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spk11: Good morning and good afternoon. Thank you for joining us today to review BioNTech's third quarter 2021 operational progress and financial results. Before we start, we encourage you to view the slides for this webcast, as well as the operational and financial results pressed for these issues this morning, both of which are accessible on our website in our investor section. As shown on slide two, 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, our estimated financial results for 2021, our continued global demand for our COVID-19 vaccine, our target vaccine production capacity for 2021, and beyond our ability to supply our COVID-19 vaccines. The planned next steps in our pipeline program, the time for enrollment, initiation, completion, and reporting of data from our clinical trials, and other risks described in our findings made with the U.S. Securities and Exchange Commission, including our most recent annual report on Form 20F. Actual results could differ from those we currently anticipate. We are therefore cautioned not to place undue reliance on any forward-looking statements which speak only as of today, shared today during this conference call and webcast. Also, please note that slide three and four provide detailed and important safety information regarding our COVID-19 vaccine. Slide five is our agenda for our call today. I'm joined today by our CEO and co-founder, Ugo Zahin, Eslento Reggie, our Chief Medical Officer and Co-Founder, John Merritt, our Chief Business and Commercial Officer, Jens Holstein, our Chief Financial Officer, Ryan Richardson, our Chief Strategy Officer, and Sid Cutting, our Chief Operating Officer. I now turn the call over to Uwe Sahin. Uwe?
spk16: Thank you, Silke. Good morning and good afternoon, and thank you to everyone joining the call today. 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 of our vaccine and of our company is having in addressing the global pandemic. We still have further to go to reach many parts of the world. We are prioritizing equitable vaccine access to low- 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 two trials and multiple first in human studies. We will present data for six of our programs at the upcoming CITSE conference, clearly demonstrating the progress in our cancer pipeline. Ersan will provide details on some of these updates in her prepared remarks. Moving to slide seven. Our strategy remains focused on bringing our board pipeline 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 technologies. Our vision is to build a high-technology company of the coming age. We are developing and extracting 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 years to come. Slide eight. We are driving innovations across multiple therapeutic platforms to harness the power of the immune system and to transform treatment paradise in infectious disease and solid tumors. The last 18 months have demonstrated the power, flexibility, and the speed of our mRNA vaccine technology. We have established a proven path to regulatory approval for our first mRNA vaccine and have created one of the largest safety databases for a pharmaceutical product. This is supported by a global manufacturing and distribution network that has capacity to provide billions of doses of vaccine supply for the world. Behind COVID-19, we are advancing a pipeline of 10 novel vaccines and immunotherapies for diseases which pose 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 two 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 remain not to be 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 disease, like autoimmune and inflammatory diseases, and even regenerative medicine. Slide nine 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. a new class of precision antibacterials through the acquisition of Phagomate, an Austrian biotechnology company. The transaction complements our infectious disease pipeline of mRNA vaccines and mRNA-encoded antibodies with a new precision antibacterial 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 trial of autogene sevomeran, or BNT122, our INS candidates for the adjuvant treatment of high-risk colorectal cancer patients who are positive for circulating tumor DNA. In addition, our fixed product candidate, BNT111, was recently granted orphan designation by the US FDA for the treatment of advanced checkpoint inhibitory refractory or resistant melanoma. In infectious diseases, in September, Pfizer initiated a first human study of BNT161, an influenza vaccine based on our mRNA technology. Moving the highlights of 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 a manufacturing capacity of up to 4 billion doses. Our COVID-19 vaccine has now received full VLA FDA approval in the United States for the use in individuals age 16 and older. The U.S. FDA has also authorized a boosting with a third dose of the vaccine for some high-risk population. In the EU, a booster dose has been approved for subjects 18 years and older. To support the extension of the vaccine label to include children age 5 to under 12, a clinical data package has been submitted to regulators around the globe. The FDA has recently granted emergency use authorization of BNT162B2 in children age 5 to under 12, and the U.S. government purchased an additional 50 million pediatric doses. I feel humbled about our team's continued exceptional work and would like to close my remarks by emphasizing that even if BioNTech is transforming, we will continue to stay true to our vision and remain focused on our goal to bring next-generation immunotherapies to patients around the world. I will now turn the call over to Sean, who will provide updates on our COVID-19 program.
spk10: Thanks, Ugo. It's a pleasure to be speaking with everyone today. Turning now to slide 11, together with our collaborators Pfizer and Fosun Pharma, 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 US, Japan, and other regions last quarter. Discussions with regard to additional contracts for 2022 and beyond remain ongoing. We anticipate that the additional 50 million pediatric doses ordered by the US government should be delivered by April 30th, 2022. With this order, the U.S. government has 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 US 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, surges in infection will be brought 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 Europharma Laboratories in Brazil to manufacture our COVID-19 vaccine. Per the agreement, Europharma will obtain drug product from facilities in the United States and manufacturing of finished doses are expected to commence in 2022. At full operational capacity, the annual production is expected to exceed 100 million finished doses annually. Additionally, we recently signed a memorandum of understanding with the Rwandan government and the Institut Pasteur de Dakar and announced plans to start the construction in mid-2022 of the first state-of-the-art manufacturing site for mRNA-based vaccines in the African Union. We believe this facility can become a node in 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 expand the global reach of our vaccines. 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 Ugo. 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 To expand our vaccine label and generate useful data in additional populations, we have multiple ongoing clinical trials which we have detailed previously, including trials in younger children and pregnant women. We currently expect data for children two to five years of age and children six months to two years of age in late Q4 2021 or early Q1 2022. Ugor already highlighted our significant process on the regulatory front, and our data in children of 5 to 11 years of age, which Özlem will cover in detail. We have further optimized our vaccine formulations to simplify access globally, and we recently received authorization from both the FDA and EMA to store our vaccine for up to nine months at minus 90 to minus 60 degrees Celsius. Additionally, following a positive opinion from EMA's CHMP, the EC approved a new formulation of BNT162B2 that further simplifies vaccine handling and with optimized storage conditions. The vials can be stored 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 scientific data. dynamics of the pandemic. Multiple trials are ongoing to address need for boosted dose of BNT162B2. We are currently studying variant specific vaccine versions. While we don't plan to commercialize a variant specific version of the vaccine at this time, we remain ready to adapt our technology and manufacturing and regulatory process to ensure our vaccine provides robust protection against COVID-19. We are very pleased with the latest clinical and regulatory developments from our vaccine, which demonstrate a strong execution in response to the COVID-19 pandemic. I'll now turn the call over to Ursuline. who will provide details of our recent vaccine study results, as well as provide an overview of our oncology programs, including positive data to be presented at the upcoming CITSE conference.
spk13: Thank you, Sean. I'm going to share with you today new data for 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 three pivotal trial with approximately 44,000 subjects, 95% efficacy after the second dose in subjects with and without evidence of infection. Through six months Following the two-dose primary series in adults and adolescents aged 16 and over, 91% efficacy against symptomatic disease and 95% efficacy against severe disease was demonstrated. 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 12 to 15-year-olds, our vaccine administered according to the same regimen as for adults demonstrated strong protection with 100% vaccine efficacy against COVID-19 infection in those with and without evidence of prior infection and 100% efficacy against severe disease. The immune response was non-inferior compared to that elicited in 16 to 25-year-olds, and BNT162b2 demonstrated a well-tolerated safety profile, similar to the safety profile seen in adults. In the 5 to 11-year-old children, a two-dose regimen of 10 micrograms administered 21 days apart, produced robust neutralizing antibody titers similar to that 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 group. Clinical trials in children six months to two years of age and two to five years of age are underway, building on our expanding label 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 given waning vaccine immunity at longer intervals following a second dose is shown. Clinical data support a third-dose booster to augment vaccine protection over time in adults over 16 years of age, 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 I and phase 2 free trials. Additionally, we have undertaken a phase 3 trial in up to 10,000 subjects to measure relative vaccine efficacy in those vaccinated with such a booster dose of BNT162b2 versus those who did not receive a booster dose following the primary two-dose series. We are constantly monitoring new 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 the real world setting. As part of a prototype approach to prepare for emerging variants of concern that may escape immunity elicited by our ancestral vaccine version, we are testing both variant-encoding monovalent and multivalent vaccines. Clinical trials are underway where our monovalent beta variant vaccine was administered to 300 vaccinated individuals in our Phase III trial as a third dose and to 300 vaccine-naive individuals. Additionally, we have undertaken trials to evaluate a multivalent Delta-alpha variant-encoding vaccine and monovalent vaccines encoding either the Delta or the Alpha variant administered as a third dose or in naive subjects in clinical trials. Data is expected in the first quarter of 2022. Data from these trials could support a flexible platform approach for product adaption 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 by this assay after seven to nine months, boosting with a first dose between seven and nine months after the dose two induces a robust neutralization response beyond what was originally observed after dose two. Serra obtained from participants one month after dose three has elicited high neutralization titers against the original ancestral strain, the beta variant and also the delta variant. Neutralization titers against the Delta variant are over 5-fold over those observed after dose 2 in the age group 18 to 55 years and even over 11-fold in the older age group 65 to 85 years old. The difference in neutralizing titers against the ancestral virus and the Beta variant narrowed after the first dose compared to after the second dose. implying that in addition to prolonging protection, a third dose booster may increase the breadth of neutralizing response against SARS-CoV-2 variants. Data in support of a booster dose is further strengthened with evidence from a phase three vaccine efficacy booster trial in 9,000 subjects. The NT162b2 demonstrated 95% Relative vaccine efficacy, which reflects the reduction in disease occurrence in the boosted group versus the non-boosted group in those 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, or 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 to see high rates of vaccine effectiveness post the primary two doses, mirroring the high efficacy demonstrated against symptomatic infections, asymptomatic infections, severe infections, hospitalizations, and deaths in real-world vaccine effectiveness trials. Real-world data confirms that vaccine effectiveness decreases over time as the interval after the second dose increases. vaccine effectiveness against hospitalization is still high. Real-world evidence shows also that high vaccine effectiveness is restored with a third-dose booster, both against severe disease as well as confirmed infections as seen in Israel in those aged 16 and older. Starting 12 days after a third-dose booster, there was a tenfold reduction in risk of confirmed infection across all age groups compared to the cohort that received the initial two-dose series. An 18-fold risk reduction in severe disease was observed in the 60 and over age group and a 22-fold risk reduction in those aged 46 to 60. With regard to COVID-19 associated deaths, A 14-fold risk reduction was observed for those aged 60 and over. Continued monitoring of real-world data and immunogenicity data is warranted 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 immuno-oncology pipeline. We have multiple assets across different therapeutic modalities with 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 in seven presentations at the ZIPC 36th Annual Meeting. In total, we now have four ongoing randomized Phase II clinical trials, three of which started in 2021. An additional randomized Phase II trial for the next generation immunomodulator BNT3-11 that we are developing with our team colleagues from GenMed, is expected to start in the fourth quarter of 2021. We have also started five first in human clinical trials in our diverse therapeutic programs. Moving to slide 20 and our INS product candidate, Autogen Sevumarin or BNT122. This program is partnered with Genentech Roche. BNT122 is designed to target patient-specific neoantigens and is a fully individualized cancer vaccine with two ongoing trials in metastatic cancers, of which one is a randomized phase 2 in first-line melanoma in combination with pembrolizumab. We are now moving into the adjuvant treatment space with a randomized phase 2 trial in colorectal cancer patients, for which we announced 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 two high risk and stage three patients with localized cancer is removal of the primary tumor and adjuvant chemotherapy followed by a watchful waiting to see if tumors recur. A substantial proportion of these patients are expected to have a recurrence of their tumor within two to three years after their surgery. For this trial, patients at high risk for recurrence will be identified with a highly sensitive blood test detecting circulating tumor DNA and will receive our vaccine following three to six months after their adjuvant chemotherapy. In circulating tumor DNA positive colorectal cancer patients after adjuvant chemotherapy, a disease-free survival of only six months is estimated. The primary endpoint of our phase two trial is disease-free survival. Further objectives include overall survival and safety. The trial also has a biomarker cohort that includes patients irrespective of circulating tumor DNA status. Slide 21 highlights our presence at the ZIPC annual meeting on November 10th to 14th. We will present data across six programs and four therapeutic platforms and two oral presentations and five posters. Overall, the data that we are presenting show favorable safety profiles and promising signs of clinical activity for all six clinical programs. In the trials we are reporting at CITSE, we observed preliminary biological or clinical activity in the Mono-European and in very difficult to treat patient population. More details will follow on the next slide. On slide 22, preliminary data of a sub-analysis from the phase one trial of our candidate BNT111 from our wholly-owned SIGSEC platform. BNT1-11 is our off-the-shelf RNA vaccine that encodes a fixed set of four shared 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 who do not respond to checkpoint inhibitor, and patients with stage 4 disease still face poor outcomes. Thus, we believe the next wave of development is combining checkpoint inhibitors with other agents. In 2020, we published promising data on BNT111 and checkpoint inhibitor experience patients with detectable disease and metastatic melanoma in nature. Those results showed that BNT111 monotherapy and in combination with checkpoint inhibition was well tolerated and induced durable objective responses in this disease setting and triggered the initiation of our phase two trial in checkpoint refractory or resistant melanoma testing BNT111 in combination with the anti-PD1 semizimab in our partnership with Regeneron. A new analysis which we are presenting at CIPSI includes a cohort of pretreated patients with stage 3 and 4 cutaneous melanoma with no evidence of disease that received BMP111 monotherapy. Overall, BNT111 had a favored safety profile with similar safety in patients with evidence of disease and without evidence of disease. Most treatment-related adverse events were mild to moderate through lag symptoms. Overall, the 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, The ex vivo ELISPOT assay results showed that similar proportions of patients in both groups responded to at least one tumor-associated antigen of a vaccine. A substantial proportion of patients presented de novo T-cell responses, only detectable after vaccination. The median disease-free survival of patients with no evidence of disease was 34.8 months. Highlighting that BNT111 monotherapy shows promising sickness of prolonged disease control in patients with no evidence of disease. The ability to induce T-cell immunity irrespective of the presence of a clinically or radiologically detectable tumor is a potential sign of tumor surveillance mediated by BNT111. We believe that these findings have the potential to translate into significant clinical benefits and encourage further development of BNT1-11 in earlier melanoma disease settings. We are also presenting data from our fixed-track BNT1-12 phase 1-2 trial shown on slide 23 at CITSE. BNT1-12 encodes a fixed set of five prostate-associated antigens. The first in-human phase 1-2 trial assesses the safety and immunogenicity of the ND1-12 monotherapy, or in combination with semiprimab in patients with metastatic castration-resistant prostate cancer and with 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. Prognosis remains poor, and novel therapeutic approaches are required. Part one of the trial, which is a BNT1-12 dose titration, is complete, and the recommended dose range for Part 2 has been determined. Part 2, the dose expansion with BNT1-12 as a monotherapy and in combination with SimuPlimab is currently recruiting. Preliminary results from the trial as of June 2021 are as follows. Nine patients have been treated with BNT1-12 monotherapy in Part 1, all with heavily pretreated stage cancer, five patients were treated in part two. Overall, most adverse events that occurred in part one were mild or moderate. There were two instances of grade three hypertension, leading to dose reductions. Both patients recovered within 24 hours, and these events did not meet the criteria of dose-limiting toxicity. All reported serious adverse events in part one were considered unrelated to BNT No safety signals or concerns were identified in Part 2, in which patients received BNT1-12 only or in combination with simulplimab. All seven patients who were at least thought valuable exhibited detectable immune responses. We also 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 had decreases in prostate-specific antigen, a well-known prostate cancer biomarker. In summary, these data suggest that BNT112 has a tolerable safety profile, and enrollment to Part 2 is ongoing in monotherapy as well as in combination with Simiblimab, with first signal of activity in patients with advanced prostate cancer. Slide 24 and moving to BNT211 that comprises two drug products, Claudine-6 CAR T cells and a CAR T cell-amplifying RNA vaccine in short CARBEC. Claudine-6 CAR T cells are equipped with a second-generation chimeric antigen receptor of high sensitivity and specificity for the tumor-specific antigen Claudine-6. Chloridin-6 is absent in healthy adult tissues, yet frequently expressed in high medical need cancers, making this tumor antigen an ideal target for CAR T-cell therapy. Preclinical studies demonstrated that CARVAC drives in vivo expansion of transferred CAR T-cells, increasing their persistence and efficacy. BNT211 is expected to overcome CAR T-cell therapy limitations in patients with solid tumors. The first in human phase 1-2 dose escalation trial evaluates the safety and efficacy of chlordine 6 CAR-T cell monotherapy and in combination with CARVEC in patients with chlordine 6 positive relapsed or refractory advanced solid tumors. Part 1 comprises chlordine 6 CAR-T monotherapy dose escalation cohorts and part 2 is a dose escalation of CAR-T combined with a fixed dose of CARVEC. 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 protein 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 to BNT2-11 clinical trial that will be presented at CIPSEA. The eight patients included in the analysis were all heavily pretreated with testicular, ovarian, and endometrial cancers and sarcoma. Five received CAR T-cell monotherapy and three CAR T-cells plus CARVEC vaccine combination therapy. Clotin-6 CAR T-cells as monotherapy or combined with CARVEC were well tolerated at the dose levels evaluated, and no dose-limiting toxicities were observed. Some cases of cytokine release syndrome occurred were manageable with no signs of neurotoxicity. Increases of interleukin-6 and C-reactive protein were transient and moderate. Patients receiving the combination therapy had transient flu-like symptoms that resolved within 24 hours. The analysis of CAR-T cell frequency in the peripheral blood of a patient revealed robust CAR-T cell engraftment up to day 17 post-infusion. Further expansion was noted in two patients with liver metastasis accompanied by elevated liver enzymes. There were also encouraging signs of clinical activity in patients for which a six-week tumor assessment was available. Three patients showed initial tumor shrinkage with tumor reductions between 18% and 27% according to resist. Signs of initial tumor shrinkage were identified even at the lowest dose tested. Data on one additional patient evaluated between the abstract submission and the conference will be shared during the presentation. The data from the trial are very encouraging, and we look forward to presenting updated data from the open cohorts, and especially for the combination part with CARVEC, at upcoming congresses. Now we move to a data update of the ongoing Phase I-II trial on our bispecific antibody, BNT3-11, which we are developing in collaboration with GenMAP. Slide 26 shows the mechanism of action of BNT3-11 and the Phase I-II trial design. BNT3-11 is a first-in-class bispecific antibody designed to elicit an anti-tumor immune response by simultaneous and complementary blockade of PD-L1 on tumor cells and conditional 4,1BB stimulation on T cells and natural killer cells. Previous analyzes presented at CIDC 2020 showed encouraging signs of clinical activity and the manageable safety profile in patients with advanced solid tumors during the dose escalation phase of this ongoing phase 1-2 trial. This data, along with a semi-mechanistic pharmacokinetic pharmacodynamic predictive model and translational work, established 100 mg of BNT311 every three weeks as the dose for expansion cohorts. Full details on this model will be presented at CITES. Since the dose escalation, we have proceeded to the dose expansion course of heavily pretreated patients with relapsed or refractory advanced and or metastatic solid tumors with preliminary data shown on slide 27. The safety data are in line with our previous disclosures, and most treatment-related adverse events were mild to moderate. Immunophenotyping of peripheral blood measurements of soluble immune mediators from serial blood samples, and immunohistochemistry analysis of tumor biopsies showed that BNT311 elicited pharmacodynamic effects consistent with its proposed mechanism of action. We identified peripheral and tumoral immune activity in patients, including the modulation of immune cytokines, the expansion of CD8 effector memory T-cells, and natural killer cell activation. Five patients had partial responses and showed a trend toward greater induction of cytokines and immune endpoints compared to non-responders. We also identified associations between disease control and the time from last anti-PD-1 therapy prior to the study treatment and PD-L1 expression on tumors. The disease control rates were higher among patients who had progressed with prior anti-PD-1 therapy within eight months prior to the first dose of BNT311. Tumor reduction of any degree occurred mainly in patients with PD-L1 positive tumors. These findings support that patient selection and or anti-PD-1 combination therapy may lead to further improved clinical efficacy. We expect to start a phase two trial of BNT3-11 as monotherapy and in combination with pembrolizumab in refractory or relapsed metastatic non-small cell lung cancer within the next weeks. On slide 28, our second first in class by specific antibody, BNT3-12, which we are also developing in collaboration with GenMod. It combines targeting and conditional activation of CD40 and 4-1-BB on immune cells, resulting in enhanced priming and activation of tumor-specific immunity. The ongoing first-in-human trial evaluates the safety and anti-tumor activity of BNT312. As shown on slide 29, as of July 1, 2021, 50 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, and patients have 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 and resolved upon corticosteroid administration. We have observed increases in peripheral monocyte and dendritic cell cytokines and also increased levels of CD8 and effector memory T-cells. This suggests biological activity that is consistent with the proposed mechanism of action for BNT-free 12. Moreover, about half of these patients who had exhausted standard therapies achieved disease control to patients with melanoma and neuroendocrine lung cancer who had confirmed partial responses. We have identified 100 mg every three weeks for dose expansion, also for this dual body. The study was recently updated to include multiple expansion cohorts, including as a frontline treatment in head and neck squamous cell carcinoma, melanoma, and pancreatic ductal adenocarcinoma. Additional expansion cords will include combination with pembrolizumab in first-line non-small cell lung cancer in combination with pembro and chemotherapy in first-line head and neck squamous cell carcinoma. As shown on slide 30, at SITC, we will also present data from a Phase I-II 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 system through the Toll-like receptor 7 pathway and to stimulate antigen-specific CD8 T cells, B cells, and innate immune cells. During the dose escalation part, patients with metastatic or unresectable solid tumors that have exhausted available treatments will receive BNT411 monotherapy at up to eight different dose levels. In a second dose escalation arm, patients with chemotherapy-naive extensive stage small cell lung cancer will receive BNT411 in combination with cytotoxic therapies and checkpoint inhibitors. The dose escalation part will be followed by dose expansion cohorts. As of July 1st, 2021, 11 heavily pretreated patients have received BNT411 monotherapy. Thus far, five of eight dose levels have been cleared for evaluation. To date, BNT411 had a tolerable safety profile with no dose-limiting toxicities. The only drug-related adverse events reported were non-serious pyrexia and mild to moderate anemia. 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 protein. Based on preliminary unclean data, the best response seen for BNT411 monotherapy in these few patients was five months of stable disease in a patient with anti-PD-1 pretreated squamous cell carcinoma of the lung. These data support the advancement of the trial into the dose escalation part in which patients received BNT411 in combination with cytotoxic therapies and checkpoint inhibitors and recruitment into the therapy arm started in June. Recruitment for the expansion cohort is expected to begin next year. This encouraging data from our oncology programs, which we will present at CITSE 2021, are indicative of significant progress in our oncology portfolio, and they represent critical steps for us towards bringing cancer immunotherapy into the next generation. I now turn over to our Chief Financial Officer, Jens Holstein, who will discuss our financial results.
spk03: Thank you, Eslen, and a warm welcome to those of you on the phone. I'll 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 euros for the third quarter of 2021, compared to 67.5 million euros for the comparative period in 2020. For the period of nine months ended September 30th, 2021, we reported estimated total revenues of around 13.4 billion euros compared to 136.9 million euros for the comparative prior year period. Total revenues increased due to this rapid increase 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 rights. A breakdown of our commercial revenues is shown on slide 33. Our third quarter 2021 commercial revenues include approximately €4.4 billion and respectively €10.2 billion for the first three quarters of 2021 that comprise our cross-profit share generated by our collaboration partners in their respective territories, as well as sales milestones. The sales milestones included in the figure just mentioned amounted to €17 million for the third quarter, and 432.8 million euros for the period of nine months ended September 30th, 2021. Similar to previous quarters, the figures for our profit share are 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 prices. 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 euros in sales to our collaboration partners of products manufactured by us and 1.4 billion euros of direct COVID-19 vaccine sales to customers in our territory, which includes Germany and Turkey. For the period of nine months ended September 30th, 2021, we had sales to our collaboration partner of 514.3 million euros and approximately 2.6 billion euros direct COVID-19 vaccine sales in Germany and Turkey. Now returning back to slide 32 and moving to cost of sales, which were estimated to be 1.2 billion euros for the third quarter of 2021 compared to to 6.8 million euros for the comparative period in 2020. For the nine months ended September 30, 2021, total cost of sales were estimated to be around 2.3 billion euros, compared to 18.3 million euros for the comparative prior year period. The increase was driven by cost of sales recognized with respect to our COVID-19 vaccine sales and included the share of gross profit that we owe our collaboration partner Pfizer on our 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 research and development expenses from the B&T 162 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 security expenses following an increase in headcount, the recognition of inventor compensation expenses, as well as expenses incurred on the share-based payment arrangements from the company. General and administrative expenses were 68.2 million euros for the third quarter of 2021 compared to 23.5 million euros for the comparative prior year period. For the nine months ended September 30th, 2021, general and administrative expenses reached 154.9 million euros compared to 58.1 million euros 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, increased expenses for purchase, management, consulting, and legal services, as well as higher insurance premiums caused by the 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 euros for the nine months ended September 30th, 2021, and were 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 euros compared to a net loss of 210 million euros for the comparative prior year period. For the nine months ended September 30th, 2021, total net profit reached approximately 7.1 billion euros compared to a total net loss of 351.7 million euros for the comparative prior year period. As of September 30th, 2021, cash and cash equivalent totaled 2.4 billion euros. Please note that the contractual settlement of the gross profit share under our COVID-19 collaboration with Pfizer has temporal offset of more than one calendar quarter. As Pfizer's fiscal quarter for subsidiaries outside the United States differs from ours, creates an additional time lag between the recognition of revenues and the payment received. Consequently, trade receivables, which were outstanding as of September 30th, 2021, were received as payments only in October 2021, improving our cash position relative to the amount at September 30th, 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 the calendar year 2021, we're providing estimated COVID-19 vaccine revenues of approximately 16 to 17 billion euros 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 the collaboration partners' territories. Please note that this figure has been estimated at constant foreign exchange rates. Please keep in mind that we will deliver a significant number of doses to middle- and low-income countries where prices are in line with income levels or at non-for-profit basis to serve the poorest. We maintain our previous cost guidance for the fiscal year 2021 and expect to incur R&D expenses in a range of 950 million euros to 1.1 billion euros, reflecting a further ramp up of R&D investments in the fourth quarter of 2021, given our plans to expand and accelerate our pipeline development. SG&A expenses are estimated to be in a range of 250 million to 300 million euros. Capital expenditures for the year 2021 are expected to be in a range of 175 million to 225 million euros. These figures have again been estimated in constant foreign exchange rates and reflect our current base case projections. Finally, please note that we still expect an estimated annual effective income tax rate of approximately 31% for the BioNTech Group. And with that, I turn the call to our Chief Strategy Officer, Ryan Richardson, for an update on our corporate development activities and concluding remarks. Thank you.
spk06: 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 license, a new class of precision antibacterials, which we believe have potential to address a wide range of pathogens and also the growing global challenge of antimicrobial resistance. In addition to its highly trained team, the acquisition brings us Phagomed's LysinBuilder technology, a proprietary and silico therapeutics platform designed to enable the rapid production of recombinant natural lysins, which are optimized for potency, stability, and manufacturing yield. The transaction, which closed in the third quarter, included an upfront cash payment of approximately 50 million euro, 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 you can see 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, spanning 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 and 19 ongoing clinical trials across four drug classes. With the new trial initiation so far this year, we now have four ongoing randomized Phase II trials in oncology. We expect our pipeline to continue to broaden as we head into 2022. I would like 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. And even where 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 US, 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.
spk12: Thank you. We'll now begin the question and answer session. Please press star and 1. If you'd like to ask a question, please limit yourself to one question per person. And your first request. It's from the line of Corey Kazima from J.P. Morgan. Please go ahead.
spk04: Hey, good morning, guys. Thank you for taking my question. I think I'm starting in 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? Thank you.
spk16: I can take this question. Sure. The oral inhibitors, of course, provide the opportunity for treatment if the disease is established. The key question is indeed whether this will come with a reduced vaccination rate in the overall population, which we can't estimate at the moment. We have to understand, first of all, how much this oil inhibitors will be available in 2022, which percentage. And we have, of course, to understand whether the high efficacy, which was reported, will last over a longer time. We know that single treatments with inhibitors in Europe viral disease often results 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 complete vaccines. I personally don't believe that this will has a huge impact on the vaccination rate in the future, but we have to monitor the field in the upcoming future.
spk04: Okay, thank you.
spk12: Thank you. Your next question is from the line of Chris Shibutani of Goldman Sachs. Please go ahead.
spk08: Great. Thank you for the question. Regarding the outlook for the booster market, there are two important opportunities that impact the intermediate and the 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 going forward longer term of subsequent boosters? For instance, 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 the advisory groups addressed the issue and got on board. What's your expectation for the kind of evidence and the debate and how this will play out for these two issues, one, the broader population for booster recommendations, and two, the frequency of subsequent boosters longer term? Thank you.
spk16: Yes. Yes, the... the value of booster vaccinations not only for the elderly but for the overall population is becoming more and more evident. So we have real-world data, particularly from Israel, showing that booster vaccinations in the overall population can reduce dramatically the rate of infections as compared to the population who did not receive the booster vaccination in the range of 15 to 24. And we have now evidence from our phase three clinical trial where we compared the efficacy of a third dose of a booster dose in a randomized fashion and observed that an additional booster increases having a relative efficacy of more than 95%, which is in line with the strong antibody responses that we observed in this population. And this was the overall population. We didn't see any differences in the elderly and in the younger population, indicating that booster vaccinations really dramatically reduced the We believe that boosters have a great value in controlling the pandemic, particularly this winter, where we have to deal on the one side with the challenge that the overall population is not, the vaccination rate is still not sufficient to control the Delta variant. And with the increasing waning of vaccine responses, we will see also in the vaccinated population an increase of infections. So we clearly see that there is a scientific rationale for boosting the overall population. How this will continue next year, we don't know. We have just to collect the data. We, of course, know that this virus is relatively early in the evolution. We will definitely see further adaptations of the infection rate. We will see adaptations of antibody escape variants coming in, which will probably require adaptation of the vaccine. But we can't say at the moment when this is going to happen, whether boosters are coming every 12 months or every 18 months or 24 months. Thank you.
spk08: Thank you.
spk12: Thank you. Our next question is from the line of Tahseen Ahmad from Boston. Please go ahead.
spk15: Okay, guys. Good morning and good afternoon. Just a couple of points of clarification for me with regards to the CC presentations. The first one for 111, should we expect to see an update on CC or CC2? 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 312, I think you're going to be giving a mini oral for that as well. Similar question, is the focus of that going to be primarily on safety, or will we get 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? Thank you.
spk16: Yes, so for 1.11, we have now started the Phase 2 clinical testing, and this trial will generate data earliest in 2023 from the Phase 2 clinical trial for 3.1, 3.12. We will update on CITSE about the clinical findings, of course, including the dose levels. And we will certainly provide updates during ASCO and ESMO next year.
spk12: Okay, thank you. Thank you. Your next question is from the line of Dana Higgins. of SVBA Living. Please go ahead.
spk11: Hi, thank you for the question. I wonder if you could give us an update of where you are with your partner Fosun in China on regulatory approval and potential distribution.
spk05: Yeah, sure. I can take that one, Dana. So we were granted emergency use authorization in Q1 in Hong Kong and Macau, which is a Fosun territory. And we've been distributing vaccine to that region over the course of the year. We've also signed a 15 million dose deal with Taiwan, which is also a Fosun commercialization territory, and have commenced shipment of vaccine to the Taiwan territory. In mainland China, we have submitted data for effectively a BLA approval, and we are still waiting for a response from the regulator and still engage with the regulator to open up the approval pathway in mainland China.
spk12: Thank you. Your next question is from the line of Akash Tiwari from Jefferies. Please go ahead.
spk07: 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 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 sales you had this year is a reasonable base case? Thanks.
spk16: I could take the first part of the question. So it is what regulators convinces is, of course, the overall data package. At the time point when we requested authorization of the booster doses, We had data from antibody responses, increases neutralizing antibody titers, and we had data coming in from real-world data from Israel. We have now an additional data package from the randomized trials, which we are going to submit to further support booster doses in the overall population. showing a 95%, more than 95% efficacy, relative efficacy in subjects who received a third dose. We believe that the increasing level of evidence for protection from disease by booster doses is an increasingly good argument to enable also authorization our vaccines in the overall population. My estimate is even though we see a good protection against severe disease, even after eight, nine, and ten months, we will see also for protection from severe disease a further decline, maybe in the direction of 80%. And if you calculate that a booster dose could increase the overall protection against severe disease from 80% to 97% or 98%, it's a good reason to provide booster doses for the overall population. So we expect that the evidence will increase over the next few weeks and months and that this could help. lead to overall authorization of booster doses for the border population.
spk02: And thank you, Ugo, maybe for the second question. Akash, this is Jens. You know that we announced that we intend to build up the capacity of production that we are able, together with Pfizer, to deliver next year to 4 billion. Overall, in terms of guiding of what the final number for revenues will be, independent now of the split between booster and standard sort of vaccination, you got to bear with us until sometime early next year, please. Generally, you can envisage that at this point in time, we're unable to give any split in terms of how much is booster and what will be actually the contribution of basic vaccination. We all know that big parts of this world are still not vaccinated at all. Percentages are very low, specifically in low and middle income countries still. And therefore, you know, we have to look how things are evolving over time. And then we will sometime next year give you an update on where we stand.
spk12: Thank you. Your next question is from the line of Daniel Vendorff of OdoBHS. Please go ahead.
spk09: Thanks for taking my question and good afternoon or good morning to everyone. My question would be in general related to vaccines eventually eligible for being booster shots against the new coronavirus. Is that something very likely only limited to the mRNA vaccines, or do you see any kind of other vaccine class potentially could be eligible for booster shots, potentially also just looking beyond the third dose if it is necessary at one point in time to potentially have regular booster shots? Thank you.
spk16: I didn't get the question. Could you specify your question again, please? I'm sorry.
spk09: So in simple terms, will it be just mRNA vaccines being eligible for being booster shot or are there any new developments, adaptations to other vaccines which would also make them likely to be available booster shots?
spk16: We can't comment on other vaccines, but I don't see see any formal reason why other vaccines should not be eligible for booster booster dosing. It will be based, of course, on the availability of data and evidence that they provide a good risk-benefit profile.
spk09: Thank you.
spk12: Thank you. Your next question is from the line of Arlinda Lee from CannaCard, please go ahead. Hi, guys.
spk01: Thanks for taking my questions. I guess 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, pricing for the children's doses at maybe one-tenth and one-third of the original adult dose? and then potentially emerging out of the pandemic control. Thank you.
spk10: I'll take that one. I think with the, with the middle income, the low income countries, as we move out of the pandemic, you still have to consider what those countries can pay. And that will be a, a consideration in how we calculate a future ex-pandemic price. With the pediatric, again, I think you have to look at it from a value perspective and not a straight reduction in milligrams or micrograms per kick in terms of the price that we would consider. Again, I would say that there will certainly be an ex-pandemic price, and of course we're currently working on that. We're still very much in the pandemic.
spk12: Okay, thank you. Thank you. And our last question today is from the line of Ellie Merrill from UBS. Please go ahead.
spk14: Hey, guys. Thanks so much for taking the question. Just on the business development strategy going forward, I guess just after the Fagomed acquisition, should we expect to see more deals of that sort? And I guess going forward, are there particular therapeutic areas or modalities that you're looking at most closely or that you think kind of synergize best with your platform and pipeline currently?
spk05: Thanks. Yeah, I can take that question. Thank you. So, yeah, I think you've seen us do two acquisitions this year. The first, the acquisition of the solid tumor assets from Kite, the TCR assets and cell therapy manufacturing facility in the United States. And then now you've seen the Phagomet acquisition. And I do think you can expect to see more of these types of deals. And our Our key criteria will be to broaden our technology base, as with Fagomed, into new classes of medicines that I think are complementary to our pipeline, but also potentially clinical stage programs in our core therapeutic areas. And by that, I would include oncology and infectious disease as two key areas of focus.
spk12: Thank you. There are no further questions. Please continue. Thank you.
spk11: So with that, we would like to close the call today. Thank you for joining today's call, and we are looking forward to talking to you in future. Thank you.
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