the first-line melanoma trial in the second half of 2020, and provide an interim data update in the second half of 2021. We and Genentech plan to initiate two additional clinical trials for RO7198457 (BNT122) in 2020 in NSCLC and colorectal cancer in the adjuvant setting.

 

Candidate

  

Antigens

  

Development Phase

  

Next Potential Milestone

RO7198457 (BNT122)    Up to 20 neoantigens selected on a patient by patient basis    Phase 2: first-line melanoma in combination with pembrolizumab    Enrollment update in 2H 2020;1 Interim data update in 2H 2021
      Phase 1a/1b: multiple solid tumors    Phase 2 trials planned in NSCLC and colorectal cancer in the adjuvant setting in 2H 2020

 

1

We expect this enrollment update to include an update on the ongoing study, including patient enrollment numbers, with full efficacy and safety data for an interim update expected in the second half of 2021.

c)     Intratumoral mRNA Immunotherapy

 

At a glance: Our Intratumoral mRNA Platform

 

   

Concept: Immunomodulator-encoding mRNA injected directly into the tumor in order to avoid off-target toxicities.

 

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mRNA Format: Nucleoside-modified mRNA engineered for minimal immunogenicity in order to avoid immune detection and allow translation of the encoded cytokines to occur within the cells.

 

   

mRNA Delivery Formulation: Various formulations, delivered by intratumoral injection.

 

   

Development Approach: Co-development and co-commercialization, at our option, in collaboration with Sanofi.

 

   

Lead Candidate: SAR441000 (BNT131) for advanced solid tumors as a monotherapy and in combination with cemiplimab.

In collaboration with Sanofi, we are leveraging our mRNA technology to develop intratumoral immunotherapies for the treatment of solid tumors. Intratumoral immunotherapy is designed to promote innate and adaptive immune responses against tumors, without toxicities related to systemic administration. Our intratumoral immunotherapy involves injection of cytokine-encoding mRNA directly into a tumor in order to alter the tumor microenvironment and promote greater T cell activity. This approach has been found in preclinical studies to boost cancer-specific immune responses locally, while also producing tumor responses in remote parts of the body due to the circulation of properly activated anti-tumor immune cells, known as an abscopal effect.

The first intratumoral immunotherapy product candidate arising from our collaboration, SAR441000 (BNT131), includes modified mRNA that encodes for the IL-15sushi, IL-12sc, GM-CSF and IFN-α cytokines. In preclinical studies, SAR441000 (BNT131) promoted increased levels of local cytokine expression within the tumor microenvironment and activated innate and adaptive immune responses against tumors.

 

 

LOGO

Therapeutic mode of action of intratumoral mRNA immunotherapy. The figure above demonstrates how SAR441000 (BNT131) promotes cytokine expression within the tumor itself.

 

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Our Intratumoral Development Plan

The lead intratumoral mRNA collaboration product candidate from our collaboration is being investigated in a Phase 1 clinical trial sponsored by Sanofi. This trial is expected to enroll approximately 264 patients with certain advanced solid tumors, as a monotherapy and in combination with cemiplimab. This trial is currently being run at four sites in Europe. A data update from this trial may be reported in the second half of 2020. As the trial is sponsored and conducted by Sanofi, the timing of data updates is not under our control, and is subject to change by Sanofi.

 

Candidate

  

Encoded Cytokines

  

Development Phase

  

Next Steps

SAR441000 (BNT131)    IL-15sushi, IL-12sc, GM-CSF and IFN-α    Phase 1: Advanced solid tumors as a monotherapy and in combination with cemiplimab    Data update in 2H 2020*

 

*

As the trial is sponsored and conducted by Sanofi, the timing of data updates is not under our control, and is subject to change by Sanofi.

2.     Infectious Disease Vaccines

 

At a glance: Our Infectious Disease Vaccine Platform

 

   

Concept: mRNA-based vaccines targeting infectious disease pathogens.

 

   

mRNA Format: Multiple.

 

   

mRNA Delivery Formulation: LNPs.

 

   

Development Approach: Collaborations with Pfizer and Fosun Pharma and exclusive option arrangement with Penn.

 

   

Lead Candidates: COVID-19 vaccine candidate BNT162; Influenza vaccine candidate BNT161.

Expanding beyond our research in oncology, we are leveraging our mRNA technologies to direct the immune system more effectively against infectious diseases. Our infectious disease vaccine candidates contain self-replicating or trans-replicating, modified mRNA-encoding antigens specific to a target pathogen, delivered in various LNP formulations in order to activate and direct T cells and B cells to fight the pathogen.

COVID-19 Vaccine

In March 2020, we entered a strategic alliance with Fosun Pharma to advance a COVID-19 vaccine in China. In July 2020, we received notice of acceptance to begin our clinical trial for BNT162b1 in China. Upon regulatory approval, Fosun Pharma will commercialize the vaccine in China, while we retained the full rights to develop and commercialize the vaccine in the rest of the world. Also in March 2020, we and Pfizer began collaborating to co-develop our potential first-in-class COVID-19 mRNA vaccine program, BNT162 aimed at preventing COVID-19. We and Pfizer are jointly conducting clinical trials for the COVID-19 vaccine candidates initially in the United States and Europe across multiple sites. We are currently developing four potential candidates utilizing multiple different mRNA formats as part of this program. In late April 2020, we and Pfizer announced that the German regulatory authority, the Paul-Ehrlich-Institut, approved the Phase 1/2 clinical trial and the first cohort of our Phase 1/2 clinical trial were dosed shortly thereafter. In early May 2020, Pfizer and we initiated a clinical trial for BNT162 in the United States and the first participants were dosed shortly thereafter. We initiated the BNT162 program in late January 2020 in response to the global COVID-19 pandemic, and initiated human testing following preclinical studies and within approximately three months of initiating the research program.

 

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During the clinical development stage, we and our partners will provide clinical supply of the vaccine from our GMP-certified mRNA manufacturing facilities in Europe. We and Pfizer are working together to scale-up manufacturing capacity at risk to provide worldwide supply in response to the pandemic. If the vaccine candidate is approved, we and Pfizer will also work jointly to commercialize the vaccine worldwide (excluding China which is covered by a collaboration with Fosun Pharma). If the vaccine candidate is approved, we and Pfizer expect to manufacture up to 100 million doses by the end of 2020 and potentially more than 1.3 billion doses by the end of 2021.

July 2020 Data Announcements

On July 1, 2020, we and Pfizer announced preliminary data from our ongoing U.S. Phase 1/2 trial of BNT162b1. The initial part of this randomized, placebo-controlled, observer-blinded study is evaluating the safety, tolerability and immunogenicity of escalating dose levels of BNT162b1, one of four vaccine candidate variants in development as part of our BNT162 program, in 45 healthy adults between 18 and 55 years of age.

The participants received two doses, 21 days apart, of placebo, 10µg or 30µg of BNT162b1, or received a single dose of 100µg of the vaccine candidate. Because of a strong vaccine booster effect, the highest neutralizing titers were observed seven days after the second dose of 10µg or 30µg on day 28 after vaccination. The neutralizing GMTs were 168 and 267 for the 10µg and 30µg dose levels, respectively, corresponding to 1.8- and 2.8-times the neutralizing GMT of 94 observed in a panel of 38 sera from subjects who had contracted SARS-CoV-2.

In all 24 subjects who received 2 vaccinations at 10µg and 30µg dose levels of BNT162b1, elevation of RBD-binding IgG concentrations was observed after the second injection with respective GMCs of 4,813 and 27,872 units/ml at day 28, seven days after immunization. These concentrations are 8- and 46.3-times the GMC of 602 units/ml in a panel of 38 sera from subjects who had contracted SARS-CoV-2.

At day 21 after a single injection, the 12 subjects who received 100µg of BNT162b1 had an RBD-binding IgG GMC of 1,778 units/ml and a SARS-CoV neutralizing GMT of 33, which are 3-times and 0.35-times, respectively, the GMC and GMT of the convalescent serum panel.

At the 10µg or 30µg dose levels, adverse reactions, including low grade fever, were more common after the second dose than the first dose. Following dose 2, 8.3% of participants who received 10µg and 75.0% of participants who received 30µg BNT162b1 reported fever ³ 38.0 °C. Local reactions and systemic events after injection with 10µg and 30µg of BNT162b1 were dose-dependent, generally mild to moderate, and transient. The most commonly reported local reaction was injection site pain, which was mild to moderate, except in one of 12 subjects who received a 100µg dose, which was severe. No serious adverse events were reported. Given higher numbers of subjects experiencing local reactions and systemic events after a single 100µg dose with no significant increases in immunogenicity compared to the 30µg dose level, the 12 participants in the 100µg group were not administered a second dose.

On July 20, 2020, we and Pfizer announced preliminary data from our ongoing German Phase 1/2 trial of BNT162b1. The initial part of this open-label, non-randomized, non-placebo-controlled study is evaluating the safety, tolerability and immunogenicity of escalating dose levels of BNT162b1, one of four vaccine candidate variants in development as part of our BNT162 program, in 60 healthy adults, between 18 and 55 years of age. The preliminary data we reported was from 12 subjects each who received two doses of 1µg, 10µg, 30µg and 50µg (except for one individual each in the 10µg and 50µg who discontinued due to non-study drug related reasons) and 12 subjects who received a single dose of 60µg. The two doses received by the participants were given 21 days apart.

In 34 of the 36 subjects who received two vaccinations at 10µg, 30µg, or 50µg dose levels of BNT162b1, RBD-specific CD4+ T cell responses were observed. All subjects but the two exceptions at the lowest dose level

 

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had cytokine profiling of the RBD-specific CD4+ T cells that demonstrated a TH1-dominant profile for these cells. While the magnitude varied between individuals, participants with the strongest CD4+ T cell responses to RBD had more than 10-fold of the memory responses observed in the same participants when stimulated with cytomegalovirus (CMV), Epstein Barr virus (EBV), influenza virus and tetanus toxoid-derived immuno- dominant peptide panels. The strength of RBD-specific CD4+ T cell responses correlated positively with both RBD-binding IgG and with SARS-CoV-2 neutralizing antibody titers. Among vaccine-induced CD8+ T cell responses, which were observed in 29 of 36 participants, strong responses were mounted by the majority of participants and were comparable with memory responses against CMV, EBV, influenza virus and tetanus toxoid in the same participants. The strength of RBD-specific CD8+ T cell responses correlated positively with vaccine- induced CD4+ T cell responses, but did not significantly correlate with SARS-CoV-2 neutralizing antibody titers. Additionally, although at 1µg the immunogenicity rate was lower (6 of 8 responding participants), the magnitude of vaccine-induced CD4+ and CD8+ T cells in some participants was almost as high as with 50µg BNT162b1.

Elevation of SARS-CoV-2 RBD-binding IgG concentrations was observed, with respective GMCs ranging from 265 units/ml to 1,672 units/ml at day 21. At day 29, seven days after the second dose, RBD-binding IgG GMCs ranged from 2,015 units/ml to 25,006 units/ml. At day 43, RBD-binding IgG GMCs ranged from 3,920 units/ml to 18,289 units/ml. These concentrations are 6.5- to 30.4-times the GMC of 602 units/ml in a panel of sera from 38 subjects who had contracted SARS-CoV-2. At day 29, the SARS-CoV-2 neutralizing GMTs reached 36 (1µg dose), 158 (10µg dose), 308 (30µg dose) and 578 (50µg dose) compared to neutralizing GMT of 94 observed in the convalescent serum panel. At day 43, SARS-CoV-2 neutralizing GMTs reached .7-fold (1µg dose) to 3.2-fold (50µg dose) compared to those of a panel of SARS-CoV-2 infection convalescent human sera. Furthermore, sera of vaccinated subjects displayed broadly neutralizing activity in pseudovirus neutralization assays across a panel of sixteen SARS-CoV-2 RBD variants represented in publicly available SARS-CoV-2 sequences and against the newly dominant D614G strain. In summary, antibody responses elicited by BNT162b1 in our German clinical trial largely mirrored those observed in our U.S. clinical trial.

At the 10µg, 30µg and 50µg dose levels, certain adverse reactions, including low grade fever, were more common after the second dose than the first dose. Following the second dose, 25.0%, 25.0% and 33.3% of participants who received the 10µg, 30µg and 50µg doses, respectively reported fever of at least 38.0 degrees Celsius. Local reactions and systemic events after injection with 10µg, 30µg and 50µg of BNT162b1 were dose- dependent, generally mild to moderate and transient, with occasional severe events (grade 3) of flu-like symptoms and injection site reactions. The most commonly reported local reaction was injection site pain, which was mild to moderate, except in one of 12 subjects who received a 60µg dose, which was severe. No serious adverse events were reported, and there were no withdrawals due to adverse events related to the vaccine. Based on the adverse reactions reported after the 50µg boost dose, a second 60µg dose was not administered to participants who had received an initial 60µg dose.

For additional information on these preliminary results, please review our reports on Form 6-K filed with the SEC on July 1, 2020 and July 20, 2020 and incorporated by reference herein.

Based on preclinical and clinical data observed to-date, we and Pfizer have decided to progress our BNT162 development program into a Phase 2b/3 trial, which is anticipated to commence in late July 2020, subject to input and approval from the appropriate regulatory bodies. For the initial Phase 2b/3 trial, we intend to select either BNT162b1 or BNT162b2. Both the BNT162b1 and the BNT162b2 vaccine candidates have received Fast Track status from the FDA. Since clinical evaluation of the BNT162b2 candidate started several weeks later than BNT162b1, only preliminary clinical data are currently available for the BNT162b2 candidate. A set of data obtained for a cohort of subjects 18-55 years of age immunized with 10µg of BNT162b2 indicates that BNT162b2 induces similar virus neutralizing antibody responses as observed for BNT162b1. The preliminary observations are subject to further data collection and analysis. Assessment of dose dependent immune response and safety profile as well as analysis of T cell responses is currently pending. On the basis of additional data expected to be collected and analyzed for BNT162b1 and BNT162b2 in the coming days, along with input from the FDA, we intend to select a lead candidate to take into a Phase 2b/3 trial. We and Pfizer currently expect to

 

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inform the FDA of our selection of the BNT162 candidate variant before the closing of this offering. Based on clinical data from our ongoing Phase 1/2 trials of BNT162b1 in the United States and Germany, BNT162b1 appears to be a viable variant to advance into a Phase 2b/3 trial. However, given that additional information relating to BNT162b2 is becoming available over the next few days, we and Pfizer plan to make the ultimate decision on the final candidate based on multiple factors, including the overall observed safety, tolerability and immunogenicity profiles for each vaccine candidate at different dose levels, a full immunogenicity data set and feedback from the FDA on the data collected for each candidate. If we ultimately move forward with the BNT162b2 variant, it will be due to the fact that based on our scientific judgment in light of the totality of preclinical data and clinical data available to us at the time of selection and the other factors described above, the BNT162b2 variant has better potential for clinical and commercial success. We do not plan to disclose which BNT162 variant has been selected until we receive FDA approval to commence the Phase 2b/3 clinical trial, and we likely will not publish any data with respect to the BNT162b2 variant before we make our selection.

Influenza Vaccine

We are collaborating with Pfizer to develop an influenza vaccine using our mRNA-based immunotherapy technology. Current influenza vaccines consist of antigens from inactivated influenza viruses, recombinant influenza haemagglutinin, or HA, proteins or live attenuated influenza viruses and are available as trivalent (containing two influenza A strains and one influenza B strain) or quadrivalent (containing two influenza A strains and two influenza B strains) vaccines. Currently available influenza vaccines are produced in chicken eggs or cell culture and take about five to six months to produce. This requires the composition of the coming

season’s vaccine to be selected by the World Health Organization, or WHO, far in advance for the vaccine to be available on time, which reduces the reliability of that prediction.

We anticipate that our mRNA-based vaccines can be manufactured within three months from the time the recommendation is published, including cloning and production and therefore the WHO’s review of the vaccine components can occur closer to the influenza season to obtain a more reliable prediction. In addition, the mRNA manufacturing process is designed to produce an HA vaccine antigen that matches the HA of circulating influenza strains, in contrast to egg- or cell-based processes which can introduce mutations in the HA amino acid sequence. The flexibility of the mRNA vaccine platform could allow for generation of vaccines against genetically drifted seasonal viruses or pandemic strains. We and Pfizer have moved the anticipated Phase 1 start for our mRNA flu vaccine program to 2021 due to the prioritization of our COVID-19 vaccine development efforts.

Other Infectious Diseases

In October 2018, we entered into a research collaboration with Penn, under which we have the exclusive option to develop and commercialize prophylactic mRNA immunotherapies for the treatment of up to 10 infectious disease indications. We expect to report our first product candidates under this collaboration, and advance our first product candidate into the clinic, in the first half of 2021.

In August 2019, we entered into a letter agreement and investment agreement with the Bill & Melinda Gates Foundation to advance the development of immunotherapies for the prevention and/or treatment of HIV and tuberculosis and up to three additional infectious diseases.

 

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3.     mRNA-based Protein Replacement Platform for Rare Diseases

 

At a glance: Our Protein Replacement Platform for Rare Diseases

 

   

Concept: Therapeutic proteins encoded by mRNA and produced in the patient as an alternative to recombinant protein replacement.

 

   

mRNA Format: Nucleoside-modified mRNA, deimmunized to avoid immune activation in order to allow for translation of the therapeutic protein in the cells.

 

   

mRNA Delivery Formulation: Liver-targeting LNPs.

 

   

Development Approach: 50:50 cost and profit share with Genevant.

By incorporating modified nucleosides into our mRNA, we are able to reduce the immunogenicity of our product candidates, thereby allowing their use for therapeutic protein production. In addition, we utilize advanced mRNA delivery methods to protect the mRNA cargo en route to its target and promote its uptake into liver cells. Current protein-based replacement therapies were developed to treat rare diseases by administering recombinant proteins. Such therapies are limited to diseases where the missing protein function is extracellular. However, mRNA-based protein replacement therapy also has the potential to treat illnesses with intracellular protein defects, as long as the mRNA can be delivered into the affected cells.

Our mRNA-based protein replacement therapy features:

 

   

Nucleoside-modified mRNA. Replacing uridines in mRNA with modified analogues is important to avoid immune activation that can provoke anti-drug antibody production and would limit efficacy of the treatment.

 

   

Liver targeted expression. mRNA encoding therapeutic proteins are formulated into LNPs using in-licensed clinically-validated LNP delivery technology owned by Genevant. The mRNA-loaded LNPs are less than 100nm in size. When injected intravenously, these particles are selectively taken up by hepatocytes, the major cell component of the liver.

 

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LOGO

Our mRNA-based protein replacement technology. The illustration above depicts our mRNA-based protein replacement process for the treatment of rare diseases.

Our protein replacement technology is designed for the treatment of:

 

   

Genetic disorders that manifest due to a missing or defective protein, where mRNA would need to be administered regularly for a lifetime.

 

   

Acute diseases caused by transient depletion of a protein, such as a hormone, where treatment of such diseases with a single or a few doses of the encoding mRNA could be curative.

Therapeutic proteins encoded by the mRNA can either act intracellularly or be secreted and act extracellularly, in order to produce the desired therapeutic effect.

mRNA-based protein replacement technology has several advantages over recombinant proteins:

 

   

No need to develop a procedure for protein purification. The development of recombinant proteins is a laborious and expensive procedure due to the requirement for a unique purification protocol for each protein. During mRNA-based protein replacement the protein is produced by the patient, which we believe avoids the need for purification and also accelerates drug development.

 

   

The protein has proper post-translational modification. To function properly, most recombinant proteins need to be modified after synthesis. Proteins produced in patients from mRNA are more likely to obtain the correct modifications than recombinant proteins produced in cultured bacterial or mammalian cells.

 

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Continuous in vivo supply of encoded protein. Recombinant proteins, especially those with short half-lives, can be cleared from the body very quickly, thereby limiting therapeutic effect. During mRNA-based therapy, the encoded therapeutic protein is produced for a longer duration (e.g., 10-14 days).

 

   

Production of intracellular proteins. Recombinant proteins have limited intracellular therapeutic effects. In contrast, proteins encoded by mRNA can reach any cellular compartment and potentially help to cure diseases where the therapeutic protein needs to function in different subcellular locations, including the mitochondria, nucleus or cell membrane.

Our Protein Replacement Development Plan in Rare Diseases

We expect to initiate our first rare disease clinical trial in the second half of 2021.

4.     RiboMabs

 

At a glance: Our RiboMab Platform

 

   

Concept: Antibodies encoded by mRNA and produced in the patient as an alternative to recombinant antibodies.

 

   

mRNA Format: Nucleoside-modified mRNA engineered for minimal immunogenicity in order to avoid immune detection and allow translation of the encoded antibodies to occur within the cells.

 

   

mRNA Delivery Formulation: Various liver-targeting LNP formulations, delivered intravenously, to ensure systemic availability and prolonged production of the antibody in vivo.

 

   

Development Approach: Worldwide rights; wholly owned.

 

   

Lead Candidate: BNT141 in multiple solid tumors.

Our RiboMab product candidates are designed to encode secreted antibodies for expression in vivo by the patient’s cells. We believe our RiboMab technology represents the next generation of antibody-based drugs. Antibody drugs are a leading class of biologics for the treatment of various diseases, but have a number of limitations. The development of antibodies is currently challenged by demanding and costly procedures of production, purification and formulation of a recombinant protein, which we believe hampers the rapid development and clinical testing of new drugs in this class. Recombinant protein antibodies require development of a cell line, establishment and adaptation of processes for production, purification and analytical testing. The whole process typically takes 18 to 30 months to optimize, scale-up and produce first clinical batches. Some of these antibodies are produced in low yields making them unsuitable for therapeutic application.

By contrast, mRNA not only involves a simpler and less expensive manufacturing process, but also is effective in much lower volumes than are required to produce similar effects using recombinant proteins. RiboMabs provide an antibody’s mRNA sequence, and the body does the production work itself. This simplicity is designed to allow for both shorter development times and a greater diversity of druggable targets. For efficient RiboMab production, the encoding mRNA is encapsulated in LNPs that deliver the mRNA to the liver cells. For cancer treatment, we focus on tumor-associated antigens to keep adverse effects for the patients as low as possible. We believe we can integrate any antibody sequence in our RiboMab-encoding mRNA.

 

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We have demonstrated the feasibility of our RiboMab technology for a variety of antibody formats, such as full immunoglobulins (Ig), primarily IgG, or different bispecific antibody variants, all of which engage the patient’s own immune cells to eradicate antigen-positive tumor cells.

 

 

LOGO

Our RiboMab technology. The figure above depicts the structure of in vitro transcribed (IVT) IgG and bi-(scFv)2 RiboMabs. IVT-mRNA encoding the therapeutic antibody is encapsulated in LNPs and injected intravenously into patients. The mRNA is delivered to the liver where it is translated into antibodies and secreted into the blood stream. Abbreviations: A100, poly adenosine tail; bi-(scFv)2, bispecific single chain variable fragment; C, C-terminus; CH, constant heavy domain; CL, constant light domain; IgG, immunoglobulin G; IVT, in vitro transcribed; L, linker; LNP, lipid nanoparticles; m1y, 1-methylpseudouridine; N, N-terminus; TAA, tumor-associated antigen; VH, variable heavy domain; VL, variable light domain; UTR, untranslated region.

We believe our broad portfolio of antibody formats will enable us to produce mRNAs encoding the appropriate antibody format for the individual patient’s medical need and the desired treatment regimen (e.g., monotherapy or combination therapy).

 

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Our RiboMab Development Plan

Our first development candidate, BNT141, is an IgG antibody, which we expect to enter the clinic in the first half of 2021 in a basket trial targeting multiple solid tumor types. We are also currently evaluating multiple additional RiboMab development candidates in the preclinical setting, including RiboMabs encoding bispecific antibodies, one of which, BNT142, we expect to enter the clinic in the first half of 2021.

 

Candidate

  

Target

  

Development Phase

  

Next Potential Milestone

BNT141 (monospecific)    Undisclosed    Preclinical    Initiate Phase 1 trial in 1H 2021
BNT142 (bispecific)    CD3xCLDN6    Preclinical    Initiate Phase 1 trial in 1H 2021

5.     RiboCytokines

 

At a glance: Our RiboCytokine Platform

 

   

Concept: Cytokines encoded by mRNA and produced in the patient as an alternative to recombinant cytokines.

 

   

mRNA Format: Nucleoside-modified mRNA engineered for minimal immunogenicity in order to avoid immune detection and allow translation of the encoded cytokines to occur within the cells.

 

   

mRNA Delivery Formulation: Various liver-targeting LNP formulations, delivered intravenously, to ensure systemic availability and prolonged production of the cytokine in vivo.

 

   

Development Approach: Worldwide rights; wholly owned.

 

   

Lead Candidate: BNT151 in multiple advanced malignancies.

Our RiboCytokine product candidates utilize mRNA that encodes the desired cytokines for expression in vivo by the patient’s cells. Cytokines represent a large group of relatively small proteins (<30 kDa) that regulate a variety of biological functions as they elicit signaling for immune and non-immune cells. In particular, cytokines play a pivotal role in orchestrating the initiation, execution and extinction of innate and adaptive immunity against pathogens as well as malignant cells. Due to their natural role as immunomodulators, recombinant cytokines are currently used for the treatment of a number of infectious, inflammatory, autoimmune and malignant diseases. One of the major challenges associated with the therapeutic use of cytokines relates to their short serum half-life and low bioavailability. This impedes therapeutic efficacy as it necessitates high and frequent dosing, which often results in dose-limiting toxicities.

 

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We have developed a wholly owned, novel mRNA-based platform technology called RiboCytokines, designed to address the limitations of recombinantly expressed cytokines.

 

 

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Concept of our RiboCytokine technology. The graphic above depicts our RiboCytokine technology, including mRNA formulated in LNPs and administered by injection, having a beneficial pharmacokinetic profile.

Our RiboCytokine platform allows for sustained delivery of the encoded cytokines with prolonged half-life, including through:

 

   

Usage of N1-methylpseudouridine modified mRNA. N1-methylpseudouridine as a nucleoside analogue prevents the recognition of mRNA by TLRs, avoiding immune attack against the RiboCytokines.

 

   

Liver targeted expression. RiboCytokines are formulated using clinically validated LNP delivery technology owned by Genevant. LNPs selectively target the liver resulting in high-level expression.

We believe that apart from a beneficial pharmacokinetic profile, our mRNA-based RiboCytokine technology has a number of additional advantages over other types of cytokine therapies:

 

   

Less immunogenic than recombinant cytokines. Expression of self and foreign antigens in the liver is associated with immune tolerance due to a unique anti-inflammatory microenvironment. We expect RiboCytokines to be less likely to trigger an immune response when compared to their recombinant counterparts.

 

   

Shorter development times and greater diversity. The development of recombinant cytokines is a challenge due to demanding and costly CMC procedures of production, purification and formulation. The simplicity of our mRNA manufacturing allows for both shorter development times and a greater diversity of druggable targets.

 

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We believe that our RiboCytokine technology is particularly well-suited to identify candidates for combination treatment with our proprietary CAR-T cell and cancer immunotherapies platforms.

Our RiboCytokine Development Plan

We expect our first two RiboCytokine product candidates, BNT151 and BNT152/BNT153 (combination), to enter the clinic in the first half of 2021 in basket trials targeting multiple advanced malignancies.

 

Candidate

  

Cytokines

  

Development Phase

  

Next Potential Milestone

BNT151    Optimized IL-2    Preclinical    Initiate Phase 1 trial in 1H 2021
BNT152/BNT153    IL-7/IL-2    Preclinical    Initiate Phase 1/2 trial in 1H 2021

IX. Our Cell Therapies Drug Class

The tailored reprogramming of autologous T cells from cancer patients to recognize and attack their tumors has become a disruptive medical innovation. Retargeting of T cells can be achieved via introduction of tumor-specific receptors into patient-derived T cells. For that purpose, T cells are mostly engineered by retroviral gene transfer to express either T cell receptors, or TCRs, or chimeric antigen receptors, or CARs. Recently, CAR expressing T cells, or CAR-T cells, became the first engineered T cell therapy to obtain FDA approval for some B cell derived hematological malignancies. Additionally, with our Neon acquisition we recently acquired an adoptive T cell platform targeting patient-specific and shared neoantigens. This platform utilizes a proprietary ex vivo co-culture process, NEO-STIM, to prime, activate and expand autologous neoantigen-specific T cells specific either for a personal set of neoantigens for each patient or for a set of selected shared neoantigens.

A. CAR-T Cells

 

At a glance: Our CAR-T Platform

 

   

Concept: Second-generation CAR-T therapy designed to overcome the shortcomings of CAR-T therapy in solid tumors.

 

   

Mechanism: T cells with CARs engineered to target cancer-specific antigens, including novel antigens selected from our proprietary antigen library and administered with an mRNA-based immune booster, which we refer to as CARVac, to enhance CAR-T cell expansion and persistence.

 

   

Development Approach: Worldwide rights; wholly owned.

 

   

Lead Candidate: BNT211 for multiple solid tumors.

 

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CARs are artificial receptors that consist of an antigen recognition domain derived from a tumor-specific antibody linked to intracellular T cell signaling domains. CARs redirect T cells to eradicate tumors through specific recognition of native surface proteins expressed on tumor cells in a non-MHC-restricted manner. Therefore, CAR-T cells can be used for the treatment of all individuals whose tumor expresses the respective target, independent of the individual’s HLA genotype. CARs can be used for redirection of both CD4+ and CD8+ T cells.

 

 

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Second-generation CAR. The figure above illustrates the basic structure of a second-generation CAR, such as those included in our BNT211 and BNT212 product candidates.

While CAR-T therapy has shown potent anti-tumor responses in patients with B cell malignancies, clinical efficacy in solid tumors so far is limited. The main hurdles for application of CAR-T therapies in solid tumors are:

 

   

Lack of highly tumor-selective targets, which are needed for safe and effective tumor targeting; and

 

   

Low anti-tumoral activity due to insufficient expansion of engineered T cells.

We are developing the next generation of engineered T cell therapies that:

 

   

target novel and known tumor-specific antigens, including mutant neoantigens, and a broad spectrum of tumor-associated antigens expressed in a wide range of cancers; and

 

   

leverage our proprietary CARVac technology for controlled in vivo stimulation, activation and expansion of engineered T cells.

 

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Our platforms for development of next-generation engineered T cell therapies. Our engineered cell therapies combine our antigen selection capabilities with our vaccine immunotherapy to enhance T cell activation and expansion.

The powerful characteristics of CAR-T cells, including their potential to eradicate targeted tumor cells in combination with their potentially life-long persistence in the host, require careful target selection. We believe the essential features of an ideal antigen for T cell-based immunotherapy are:

 

   

Absence of expression from any toxicity-relevant non-malignant tissue, to prevent off-tumor/on-target toxicity; and

 

   

Expression on the cell surface of tumor cells at sufficient levels to allow for recognition and lysis by CAR-T cells.

We are developing CAR-T programs targeting two different members of the Claudin family, namely CLDN6 and CLDN18.2. Claudins, or CLDNs, are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Most of the CLDNs are broadly expressed, while CLDN6 and CLDN18.2 are exclusively expressed in different high medical need cancers. Disturbance and dysregulation of tight junction molecules is a frequent hallmark of cancer cells and often associated with malignant transformation and metastasis and, hence, disease progression.

CLDN6 is an oncofetal cell surface antigen expressed in embryonic stem cells during fetal development. The gene encoding CLDN6 is strictly silenced and not expressed in healthy adult tissues but re-activated in different cancers with a high medical need including ovarian, endometrial, testicular and lung cancers.

In contrast to CLDN6, CLDN18.2 is a tissue restricted marker that is exclusively expressed in short-lived differentiated cells of the gastric mucosa. CLDN18.2 is observed in a large fraction of gastric cancers. In addition, CLDN18.2 is aberrantly activated in a variety of tumor entities, including esophageal cancer, pancreatic adenocarcinoma and cholangiocarcinoma.

In-vivo expansion of engineered T cells using liposomally formulated mRNA

Besides targeting an ideal tumor-specific antigen, the frequency and the persistence of CAR-T cells in the respective patient is a critical factor determining antitumor efficacy. A positive correlation between clinical outcome and CAR-T cell engraftment and persistence has been shown in several CD19-targeting CAR-T trials. Both tend to be much more limited in the solid tumor setting, likely due to the lack of circulating antigen-presenting cells, or APCs, such as dendritic cells expressing the target CAR antigen.

 

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To address this critical factor, we developed an approach for in vivo stimulation of CAR-T cells that relies on our proprietary FixVac technology for systemic mRNA delivery in combination with our CAR-T product candidates. Intravenous administration of a FixVac encoding for the tumor antigen induces expression of the desired target on antigen-presenting cells in secondary lymphoid tissues. FixVac treatment facilitates in vivo expansion of CAR-T cells in a dose-dependent manner. Moreover repetitive administration of FixVac results in an improved CAR-T cell persistence as well as increased anti-tumor activity.

 

 

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Our CAR-T cell immunotherapies combined with CARVac-mediated in vivo expansion. (A) Autologous T cells engineered to express a CAR are adoptively transferred into the patient. (B) Full-length CAR target-encoding mRNA is complexed with liposomes to form RNA-LPX lipoplexes (CARVac). (C) Intravenously administered CARVac selectively targets APCs in secondary lymphoid organs facilitating uptake, antigen expression and maturation of APCs. Exposure of CAR-T cells to their target results in CAR-T cell in vivo expansion. (D) CARVac can be administered repetitively to achieve controlled expansion and persistence of CAR-T cells within the therapeutic window.

Our CAR-T Development Plan

Our first CAR-T product candidate, BNT211, includes a second-generation CAR directed against CLDN6. Our second product candidate is BNT212, which includes a CLDN18.2-targeting CAR. We expect to initiate a Phase 1/2 basket trial of our novel combination CLDN6 CAR-T cell and CLDN6 CARVac product candidate in multiple solid tumors in the second half of 2020.

 

Candidate

  

Antigen Target

  

Development Phase

  

Next Potential Milestone

BNT211    CLDN6    Preclinical    Initiate Phase 1/2 trial in 2H 2020
BNT212    CLDN18.2    Preclinical    —  

 

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B. Neoantigen-targeting T Cells

 

At a glance: Our Neoantigen-targeting T Cell Platform

 

   

Concept: Adoptive T cell therapies targeting personal or shared sets of cancer neoantigens.

 

   

Mechanism: Autologous, neoantigen-specific T cells primed, activated and expanded utilizing a proprietary antigen-specific T cell induction protocol, NEO-STIM, to target either a personal set of neoantigens for each patient or a set of selected shared neoantigens.

 

   

Development Approach: Worldwide rights.

 

   

Lead Candidate: BNT221 for metastatic melanoma and other potential cancer indications.

Through our recent Neon acquisition, we obtained a neoantigen-targeting T cell platform. This platform can be utilized to develop product candidates across several neoantigen-targeting non-engineered and engineered T cell therapies using two distinct approaches:

 

   

An individualized approach enabling neoantigen-targeted therapies that are tailored for the individual profile of each patient’s tumor.

 

   

A shared neoantigen approach enabling neoantigen therapies that target prevalent neoantigens that are shared across subsets of patients or tumor types.

Our RECON bioinformatics engine is designed to predict the most therapeutically-relevant neoantigen targets associated with each patient’s tumor. Effective prediction is critical because, although many mutations within a patient’s tumor will lead to the production of a mutated protein, not all mutated proteins lead to suitable therapeutic neoantigen targets. RECON uses a number of inputs from each patient, including DNA sequences from samples of tumor and normal tissue, RNA sequences from tumor samples, and the patient’s specific MHC allele profile. RECON processes data from these inputs using a proprietary combination of algorithms in order to produce a prioritized list of neoantigen-targeting peptides that can be manufactured for use in product candidates. After selection of the target neoantigens, our proprietary method for ex vivo T cell stimulation, which we call NEO-STIM, allows us to directly prime, activate and expand antigen-specific T cells.

 

 

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Our Neoantigen-targeting T Cell Processes. The illustrations above show our processes for neoantigen-targeting T cell development under our individualized and shared neoantigen approaches.

Our Neoantigen-targeting T Cell Development Plan

Our lead product candidate under this platform is our individualized neoantigen-targeting T cell therapy, NEO-PTC-01 (BNT221). We expect to initiate a Phase 1 dose escalation trial of NEO-PTC-01 (BNT221) in metastatic melanoma in the second half of 2020. The second planned indication for NEO-PTC-01 (BNT221) is metastatic ovarian cancer.

 

Candidate

  

Antigen Target

  

Development Phase

  

Next Potential Milestone

BNT221

   Individualized    Preclinical    Initiate Phase 1 trial in 2H 2020

C. TCRs

The T cell receptor, or TCR, is part of a complex signaling machinery, which includes the TCR a and ß chains that are responsible for antigen recognition, the co-receptor CD4+ or CD8+ and the CD3 signal transduction complex. TCRs recognize antigens presented on the cell surface as small peptides loaded on the patients’ HLA molecules. Those peptides are derived from proteins after intracellular degradation. In contrast to CARs that recognize solely native membrane proteins, the repertoire of suitable TCR target antigens include TAAs and mutant neoantigens.

 

 

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TCR Complex. The illustration above shows the basic structure of a TCR complex.

Our TCR Discovery and Validation Platform

We have developed an integrated technology platform for the systematic identification of functional, fully human TCRs from single antigen-reactive T cells. This technology consists of a proprietary high-throughput approach for the fast retrieval, cloning and rapid validation of novel paired T cell receptor sequences. Our approach facilitates the isolation of tumor cell specific TCRs against multiple antigens and various HLA class I and II alleles.

 

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We believe our TCR discovery technology has the potential to unlock an array of patient- and tumor-specific TCRs suitable for clinical use. We believe this technology has potential utility for:

 

   

therapeutic TCR products encompassing single TCRs to target a specific antigen;

 

   

a therapeutic TCR warehouse encompassing multiple TCRs to target one or more tumor antigens; or

 

   

individualized T cell therapy involving on-demand identification and timely manufacturing of customized, engineered T cells with autologous TCRs against neoepitopes for adoptive transfer.

X. Our Antibodies Drug Class

In the past decades, monoclonal antibodies, or mAbs, have transformed from scientific tools to powerful human therapeutics. As one of the fastest growing classes of drugs, to date, more than 40 mAbs have been approved to treat a variety of diseases including cancer, inflammation, autoimmune diseases and others. In addition, identified antigen-binding domains are also fundamental elements for the construction of novel therapeutic formats and formulations, such as CAR-T cells, bispecific therapeutics and targeted nanoparticles.

We have developed and integrated multiple complementary antibody and antibody-mimetic protein technologies into our overall portfolio of treatment approaches.

A. Our Next-generation Checkpoint Immunomodulators

 

At a glance: Our Next-generation Checkpoint Immunomodulators

 

   

Concept: Bispecific antibodies for dual immunomodulation, initially targeting 4-1BB, an immune checkpoint that is expressed on T cells and NK cells and can enhance immune cell proliferation and activation, in combination with simultaneous checkpoint inhibition.

 

   

Mechanism: Conditional activation of 4-1BB checkpoint only upon simultaneous binding of PD-L1 or CD40 (in the case of our initial candidates), potentially avoiding toxicities seen in prior attempts at 4-1BB agonism by localizing 4-1BB activation to the tumor environment.

 

   

Development Approach: 50:50 cost and profit share with Genmab, combining our and Genmab’s immunostimulatory antibodies and extensive immunology expertise with Genmab’s DuoBody® bispecific antibody platform.

 

   

Lead Candidate: GEN1046 (BNT311), our PD-L1x4-1BB product candidate for multiple solid tumors.

Following the success of immune checkpoint-blocking antibodies targeting CTLA-4, PD-1 or PD-L1 in cancer treatment, bispecific antibody approaches represent the next generation of emerging immunotherapies with the potential to further improve clinical efficacy. In addition to bispecific T cell engager formats, which redirect T-cell cytotoxicity to malignant cells, bispecific antibodies can be formatted as tumor-targeted immunomodulators and dual immunomodulators. Tumor-targeted immunomodulators direct potent immune costimulation to the tumor-infiltrating immune cells, whereas dual immunomodulators simultaneously address two immunomodulating targets, resulting in blockade of inhibitory targets, depletion of suppressive cells or activation of immune effector cells.

We are developing, in collaboration with Genmab, bispecific antibodies that function as tumor-targeted and dual immunomodulators, applying Genmab’s proprietary DuoBody® technology in combination with our joint target identification and product concept expertise. These next-generation checkpoint immunomodulators are thought to induce beneficial co-stimulation, promoting specific T cell activation, survival, proliferation and T cell effector functions. Our collaboration encompasses three potential classes of immunotherapeutic bispecific antibodies:

 

   

Tumor-targeted DuoBody® molecules are bispecific antibodies targeting a tumor-specific antigen expressed by the malignant cell, and an immunomodulatory receptor expressed by tumor-infiltrating immune cells. This is expected to induce powerful activation of tumor-specific effector immune cells with reduced risk of immune-related adverse events.

 

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Cis-activating DuoBody® molecules are bispecific antibodies that bind two distinct immunomodulating targets presented on the same cell. These targets are specifically expressed on activated immune cells with the rationale to boost existing immune responses by additive or synergistic effects of dual immunomodulation.

 

   

Trans-activating DuoBody® molecules are bispecific antibodies that bind two distinct immunomodulating targets expressed on two separate cell subsets. By simultaneously targeting, for example, effector immune cells and antigen-presenting cells, these compounds are thought to amplify the immune cell priming process and augment subsequent effector responses.

 

 

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Next-generation checkpoint immunomodulators. Our collaboration with Genmab potentially includes bispecific antibodies from three different classes: trans-activating, cis-activating and tumor-targeting antibodies.

Our Next-generation Checkpoint Immunomodulator Development Plan

We are currently developing two next-generation checkpoint immunomodulator product candidates in collaboration with Genmab: GEN1046 (BNT311), our jointly owned PDL1x4-1BB bispecific antibody, and GEN1042 (BNT312), our jointly owned CD40x4-1BB bispecific antibody.

 

Candidate

  

Targets

  

Development Phase

  

Next Potential Milestone

GEN1046 (BNT311)

   PD-L1x4-1BB    Phase 1/2a trial in multiple solid tumors    Data update in 2H 2020

GEN1042 (BNT312)

   CD-40x4-1BB    Phase 1/2a trial in multiple solid tumors    —  

B. Our Antibody Discovery Engines

We believe that our multiple antibody discovery engines significantly expand our targeting repertoire and enable us to directly, rapidly and efficiently produce new mAb candidates. In addition, antigen-binding domain sequences identified through our antibody discovery engines also feed into our proprietary CAR-T cell and mRNA-encoded RiboMab platforms as well as our next-generation checkpoint immunomodulator collaboration. For instance, binders to human 4-1BB were identified from a previous antibody generation campaign and are currently under clinical and preclinical development as part of our next-generation checkpoint immunomodulator collaboration with Genmab. HuMab, our human antibody discovery engine acquired from MabVax Therapeutics in 2019, led to the clinical development of our fully human IgG1 monoclonal antibody product candidate targeting Sialyl Lewisa (sLea), a carbohydrate moiety that is present in over 90% of pancreatic and a large percentage of gastrointestinal cancers.

 

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1.     Our Rabbit-based Antibody Discovery Engine

With the acquisition of MAB Discovery GmbH’s antibody generation unit in 2019, we integrated a unique and proprietary rabbit-based antibody discovery platform that can generate and develop high quality, functional mAbs targeting traditional proteins and receptors as well as a wide variety of more challenging targets. Rabbit monoclonal antibodies are highly diverse and do not require affinity maturation, due to consistently high affinities. They often recognize epitopes on human antigens that are not immunogenic in rodents, thus increasing the total number of targetable epitopes. The mechanisms of antibody diversification in rabbits allow an easy and quick translation of preclinical data into the clinic with an improved probability of success. We established a streamlined semi-automated process of rabbit immunization for the efficient production of high-affinity rabbit mAbs.

 

 

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Our rabbit-based antibody discovery engine. The figure above depicts our semi-automated process for the discovery and production of high-affinity rabbit mAbs.

2.     Our Fully Human Antibody Discovery Engine

Our HuMab discovery technology focuses on abnormal carbohydrate targets upregulated on solid tumors. Aberrant glycosylation is a common phenotypic change of cancer cells that mainly affects the outer part of glycans. These abnormal carbohydrate structures are known as tumor-associated carbohydrate antigens, or TACAs, and are associated with malignancy grade, invasion, metastasis and poor prognosis. TACAs are considered promising novel targets for therapeutic intervention using, in particular, mAbs or CAR-T cells. However, TACAs usually induce only low-affinity humoral immune responses, since carbohydrate moieties do not trigger the necessary T cell responses.

Using B cell sorting, hit identification, sequencing, antibody production and high-throughput antibody screening, we are able to select optimal TACA-specific antibodies from multiple clinically confirmed

 

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immunotherapy responders. All antibodies emanating from this platform are fully human with no need for additional humanization at minimal risk for immunogenicity.

 

 

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Our fully human antibody discovery engine. The figure above shows our proprietary approach to the discovery and development of novel fully human antibody therapeutic and diagnostic agents.

Our Targeted Cancer Antibody Development Plan

 

Candidate

  

Targets

  

Development Phase

  

Next Potential Milestone

MVT-5873 (BNT321)

   sLea    Phase 1 basket trial in multiple solid tumors; first patient enrolled    —  

XI. Our Small Molecule Immunomodulator Drug Class

 

At a glance: Our Small Molecule Immunomodulators

 

   

Concept: Small molecule therapies, with a specific focus on TLRs, that can be used synergistically with other cancer therapeutics, including other product candidates in our portfolio.

 

   

Development Approach: Worldwide rights; wholly owned.

 

   

Lead Candidate: BNT411, our TLR7 agonist product candidate intended as a monotherapy or in combination with chemotherapy and/or checkpoint inhibitors.

Small molecule cancer therapeutics can be used to regulate cancer growth, halt blood vessel formation in tumors, deliver toxins to cancer cells and mark cancer cells for destruction by the immune system. Unlike larger antibody-based cancer therapies, small molecule compounds are often developed for targets located within cells since they can enter the cells more easily as a result of their physical properties and low molecular weight. Small molecules also often have other intrinsic benefits including relative ease and cost of production compared to larger compounds, as well as more frequently having the potential for oral administration to patients. They can also often be used synergistically in combination with other therapeutics such as mRNA, checkpoint inhibitors, radiation therapy and chemotherapy.

We aim to discover and develop the next generation of small molecule immunomodulatory compounds to improve the standard of care. We have a team of approximately 25 scientists and technicians, with extensive small molecule experience, focused on drug discovery.

 

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Our immunomodulatory small molecule product class focuses on a range of endosomal and intracellular targets that are known to stimulate the activity of a wide range of immune cells. We have a particular emphasis on TLRs. TLRs are a family of pattern recognition receptors that function as primary sensors of the innate immune system to recognize pathogens. We believe TLRs represent a promising target class for cancer immunotherapy, particularly for inflammatory re-programming of the tumor microenvironment. In many cancers, tumors are protected by an anti-inflammatory environment, which reduces the ability of the immune system to attack the cancer cells. TLR7 agonists are able to initiate a direct cellular immune response, for example, by activating immature dendritic cells, cytotoxic T cells and NK cells, as well as stimulating the release of signal molecules such as cytokines and chemokines including IFN-a and IP-10, which can be directed against tumor cells. The activation of the innate and adaptive immune system and the release of cytokines and chemokines, for instance by our small molecule TLR7 agonist, results in the potent stimulation of antigen-specific T cells, B cells and innate immune cells such as NK cells and macrophages.

Our initial focus is on small molecule product candidates that activate the innate and adaptive immune system via TLR7 and are designed to be used in combination with chemotherapeutics as well as checkpoint inhibitors.

Our Small Molecule Immunomodulator Development Plan

Our initial development candidate is a potent TLR7 agonist, which we are developing as a monotherapy or a combination therapy for small cell lung cancer and other solid tumors.

 

Candidate

  

Target

  

Development Phase

  

Next Potential Milestone

BNT411

   TLR7   

Phase 1/2a trial in extensive-stage small-cell lung carcinoma

  

XII. OUR PRODUCT CANDIDATES

We are developing a broad and deep pipeline of over 20 product candidates across our four drug classes. Our product candidates are currently being investigated in 12 clinical trials.

 

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A. Our mRNA Product Class in Oncology

1.     FixVac

FixVac is our wholly owned, systemic, off-the-shelf mRNA-based cancer immunotherapy platform, from which we are developing several first-in-human and potential first-in-class product candidates. Our FixVac product candidates contain selected combinations of pharmacologically optimized uridine mRNA encoding known cancer-specific shared antigens. FixVac product candidates feature our proprietary immunogenic mRNA backbone and proprietary RNA-LPX delivery formulation, which are designed to enhance stability and translation as well as trigger both innate and adaptive immune responses.

a)     BNT111: Our FixVac Cancer Immunotherapy for the Treatment of Advanced Melanoma

We are developing our mRNA-based FixVac product candidate BNT111 for the treatment of advanced melanoma in patients with metastatic tumors and as an adjuvant treatment after tumor resection. We are currently studying BNT111 in an ongoing Phase 1 clinical trial.

Melanoma

Melanoma is an increasingly prevalent, deadly form of skin cancer in which melanocytes, which are the cells that color the skin, form malignant cells. With 132,000 new cases diagnosed globally each year, melanoma constitutes less than five percent of all skin cancers. In recent decades, however, the incidence rate of melanoma has risen faster than almost any other cancer type, on average by 1.5% per year over the last 10 years. In 2018, approximately 91,000 new melanoma cases were diagnosed in the United States, representing 5.3% of all new cancer cases in the United States.

Melanoma is the most lethal form of skin cancer, accounting for the majority of skin cancer deaths. There were an estimated 9,300 deaths from melanoma in the United States in 2018. While the five-year survival rate for melanoma, regardless of disease stage, is approximately 91.8%, patients with stage III melanoma have a five-year survival rate of approximately 63%. The five-year survival rate for metastatic melanoma (stage IV) is approximately 20%.

The current treatment regimen involves surgical removal for earlier stages, while a number of targeted therapies, such as BRAF and MEK inhibitors, and checkpoint inhibitors, or CPIs, are approved for advanced disease. CPIs include nivolumab (Opdivo) for advanced or metastatic melanoma after resection, and pembrolizumab (Keytruda) in unresectable or metastatic disease.

Our BNT111 Targets

BNT111 is designed to elicit an immune response to the following four antigens that have each been found to be associated with melanoma:

 

   

New York esophageal squamous cell carcinoma 1, or NY-ESO-1, a well-known cancer-testis antigen that is also expressed in numerous cancers, including melanoma;

 

   

melanoma-associated antigen A3, or MAGE-A3, which is not expressed in normal tissues, except the testis and the placenta;

 

   

tyrosinase, an enzyme that is required for melanin production and that is produced in increased levels in melanoma; and

 

   

trans-membrane phosphatase with tensin homology, or TPTE, a novel cancer/testis antigen that we discovered internally.

We sequenced 337 melanoma tumors and detected at least one of these four antigens in over 90% of such melanoma tumors.

 

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BNT111 antigens detected in over 90% of melanoma tumors. The graphic above shows expression of BNT111 target antigens on a patient by patient basis. Each row at the bottom of the graphic represents an antigen, and each vertical line represents a patient, depicting whether or not that patient expressed each antigen.

Our BNT111 Clinical Trials

Ongoing Phase 1 Trial in Advanced Melanoma Patients (LIPOMERIT study)

We are conducting a multi-center, open-label, first-in-human, Phase 1 dose escalation study evaluating the safety and tolerability of multiple intravenous administrations of BNT111 in patients with advanced melanoma. This is the first clinical trial worldwide in which an mRNA-based cancer immunotherapy is administered intravenously for systemic treatment.

The trial employs a conventional 3+3 design in which patients are dosed in groups of three at incrementally greater dosages until the maximum tolerated dose is identified, during the dose escalation phase, which is then followed by expanded dose cohorts. Patients are treated with doses from 7.2µg up to the highest administered dose of 400µg of total mRNA.

July 2019 Interim Data

As of the July 2019 interim cut-off date, 95 patients with metastatic melanoma had been dosed at least once at one of four centers in Germany. Baseline and demographic characteristics were largely as expected for a trial recruiting advanced stage IIIB-IIIC and stage IV melanoma patients with and without measurable disease. Approximately half of the patients were resected and had radiographically non-evaluable disease at baseline. The other half of the patients had radiographically evaluable disease at baseline and most of these patients were heavily pretreated. Only the subset of patients with evaluable disease at baseline was assessed for preliminary clinical activity.

Immunogenicity. Immune responses induced by BNT111 were assessed using various orthogonal assay systems by analyzing T cells against each vaccine antigen in pre- and post-treatment blood samples of patients. So far, about half of the dosed patients have been analyzed for immune responses in this ongoing study. A first analysis in a subset of 18 patients evaluated vaccine antigen reactivity of CD4+ and CD8+ T cells by IFN-α ELISpot after in vitro stimulation. All tested patients showed either a de novo or an augmented (as compared to baseline) immune response against at least one of the BNT111-encoded tumor antigens. Most patients exhibited either CD4+ or concurrently CD4+ and CD8+ T cell responses against the individual vaccine targets. A second analysis looked at the magnitude of immune responses on the individual level by using an ex vivo IFN-α ELISpot, which due to its sensitivity level would capture only very strong T cell responses, and showed that more than 75% of patients exhibited vaccine-induced CD4+ or CD8+ T cell responses. The kinetics of de novo-induced CD8+ T cells were further characterized in selected patients of interest by a third method using ex vivo MHC peptide multimer staining of blood samples collected at baseline and at different time points after start of vaccination. Mostly, antigen-specific T cell counts showed a fast ramp-up from being undetectable at baseline to levels ranging from 1,000 to more than 100,000 per million circulating CD8+ T cells within the first 4-8 weeks. Under monthly maintenance treatment, frequencies of individual antigen-specific T cells continued to slowly increase or remained stable up to over one year.

Clinical activity. As of the July 2019 cut-off date, in our review of interim data, we assessed 42 patients with radiographically evaluable, measurable disease at baseline for preliminary clinical activity according to

 

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Response Evaluation Criteria in Solid Tumors, Version 1.1, or RECIST v1.1. Twenty-five of these 42 patients received BNT111 as a monotherapy, and 17 patients received BNT111 in combination with an anti-PD-1 checkpoint inhibitor, or CPI (either pembrolizumab or nivolumab).

In the BNT111 monotherapy cohort, we observed clinical activity for all 25 patients. All of these patients had received at least one line of prior treatment with a checkpoint inhibitor, and 24 of the 25 patients had failed prior sequential or combination treatment with anti-PD-1 and anti-CTLA4 antibodies. Three of 25 patients (12%) showed a partial response, or PR, one patient had a metabolic complete response as measured by FGD-PET imaging and seven patients (28%) demonstrated stable disease. The clinical benefit rate, or CBR, is 44%. Two of the PRs manifested early on during treatment (at imaging day 90); the two others manifested at imaging days 180 and 360, respectively.

In the BNT111 in combination with anti-PD-1 checkpoint inhibitor cohort, 16 of the 17 patients had prior treatment with CPI. Six patients (35%) showed a partial response, and two patients (12%) demonstrated stable disease. The CBR is 47%. Objective responses were observed across all dose levels explored in expansion cohorts (14µg, 50µg and 100µg). Five of 10 (50%) patients who received the highest target dose of 100µg demonstrated a PR. By contrast, the expected ORR for anti-PD1 treatment in an anti-PD1 experienced patient population is in the range of 10%.

Safety. As of the July 2019 cut-off date, no dose-limiting toxicities to BNT111 have been reported. The highest explored dose level is 400µg total mRNA and doses up to 100µg total mRNA were tested further in expansion cohorts. The overall adverse event profile was dominated by mild-to-moderate, transient and manageable flu-like symptoms. This profile may have been driven by the mode of action of the RNA-LPX, which activates antigen presenting cells via signaling of TLRs, resulting in a temporary, self-limiting release of a distinct range of pro-inflammatory cytokines upon intravenous application. These symptoms were managed by pre-medication with non-steroidal antipyretics, such as ibuprofen and acetaminophen. Eight subjects dosed with BNT111 experienced related treatment-emergent serious adverse events, or TESAEs. The related TESAEs were comprised of two cases of Grade 2 pyrexia, and one case each of Grade 2 asthenia, Grade 2 dizziness, Grade 3 anaphylactic reaction, Grade 3 dizziness, Grade 3 syncope, Grade 3 exudative retinopathy, Grade 3 posterior reversible encephalopathy syndrome, Grade 3 epileptic seizure, and Grade 2 suspected pancreatitis. There were confounding factors, such as treatment with other therapies or underlying medical conditions, for the subjects with related TESAEs. We could not establish a clear causal relationship between BNT111 and the cases of anaphylactic reaction, retinopathy, encephalopathy syndrome, seizure and suspected pancreatitis. There have been no deaths in this study that were assessed by the investigators as related to BNT111.

Completed Phase 1 Trial in Patients with Advanced Melanoma (MERIT study)

In 2016, we published results of a first-in-human dose escalation study evaluating the safety and tolerability of intranodal administration of an earlier generation of BNT111 in patients with advanced melanoma. In this study, the earlier formulation of BNT111 targeted only NY-ESO-1 and tyrosinase.

This international, multi-center, open-label interventional study’s primary endpoints were the maximum tolerated dose for multiple dosing, safety and adverse reactions and tolerability profile of multiple dosing. The secondary endpoints were (i) to observe immunotherapy-induced immune responses following multiple treatment cycles and (ii) clinical benefit (complete response, partial response and stable disease).

Five dosages were administered to patients sequentially: 50µg, 100µg, 300µg, 600µg, and 1,000µg. The sample size for the first three doses was three each. The 600µg dose cohort was comprised of 13 patients and the 1,000µg dose cohort was comprised of seven patients. In the 100µg, 300µg and 600µg dose cohorts, seven patients in total received continued treatment. The overall individual treatment period was 43 to 51 days and comprised eight treatment cycles of ultrasound-guided intranodal injections on days one, four, eight, 11, 15-17, 22-26, 29-35 and 43-51. In case of an optional continued treatment for patients who neither exhibited

 

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unacceptable drug-related toxicity nor disease progression, four additional treatment cycles were administered at the same dosage that the patient had received in his or her cohort. The first cycle of continued treatment was scheduled 14-42 days after the last visit, with the second and third additional treatment cycles following after a one-month interval each. The fourth treatment cycle then followed after an interval of three months.

The occurrence of new measurable lesions was observed in only one patient of the 1,000µg dose cohort, while new non-measurable lesions were identified in seven patients. Twenty-one patients, or 75%, were classified as having immune-related stable disease and six patients, or 21.4%, had immune-related progressive disease.

The most frequent adverse events included administration-site conditions, infections and infestations, musculoskeletal and connective tissue disorders, nasopharyngitis, fatigue, headache and back pain. No life-threatening adverse events nor deaths occurred in this study. Thirteen severe adverse events were reported, including infections and infestations and vascular disorders. Sixteen patients were affected by adverse events with a suspected relationship to the study drug. These were most frequently fatigue, application site erythema and application site pain. None of the drug-related adverse events was categorized as serious. No dose-limiting toxicities were observed.

Next Steps

We expect to report Phase 1 data from the LIPOMERIT trial and to initiate a Phase 2 clinical trial with registrational potential for BNT111 in the second half of 2020.

b)    BNT112: Our FixVac Cancer Immunotherapy for the Treatment of Prostate Cancer

We are developing BNT112 for the treatment of prostate cancer.

Prostate Cancer

Prostate cancer is the second most common cancer amongst men worldwide and the fourth most commonly occurring cancer overall, with around 1.3 million new cases recorded worldwide in 2018 and 174,650 cases expected in 2019 in the United States alone. The stage of the prostate cancer (I-IV), alongside the prostate-specific antigen and Gleason score, are the key factors for defining the treatment options for individual cases. Surgical or radiation based approaches are often used in first-line therapy, however after relapse (up to 30-40% of patients), androgen-deprivation therapies are employed, which in turn also often becomes redundant (metastatic castration-resistant prostate cancer, or mCRPC) at which point patients are treated with either further hormonal agents or chemotherapy.

 

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Our BNT112 Targets

BNT112 is designed to elicit an immune response to five prostate cancer-specific antigens, including prostate-specific antigen, or PSA, a transmembrane protein that is expressed by virtually all prostate cancers, prostatic acid phosphatase, or PAP, and three additional tumor-associated antigens.

 

 

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Our BNT112 Clinical Trials

Phase 1/2 Clinical Trial

We enrolled the first patient in an open-label, multi-center, first-in-human Phase 1/2 individual dose titration study of BNT112 in patients with mCRPC and high-risk localized prostate cancer, or LPC, in the second half of 2019. Eligible patients have newly-diagnosed, high-risk, localized prostate cancer and will be treated with BNT112 as a single agent, in combination with cemiplimab and goserelin acetate or in combination with goserelin acetate alone. We anticipate a total enrollment of 60 to 80 patients at up to 20 investigational sites.

The study is designed to evaluate the safety, tolerability, immunogenicity and preliminary efficacy of BNT112 in mCRPC and LPC patients. The primary objective of this study will be to establish the safety and tolerability of BNT112 alone, or in combination with goserelin acetate with or without cemiplimab. The secondary objectives of the trial will be to examine the immunogenicity of BNT112 alone or in combination with goserelin acetate with or without cemiplimab, and to evaluate anti-tumor activity based on levels of prostate-specific antigen, or PSA.

The study will consist of three arms. The first arm will start with a dose titration phase for the initial safety assessment and recommended expansion dose range assessment. We anticipate enrollment of approximately 20 patients in arm one who will receive BNT112 alone, with up to nine patients participating in the dose titration part of the arm (with staggered starting groups of three patients one week apart). Titration will continue until unacceptable toxicity or disease progression. Efficacy in the first arm will be assessed by on-treatment imaging and in the second and third arms by tumor volume measurement.

 

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After at least six patients are treated and evaluable for at least one treatment cycle, we plan to commence enrollment of the second and third arms, each enrolling approximately 20 patients with newly diagnosed LPC. Patients in the second arm will receive BNT112 combined with goserelin acetate and cemiplimab, and patients in the third arm will receive BNT112 combined with goserelin acetate alone. Treatment periods in the second and third arms will last until unacceptable toxicity or until the end of the eighth cycle, which will be followed by planned radical prostatectomy.

 

  c)

BNT113: Our FixVac Cancer Immunotherapy for the Treatment of HPV+ Head and Neck Cancer

We are developing BNT113 for the treatment of HPV+ head and neck cancer. BNT113 is currently being studied by the University of Southampton in an ongoing investigator-sponsored Phase 1/2 basket study in HPV+ cancers, including head and neck cancer.

HPV+ Head and Neck Cancer

Head and neck cancer defines a heterogeneous group of tumors originating in the squamous cells that line the moist, mucosal surfaces inside the head and neck. Head and neck cancer is the sixth most common malignancy worldwide, accounting for approximately 6% of all cancer cases, and is responsible for 1-2% of all cancer deaths. An increasing percentage of this cancer is now attributed to HPV infection in the United States and Europe, particularly those arising from the oropharynx. In the U.S., HPV-related oropharynx cancer, or OPC, is one of only five cancers with rising incidence and prevalence. The percentage of OPC related to HPV rose from approximately 16% in 1984 to 1989 to approximately 72% during 2000 to 2004. Early stage head and neck cancer is typically either treated with surgery or radiation alone, however approximately 66% of patients present with advanced disease and fewer than 30% of these are cured. The management of advanced disease consists of multiple-modality therapy with surgery, radiation and chemotherapy. Long-term survival rates in these patients have not increased significantly in the past 30 years: five-year survival rates are 60-80%.

Our BNT113 Targets

BNT113 is designed to elicit an immune response against the well-characterized HPV16-derived oncoproteins E6 and E7, which are strongly immunogenic, viral neoantigens that are found in HPV16+ solid cancers such as head and neck squamous cell carcinoma.

Our BNT113 Clinical Trials

Ongoing Phase 1/2 Basket Study (Investigator-Sponsored)

BNT113 is being studied in an investigator sponsored open-label, Phase 1/2 dose escalation basket study with two different arms in approximately 44 patients with HPV+ head and neck and other cancers. The first arm will perform dose escalation in patients with previously treated HPV+ head and neck cancer using two dose cohorts to establish a safe, tolerable and recommended dose of BNT113. The second arm will perform dose escalation in patients with advanced HPV+ cancers, including head and neck, anogenital, penile and cervical cancers, using a single cohort to establish a safe, tolerable and recommended dose.

Next Steps

We intend to initiate a Phase 2 trial with registrational potential of BNT113 in HPV+ cancers by the end of 2020.

 

  d)

BNT114: Our FixVac Cancer Immunotherapy for the Treatment of Triple Negative Breast Cancer

 

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We are currently studying antigens selected for BNT114 in a three-arm clinical trial as both a monotherapy and in combination with our RO7198457 (BNT122) individualized iNeST immunotherapy in patients with triple negative breast cancers.

Triple Negative Breast Cancer (TNBC)

Breast cancer is the most commonly occurring cancer in women and the second most common cancer overall with over two million new cases globally in 2018 with an expected 268,600 cases in 2019 in the United States alone. There are three broadly defined categories of breast cancer. About 80% of breast cancers are defined as ER+, meaning that they grow in response to the hormone estrogen, while 65% of these are also defined as PR+, as they also grow in response to another hormone, progesterone. Such cancers can be identified by the presence of estrogen receptors, or ER, and/or progesterone receptors, or PR, on the cancer cell surface and are more likely to be treatable by hormone therapies than cancers that are ER or PR negative. In about 20% of cancers, the tumor can be identified by its production of an excess of the HER2 protein. Such HER2+ cancers tend to be aggressive and fast moving. Breast cancers that neither express ER or PR, nor over-express HER2-, are known as triple negative breast cancers, or TNBCs. TNBC patients represent approximately 12-15% of all breast cancer cases, however it remains an area of high unmet medical need given it is typically the most aggressive form of breast cancer. There are currently no effective treatments for TNBC. While initial treatment options include surgery or chemotherapy, TNBC is characterized by rapid resistance to chemotherapy, and few remaining treatment options remain thereafter.

Our BNT114 Targets

BNT114 is designed to elicit an immune response to selected antigens that are found in breast cancers.

Our BNT114 Clinical Trials

Ongoing Phase 1 Clinical Trial (BNT114 monotherapy and in combination with RO7198457 (BNT122))

We are currently conducting an international, multi-center, open-label, three-arm Phase 1 study of BNT114 as a monotherapy and in combination with our RO7198457 (BNT122) individualized iNeST immunotherapy in 39 TNBC patients who had previously received the standard of care therapy (i.e., surgery, chemotherapy and/or radiotherapy). The primary endpoints of the study are to assess safety and tolerability. Safety will be analyzed by adverse event documentation and clinical observation and tolerability will be analyzed based on patients’ vital signs and clinical chemistry. The secondary endpoint of the study is the observation of the treatment-induced immune responses, expressed as treatment-induced T cell responses, resulting from multiple treatment cycles.

Patients in the first arm receive BNT114, patients in the second arm receive BNT114 in combination with RO7198457 (BNT122) and patients in the third arm receive BNT114 in combination with mRNA encoding tetanus-toxin help epitopes.

Next Steps

We expect to report a data update in the second half of 2020 and assess the immunogenicity of the selected antigens.

 

  e)

BNT115: Our FixVac Cancer Immunotherapy for the Treatment of Ovarian Cancer

We are developing BNT115 for the treatment of ovarian cancer. BNT115 is currently being studied in an ongoing investigator-sponsored Phase 1 study in ovarian cancer.

Our BNT115 Targets

BNT115 is designed to elicit an immune response to selected antigens that are found in ovarian cancers.

 

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Our BNT115 Clinical Trial

Ongoing Phase 1 Trial (Investigator Sponsored)

BNT115 is being studied in a 10 patient investigator sponsored, first-in-human, open label, Phase 1 dose escalation study in ovarian cancer patients eligible for standard-of-care treatment with neo-adjuvant chemotherapy. Eight doses of BNT115 will be administered prior to and in combination with the neo-adjuvant chemotherapy to induce an anti-tumor immune response. Systemic immune responses will be determined using peripheral blood mononuclear cells collected before, during and after vaccinations. Intratumoral accumulation of T-cells recognizing vaccine-encoded tumor associated antigens will be determined before vaccination in a tumor biopsy and after 3 cycles of chemotherapy and the 5th vaccination using tumor tissue derived from interval surgery.

 

  f)

Other FixVac Indications

We are also exploring FixVac development candidates in other cancer indications, including non-small cell lung cancer.

 

  2.

Individualized Neoantigen Specific Immunotherapy (iNeST)

Our iNeST product candidate is an individualized cancer immunotherapy that targets specific neoantigens that are present on a patient’s tumor. Our iNeST immunotherapies contain pharmacologically optimized uridine mRNA encoding up to 20 patient-specific neoantigens, as well as our proprietary RNA-LPX formulation. We are developing our iNeST cancer immunotherapy in collaboration with Genentech.

 

  a)

BNT122: Our iNeST Cancer Immunotherapy for Multiple Potential Indications

We and our collaborator Genentech are developing RO7198457 (BNT122) for the treatment of metastatic melanoma and other solid tumors. We are currently conducting a randomized Phase 2 trial of RO7198457 (BNT122) in collaboration with Genentech in first-line melanoma in combination with pembrolizumab. In collaboration with Genentech, we are also studying RO7198457 (BNT122) as a monotherapy and in combination with atezolizumab in a Phase 1a/1b study of patients with locally advanced or metastatic solid tumors (including in melanoma, non-small cell lung cancer, bladder cancer as well as other solid tumors). The Phase 1a/1b trial is a non-registrational, signal-seeking study recruiting mostly patients with late-stage advanced cancers including patients who failed multiple lines of prior treatment.

Our RO7198457 (BNT122) Targets

RO7198457 (BNT122) is an individualized neoantigen-specific immunotherapy. Each RO7198457 (BNT122) dose includes up to 20 different neoepitopes selected on a patient-by-patient basis. We believe that neoepitope-specific T cells induced by RO7198457 (BNT122) can enhance the therapeutic efficacy of immune checkpoint blockade.

Our RO7198457 (BNT122) Clinical Trials

Ongoing Phase 2 Clinical Trial (First-line with pembrolizumab)

In January 2019, we and Genentech initiated a Phase 2, open-label, multi-center, randomized clinical trial investigating the safety and efficacy of RO7198457 (BNT122) in combination with pembrolizumab in 132 patients with previously untreated metastatic melanoma. Patients in the experimental arm will receive pembrolizumab by intravenous infusion every three weeks, plus a selected dose of RO7198457 (BNT122) at defined intervals. Patients in the active comparator arm will receive 200mg of pembrolizumab by intravenous infusion every three weeks. Following treatment in the comparator arm, patients will be permitted to cross over to combination therapy with RO7198457 (BNT122).

 

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The primary endpoint is:

 

   

progression-free survival, or PFS, of patients treated with RO7198457 (BNT122) compared with patients receiving pembrolizumab alone, according to RECIST v1.1.

Secondary endpoints include:

 

   

objective response rate, or ORR, in patients treated with RO7198457 (BNT122) compared with patients receiving pembrolizumab alone, defined as the proportion of participants with complete response, or CR, or partial response, or PR;

 

   

overall survival, or OS, of patients treated with RO7198457 (BNT122) compared with patients receiving pembrolizumab only;

 

   

duration of response according to RECIST v1.1 of patients treated with RO7198457 (BNT122) compared with patients receiving pembrolizumab only;

 

   

mean change in health-related quality of life, scores of patients treated with RO7198457 (BNT122) compared with patients receiving pembrolizumab only;

 

   

percentage of patients with CR or PR following cross-over from pembrolizumab monotherapy to combination therapy following cross-over, according to RECIST v1.1; and

 

   

incidence and severity of adverse events.

Ongoing Phase 1 Clinical Trial

The iNeST Phase 1a (monotherapy)/1b (in combination with atezolizumab) trial is a non-registrational, signal seeking study recruiting patients with locally advanced or metastatic solid tumors, including patients with melanoma, non-small cell lung cancer, bladder cancer, colorectal cancer, TNBC, renal cancer, head and neck cancer and sarcomas. The study is designed to enroll both patients with and without prior checkpoint inhibitor regimens.

The primary objective of the study was to assess safety (including dose-limiting toxicities), and additional objectives included evaluation of immunogenicity and preliminary assessment of anti-tumor activity. The trial included a Phase 1a (monotherapy) dose escalation, a Phase 1b (combination) dose escalation, and multiple Phase 1b expansion cohorts. Patients received nine doses of the vaccine administered I.V. in weekly and bi-weekly intervals during the induction phase and every eight cycles during the maintenance phase. In the Phase 1b portion of the trial, atezolizumab was administered on day one of each 21-day cycle.

BNT122 was manufactured on a per-patient basis including in-house determination of cancer mutation profiles, computational prediction of neoantigens, design, and manufacturing of the iNeST vaccine based on liposomally formulated RNA (RNA-LPX). Each vaccine contained up to 20 patient-specific neoepitopes. Importantly, the manufacturing of BNT122 for individual patients within clinical practice compatible turn-around times was shown to be feasible using clinical biopsies or routine clinical specimens across a range of tumor types including those with low or intermediate tumor mutational burden.

June 2020 Data Updates

In June 2020, we presented data from a monotherapy dose-finding cohort of our RO7198457 (BNT122) Phase 1 trial in multiple solid tumors in which RO7198457 (BNT122) was observed to have a manageable safety profile and induced strong neoantigen-specific immune responses in patients with low and intermediate mutational load tumors types. This data related to 31 patients enrolled in cohorts with doses ranging from 25-100µg. Most patients enrolled had a low level of PD-L1 expression in the tumor as determined by immunohistochemistry. The majority of adverse events were Grade 1 or Grade 2 and those occurring in more

 

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than 20% of patients included infusion related reaction (IRR), fatigue, cytokine release syndrome (CRS), nausea, and diarrhea. IRR and CRS were transient and reversible and presented primarily as Grade 1 or Grade 2 chills and fever. A single dose-limiting toxicity of Grade 3 CRS occurred at the 100µg dose level. None of the patients discontinued RO7198457 (BNT122) due to AEs. Ex vivo T cell responses were detected in approximately 86% of patients treated with RO7198457 (BNT122) as a monotherapy. RO7198457 (BNT122) induced T cells against multiple neoantigens were detected in post-treatment tumor biopsies. Of 26 patients that underwent at least one tumor assessment, one patient with gastric cancer and metastatic liver lesions had a durable best response of confirmed complete response and remains on study after 1.5 years (3.8%) and 12 patients had stable disease (46.2%).

Later in June 2020, we presented data from 132 patients enrolled in cohorts with doses ranging from 15µg to 50µg of RO7198457 (BNT122) in combination with 1200mg atezolizumab. The most common tumor types enrolled were NSCLC, TNBC, melanoma and colon cancer with a median of three lines of prior therapies (range 1-11). Most patients enrolled had low level of PD-L1 expression in the tumor as determined by immunohistochemistry (93% patients with <5% PD-L1 expression on tumor cells (TC0/1) and 79% patients with <5% PD-L1 expression on immune cell (IC0/1)). The majority of adverse events were Grade 1 or Grade 2 and those occurring in more than 15% of patients included infusion related reaction (IRR), fatigue, nausea, cytokine release syndrome (CRS) and diarrhea. IRR and CRS were transient and reversible and presented primarily as Grade 1 or Grade 2 chills and fever. There were no dose limiting toxicities. Eight patients (5.6%) discontinued due to AEs related to study drugs. RO1798457 (BNT122) induced a self-limiting increase of pro-inflammatory cytokines with each dose, consistent with the TLR agonist activity of RNA. Ex vivo T cell responses were observed in peripheral blood in 46 out of 63 (73%) patients. Induction of up to 5.7% MHC multimer-stained CD8+ T-cells with effector memory phenotype was observed in the peripheral blood. RO7198457 (BNT122) induced T cells against multiple neoantigens were detected in post-treatment tumor biopsies. Of 108 patients that underwent at least one tumor assessment, 1 patient had a complete response as their best response (0.9%), 8 patients had partial responses (7.4%), and 53 patients had stable disease (49.1%).

Based on data from our study of BNT121 as an adjunct to surgery in patients with metastatic melanoma, we believe that RO7198457 (BNT122) is potentially well suited to control metastatic relapses in patients with a lower tumor burden. Additionally, RO7198457 (BNT122) as a monotherapy and in combination with atezolizumab has been observed to have a manageable safety profile to date and to induce significant levels of neoantigen-specific immune responses, even in late-stage, heavily pre-treated patients. Accordingly, we and our collaborator, Genentech, intend to initiate two additional randomized Phase 2 trials in the second half of 2020 in early and adjuvant stage NSCLC and colorectal cancer, where we believe the mechanism of action of RO7198457 (BNT122) is best suited. We also continue to investigate RO7198457 (BNT122) in our ongoing Phase 2 trial in first line melanoma in combination with pembrolizumab.

Completed Phase 1 Clinical Trial (BNT121 First Generation iNeST)

In 2017, we published the results of a 13-patient, first-in-human trial of our first-generation intranodal iNeST product candidate, BNT121, in patients with late-stage malignant melanoma. The objective of this clinical trial was to study the feasibility, safety, tolerability, immunogenicity and potential anti-tumoral activity of iNeST. All patients had stable disease at enrollment with a high risk for relapse.

All 13 patients developed T cell immune responses against multiple immunotherapy neoepitopes at up to high single-digit percentages. As shown below, 60% of the selected neoepitopes elicited a T cell response. The detected immune response was elicited by both CD4+ and CD8+ T cells and the majority was induced de novo, which we believe to be an important requirement for an effective immune response and an added benefit beyond checkpoint inhibition alone.

 

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No severe adverse drug reactions were reported in the study. Common adverse events included flu-like symptoms.

 

 

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Immune responses documented in our prior BNT121 study. Patients showed immune responses, including both CD4+ and CD8+ responses, against multiple neoantigens. Source: Nature 547, 222-226 (13 July 2017).

 

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In addition, metastases resected from two patients following treatment with BNT121 demonstrated evidence of treatment-induced infiltration with BNT121-induced neoepitope-specific T cells and neoepitope-specific killing of tumor cells. The cumulative rate of metastatic events was significantly reduced after the start of treatment, resulting in a sustained progression-free survival. Of the 13 patients entering the trial, eight patients that had no radiologically detectable lesions at start of neo-epitope vaccination were relapse free and remained recurrence-free for the whole follow-up period (12 to 23 months). Five patients experienced melanoma relapses shortly after inclusion in the trial and despite initiation of standard treatment had progressing metastases at start of their neoepitope treatment. Of these, three patients developed neoepitope treatment-related objective clinical responses. One of these patients exhibited a complete response and remained relapse-free for 26 months. The second patient had an immunotherapy-related partial response. This patient had a late relapse owing to outgrowth of ß2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to treatment in combination with PD-1 blockade therapy.

 

 

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Metastatic relapses before and after treatment with BNT121. The chart above shows the metastatic relapses of patients before and after treatment with BNT121. Each horizontal line represents the time course of a single patient. The vertical line indicates the treatment start of BNT121. Source: Nature 547, 222-226 (13 July 2017).

 

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As of October 2019, nine out of 13 patients had remained recurrence-free through follow-up of up to 41 months post-vaccination.

 

 

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Next Steps

We expect to report an enrollment update from our RO7198457 (BNT122) first-line Phase 2 melanoma trial in the second half of 2020. We and Genentech plan to initiate two additional clinical trials for RO7198457 (BNT122) in 2020 in first-line solid cancers in the adjuvant setting, one in combination with atezolizumab and the other as a monotherapy.

3.    Intratumoral Immunotherapy

We, in collaboration with Sanofi, are developing intratumoral immunotherapies utilizing our proprietary mRNA technology. These immunotherapies are designed to be administered directly into the tumor in order to alter the tumor microenvironment and enhance the immune system’s ability to recognize and fight cancer within the tumor (proximal) as well as in other untreated locations (distal).

 

  a)

SAR441000 (BNT131): Our Initial Intratumoral Immunotherapy for the Treatment of Solid Tumors

We and Sanofi are developing SAR441000 (BNT131) as an intratumoral immunotherapy for the treatment of solid tumors. SAR441000 (BNT131) consists of modified mRNA that is injected directly into the tumor, where it is thought to express cytokines to alter the tumor microenvironment. SAR441000 (BNT131) is being studied in a Sanofi-sponsored Phase 1 clinical trial as a monotherapy in patients with advanced melanoma and in combination with an anti-PD-1/PD-L1 checkpoint inhibitor in patients with advanced melanoma and certain advanced solid tumors.

Our SAR441000 (BNT131) Targets

SAR441000 (BNT131) comprises mRNA that encodes the cytokines IL-12sc, IL-15sushi, IFN-α and GM-CSF. By expressing these cytokines in the tumor microenvironment, the immune system may more easily recognize and fight cancer.

Our SAR441000 (BNT131) Clinical Trials

Ongoing Phase 1 Clinical Trial

Sanofi, in collaboration with BioNTech, has commenced a first-in-human, multi-center, open-label, Phase 1, dose escalation and expansion trial to evaluate the safety, pharmacokinetics, pharmacodynamics and anti-tumor

 

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activity of SAR441000 (BNT131) administered intratumorally as monotherapy and in combination with cemiplimab, with an estimated enrollment of 264 patients with certain advanced solid tumors.

Our SAR441000 (BNT131) Preclinical Studies

In collaboration with Sanofi, we conducted a preclinical study of SAR441000 (BNT131) in mouse tumor models. In these in vivo models, the anti-tumor activity of cytokines encoded by mRNA was driven by the action of T cells as well as NK cells and was accompanied by robust intratumoral induction of interferon gamma, systemic expansion of antigen-specific T cells and increased granzyme B positive CD8+ T cell infiltration.

SAR441000 (BNT131) was shown to form immunological memory toward both dominant and subdominant antigens, which protected long-term survivors from re-challenge with autologous tumors. Importantly, although cytokine mRNAs were administered intratumorally, resulting in local target expression, anti-tumor activity extended beyond the injected tumor to effectively control the growth of distal tumors in both a dual-tumor model and an experimental lung metastasis model. Finally, SAR441000 (BNT131) demonstrated improved overall survival and higher incidence of complete tumor regressions across several preclinical models.

 

 

LOGO

Systemic anti-tumor effects in mouse model. As shown above, BNT131 demonstrated local and systemic anti-tumor effects of intratumoral cytokine mRNA. In this study, mice were implanted with a tumor on each of the right and left flank. One tumor was injected with intratumoral cytokine mRNA (or control mRNA) while the other was not. The top center figure shows the tumor volume of the treated tumor (red line) against the control (blue line). The top right figure shows an anti-tumor effect on the untreated tumor (red line) against the control (blue line). The figures on the bottom show the abscopal effect of an intratumoral cytokine mRNA (center bottom) on distal lung metastases compared to the control mRNA (right bottom). Source: Wagenaar et al., Local immunotherapy with a mixture of mRNAs encoding pro-inflammatory cytokines promotes potent anti-tumor immunity and tumor eradication across multiple preclinical tumor models; poster presented at SITC 2018.

Based on these preclinical results, we intend to investigate whether our synthetic mRNA technology can potentially deliver localized cytokine-based cancer immunotherapy with broad anti-tumor activity against treated and untreated lesions.

 

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Next Steps

A data update from this trial may be reported in the second half of 2020. As the trial is sponsored and conducted by Sanofi, the timing of data updates is not under our control, and is subject to change by Sanofi.

4.    RiboMabs

Our RiboMab product candidates are designed to encode secreted antibodies for expression in vivo by the patient’s cells. RiboMab product candidates consist of our proprietary nucleoside-modified mRNA that is designed to minimize the immunomodulatory activity of the mRNA, and these candidates are formulated using liver-targeting LNPs for intravenous delivery. RiboMabs potentially address the limitations of recombinant antibodies, including costly manufacturing processes and unfavorable pharmacokinetics, such as short plasma half-life. We are conducting preclinical studies for two development candidates, and have published compelling preclinical data.

RiboMab Preclinical Studies

We have generated RiboMabs targeting different tumor antigens and tested their therapeutic potency in mice engrafted with human tumors that were repopulated with human immune cells. We demonstrated in preclinical studies that injection with a RiboMab product candidate encoding bispecific RiboMabs directed against CD3 and CLDN6 antigens resulted in elimination of aggressively growing, large tumors. Intravenously administering a microgram dose of mRNA encoding RiboMabs resulted in bispecific RiboMab production in the liver cells and rapid secretion into circulation, reaching peak plasma concentration within hours and remaining at therapeutically effective levels for one week. The dosage and frequency of dosing of recombinant bispecific antibodies required to produce similar effects was substantially greater. This was the first preclinical study to demonstrate in vivo application of mRNA-encoded antibodies for the successful treatment of cancer.

a)    BNT141: Our Initial RiboMab for the Treatment of Solid Tumors

BNT141 is our RiboMab product candidate for the treatment of solid tumors. BNT141 is designed to encode secreted IgG antibodies.

Our BNT141 Targets

BNT141 is designed to encode secreted antibodies that target multiple epithelial solid tumors, including gastric and pancreatic cancers.

Next Steps

We expect to initiate a Phase 1 basket trial of BNT141 for the treatment of various solid tumors, including gastrointestinal tumors, in the first half of 2021.

b)    BNT142: Our Second RiboMab for the Treatment of Solid Tumors

BNT142 is our RiboMab product candidate for the treatment of solid tumors. BNT142 is designed to encode a secreted bispecific antibody that targets CD3 and CLDN6.

Our BNT142 Targets

BNT142 is designed to encode bispecific antibodies that target CD3, a T cell receptor that plays a key role in the activation of CD8+ and CD4+ T cells, and CLDN6, a highly specific oncofetal cell surface antigen that is found in solid tumors, but not in normal cells.

 

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Next Steps

We expect to initiate a Phase 1 basket trial of BNT142 for the treatment of numerous solid tumors in the first half of 2021.

5.    RiboCytokines

Our RiboCytokine product candidates utilize mRNA that encodes the desired cytokines for expression in vivo by the patient’s cells. RiboCytokine product candidates consist of modified mRNA designed to encode secreted cytokines that are formulated to use liver-targeting LNP for intravenous delivery.

Our RiboCytokine product candidates are designed to address the limitations of recombinantly expressed cytokines, including limited serum half-life and production costs. We are developing RiboCytokines to be used primarily in combination with other drugs, including our other pipeline candidates.

 

 

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In a preclinical mouse model, we observed RiboCytokines boost the activity of our RNA-LPX vaccination and a PD-L1 blockade in large tumors. Two out of 11 mice treated with our RNA-LPX vaccination and an anti PD-L1 alone achieved complete response. We observed three out of 11 mice achieve complete response with our RNA-LPX vaccination, an anti PD-L1 and IL7 RiboCytokine, six out of 11 mice with complete response after receiving our RNA-LPX vaccination, an anti PD-L1 and IL2 RiboCytokine and 11 out of 11 mice with complete response when given our RNA-LPX vaccination, an anti PD-L1 and both IL7 and IL2 RiboCytokines.

a)    BNT151: Our Initial RiboCytokine for the Treatment of Solid Tumors

We are developing BNT151, our RiboCytokine designed to encode a modified version of the human interleukin-2, or optimized IL-2, cytokine for the treatment of solid tumors. BNT151 is designed to stimulate T cells without triggering immunosuppression in the tumor microenvironment.

Our BNT151 Target

BNT151 comprises our nucleoside-modified mRNA that encodes mRNA for a function-modified IL-2. IL-2 is a key cytokine in T cell immunity, supporting the differentiation, proliferation, survival and effector functions of T cells.

 

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Recombinant IL-2, aldesleukin, was the first approved cancer immunotherapy, and has been marketed globally for the treatment of late stage melanoma and renal cell cancer for decades. Most patients with complete responses after IL-2 treatment remain regression free for more than 25 years after initial treatment, but overall response rates are low due in part to the limitations of recombinant cytokines. Recombinant IL-2 has a very short half-life, requiring high and frequent dosing and a partially unfavorable activity profile, which leads to increased side effects, thus limiting its utility as a cancer treatment.

Next Steps

We expect to initiate a Phase 1 clinical basket trial of BNT151 for the treatment of multiple solid tumors in the first half of 2021.

b)    BNT152: Our Second RiboCytokine for the Treatment of Solid Tumors

We are developing BNT152, our RiboCytokine designed to encode IL-7 for the treatment of solid tumors.

Next Steps

We expect to initiate a Phase 1/2 clinical trial of BNT152 in combination with BNT153 for the treatment of multiple solid tumors in the first half of 2021.

c)    BNT153: Our IL-2 variant RiboCytokine for the Treatment of Solid Tumors

We are developing BNT153, our RiboCytokine designed to secrete IL-2 for the treatment of solid tumors.

Next Steps

We expect to initiate a Phase 1/2 clinical trial of BNT153 in combination with BNT152 for the treatment of multiple solid tumors in the first half of 2021.

B. Our Oncology Cell Therapy Product Candidates

1. CAR-T

We are advancing multiple CAR-T product candidates, the most advanced of which, BNT211, is targeting the novel and highly specific target CLDN6+ in solid tumors, and which we expect to enter the clinic in the second half of 2020 for the treatment of CLDN6+ solid tumors, including ovarian cancer. We plan to use our initial CAR-T cell product candidates in combination with a FixVac immunotherapy that encodes the same target as the CAR-T. The FixVac selectively targets dendritic cells, which leads to uptake, antigen expression and maturation of the dendritic cells. The co-stimulation provided by dendritic cell maturation has been shown in preclinical studies to amplify and expand CAR-T cells in vivo, leading to increased persistence of the CAR-T.

a)    BNT211: Our CAR-T Cell Therapy for the Treatment of CLDN6+ Solid Tumors

BNT211 is our CAR-T cell therapy for the treatment of CLDN6+ solid tumors. BNT211 targets CLDN6 and will initially be evaluated in combination with a CARVac that encodes CLDN6.

Our BNT211 Target

BNT211 targets Claudin 6, or CLDN6, a highly specific oncofetal cell surface antigen that is found in multiple cancers, including ovarian, testicular and lung cancers, but not in normal cells.

 

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Our BNT211 Trials

Planned Phase 1/2 Clinical Trial

We anticipate initiating a Phase 1/2 open-label, multi-center dose escalation and dose expansion basket study of BNT211 with or without a CLDN6 CARVac immunotherapy in the second half of 2020. We anticipate enrolling patients with advanced solid tumor malignancies who express CLDN6. While our preclinical focus has been on ovarian cancer, we expect patients with uterine, testicular, lung and gastric cancers may also be enrolled in our upcoming CAR-T trials.

Preclinical Studies

We have observed compelling preclinical data of BNT211 demonstrating potent anti-tumoral activity, including eradication of advanced tumors in an ovarian carcinoma xenograft model.

 

 

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Potent anti-tumoral activity. As shown above, BNT211 demonstrated eradication of advanced tumors in a mouse model.

In January 2020, we published results for a preclinical study in which BNT211 was evaluated both in vitro in tumor cell lines and in vivo in mice with human ovarian cancer transplants. In mice, BNT211 demonstrated complete tumor regression of transplanted large human tumors within two weeks after treatment initiation. Furthermore, the combination with CARVac achieved improved engraftment, proliferation and expansion of CAR-T cells in vivo, resulting in tumor regression even at sub-therapeutic CAR-T doses. CARVac was also successfully applied for CAR-T cells targeting the pan-cancer antigen CLDN18.2 and CD19, the target of approved CAR-T cell therapies. The combination of CAR-T cell therapy with CARVac underlines the value of cross-platform synergies to address key development challenges in the treatment of cancer.

Next Steps

We are planning to initiate a Phase 1/2 clinical trial of the combination of BNT211 and a CLDN6-encoded CARVac in the second half of 2020 for the treatment of CLDN6+ solid tumors, including ovarian, testicular, uterine and lung cancer.

 

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b)    BNT212: Our CAR-T Cell Therapy for the Treatment of CLDN18.2+ Solid Tumors

BNT212 is our CAR-T cell therapy for the treatment of CLDN18.2-positive solid tumors. BNT212 will initially be evaluated in combination with a CARVac that encodes CLDN18.2.

Our BNT212 Target

BNT212 targets Claudin 18.2, or CLDN18.2, a highly specific target that is only expressed in cancer and in differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is expressed in numerous epithelial solid tumors, including gastric, pancreatic, esophageal, ovarian and lung tumors.

2. Neoantigen-Targeting T Cells.

We are advancing multiple neoantigen-targeting T cell product candidates, the most advanced of which, NEO-PTC-01 (BNT221), is targeting individualized sets of selected neoantigens, and which we expect to enter the clinic in the second half of 2020 for the treatment of metastatic melanoma. We are also developing NEO-STC-01 (BNT222), targeting shared RAS neoantigens prevalent across many solid tumor types.

 

  a)

NEO-PTC-01 (BNT221): Our Individualized Neoantigen-targeting T Cell Therapy for the Treatment of Cancer

NEO-PTC-01 (BNT221) is our individualized neoantigen-targeting T cell therapy for the treatment of cancer. NEO-PTC-01 (BNT221) targets selected sets individualized neoantigens. The second planned indication for NEO-PTC-01 (BNT221) is metastatic ovarian cancer.

Our NEO-PTC-01 (BNT221) Target

NEO-PTC-01 (BNT2211) targets sets of individualized neoantigens selected using our RECON bioinformatics engine.

Our NEO-PTC-01 (BNT221) Trials

Planned Phase 1 Clinical Trial

We are focusing the initial clinical development of NEO-PTC-01 (BNT221) in solid tumors where we believe we can generate de novo neoantigen T cell populations ex vivo. A CTA was filed with the Dutch Health Authority in December 2019 to evaluate NEO-PTC-01 (BNT221) in a first-in-human clinical trial in patients that are refractory to checkpoint inhibitors. We plan to initiate a Phase 1 dose escalation clinical trial in patients with metastatic melanoma who are refractory to checkpoint inhibitors in collaboration with the Netherlands Cancer Institute in the second half of 2020. The primary objectives of this trial will be to evaluate the safety and feasibility of administering NEO-PTC-01 (BNT221) to patients. Additional objectives will be to evaluate immunogenicity and clinical efficacy.

Based on the data from the first exploratory trial, we will decide how to best proceed with further clinical development of NEO-PTC-01 (BNT221), including expanding to other tumor types and potential development in the United States.

Preclinical Studies

Preclinical data relating to NEO-PTC-01 (BNT221) was presented at the Society of Immunotherapy of Cancer 2019 meeting, highlighting the proof of feasibility of our NEO-STIM induction protocol. These data demonstrated reproducibly across multiple patient samples, the ability to generate multiple CD8+ and CD4+ T

 

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cell populations in each patient sample from the memory and naïve compartment. These T cells were highly functional and were specific for mutant neoantigens. In addition, these data showed that these cells were capable of in vitro cell killing and NEO-PTC-01-induced T cell cultures directly recognize autologous tumor sample material. We can now reproducibly generate these cell populations from patient material at a therapeutic manufacturing scale.

Our NEO-STIM induction protocol generates a polyclonal population of T cells. Once generated, we deeply characterize this cell product to understand the specificity and functionality of the induced cells. Data analyzed from a melanoma patient shows that NEO-STIM can induce CD8+ T cell responses towards patient-specific neoantigens in autologous patient peripheral blood mononuclear cells, or PBMCs. Specifically, in this patient, as the charts below and to the left illustrate, a pre-existing memory response was expanded 16-fold, from 4.5% of CD8+ T cells to 72.1% of CD8+ T cells being specific for the selected neoantigen. Additionally, as the charts below and to the right illustrate, we induced two CD8+ T cell responses from the naïve compartment, generating 6.5% and 13.4% of CD8+ T cells, respectively. Finally, in this patient, we induced three neoantigen specific CD4+ T cell responses as well.

 

 

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Next Steps

We are planning to initiate a Phase 1 dose escalation trial of NEO-PTC-01 (BNT221) in the second half of 2020 for the treatment of metastatic melanoma.

C.    Our Antibody Product Candidates in Oncology

1.    Next-Generation Checkpoint Immunomodulators

In our 50:50 collaboration program with Genmab, we are currently studying two bispecific antibody checkpoint immunomodulators.

 

  a)

GEN1046 (BNT311): Our Jointly Owned DuoBody® PD-L1x4-1BB Bispecific Antibody for the Treatment of Solid Tumors

GEN1046 (BNT311), our jointly owned PD-L1x4-1BB product candidate, is a potential first-in-class bispecific antibody combining PD-L1 checkpoint inhibition with 4-1BB checkpoint activation. The first patient in a Phase 1/2a trial of GEN1046 (BNT311) for the treatment of malignant solid tumors was dosed in May 2019.

 

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Our GEN1046 (BNT311) Targets

GEN1046 (BNT311) is a PD-L1x4-1BB bispecific antibody that induces conditional activation of T cells through 4-1BB stimulation which is dependent on simultaneous binding to PD-L1. In addition, the PD-L1-specific arm of DuoBody-PD-L1x4-1BB functions as a classical immune checkpoint inhibitor by blocking the PD-1/PD-L1 axis, also in the absence of 4-1BB binding. PD-L1 is a validated target that is expressed on tumor cells. 4-1BB is a trans-membrane receptor belonging to the TNF super-family and is expressed predominantly on activated T cells. DuoBody® is a registered trademark of Genmab.

GEN1046 (BNT311) Trials

Ongoing Phase 1/2a Clinical Trial

The ongoing Phase 1/2a, open-label, single-arm GEN1046 (BNT311) trial with multiple expansion cohorts, conducted in collaboration with Genmab, is expected to enroll approximately 192 patients with malignant solid tumors. The trial consists of a dose escalation part and an expansion part. The dose escalation part will determine the safety profile of GEN1046 (BNT311) in subjects with certain relapsed or refractory, advanced and/or metastatic malignant solid tumors who are no longer candidates for standard therapy. The expansion part will be initiated once the recommended Phase 2 dose has been established in Phase 1. In the expansion part, GEN1046 (BNT311) will be administered intravenously once every 21 days. The primary endpoints of the trial are dose-limiting toxicities, adverse events and safety laboratory parameters, including hematology, biochemistry, coagulation and endocrinology.

Preclinical Studies

In preclinical settings, GEN1046 (BNT311) induces conditional activation of T cells through 4-1BB stimulation which is dependent on simultaneous binding to PD-L1. In addition, the PD-L1-specific arm of DuoBody-PD-L1x4-1BB functions as a classical immune checkpoint inhibitor by blocking the PD-1/PD-L1 axis.

Next Steps

We expect to report a data update for our ongoing Phase 1/2 trial in the second half of 2020.

 

  b)

GEN1042 (BNT312): Our Jointly Owned DuoBody® CD40x4-1BB Bispecific Antibody for the Treatment of Solid Tumors

GEN1042 (BNT312), our jointly owned CD40x4-1BB antibody product candidate, is a potential first-in-class bispecific antibody designed to induce conditional immune activation by crosslinking CD40 and 4-1BB positive cells. We and Genmab began recruitment and screening for a Phase 1/2a trial of GEN1042 (BNT312) for the treatment of malignant solid tumors in August 2019.

GEN1042 (BNT312) Targets

GEN1042 (BNT312) is a bispecific antibody designed to enhance an anti-tumor immune response through conditional CD40-mediated stimulation of antigen presenting cells cross-linked with conditional stimulation of 4-1BB+ T cells. It has demonstrated increased tumor infiltrating lymphocyte expansion in human tumor tissue cultures ex vivo and has induced tumor regression of murine tumors superior to pure PD-L1 blockage associated with an increase in tumor-specific CD8 T-cells. The cell surface molecule CD40 is a member of the tumor necrosis factor receptor superfamily.

GEN1042 (BNT312) Preclinical Studies

GEN1042 (BNT312) is designed to target CD40 and 4-1BB to enhance both dendritic cell and antigen-dependent T cell activation. In preclinical settings, GEN1042 (BNT312) activated antigen presenting cells and enhanced T cell activation. Preclinical studies also indicated the conditional activation and (clonal) expansion of previously activated CD8+ T cells and cytokine production resulting from GEN1042 (BNT312).

 

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2.    Targeted Cancer Antibodies

 

  a)

MVT-5873 (BNT321): Our Targeted Cancer Antibody for the Treatment of Pancreatic Cancer

In May 2019, we acquired certain antibody assets from MabVax Therapeutics Holding, Inc., including MVT-5873 (BNT321), a clinical-stage targeted cancer antibody.

Pancreatic Cancer

In 2019, the American Cancer Society estimated that approximately 56,770 people will be diagnosed with pancreatic cancer in the United States annually. Pancreatic cancer is an aggressive cancer, with a five-year survival rate from diagnosis, across all stages combined, of 9%.

Our MVT-5873 (BNT321) Target

MVT-5873 (BNT321) is a fully human IgG1 monoclonal antibody targeting sialyl Lewis A (sLea), an epitope on CA19-9 that is expressed in pancreatic and other gastrointestinal cancers that plays a role in tumor adhesion and metastasis formation, and is a marker of an aggressive cancer phenotype.

Our MVT-5873 (BNT321) Trials

MVT-5873 (BNT321) is being investigated in an open-label, multi-center, non-randomized dose escalation Phase 1/2 study evaluating the safety and recommended Phase 2 dose of MVT-5873 (BNT321) both as a monotherapy and in combination with a standard of care chemotherapy in approximately 68 subjects with pancreatic and other CA19-9+ malignancies. Secondary objectives include evaluating tumor response rate by RECIST 1.1, duration of response, and determining pharmacokinetics. This study utilizes a conventional 3+3 design to identify the recommended Phase 2 dose.

Interim data for the combination cohort was reported in February 2018. In this cohort, MVT-5873 (BNT321) was given in combination with nab-paclitaxel and gemcitabine to patients newly diagnosed with CA19-9+ pancreatic cancer. MVT-5873 (BNT321) at a dose of 0.125mg/kg when added to first-line chemotherapy was generally well tolerated by all subjects. All six patients evaluated had measurable tumor reductions by RECIST, with four patients meeting the criteria for partial response and two patients meeting the criteria for stable disease.

We have resumed this trial and dosing has begun.

D.    Our Oncology Small Molecule Immunomodulator Product Candidates

1.    BNT411: Our Small Molecule TLR7 Agonist for the Treatment of Solid Tumors, Including Small Cell Lung, Colorectal and Bladder Cancer

BNT411 is our novel small molecule TLR7 agonist product candidate. BNT411 is designed to activate both the adaptive and innate immune system through the TLR7 pathway. We are designing BNT411 to be used both as a monotherapy and in combination with chemotherapy and checkpoint inhibitors. We filed an IND for BNT411 in November 2019 and dosed the first patient in our Phase 1 trial in July 2020.

Our BNT411 Target

BNT411 is a TLR7 agonist that is designed to activate both the adaptive and innate immune system through the TLR7 pathway. This activity and the release of cytokines and chemokines are designed to result in the potent stimulation of antigen-specific CD8+ T cells, B cells and innate immune cells such as NK cells and macrophages.

 

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Our BNT411 Preclinical Studies

In preclinical studies, BNT411 (SC1.2/Ago1.2) was shown to be more potent in the induction of IFN-α compared to the clinical competitor compound resiquimod (R848), even at lower concentrations (minimal effective concentration of BNT411 in vitro is 4nM). In contrast to the tested competitor compound, BNT411 was shown to induce at low concentrations especially IFN-α whereas other (pro-)inflammatory and CRS-related cytokines (IL-6, IL-10, TNF-a, IL-8) are only observed at higher concentrations.

 

 

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E.    Our Infectious Disease mRNA Product Candidates

1.    Prophylactic Vaccine for the Prevention of COVID-19

We are collaborating with Pfizer and Fosun Pharma for the development of a vaccine for the prevention of COVID-19 under our BNT162 program. We and Pfizer are jointly conducting clinical trials for the COVID-19 vaccine candidates initially in the United States and Europe across multiple sites.

We have begun development of four product candidate variants under our BNT162 program, including one prime-only and three prime-boost immunization strategies, utilizing different mRNA formats. In addition, we continue to develop additional product candidate variants and may bring additional candidates into the clinic if the preclinical data supports it.

 

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Our BNT162 Targets and mRNA Formats

We are developing multiple vaccine candidate variants, some of which target the entire 2P-mutated full Spike protein antigen and others which target the more specific receptor binding domain subunit of the antigen protein.

 

 

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In addition, we are studying three different mRNA formats in our four vaccine candidate variants.

 

BNT 162 Candidate

   Target    mRNA Format

162a1

   RBD subunit    uRNA (prime/boost)

162b1

   RBD subunit    modRNA (prime/boost)

162b2

   2P-mutated full Spike protein    modRNA (prime/boost)

162c2

   2P-mutated full Spike protein    saRNA (single injection)

The graphic below illustrates the potential benefits and rationale for each mRNA format used in our candidate variants.

 

 

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Our BNT162 Clinical Trial

We are conducting a multi-site, open label, Phase 1/2, two-part, dose-escalation trial investigating the safety and immunogenicity of our four BNT162 candidate variants using different dosing regimens in healthy adults. The trial is being conducted in multiple locations in Germany and the United States. The trial has two parts: a dose-finding part (Part A) with four dose cohorts (treatment groups) for each vaccine candidate variant and one pre-defined and one optional dose level for a de-escalation approach and a second part (Part B) dedicated to recruit expansion cohorts with dose levels which are selected from data generated in Part A. The vaccine candidate variants BNT162a1, BNT162b1, and BNT162b2 will be administered using a prime/boost regimen. The vaccine candidate variant BNT162c2 will be administered using a single-dose regimen.

July 2020 Data Announcements

On July 1, 2020, we and Pfizer announced preliminary data from our ongoing U.S. Phase 1/2 trial of BNT162b1. The initial part of this randomized, placebo-controlled, observer-blinded study is evaluating the safety, tolerability and immunogenicity of escalating dose levels of BNT162b1, one of four vaccine candidate variants in development as part of our BNT162 program, in 45 healthy adults between 18 and 55 years of age.

The participants received two doses, 21 days apart, of placebo, 10µg or 30µg of BNT162b1, or received a single dose of 100µg of the vaccine candidate. Because of a strong vaccine booster effect, the highest neutralizing titers were observed seven days after the second dose of 10µg or 30µg on day 28 after vaccination. The neutralizing GMTs were 168 and 267 for the 10µg and 30µg dose levels, respectively, corresponding to 1.8- and 2.8-times the neutralizing GMT of 94 observed in a panel of 38 sera from subjects who had contracted SARS-CoV-2.

In all 24 subjects who received 2 vaccinations at 10µg and 30µg dose levels of BNT162b1, elevation of RBD-binding IgG concentrations was observed after the second injection with respective GMCs of 4,813 and 27,872 units/ml at day 28, seven days after immunization. These concentrations are 8- and 46.3-times the GMC of 602 units/ml in a panel of 38 sera from subjects who had contracted SARS-CoV-2.

At day 21 after a single injection, the 12 subjects who received 100µg of BNT162b1 had an RBD-binding IgG GMC of 1,778 units/ml and a SARS-CoV neutralizing GMT of 33, which are 3-times and 0.35-times, respectively, the GMC and GMT of the convalescent serum panel.

At the 10µg or 30µg dose levels, adverse reactions, including low grade fever, were more common after the second dose than the first dose. Following dose 2, 8.3% of participants who received 10µg and 75.0% of participants who received 30µg BNT162b1 reported fever ³ 38.0 °C. Local reactions and systemic events after injection with 10µg and 30µg of BNT162b1 were dose-dependent, generally mild to moderate, and transient. The most commonly reported local reaction was injection site pain, which was mild to moderate, except in one of 12 subjects who received a 100µg dose, which was severe. No serious adverse events were reported. Given higher numbers of subjects experiencing local reactions and systemic events after a single 100µg dose with no significant increases in immunogenicity compared to the 30µg dose level, the 12 participants in the 100µg group were not administered a second dose.

On July 20, 2020, we and Pfizer announced preliminary data from our ongoing German Phase 1/2 trial of BNT162b1. The initial part of this open-label, non-randomized, non-placebo-controlled study is evaluating the safety, tolerability and immunogenicity of escalating dose levels of BNT162b1, one of four vaccine candidate variants in development as part of our BNT162 program, in 60 healthy adults, between 18 and 55 years of age. The preliminary data we reported was from 12 subjects each who received two doses of 1µg, 10µg, 30µg and 50µg (except for one individual each in the 10µg and 50µg who discontinued due to non-study drug related reasons) and 12 subjects who received a single dose of 60µg. The two doses received by the participants were given 21 days apart.

 

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In 34 of the 36 subjects who received two vaccinations at 10µg, 30µg, or 50µg dose levels of BNT162b1, RBD-specific CD4+ T cell responses were observed. All subjects but the two exceptions at the lowest dose level had cytokine profiling of the RBD-specific CD4+ T cells that demonstrated a TH1-dominant profile for these cells. While the magnitude varied between individuals, participants with the strongest CD4+ T cell responses to RBD had more than 10-fold of the memory responses observed in the same participants when stimulated with cytomegalovirus (CMV), Epstein Barr virus (EBV), influenza virus and tetanus toxoid-derived immuno- dominant peptide panels. The strength of RBD-specific CD4+ T cell responses correlated positively with both RBD-binding IgG and with SARS-CoV-2 neutralizing antibody titers. Among vaccine-induced CD8+ T cell responses, which were observed in 29 of 36 participants, strong responses were mounted by the majority of participants and were comparable with memory responses against CMV, EBV, influenza virus and tetanus toxoid in the same participants. The strength of RBD-specific CD8+ T cell responses correlated positively with vaccine- induced CD4+ T cell responses, but did not significantly correlate with SARS-CoV-2 neutralizing antibody titers. Additionally, although at 1µg the immunogenicity rate was lower (6 of 8 responding participants), the magnitude of vaccine-induced CD4+ and CD8+ T cells in some participants was almost as high as with 50µg BNT162b1.

Elevation of SARS-CoV-2 RBD-binding IgG concentrations was observed, with respective GMCs ranging from 265 units/ml to 1,672 units/ml at day 21. At day 29, seven days after the second dose, RBD-binding IgG GMCs ranged from 2,015 units/ml to 25,006 units/ml. At day 43, RBD-binding IgG GMCs ranged from 3,920 units/ml to 18,289 units/ml. These concentrations are 6.5- to 30.4-times the GMC of 602 units/ml in a panel of sera from 38 subjects who had contracted SARS-CoV-2. At day 29, the SARS-CoV-2 neutralizing GMTs reached 36 (1µg dose), 158 (10µg dose), 308 (30µg dose) and 578 (50µg dose) compared to neutralizing GMT of 94 observed in the convalescent serum panel. At day 43, SARS-CoV-2 neutralizing GMTs reached .7-fold (1µg dose) to 3.2-fold (50µg dose) compared to those of a panel of SARS-CoV-2 infection convalescent human sera. Furthermore, sera of vaccinated subjects displayed broadly neutralizing activity in pseudovirus neutralization assays across a panel of sixteen SARS-CoV-2 RBD variants represented in publicly available SARS-CoV-2 sequences and against the newly dominant D614G strain. In summary, antibody responses elicited by BNT162b1 in our German clinical trial largely mirrored those observed in our U.S. clinical trial.

At the 10µg, 30µg and 50µg dose levels, certain adverse reactions, including low grade fever, were more common after the second dose than the first dose. Following the second dose, 25.0%, 25.0% and 33.3% of participants who received the 10µg, 30µg and 50µg doses, respectively reported fever of at least 38.0 degrees Celsius. Local reactions and systemic events after injection with 10µg, 30µg and 50µg of BNT162b1 were dose- dependent, generally mild to moderate and transient, with occasional severe events (grade 3) of flu-like symptoms and injection site reactions. The most commonly reported local reaction was injection site pain, which was mild to moderate, except in one of 12 subjects who received a 60µg dose, which was severe. No serious adverse events were reported, and there were no withdrawals due to adverse events related to the vaccine. Based on the adverse reactions reported after the 50µg boost dose, a second 60µg dose was not administered to participants who had received an initial 60µg dose.

For additional information on these preliminary results, please review our reports on Form 6-K filed with the SEC on July 1, 2020 and July 20, 2020 and incorporated by reference herein.

Next Steps

Based on preclinical and clinical data observed to-date, we and Pfizer have decided to progress our BNT162 development program into a Phase 2b/3 trial, which is anticipated to commence in late July 2020, subject to input and approval from the appropriate regulatory bodies. For the initial Phase 2b/3 trial, we intend to select either BNT162b1 or BNT162b2. Both the BNT162b1 and the BNT162b2 vaccine candidates have received Fast Track status from the FDA. Since clinical evaluation of the BNT162b2 candidate started several weeks later than BNT162b1, only preliminary clinical data are currently available for the BNT162b2 candidate. A set of data obtained for a cohort of subjects 18-55 years of age immunized with 10µg of BNT162b2 indicates that BNT162b2 induces similar virus neutralizing antibody responses as observed for BNT162b1. The preliminary

 

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observations are subject to further data collection and analysis. Assessment of dose dependent immune response and safety profile as well as analysis of T cell responses is currently pending. On the basis of additional data expected to be collected and analyzed for BNT162b1 and BNT162b2 in the coming days, along with input from the FDA, we intend to select a lead candidate to take into a Phase 2b/3 trial. We and Pfizer currently expect to inform the FDA of our selection of the BNT162 candidate variant before the closing of this offering. Based on clinical data from our ongoing Phase 1/2 trials of BNT162b1 in the United States and Germany, BNT162b1 appears to be a viable variant to advance into a Phase 2b/3 trial. However, given that additional information relating to BNT162b2 is becoming available over the next few days, we and Pfizer plan to make the ultimate decision on the final candidate based on multiple factors, including the overall observed safety, tolerability and immunogenicity profiles for each vaccine candidate at different dose levels, a full immunogenicity data set and feedback from the FDA on the data collected for each candidate. If we ultimately move forward with the BNT162b2 variant, it will be due to the fact that based on our scientific judgment in light of the totality of preclinical data and clinical data available to us at the time of selection and the other factors described above, the BNT162b2 variant has better potential for clinical and commercial success. We do not plan to disclose which BNT162 variant has been selected until we receive FDA approval to commence the Phase 2b/3 clinical trial, and we likely will not publish any data with respect to the BNT162b2 variant before we make our selection.

2.    Prophylactic Vaccine for the Prevention of Influenza

We are collaborating with Pfizer to develop an influenza vaccine based on our mRNA drug classes. The product candidate, BNT161, will encode influenza virus antigens selected by the WHO in advance of the flu season. We and Pfizer have moved the anticipated Phase 1 start for our mRNA flu vaccine program to 2021 due to the prioritization of our COVID-19 vaccine development efforts.

Next Steps

We anticipate beginning a first clinical trial for BNT161 in 2021.

3.    Other Infectious Diseases

We have a research collaboration with Penn, under which we have the exclusive option to develop and commercialize prophylactic mRNA immunotherapies for the treatment of up to 10 infectious disease indications. On September 20, 2019, Penn announced positive preclinical results of a vaccine product candidate using its mRNA technology. The preclinical study vaccinated mice and guinea pigs against Herpes simplex virus type 2. Penn reported that the immunization led to “mostly sterilizing immunity” from the virus.

Next Steps

We expect to initiate our first Phase 1 clinical trial under Penn collaboration in the first half of 2021.

F.    Our Rare Disease Protein Replacement mRNA Product Candidates

We are collaborating with Genevant, in order to combine our mRNA technology with Genevant’s LNP delivery technology, to create up to five mRNA protein replacement therapies for the treatment of rare diseases with high unmet medical needs. We expect our first compound from this collaboration to enter the clinic in the second half of 2021. The first product candidate under the Genevant collaboration, BNT171, is currently being developed for an undisclosed indication. Our mRNA replacement product candidate is associated with a favorable tolerability profile and good protein expression (in mice) and demonstrated phenotype rescue in a mouse disease model.

 

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G.    Other

Our legacy commercial stage product, MammaTyper, is a molecular in vitro diagnostic test for the quantitative detection of the mRNA expression of ERBB2, ESR1, PGR and MKI67 in breast cancer tissue. MammaTyper has been shown in a variety of scientific publications to offer superior diagnostics insights compared to conventional immunohistochemical detection methods.

XIII.    Manufacturing

We are building a fully integrated biotechnology company, with operations spanning from research through clinical development, and manufacturing through sales and marketing. We operate three GMP-certified manufacturing facilities in Germany, where we manufacture mRNA therapeutics and engineered cell therapies for our own pipeline and for external customers. We operate a fourth facility in Germany where we manufacture custom peptides to support our extensive immunomonitoring activities within our development programs. Our subsidiary BioNTech Innovative Manufacturing Services GmbH, or BioNTech IMFS, has been manufacturing GMP-certified cellular products since 1999. It was granted its first GMP license for manufacturing mRNA in 2011 and has been manufacturing individualized mRNA products since 2014.

We have expanded our capability to produce and supply drug products to support clinical development of our, and our collaborators’, product candidates. To date, we have manufactured about 1000 drug substance batches in our manufacturing facilities.

Our approach has been to proactively build capacity in anticipation of demand from internal research and development, as well as from our collaborators. We have done so by continuing to make significant investments in manufacturing infrastructure and increasingly expanding our capacity to manufacture mRNA, viral vectors, cellular products and peptides. We believe the development and optimization of our manufacturing processes in parallel to drug development is crucial to our success. We have also collaborated with Siemens to develop a process for a fully-automated, on-demand production of mRNA therapies.

Our Manufacturing Operations

mRNA. We believe scaling up manufacturing for mRNA can best be executed as part of a proprietary manufacturing approach, not as part of an outsourcing strategy. We believe this approach allows us to maintain control of our proprietary processes and gives us the flexibility we need for scheduling batch production for our drug substances to match our development plans as they evolve. Our mRNA manufacturing is currently conducted at our in-house BioNTech IMFS facility and our BioNTech East Wing facility, the latter being dedicated to iNeST and bulk mRNA manufacturing. Our mRNA manufacturing process involves standardized production of all mRNA constructs and minimal restrictions in construct length. We have the capacity to undertake sterile filtration and final filling in up to 1,200 vials of various sizes. Batch sizes range from a few milligrams for individualized applications (i.e., iNeST) to 10g for standard mRNA applications (i.e., FixVac, intratumoral immunotherapies and infectious diseases, e.g., COVID-19), with batch sizes of up to 250g planned for Q4 2020.

To date, we have produced about 1000 batches of mRNA drug substance to support our studies. We currently have infrastructure capable of producing more than 100 batches of mRNA drug substance and formulated drug product per month with a turnaround time of about 30 to 40 days from sequence identification to released product. We believe we currently have the capacity to supply needs of our product candidates in clinical trials up to registration.

In recent years, we have successfully decreased the time required to deliver individualized immunotherapy to patients. In 2014, it took us over three months to manually manufacture and deliver individualized immunotherapies to patients. Since December 2017, with the implementation of semiautomatic GMP

 

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manufacturing in collaboration with Siemens, we have been consistently manufacturing and delivering individualized immunotherapies in under six weeks. This advancement represents significant progress toward our target commercial manufacturing turnaround time of less than 28 days. We believe this is achievable, and we plan to continue to develop additional process improvements, which we expect will further reduce our turnaround times as we progress through clinical development.

Cell Therapy Products. We have end-to-end capabilities and over 20 years of experience in cell therapy manufacturing. Our manufacturing process for cellular products involves the isolation of primary human cells and subpopulations, including CD34+ and CD3+ cells. We engage in the culturing, expansion and genetic modification of primary human cells as well as mammalian cell lines. Our processes include vector production for transfection of cells with CARs, cell banking and cryopreservation.

We have set up a broad range of quality control assays for the characterization of cell therapy products that allow us to certify the manufactured drug products in a short time. We are a leader in the production of gamma retroviral vectors. To date, we have produced more than 50 different cell therapy products.

Peptides. Our custom peptide synthesis business has developed unique technologies to produce several million peptides during the past three years to support our growing clinical pipeline. These include fast small-scale manufacturing of peptides for target and epitope discovery as well as for neoepitope characterization and production of high content arrays. It is important to synthesize highly purified peptides in order to avoid false positives in immunomonitoring in our mRNA immunotherapy trials. We also use these peptides as starting material in our engineered cell therapies. We have developed know-how to produce highly complex and purified peptide pools that consist of overlapping peptides spanning entire antigens or neoepitopes. We plan to establish a new production facility, which will roughly double our current capacity.

Our Manufacturing Facilities

We operate four manufacturing and packaging facilities in Germany. In these facilities, we manufacture and package individualized mRNA, bulk mRNA, retroviral vectors, cellular products and peptides. In Mainz, we are currently constructing another facility for iNeST manufacturing at a commercial scale, which is planned to start manufacturing in 2022 and will supply markets mainly in Europe and the United States