Earnings Call Transcript - BNTX Q3 2021

Operator, Operator

Thank you for standing by, and welcome to BioNTech's Third Quarter 2021 update call. At this time, all participants are in listen-only mode. We would like to ask you to please limit yourself to one question per person. I must advise you this call is being recorded today, Tuesday November 9, 2021, and I would now like to hand the meeting over to the Vice President, Investor Relations and Strategy, Sylke Maas. Please go ahead.

Sylke Maas, Vice President, Investor Relations and Strategy

Good morning and good afternoon. Thank you for joining us today to review BioNTech's Third Quarter 2021 operational updates and financial results. Before we start, we encourage you to view the slides for this webcast, as well as the operational and financial results relevant to these issues this morning, both of which are accessible on our website in the Investor section. As shown on Slide 2, during today's presentation, we will be making several forward-looking statements. These forward-looking statements include, but are not limited to, our current estimated COVID-19 vaccine revenues based on current contracted supply orders, particularly for those figures that are derived from preliminary estimates provided by our partners or estimated financial results for 2021. Additionally, we will discuss our continued global demand for our COVID-19 vaccine, our target vaccine production capacity for 2021 and beyond, and the ability to supply our COVID-19 vaccine, along with plans for steps in our pipeline programs, timelines for enrollment, initiation, completion, and reporting of data from our clinical trials, and other risks described in our filings made to the U.S. Securities and Exchange Commission, including our most recent annual report on Form 20-F. Accurate results could differ from those we currently anticipate. Therefore, you are cautioned not to place undue reliance on any forward-looking statements, which speak only as of today during this conference call and webcast. Also, please note that Slides 3 and 4 provide detailed and important safety information regarding our COVID-19 vaccine. Slide 5 is our agenda for our call today. I am joined today by our CEO and Co-Founder, Ugur Sahin, Ozlem Tureci, our Chief Medical Officer and Co-Founder, Sean Marett, our Chief Business and Commercial Officer, Jens Holstein, our Chief Financial Officer, Ryan Richardson, our Chief Strategy Officer, and Sierk Poetting, our Chief Operating Officer. I now turn the call over to Ugur Sahin.

Ugur Sahin, CEO and Co-Founder

Thank you, Sylke. Good morning and good afternoon. And thank you to everyone joining the call today. I will walk you through the key highlights of last quarter's performance before inviting my team to go into further detail. Our strong performance continued in the third quarter in terms of commercial execution and clinical pipeline advancement. With our partner Pfizer, we have shipped more than 2 billion doses of our COVID-19 vaccine to more than 152 countries or regions worldwide. We continue to be humbled by the impact our vaccine and our company are having in addressing the global pandemic. However, we still have further to go to reach many parts of the world. We are prioritizing equitable vaccine access to lower and middle-income countries. In the first three quarters of 2021, we expanded our oncology pipeline faster than during any other period in our company's history. We initiated three randomized Phase 2 trials and multiple research in human studies. We will present data for six of our programs at the upcoming SITC conference, clearly demonstrating the focus in our cancer pipeline. Moving to Slide 7; our strategy remains focused on bringing both our patent of next-generation immunotherapies and vaccines to patients worldwide to address cancer and a growing list of infectious diseases. The transformation of BioNTech into a global fully integrated immunotherapy powerhouse is continuing at a rapid pace. We are adding talent to our team. We are expanding our capabilities and geographic presence. We are increasing our investment in automation, digitalization, and AI technology. Our vision is to build a tech-forward company of the coming age. We are developing exciting innovations at the intersection of immunology and synthetic biology. We believe our innovations can make a profound difference for people around the world, and we remain committed to investing in the company to deliver on this vision in the coming years. Slide 8. We are driving innovations across multiple therapeutic platforms to harness the power of the immune system and to transform treatment paradigms in infectious diseases and solid tumors. The last 18 months have demonstrated the power, flexibility, and speed of our mRNA vaccine technology. We have established a proven path to regulatory approval for our first vaccine and have created one of the largest safety databases for pharmaceutical products. This is supported by our global manufacturing and distribution network that has the capacity to provide millions of doses of vaccine supply for the world. Behind COVID-19, we are advancing a pipeline of 10 mRNA vaccines and immunotherapies for diseases that cause major global health challenges, including influenza, HIV, tuberculosis, and malaria. We plan to accelerate our efforts here and aim to initiate multiple clinical trials in the next 18 months. In oncology, we are building a toolbox of technologies across a range of drug classes. We now have 15 oncology product candidates in 19 ongoing clinical trials, including four active Phase 2 trials. We are addressing a wide range of therapeutic targets with diverse and complementary modes of action. We believe that this multi-modal approach opens up new and powerful combination therapy opportunities across a broad range of solid tumors where current standards of care are not sufficient. Finally, we believe that the broad spectrum of our technologies will enable us to bring forward new treatment approaches that have the potential to broaden the disease horizon beyond oncology and infectious diseases to include autoimmune and inflammatory diseases, and even personalized medicine. Slide 9 summarizes the key highlights for the third quarter. Our financial performance continues to be strong. We recorded in Q3 revenues of approximately 6 billion euros driven by the continued ramp-up of COVID-19 vaccine production and delivery worldwide. Today, we are announcing a new expansion of our infectious disease toolkit with a new class of precision antibacterials through the acquisition of a biotechnology company. This acquisition complements our infectious disease pipeline of mRNA vaccines and mRNA-encoded antibodies with a new precision NPA technology that we believe could be useful against the global challenge of antimicrobial resistance. In the third quarter, we initiated dosing in our randomized Phase 2 trials of autogene cevumeran or BNT122, one of our iNeST candidates for the adjuvant treatment of high-risk stage III melanoma patients who are positive for circulating tumor DNA. Additionally, our fixed mRNA product candidate BNT111 was recently granted Orphan designation by the US FDA for the treatment of advanced melanoma. In our infectious diseases segment, we initiated a human study of BNT161, an influenza vaccine, based on our mRNA technology. With regard to our COVID-19 vaccine, we have now distributed a total of more than 2 billion vaccine doses globally. We expect to produce up to 3 billion doses for 2021 and expect to deliver up to 2.5 billion COVID-19 doses by the end of this year. In 2022, we expect our manufacturing capacity to reach up to 4 billion doses. Our COVID-19 vaccine has now received BLA FDA approval in the United States for individuals aged 16 and older. The U.S. FDA has also authorized a booster dose of the vaccine for some higher-risk populations. In the EU, a booster dose has been approved for subjects aged 18 years and older. To support the extension of the vaccine label to include children aged 5 to under 12, we have submitted a clinical data package to regulators globally. The FDA has recently granted Emergency Use Authorization for BNT162B2 in children aged 5 to under 12, and the U.S. government purchased an additional 50 million pediatric doses. I feel humbled by our team's continued exceptional work, and I would like to close my remarks by emphasizing that even as BioNTech is transforming, we will continue to stay true to our vision and remain focused on our goal to bring the next-generation immunotherapy to patients around the world. I will now turn the call over to Sean, who will provide updates on our COVID-19 program.

Sean Marett, Chief Business and Commercial Officer

Thanks, Ugur. It's a pleasure to be speaking with everyone today. Turning now to Slide 11, together with our collaborators Pfizer and others, we have established a global development program and distribution network for our COVID-19 vaccine. Our order book for 2021 continues to be strong with the addition of several new orders from the U.S., Japan, and other regions last quarter. Discussions regarding additional contracts for 2022 and beyond remain ongoing. We anticipate that the additional 50 million pediatric doses ordered by the U.S. government should be delivered by April 30th, 2022. With this order, the U.S. government exercised its final purchase option under its existing supply agreement, bringing the total number of BNT162B2 doses secured under this agreement since the start of the pandemic to 600 million. We continue to lead in ensuring equitable vaccine access to low- and middle-income countries. BioNTech has pledged 2 billion doses by the end of 2022, and a significant amount of our remaining 2021 manufacturing will be allocated to equitable vaccine access. Importantly, we have expanded our agreement with the U.S. government from 500 million to 1 billion doses at a not-for-profit price for 2021 and 2022. These doses are intended for donation to low and lower-middle-income countries and organizations that support them. Our hope is that by increasing vaccine access in these regions, we can bring surges in infections under control in many parts of the world. We and our partner Pfizer are also expanding our global manufacturing capabilities with regional solutions in Africa and Latin America. This includes the letter of intent we signed with Eurofarma Laboratories in Brazil to manufacture our COVID-19 vaccine. Per this agreement, Eurofarma will obtain drug product from facilities in the United States, and manufacturing of finished doses is expected to commence in 2022. At full operational capacity, the annual production is expected to exceed 100 million finished doses. Additionally, we recently signed a memorandum of understanding with the Rwandan government and Institute Pasteur de Dakar and announced plans to start construction in mid-2022 of the first stage of a manufacturing site for mRNA technology in the African Union. We believe this facility can become a key part of a decentralized and robust African end-to-end manufacturing network to provide sustainable vaccine supply on the African continent. Establishment of this regional network is expected to enable annual manufacturing capacity of several hundreds of millions of mRNA vaccine doses. Moving to Slide 12, I will provide an update on our strategic key levers to explain the global reach of our vaccine. The slide provides an overview of progress across all areas, but I will only be highlighting those details which haven't already been touched on by Ugur. Starting with our manufacturing capacity, we have worked continually with our partner Pfizer to increase the capacity of the global supply chain and manufacturing network, which now includes more than 20 facilities across four continents. We have multiple ongoing clinical trials in place to expand our vaccine label and generate useful data in additional populations, including trials in younger children and pregnant women. We are currently expecting data for children aged 2 to 5 years and children aged 6 months to 2 years in late Q4 2021 or early Q1 2022. Ugur already highlighted our significant progress on the regulatory front and our data for children aged 5 to 11 years, which Ozlem will cover in detail. We have further optimized our vaccine formulations to simplify global access, and we recently received authorizations from both the FDA and EMA to store our vaccine for up to nine months at -92 to -60 degrees Celsius. Additionally, following a positive opinion from CHMP, the European Commission approved a new formulation of BNT162B2 that further simplifies vaccine handling and storage conditions. The vials can now be stored for up to 10 weeks at standard refrigeration temperatures of 2 to 8 degrees Celsius. Our understanding of the human immune response to COVID-19, as well as emerging variants, continues to evolve, and our team is continuously evaluating the data, alongside our own clinical studies, to rapidly respond to the changing dynamics of the pandemic. Multiple trials are ongoing to address the need for boosted doses of BNT162B2. While we don't plan to commercialize a specific version of the vaccine at this time, we remain ready to adapt our technology, manufacturing, and regulatory processes to ensure our vaccine provides robust protection against COVID-19. We are very pleased with the latest clinical and regulatory developments for our vaccine, which demonstrate our strong execution in response to the COVID-19 pandemic.

Ozlem Tureci, Chief Medical Officer and Co-Founder

Thank you, Sean. I'm going to share with you today new data for our BNT162B2 and our future vaccine strategy to combat the COVID-19 pandemic. As summarized on Slide 13, BNT162B2 has demonstrated high efficacy in our Phase 3 pivotal trial with approximately 44,000 subjects, showing 95% efficacy after the second dose, both in subjects with and without evidence of prior infection. Through six months following the primary series in adults and adolescents, we observed 91% efficacy against symptomatic disease and 95% efficacy against severe disease. We estimate our vaccine has now been administered to over 1 billion adults and adolescents globally. As we recognize that the prevention of disease in children and reaching herd immunity are equally important, we have expanded our clinical trials in children. In the 12 to 15-year-old group, our vaccine administered according to the same regimen as for adults demonstrated strong protection with 100% vaccine efficacy against COVID-19 infection, both in those with and without evidence of prior infection, and 100% efficacy against severe disease. The immune response was not inferior compared to that seen in 16 to 25-year-olds. In the 5 to 11-year-old group, a two-dose regimen of 10 micrograms administered 21 days apart produced robust neutralizing antibody titers similar to those observed in adults aged 16 to 25 and was well tolerated. Vaccine efficacy against symptomatic COVID-19 infection was 90.7% up to one month following the second dose, and no cases of severe COVID-19 were seen in the BNT162B2 clinical trials. Clinical trials in children aged 6 months to 2 years and 2 to 5 years are ongoing, building on our expanding efforts to make BNT162B2 accessible for all ages. We expect data to be available from those age cohorts in the fourth quarter of 2021 or early first quarter 2022. On Slide 14, our clinical strategy addressing the need for a third dose booster to restore neutralizing antibody titers and vaccine efficacy, giving waning vaccine immunity at normal intervals after the second dose, is shown. Clinical data support the need for a booster in adults aged over 16 years, including high-risk populations and immunocompromised individuals. We are evaluating the impact of a third dose booster on neutralizing antibody titers and T-cell responses in approximately 300 subjects in our Phase 1 and Phase 2/3 trials. Additionally, we have undertaken a Phase 3 trial with up to 10,000 subjects to measure relative vaccine efficacy in those vaccinated with a booster dose of BNT162B2 versus those who did not receive a booster dose after the primary two-dose series. We are continuously monitoring emerging variants and assessing the ability of BNT162B2 to neutralize these variants of concern. BNT162B2 has demonstrated high efficacy against variants of concern in both its ability to elicit antibodies that neutralize variants and from a vaccine effectiveness perspective in real-world settings. As part of a prototype approach to prepare for emerging variants that may escape immunity elicited by our ancestral vaccine version, we are testing both monovalent and multivalent vaccines. Clinical trials are underway where our monovalent variant vaccine was administered to 300 vaccinated individuals in our Phase 3 trial and another 316 naïve individuals. Additionally, we have undertaken trials to evaluate a multivalent vaccine encoding both the Delta and Alpha variants, as well as monovalent vaccines encoding either the Delta or Alpha variant, administered as the first dose or during the recall phase in clinical trials. Data is expected in the first quarter of 2022, and this data could support a flexible platform approach for product adaptation, should it be needed. Now to Slide 15, the graph on the left shows that in elderly adults, neutralization has almost fallen to the level of detection after 7 to 9 months. Boosting with a third dose, administered between 7 and 9 months after the second dose, induces a robust neutralization response, beyond what was originally observed after the second dose. Serum obtained from participants one month after the third dose shows high neutralization titers against the original infective strain, the Beta variant, and also the Delta variant. Neutralization titers against the Delta variant are over 10-fold higher than those observed after the second dose in the age group 18 to 55 years and even over 11-fold in the older age group 65 to 85 years. The difference in neutralizing titers against the ancestral virus and the Delta variant narrowed after the third dose compared to after the second dose, indicating that in addition to prolonging protection, a third dose booster may increase the breadth of neutralizing response against SARS-CoV-2 variants. Data supporting the booster dose is further strengthened with evidence from a Phase 3 vaccine efficacy booster trial involving 9,000 subjects. BNT162B2 demonstrated 95% relative vaccine efficacy, reflecting the reduction in disease occurrences in the boosted group versus the non-boosted group without evidence of prior SARS-CoV-2 infection, at a median of 11 months following the second dose. Relative vaccine efficacy was consistent irrespective of age, sex, race, ethnicity, and comorbid conditions. BNT162B2 was well tolerated, and adverse events were similar to those observed previously in the clinical development program. Moving to Slide 16, the global distribution of BNT162B2 has generated a vast array of real-world vaccine effectiveness data in diverse populations. It is reassuring to see higher rates of vaccine effectiveness for both primary doses mirroring the high efficacy demonstrated against symptomatic infections, asymptomatic infections, severe infections, hospitalizations, and deaths in real-world vaccine effectiveness trials. Our analyses confirm that vaccine effectiveness decreases over time, and although protection against severe disease remains high, we also observe that booster doses can enhance this efficacy. Continuing to monitor real-world data and immunogenicity data is crucial to understand the effect of booster doses on vaccine effectiveness against COVID-19 caused by SARS-CoV-2 and emerging variants. Now starting with Slide 18, the update on our immune-oncology pipeline. We have multiple assets across different therapeutic modalities with the potential to tackle tumors using complementary strategies, either by targeting tumor cells directly or by modulating the immune response against the tumor. Many of our product candidates have the potential to be combined with other pipeline assets. Slide 19 highlights our strong clinical execution in 2021. We are presenting several of these data updates at the upcoming SITC Annual Meeting. In total, we now have four ongoing randomized Phase 2 clinical trials, three of which started in 2021. An additional randomized Phase 2 trial for the next-generation immunomodulators we are developing with our partners from Genentech is expected to start in the fourth quarter of 2021. Moving to Slide 20 and our IMS product candidate autogene cevumeran or BNT122. This program is partnered with Genentech Roche. BNT122 is designed to target patient-specific neoantigens and is an individualized cancer vaccine now undergoing two ongoing trials in metastatic cancers, of which one is a randomized Phase 2 trial in first-line melanoma in combination with pembrolizumab. We are moving into the adjuvant treatment phase with a randomized Phase 2 trial in colorectal cancer patients, for which we announced the first patient dose in October 2021. As the second deadliest cancer worldwide, the medical need for novel therapies to treat colorectal cancer remains high. The current standard of care for Stage 2 high-risk and Stage 3 patients with localized cancer is the removal of the primary tumor and adjuvant chemotherapy, followed by watchful waiting to see if tumors recur. A significant proportion of these patients are expected to have a recurrence of their tumor within 2 to 3 years after surgery. For this trial, patients with high-risk, poorly prognostic factors will be identified by highly sensitive blood tests detecting circulating tumor DNA, and they will receive our vaccine following 3 to 6 months after their standard adjuvant chemotherapy. In clinically identifiable colorectal cancer patients, a disease-free survival of only 6 months is estimated. The primary endpoint of our Phase 2 trial is disease-free survival, and objectives include overall survival and safety. The trial also includes a biomarker component allowing for the inclusion of patients irrespective of circulating tumor DNA status. Slide 21 highlights our presence at the SITC Annual Meeting on November 10 to 14. We will present data across six programs and four therapeutic platforms, as well as two oral presentations and five posters. Overall, the data being presented show favorable safety profiles and promising signs of clinical activity for all six clinical programs. In the trials we are reporting at SITC, we observe preliminary biological or clinical activity in difficult-to-treat patient populations. On Slide 22, we share data from the Phase 1 trial of our candidate BNT111 from our wholly-owned 6X platform. BNT111 is our off-the-shelf RNA vaccine that includes a fixed set of tumor-associated antigens covering up to 95% of cutaneous melanoma patients. Melanoma remains an area of unmet need, particularly for patients who have progressed upon checkpoint inhibitor treatment. More than half of those patients do not respond to checkpoint inhibitors, and patients with stage 4 disease still face poor outcomes. We believe the next wave of development involves combining checkpoint inhibitors with other agents. In 2020, we published promising data on BNT111 in checkpoint inhibitor-experienced patients with detectable disease and metastatic melanoma, demonstrating that immunotherapy in combination with checkpoint inhibition was effective and induced durable objective responses in this disease setting, triggering the initiation of our Phase 2 trials in checkpoint-refractory or resistant melanoma testing BNT111 in combination with anti-PD-1 therapy in partnership with Regeneron. A new analysis presented at the SITC includes a cohort of pre-treated patients with Stage 3 and 4 cutaneous melanomas without evidence of disease receiving BNT111. Overall, BNT111 has a favorable safety profile with similar safety in patients with and without evidence of disease. Most treatment-related adverse events were mild to moderate. The overall rate of serious adverse events was low. In line with our previous data on patients with evidence of disease, BNT111 induced CD4 and CD8 T-cell responses, indicating that similar proportions of patients in both groups responded to at least one tumor-associated antigen of the vaccine. A substantial proportion of patients presented T-cell responses only detectable after vaccination. The median disease-free survival of patients with no evidence of disease was 34.8 months, indicating that BNT111 monotherapy shows promising signs of prolonged disease control in patients without evident tumor. We believe these findings have the potential to translate into significant clinical benefits and encourage the further development of BNT111 in earlier melanoma disease settings. We are also presenting data from our FixVac BNT112, Phase 1/2 trials shown on Slide 23. FixVac BNT112 encodes a fixed set of prostate-associated antigens. The first-in-human Phase 1/2 trial assesses the safety and immunogenicity of BNT112 monotherapy or in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer and newly diagnosed high-risk localized prostate cancer. Prostate cancer is a major health issue with 1.3 million new cases worldwide each year. Localized prostate cancer frequently becomes metastatic, which is invariably fatal, and prognosis remains poor. Part 1 of the trial, which is a BNT122 dose titration, has been completed, and the recommended dose range for part 2 has been determined. Part 2, the dose expansion with BNT112 as monotherapy and in combination with cemiplimab, is currently recruiting. Preliminary results from the trial as of June 2021 are as follows: nine patients have been treated with BNT112 monotherapy in Part 1, all of whom had heavily pre-treated late-stage cancer. Patients were treated in Part 2. Overall, most adverse events that occurred in Part 1 were mild or moderate. There were two instances of Grade 3 hypertension, leading to dose reductions. Both patients recovered within 24 hours, and these events did not meet the criteria for dose-limiting toxicity. All reported serious adverse events in Part 1 were considered unrelated to BNT112. No safety signals or concerns were identified in Part 2, in which patients received BNT112 only or in combination with cemiplimab. All patients who were evaluable exhibited detectable immune responses. We confirmed that all five tumor-associated antigens were immunogenic and identified T-cell responses to each antigen in at least two patients. Two patients with late-stage cancer treated with BNT112 monotherapy reported decreases in prostate-specific antigen, a well-known prostate cancer biomarker. In summary, these data suggest that BNT122 possesses a favorable safety profile and enrollment in Part 2 is ongoing in monotherapy and in combination with cemiplimab, with early signs of activity in patients with advanced prostate cancer. Slide 24 presents our BNT211 program, which comprises two drug products: Claudin-6 CAR-T cells and a CAR-T cell amplifying RNA vaccine. Claudin-6 CAR-T cells are designed with a second-generation chimeric antigen receptor, providing high sensitivity and specificity for the tumor-specific antigen Claudin-6. Claudin-6 is absent in healthy tissues but frequently expressed in specific cancers, making it an ideal target for CAR-T cell therapy. Pre-clinical studies show that CARVac enhances the expansion of transferred CAR-T cells, increasing the depth of response and efficacy. The first-in-human Phase 2 dose escalation trial evaluates the safety and efficacy of Claudin-6 CAR-T cell monotherapy and in combination with CARVac in patients with Claudin-6-positive advanced solid tumors. Part 1 consists of Claudin-6 CAR-T monotherapy dose escalation cohorts, and Part 2 focuses on dose escalation of CAR-T combined with a fixed dose of CARVac. There are three dose level cohorts for each part. The subsequent dose expansion will focus on ovarian, testicular, and endometrial cancers, as well as other Claudin-6-positive cancers. As of July 23rd, dose level 2 of part 1 and dose level 1 of part 2 are ongoing. On Slide 25, we show preliminary results from the Phase 1/2 BNT211 clinical trial. Eight patients included in the analysis were all heavily pre-treated with testicular, ovarian, and endometrial cancers. Claudin-6 CAR-T, as monotherapy or combined with CARVac, were well tolerated at the evaluated dose levels, with no dose-limiting toxicities observed. Some cases of cytokine release syndrome occurred but were manageable, with no signs of neurotoxicity. Increases in certain inflammatory markers were transient and moderate. Patients receiving the combination therapy showed an increase in CAR-T cell engraftment rates, and further expansion was noted in two patients with liver metastases accompanied by tumor reduction. Encouraging signs of clinical activity were observed in three patients with available six-week tumor assessments, showing tumor shrinkage between 18% and 27% according to RECIST criteria, indicating initial signs of efficacy even at the lowest dose tested. Data on one additional patient evaluated will be shared during the upcoming presentation. Now we move to a data update of our ongoing Phase 1/2 trial on our bi-specific antibody candidate BNT311, which we are developing in collaboration with Genmab. Slide 26 shows the mechanism of action and the Phase 1/2 trial design. BNT311 is a first-in-class bi-specific antibody designed to elicit an anti-tumor immune response by simultaneous blockade of PD-1 on tumor cells and conditional activation of 4-1BB on T-cells and NK cells. Previous analyses presented at SITC 2020 showed encouraging signs of clinical activity and a manageable safety profile in patients with advanced solid tumors during the dose escalation phase of this ongoing trial. This data, along with a semi-mechanistic pharmacokinetic/pharmacodynamic predictive model, and translational work established 100 milligrams of BNT311 every 3 weeks as the dose for expansion cohorts. For details on this model, we will provide further updates. Since the dose escalation, we have proceeded to the dose expansion cohorts of heavily pre-treated patients with relapsed or refractory advanced solid tumors, with preliminary data presented on Slide 27. The safety data are consistent with our previous disclosures, with most treatment-related adverse events being mild to moderate. Immunophenotyping of peripheral blood and measurements of soluble immune mediators consistently show that BNT311 elicited a pharmacodynamic effect consistent with its mechanism of action. We identified peripheral and tumor immune activity in patients, including modulation of immune cytokines, expansion of CD8+ effector and memory T-cells, and overall immune activation. Five patients showed partial responses, with trends toward greater induction of cytokines and immune endpoints in comparison to non-responders. Notably, we also found associations between disease control and the time from the last anti-PD-1 therapy prior to study treatment, as well as PD-1 expression on tumors. Disease control rates were higher among patients who had progressed with previous anti-PD-1 therapy within 8 months prior to the first dose of BNT311. Tumor reduction of any degree primarily occurred in patients with PD-L1 positive tumors. This supports the hypothesis that patient selection and/or anti-PD-1 combination therapy may further enhance clinical efficacy. We expect to start a Phase 2 trial of BNT311 as monotherapy and in combination with pembrolizumab in refractory or relapsed metastatic non-small cell lung cancer within the next few weeks. On Slide 28, we present our second bi-specific antibody, BNT312, which we are also developing in collaboration with Genmab. This candidate combines targeting and conditioning activation of CD4 and 41BB on immune cells, resulting in enhanced priming and activation of tumor-specific immunity. Ongoing first-in-human trials evaluate the safety and anti-tumor activity of BNT312. As shown on Slide 29, as of July 1st, 2021, 60 patients have received BNT312 monotherapy in the dose escalation part. The most common types of cancer include colorectal cancer, melanoma, and non-small cell lung cancer, with patients having undergone a median of 2.5 treatment cycles. To date, the maximum tolerated dose has not been reached, and BNT312 has demonstrated a favorable safety profile, with treatment-related adverse events being mostly mild to moderate. One dose-limiting toxicity of transaminase elevation occurred at the 200-milligram dose but was resolved with corticosteroid administration. We have observed increases in immune markers and also levels of CD8 T-cells consistent with biological activity. Of these patients who had exhausted standard therapies, over half achieved disease control, including two patients with melanoma and neuroendocrine lung cancer who confirmed partial responses. The study was recently updated to include multiple expansion cohorts, including frontline treatments for head and neck squamous cell carcinoma, melanoma, and pancreatic ductal adenocarcinoma. As shown on Slide 30, at SITC we will also present data from a Phase 1/2 trial in patients with solid tumors of our toll-like receptor 7 agonist product candidate BNT411. BNT411 is a small molecule designed to activate both the adaptive and innate immune systems through the toll-like receptor 7 pathway, stimulating antigen-specific CD8 T-cells and innate immune responses. During the dose escalation part of the trial in patients with metastatic or unresectable solid tumors who have exhausted available treatments, BNT411 will be administered at eight different dose levels. A second dose escalation is planned for patients with extensive-stage small-cell lung cancer, where BNT411 will be evaluated in combination with cytotoxic therapies and checkpoint inhibitors. The dose escalation will be followed by a dose expansion cohort. As of July 1st, 2021, 11 heavily pre-treated patients have received BNT411, with a total of eight dose levels cleared for evaluation. To date, BNT411 has demonstrated a favorable safety profile with no dose-limiting toxicities. The only drug-related adverse events reported were non-serious and of moderate severity. The biological activity of BNT411 was consistent with its mechanism of action as indicated by the induction of plasma cytokines and increased levels of interferon gamma-induced proteins. Based on preliminary clinical data, the best response observed for BNT411 monotherapy included 5 months of stable disease in a patient with anti-PD-1 pre-treated disease. This supports our vision to improve the therapeutic landscape and enhance outcomes for solid tumors. The encouraging data from our oncology programs, which we will present at SITC 2021, indicate significant progress in our oncology portfolio and represent critical steps toward bringing cancer immunotherapy into the next generation. I now turn over to our Chief Financial Officer, Jens Holstein, who will discuss our financial results.

Jens Holstein, Chief Financial Officer

Thank you, and a warm welcome to those of you on the phone. I will start my section by moving to our financial results for the third quarter of 2021 as shown on Slide 32. Total revenues were estimated to be approximately €6.1 billion for the third quarter of 2021, compared to €67.5 million for the comparative period in 2020. For the nine-month period ending September 30, 2021, we reported estimated total revenues of around €13.4 billion compared to €136.9 million for the comparative prior year period. Total revenues increased due to the rapid rise in supply and sales of our COVID-19 vaccine worldwide. As a reminder, on our COVID-19 vaccine collaborations, territories have been allocated between us, Pfizer, and Fosun Pharma based on marketing and distribution revenue. A breakdown of our commercial revenues is shown on Slide 33. Our third quarter 2021 commercial revenues include approximately €4.4 billion, with prospective €10.2 billion for the first three quarters of 2021. These figures comprise our cross-profit share generated by our collaboration partners in their respective territories, as well as sales milestones. The sales milestones included in this figure amounted to €17 million for the third quarter and €432.8 million for the nine-month period ending September 30, 2021. Similar to previous quarters, the profit share is estimated based on preliminary data shared between Pfizer and us and may be subject to adjustment pending final data on input parameters like sales volume and values, as well as transfer pricing. Any changes in our share of collaboration partners' gross profit will be recognized prospectively. Our COVID-19 vaccine commercial revenues in the third quarter also include €312.3 million in sales to our collaboration partners of products manufactured by us and €1.4 billion in direct COVID-19 vaccine sales to customers in our territory, which includes Germany and Turkey. For the nine-month period ending September 30, 2021, we had sales to our collaboration partners of €514.3 million and approximately €2.6 billion in direct COVID-19 vaccine sales in Germany and Turkey. Now returning to Slide 32 and moving to cost of sales, which were estimated to be €1.2 billion for the third quarter of 2021 compared to €6.8 million for the comparative period in 2020. For the nine months ended September 30, 2021, total cost of sales was estimated to be around €2.3 billion compared to €18.3 million for the comparative prior year period. This increase was driven by costs associated with our COVID-19 vaccine sales and included the share of gross profit that we owe our collaboration partner Pfizer on all sales. Research and Development expenses were €260.4 million for the third quarter of 2021 compared to €227.7 million for the comparative period in 2020. For the nine months ended September 30, 2021, Research and Development expenses reached €677.7 million compared to €388 million for the comparative prior year period. The increase was mainly due to an increase in R&D expenses from the BNT162 program. As a reminder, development costs are shared equally between Pfizer and us. The increase was further driven by an increase in wages, benefits, and social expenses following an increase in headcount, alongside recognition of stock-based compensation expenses as well as expenses incurred on share-based payment arrangements from the company. General and Administrative expenses were €68.2 million for the third quarter of 2021 compared to €23.5 million for the comparative prior year period. For the nine months ended September 30, 2021, General and Administrative expenses reached €154.9 million compared to €58.1 million for the comparative prior year period. Similar to R&D, the increase in G&A was driven by an increase in headcount and expenses incurred under the company's share-based payment arrangement. An increase in expenses for purchased management consulting and legal services, as well as higher insurance premiums due to increased business volume. Interim income taxes were accrued in an amount of approximately €1.5 billion for the third quarter of 2021 and around €3.2 billion for the nine months ended September 30, 2021, recognized using the estimated annual effective income tax rate of approximately 31%. For the third quarter of 2021, net profit reached approximately €3.2 billion compared to a net loss of €210 million for the comparative prior year period. For the nine months ended September 30, 2021, total net profit reached approximately €7.1 billion compared to a net loss of €351.7 million for the comparative prior year period. As of September 30, 2021, cash and cash equivalents totaled €2.4 billion. Please note that the contractual settlement of the gross profit share under our COVID-19 collaboration with Pfizer has a temporal offset of more than one calendar quarter. As far as the fiscal quarter for subsidiaries outside the United States defers ours, creates an additional time lag between the recognition of revenues and the payment proceeds. Consequently, trade receivables at September 30, 2021, were received as payments only in October 2021, improving our cash position relative to the amount at September 30, 2021. Moving to Slide 34, our outlook for the 2021 financial year has been updated based on planned deliveries of up to 2.5 billion doses in 2021, providing estimated COVID-19 vaccine revenues of approximately €16 billion to €17 billion for the full 2021 financial year. This estimate reflects expected revenues from direct COVID-19 vaccine sales to customers in our territory, expected revenues from sales to our collaboration partners, expected sales milestone payments from our collaboration partners, and expected revenues related to our share of gross profit from COVID-19 vaccine sales in collaboration territories. Please note that this figure has been estimated at constant foreign exchange rates. We will deliver a significant number of doses to middle- and low-income countries, with prices set in line with their income levels or on a not-for-profit basis to serve their needs. We maintain our previous cost guidance for the fiscal year 2021 and expect to incur R&D expenses in the range of €950 million to €1.1 billion, reflecting further ramp-up of R&D investments in the fourth quarter of 2021, given our plans to expand our investment further. Capital expenditures for the year 2021 are expected to be in the range of €175 million to €225 million. These figures have again been estimated in constant foreign exchange rates and reflect our current base case projections. Lastly, please note that we expect an estimated annual effective income tax rate of approximately 31% for the BioNTech group. And with that, I turn the call over to our Chief Strategy Officer, Ryan Richardson, for an update on our corporate development activities and concluding remarks. Thank you.

Ryan Richardson, Chief Strategy Officer

Thanks, Jens. Moving now to Slide 36, in the third quarter, we acquired PhagoMed, a biotechnology company based in Vienna, Austria. The acquisition expands our infectious disease toolkit into synthetic licenses—a new class of precision antibacterials, which we believe have the potential to address a wide range of pathogens, including the growing global challenge of antimicrobial resistance. In addition to its highly trained team, the acquisition brings us PhagoMed's Lysin Builder technology, a proprietary in silico therapeutics platform designed to enable the rapid production of recombinant natural lysins optimized for potency, stability, and manufacturing yields. The transaction closed in the third quarter and included an upfront cash payment of approximately €50 million, in addition to potential future performance-based development milestones of up to €100 million. PhagoMed now operates as BioNTech R&D Austria and will serve as BioNTech's R&D hub for precision antibacterials. We are pleased to add this new class of precision therapies to our infectious disease portfolio of mRNA vaccines and mRNA-encoded antibodies. As shown on Slide 37, we continue to expand our infectious disease capabilities and pipeline to address global health challenges. In addition to our COVID-19 and influenza vaccine programs, which are partnered with Pfizer, we now have active research and preclinical development programs against more than 10 distinct infectious diseases, including both vaccine and therapeutic approaches. Several of these programs could represent accelerated development opportunities. For example, we plan to initiate first-in-human trials for our malaria and tuberculosis mRNA vaccine candidates in 2022 and look forward to providing further program updates in the coming months. Slide 38 depicts our clinical stage oncology pipeline, comprising 15 programs in 19 ongoing clinical trials across four drug classes. With the new trials initiated this year, we now have four ongoing randomized Phase 2 trials in oncology. We expect our pipeline to continue to broaden as we move into 2022. I want to point out that even though we have strong partners for certain programs, including Roche, Genmab, and Sanofi, the majority of our programs are fully-owned. Even when we have partnered, we have retained the right to co-commercialize our products in major markets alongside our partners. To close on Slide 39, we are poised to further accelerate the company's transformation as we head into the final stage of the year. Our COVID-19 vaccine continues to be in strong demand globally, and our production network continues to deliver at scale. Our oncology pipeline is advancing on multiple fronts, and we are similarly broadening our infectious disease pipeline of novel vaccines and therapeutics behind COVID-19. Hiring top talent continues to be a strategic priority, and we have now expanded our team to more than 2,800 employees globally. We will continue to make investments in digital automation and manufacturing, with further mRNA production centers planned in Singapore and Africa. Finally, we continue to expand our global footprint across geographies, including in Europe, the U.S., Africa, and Asia, as we look to build long-term value for patients, our shareholders, and society. And with that, we can now open up.

Operator, Operator

Thank you. We'll now begin the question-and-answer session. Your first question is from the line of Cory Kasimov from JP Morgan. Please go ahead.

Cory Kasimov, Analyst

Hey. Good morning, guys. Thank you for taking my question. I think I'm starting at a pretty obvious place, but on a broad level, can you talk about the type of impact you see the oral antivirals having on the demand for COVID-19 vaccines and boosters over both the short and long-term?

Ugur Sahin, CEO and Co-Founder

I can take this question. I hope that you can hear me. I am at the airport and there might be background noise. So, overall inhibitors provide the opportunity for treatment if the disease is established. The key question is indeed that—does this impact the vaccination rate in the overall population, which we cannot estimate at the moment? We need to understand, first of all, how much of this oral inhibitor will be available in 2022 at which percentage? Of course, we also need to understand that the highest efficacy reported has been established over a long time. We know that single treatments plus inhibitors in viral disease could lead to research in development of resistance. We have to wait and see how this type of additional treatment, which is fantastic to have now on the market, will complement or even replace vaccines. Personally, I don't believe this will have a huge impact on the vaccination rate in the future, but we must monitor the field in the upcoming future.

Cory Kasimov, Analyst

Okay. Thank you, Ugur.

Operator, Operator

Thank you. Your next question is from the line of Chris Shibutani of Goldman Sachs. Please go ahead.

Chris Shibutani, Analyst

Great. Thank you for the question regarding the outlook for the booster market. There are two important opportunities that impact the intermediate and longer-term outlook for your vaccine revenues. One being boosters for the broader adult population, not just the high-risk or elderly, and the second being what would be the potential frequency of subsequent boosters going forward. Will it be annual? If we look back at how this played out for the original boosters, the evidence came a few months before regulators and advisory groups addressed the issue and got onboard. What's your expectation for the evidence and the debate, and how this will play out for these two issues: 1) the broader population for booster recommendation; and 2) the frequency of subsequent boosters longer-term? Thank you.

Ugur Sahin, CEO and Co-Founder

Yes. The value of booster vaccinations, not only for the elderly but for the overall population, is becoming increasingly evident. We have real-world data, particularly from Israel, showing that booster vaccinations in the overall population can dramatically reduce the rate of infections as compared to the population who did not receive the booster vaccination. We have evidence from our Phase 3 clinical trial that compared the efficacy of a third booster dose and observed an additional efficacy increase of more than 95%, similar to the strong responses that we observed overall. We didn't see differences between the elderly and younger populations, indicating that booster vaccinations will dramatically reduce infection rates. We believe boosters have great value in controlling the pandemic, particularly this winter, as we face the challenge of an insufficient vaccination rate to control the Delta variant. We will see higher infection rates among the vaccinated as well. So, we see a scientific rationale for boosting the overall population.

Chris Shibutani, Analyst

Thank you.

Operator, Operator

Thank you. Our next question is from the line of Tazeen Ahmad. Please go ahead.

Tazeen Ahmad, Analyst

Okay, guys. Good morning and good afternoon. Just a couple of points of clarification for me with regard to the presentations. The first one is for BNT111; should we expect to see an update on safety, or will there be an update on efficacy? Specifically, I think back in March you had provided an update on disease-free survival numbers. Should we expect to see that updated at all? And then secondly, for BNT312, I think you're going to be keeping in many oral for that as well. Similar question: is the focus of that going to be primarily on safety, or are we getting a little bit more granularity on the doses that you're using in the dose escalation portion and what kind of efficacy to expect there?

Ugur Sahin, CEO and Co-Founder

For BNT111, we have started the Phase 2 clinical testing, and this trial will generate data at the earliest in 2023. For BNT312, we will update on clinical findings regarding dose levels and efficacy during ASCO and ESMO next year.

Tazeen Ahmad, Analyst

Okay. Thank you.

Operator, Operator

Thank you. Your next question is from the line of Daina Graybosch from SVB Leerink. Please go ahead.

Daina Graybosch, Analyst

Thank you for the question. I wonder if you could give us an update of where you are with your partners regarding regulatory approval and potential distribution in China.

Ryan Richardson, Chief Strategy Officer

Yes, sure. I can take that one, Daina. We were granted Emergency Use Authorization in Q1 in Hong Kong and Macau, which is a Fosun territory, and we have begun distributing the vaccine to that region over the year. We have also signed a 15 million dose deal with Taiwan, which is also a Fosun commercialization territory, and we have commenced shipment of the vaccine to the Taiwan territory. In Mainland China, we have submitted data for an effective BLA approval, and we are still waiting for a response from the regulator and are engaged with them to open up the approval pathway in mainland China.

Operator, Operator

Thank you. Your next question is from the line of Akash Tewari from Jefferies. Please go ahead.

Akash Tewari, Analyst

Hey, thanks so much. Just a few. To follow up on a prior question, what specifically in your feedback with the Agency would you have to show to support boosters for all? Do you feel like the Agency is focused on a drop in protection for severe disease for the general population? And if so, what is the kind of threshold of protection that you think would support boosters for all versus not supporting boosters for all? And then, I noticed consensus estimates for your COVID vaccine next year are around €16 billion, so in the ballpark of what you're tracking for 2021. Can you talk about how many booster-specific contract doses you've already locked up, and if replicating the deliveries you had this year is a reasonable base case?

Ugur Sahin, CEO and Co-Founder

I can take the first part of the question. As regarding the overall data package at the time of our request to access authorization for booster doses, we presented data showing antibody responses and increased neutralizing antibody titers. We had data from Israel to support this. We now have an additional data package from randomized trials demonstrating over 95% efficacy in subjects who received a third dose. We believe the increasing level of data supporting booster doses will strengthen our case for authorization in the overall population. My estimate is that we will see a decline in protection against severe disease, possibly down to 80%, and if a booster dose increases the overall protection from 80% to around 97%-98%, this will certainly support the need for booster doses. We anticipate that further evidence will continue to emerge over the next weeks and months leading to broader authorization for booster doses.

Jens Holstein, Chief Financial Officer

Thank you, Ugur. For the second part of the question, we announced an intention to expand our production capacity, enabling us, together with Pfizer, to deliver 4 billion doses next year. Overall, while guiding the final revenue number is challenging, we should aim to have additional disclosures by early next year. We cannot provide a specific split between booster and standard vaccinations at this time due to varying vaccination rates globally, particularly in low- and middle-income countries.

Operator, Operator

Thank you. Your next question is from the line of Daniel Wendorff. Please go ahead.

Daniel Wendorff, Analyst

Thanks for taking my question and good morning to everyone. My question would be related to whether two vaccines are eventually eligible for being booster shots against the new coronavirus. Is that something likely to be limited to mRNA vaccines, or do you see any other vaccine class potentially being eligible for booster shots, particularly looking beyond the third dose?

Ugur Sahin, CEO and Co-Founder

I didn't get the question. Could you just specify your question again, please? I'm sorry.

Daniel Wendorff, Analyst

Yes. In simple terms, will it be just mRNA vaccines being eligible for booster shots, or are there any developments or adaptations to other vaccines that would also make them likely candidates for booster shots?

Ugur Sahin, CEO and Co-Founder

We can't comment on other vaccines, but I don't see any firm reasons why other vaccines should not be eligible for booster dosing. It will depend, of course, on the availability of data and evidence that they provide a good risk-benefit profile.

Operator, Operator

Thank you. Your next question is from the line of Arlinda Lee from Canaccord. Please go ahead.

Arlinda Lee, Analyst

Hi, guys. Thanks for taking my question. With your commitment to equitable access and certain price points during the pandemic, how do you think about pricing and access in terms of boosters for those that still don't have access, maybe at one-tenth and one-third of the original adult dose? And then potentially emerging out of this pandemic? That's all, thank you.

Sean Marett, Chief Business and Commercial Officer

I'll take that one. I think with middle-income and lower-income countries, as we evolve out of this pandemic, you need to consider what those countries can sustainably afford. That will inform how we calculate pricing for boosters post-pandemic. Regarding pediatrics, I think you need to view this from a value perspective, and not a straight reduction in milligrams or micrograms per kid in terms of pricing. But again, that will certainly be an ex-pandemic price, and of course, we're working on that as we are still very much in the pandemic.

Operator, Operator

Thank you. The final question today is from the line of Ali Merrill from UBS. Please go ahead.

Ali Merrill, Analyst

Thanks so much for taking the question. Can you discuss your business development strategy going forward? After the PhagoMed acquisition, should we expect to see more deals of that sort? And going forward, are there particular therapeutic areas or modalities that you are looking at closely or those that you think synergize best with your current platform and pipeline?

Ryan Richardson, Chief Strategy Officer

Yes. I can take that question. Thank you. Yes, we’ve executed two acquisitions this year: one being the acquisition of the solid tumor assets from Kite, along with their TCR assets and the cell therapy manufacturing facility, and now the PhagoMed acquisition. I think you can expect to see more of these types of deals. Our key criteria would be to broaden our technology base, as with PhagoMed, and to explore new classes of medicines that we think complement our pipeline, but also target clinical-stage programs in our core therapeutic areas, which include oncology and infectious diseases.

Ozlem Tureci, Chief Medical Officer and Co-Founder

Thank you. With that we would like to close the call today. Thank you for joining today's call, and we're looking forward to talking to you in the future. Thank you. Bye.

Operator, Operator

That concludes the presentation today. Thank you for participating. You may disconnect.