Biontech SE (BNTX) 2021 Q3 法說會逐字稿

Welcome to BioNTech Third Quarter 2021 Update Call. (Operator Instructions) I must advise you this call is being recorded today, Tuesday, the 9th of November 2021. And I would now like to hand the meeting over to the Vice President, Investor Relations and Strategy, Sylke Maas. Please go ahead.

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 quote you to view the slides for this webcast as well as the operational and financial results' press release issued this morning, both of which are accessible on our website in our 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 revenue 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 targets vaccine production capacity for 2021 and beyond, our ability to supply our COVID-19 vaccine.The plan 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 filings made with the U.S. Securities and Exchange Committee, including almost recent annual report on Form 20-F.

Actual results could differ from those we currently anticipate. You 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 3 and 4 provide detailed and important safety information regarding our COVID-19 vaccine. Slide 5 is our agenda for our call today. I'm 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; and 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?

Thank you, Serge. 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 3 quarters of 2021, we expanded our oncology pipeline faster than during any other period in our company's history. We initiated 3 randomized Phase 2 trials and multiple first-in-human trials. We will present data for 6 of our programs at the upcoming SITC conference, clearly demonstrating the progress in our cancer pipeline. [Jansen] will provide detail on some of these updates in her prepared remarks.

Moving to Slide 7. Our strategy remains focused on bringing our broad pipeline of next-generation immunotherapies and vaccines to patients were applied 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 exporting 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 8. We are driving innovations across multiple therapeutic platforms to harness the power of the immune system and to transform treatment paradigm 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 our global manufacturing and distribution network that had capacity to provide millions 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 4 active Phase 2 trials. We are addressing a wide range of therapeutic targets with diverse and complementary modes of action. We believe that this multimodal 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 9 summarizes the key highlights for the third quarter. Our financial performance continues to be strong. We recorded in Q3 revenues of approximately EUR 6 billion, 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 PhagoMed, an Austrian biotechnology company. The transaction complements our infectious disease pipeline of mRNA vaccines and mRNA encoded antibody 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 cevumeran or BNT122, our iNeST candidate for the adjuvant treatment of higher vet colorectal cancer patients who are positive for circulating tumor DNA.

In addition, our FixVac product candidate, BNT111 was recently granted orphan designation by the U.S. FDA for the treatment of advanced checkpoint inhibitory refractory or resistant melanoma. In infectious diseases in September [5] highly initiated a first human study of BNT161, an influenza vaccine based on our mRNA technology. Moving to 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 our manufacturing capacity of up to 4 billion doses. Our COVID-19 vaccine has now received full BLA FDA approval in the United States for the use in individuals aged 16 and older. The U.S. FDA has also authorized a boosting with a third dose of the vaccine for some high-risk population than the AU, a booster dose has been approved for subjects, 18 years and older.

To support the extension of the vaccine label to include children aged 5 to <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 aged 5 to 1 and the U.S. government purchase 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 at 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.

Thanks, Ugur. It's a pleasure to be speaking with everyone today. Turning now to Slide 11. Together with our collaborated 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 U.S., 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 U.S. government should be delivered by April 30, 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 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, surges and 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 Eurofarma 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 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 million 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 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 4 continents.

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 2 to 5 years of age and children 6 months to 2 years of age in late Q4 2021 or early Q1 2022. Ugur already highlighted our significant process on the regulatory front and our data in children of 5 to 11 years of age, which Ozlem 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 9 months at -90 degree Celsius to -60 degrees Celsius.

Additionally, following a positive opinion from EMA CHMP, the EC approved a new formulation of BNT162b2 that further simplifies vaccine handling and with optimized storage conditions. The virus 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 (inaudible) scientific data as well as data from our own clinical studies to rapidly respond to the changing dynamics of the pandemic. Multiple trials are ongoing to address the need for boosted dose of BNT162b2. We are currently studying very specific vaccine versions.

While we don't plan to commercialize a very specific version of the vaccine at this time, we remain ready to adapt our technology 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 our strong execution in response to the COVID-19 pandemic. I'll now turn the call over to Ozlem 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 SITC conference.

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 3 pivotal trial with approximately 44,000 subjects, 95% efficacy after the second dose and subjects with and without evidence of infection. For 6 months following the 2-dose primary series in adults and adolescents aged 16 and over, 91% efficacy against symptomatic disease and 95% efficacy against the new disease was demonstrated. We estimate our vaccine has now been administered to over 1 billion adults and adolescents globally.

As we have recognized that the prevention of disease in children is 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-old 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 2-dose regimen of 10 micrograms administered 21 days apart produced robust neutralizing antibody titers, similar to that observed in adults age 16 to 25 and was well-tolerated. Vaccine efficacy against symptomatic COVID-19 infection was 98.7%, up to 1 month following the second dose and no cases of severe COVID-19 were seen in the BNT162b2 group. Clinical trials in children 6 months to 2 years of age and 2 to 5 years of age are underway. Building on our expanding label to make BNT162b2 acceptable 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 3rd dose booster to restore neutralizing antibody titers and vaccine efficacy given waning vaccine immunity at longer interval following a second dose is shown. Clinical data support a 1st 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 1st 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 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 2-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 variance 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 concerns that may escape immunity, is elicited by our [ancestry] vaccine version. We are testing both variant encoding monovalent and multivalent vaccine. Clinical trials are underway, where our monovalent beta variant vaccine was administered to 300 vaccinated individuals in our Phase 3 trial as a 3rd dose and to 300 vaccine naive individuals.

Additionally, we have undertaken trials to evaluate a multivalent delta+alpha variant-encoding vaccine and monovalent vaccines, including either the data or the alpha variant administered as the first 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 adaptation should 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 7 to 9 months, boosting with observed dose between 7 and 9 months after the dose 2 induces a robust neutralization response beyond what was originally observed after dose 2. [Sera] obtained from participants 1 month after all 3 elicited high neutralization titers against the original ancestral strains, 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 year old. The difference in neutralizing titers against the ancestral virus and the beta variant narrowed after the 1st dose compared to after the second dose, implying that in addition to prolonging protection, a 3rd dose booster may increase the breadth of neutralizing response against SARS-CoV-2 Variants. Data and support of a booster dose is further strengthened with evidence from a Phase 3 vaccine efficacy booster trials in 9,000 subjects. BNT162b2 demonstrated 95% relative vaccine efficacy, which reflects the reduction in disease occurrence in the booster group versus the nonboosted group in those without evidence of prior SARS-CoV-2 infection at a median of 11 months following the 2nd 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 area of real-world vaccine effectiveness data in diverse population. It is reassuring to see higher rates of vaccine effectiveness post the primary 2 doses mirroring the high efficacy demonstrated against symptomatic infections, asymptomatic infections, severe infections, hospitalization and death 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 higher vaccine effectiveness is restored with the 3rd dose booster, both against severe disease as well as confirmed infections as seen in Israel in those age 16 and older. Starting 12 days after a 3rd dose booster, there was a 10 fold reduction in risk of confirmed infection across all age groups compared to the cohort that received the initial 2-dose series. And 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, 14-fold risk reduction was observed for those age 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 7 presentations at the SITC 36th annual meeting. In total, we now have 4 ongoing randomized Phase 2 clinical trials, 3 of which started in 2021, an additional randomized Phase 2 trial for the next-generation immunomodulator, BNT311 that we are developing with our esteemed colleagues from Genmab is expected to start in the fourth quarter of 2021. We have also started 5 First-in-human clinical trials in our diverse therapeutic program.

Moving to Slide 20 and our iNeST product candidate, autogene cevumeran or BNT122. This program is partnered with Genentech, Roche. BNT122 is designed to target patient-specific neo-antigensand is a fully individualized cancer vaccines with 2 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. And 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 II (high-risk) and Stage III 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 the recurrence of the tumor within 2 to 3 years after that surgery. For this trial patients at high risk for recurrence will be identified with a highly sensitive drug test, detecting circulating tumor DNA and will receive our vaccine following 3 to 6 months after their adjuvant chemotherapy. In circulating tumor DNA positive colorectal cancer patients after adjuvant chemotherapy, a disease-free survival of only 6 months is estimated. The primary endpoint of our Phase II trial is disease free survival. Further objectives include overall survival and safety. The trial also has a biomarker cohort that includes patients irrespective of (inaudible) in tumor DNA status.

Slide 21 highlights our presence at the SITC Annual Meeting on November 10 to 14. We will present data across 6 programs and 4 therapeutic platforms and through our presentations and posters. Overall, the data that we are presenting show favorable safety profiles and promising signs of clinical activity for all 6 clinical programs. In the trials, we are reporting at SITC. We observed preliminary biological or clinical activity in the one of [European] and it's 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 I trial of our candidate BNT111 from our wholly owned FixVac platform. BNT111 is our official (inaudible) vaccine that encodes a fixed set of 4 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 in 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 in checkpoint inhibitor experienced 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 II trial in checkpoint refractory or resistant melanoma testing BNT111 in combination with the anti-PD-1 cemiplimab in our partnership with Regeneron.

A new analysis, which we are presenting at SITC includes a cohort of pretreated patients with Stage 3 and 4 cutaneous melanoma with no evidence of disease that received BNT111 monotherapy. Overall, BNT111 had a favorable 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 flu like 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 spot SA results showed that similar proportions of patients in both groups responded to at least 1 tumor-associated antigen of the vaccine.

A substantial proportion of patients presented the novel 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 showed promising thickness of prolonged disease control in patients with no evidence of disease. The ability to induce T-cell immunity irrespective of the presence of 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 a significant clinical benefit and encourage further development of BNT111 in earlier melanoma disease setting. We are also presenting data from our FixVac BNT112 Phase I/II trial shown on Slide 23, at SITC. BNT112 encodes a fixed set of 5 prostate associated antigens. The first in human Phase I/II trial assesses the safety and immunogenicity of BNT112 monotherapy or in combination with cemiplimab 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 1 of the trial, which is BNT112 dose titrations is complete and the recommended dose range for Part 2 has been determined. Part 2, the dose expansion with BNT112 as a 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 I all with heavily pretreated late-stage cancer, 5 patients were treated in Part 2. Overall, most adverse events that occurred in Part 1 were mild or moderate.

There were 2 instances of Grade 3 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 1 were considered unrelated to BNT112. No safety signals of concerns were identified in part 2 in which patients received BNT112 only or in combination with cemiplimab. All 7 patients who were ELISpot-evaluable exhibited detectable immune responses. We also confirm that all 5 tumor-associated antigens were immunogenic and identified T-cell responses to each antigen in at least 2 patients. Two patients with late-stage cancer treated with BNT112 monotherapy had decreases in prostate-specific antigen, the 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 cemiplimab with first signal of activity in patients with advanced prostate cancer. Slide 24 and moving to BNT211 that comprises 2 drug products. Claudin-6 CAR-T cells and a CAR-T cell amplifying RNA vaccine in short CARVac. Claudin-6 CAR-T cells are equipped with a second-generation chimeric antigen receptor of high sensitivity and specificity for the tumor-specific antigen Claudin-6. Claudin-6 is absent in healthy adult tissues yet frequently expressed in high medical need cancer, 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 I/II 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, relapsed or refractory advanced solid tumors. Part 1 comprises Claudin-6 CAR-T monotherapy dose escalation cohorts and part 2 is a dose escalation of CAR-T combined with a fixed dose of CARVac. There are 3 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 21, 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 I/II BNT211 clinical trial that will be presented at SITC. The 8 patients included in the analysis were all heavily pretreated with testicular ovarian and endometrial cancers and sarcoma. Patients received CAR-T cell monotherapy and free CAR-T-cells plus CARVac vaccine combination therapy. Claudin-6 CAR-T cells as monotherapy or combined with CARVac were well tolerated at the dose levels evaluated and no dose-limiting toxicities were observed. Some cases of cytokine release syndrome occurred while manageable with no signs of neurotoxicity. Increases of interleukin-6 and (inaudible) 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 blood of a patient who revealed robust CAR-T cell engraftment up to day 17 post infusion. Further expansion was noted in 2 patients with liver metastasis accompanied by elevated (inaudible) . There were also encouraging signs of clinical activity in patients for which a 6-week tumor assessment was available. Three patients showed initial tumor shrinkage with tumor reduction between 18% and 27% according to RECIST. Signs of initial tumor shrinkage were identified even at the lowest dose tested. Data on the 1 additional patient evaluated between the abstract submission and the conference will be shared during the SITC 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 CARVac at upcoming congresses. Now we move to a data update of our ongoing Phase I/II trial on our bispecific antibody, BNT311 which we are developing in collaboration with Genmab. Slide 26 shows the mechanism of action of BNT311 and the Phase I/II trial design. BNT311 is the first-in-class bispecific antibody designed to elicit an antitumor 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 analysis presented at SITC 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 I/II trial. This data, along with a semi-mechanistic pharmacokinetic pharmacodynamic predictive model and translational work established 100-milligram of BNT311 every 3 weeks as the dose for expansion cohorts.

For details on this model will be presented at SITC. Since the dose escalation, we have proceeded to the dose expansion cohort 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 disclosure 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 effect consistent with its proposed mechanism of action. We identified peripheral and tumor immune activity in patients, including the moderation of immune cytokines, the expansion of CD8 effector memory T cells and natural killer cell activation. 5 patients had partial responses and showed a trend towards greater induction of cytokines and immune endpoints compared to nonresponders.

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 have progressed with prior anti-PD-1 therapy within 8 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 II trial of BNT311 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 bispecific antibody, BNT312, which we are also developing in collaboration with Genmab. It combines targeting and conditional activation of CD40 and 4-1BB on immune cells, resulting in enhanced priming and activation of tumor-specific immunity. The ongoing first-in-human trial evaluates the safety and antitumor 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 type 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. 1 dose-limiting toxicity of transaminases elevation occurred at the 200-milligram dose and resolved upon corticosteroid administration. We have observed increases in peripheral monocytes 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 BNT312. Moreover about half of these patients who had exhausted standard therapies achieved disease control, 2 patients with melanoma and neuroendocrine lung cancer who had confirmed partial responses. We have identified 100 milligrams every 3 weeks for dose expansion also for the (inaudible) 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 cohorts 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 the 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 for 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 received BNT411 monotherapy at up to 8 different dose levels. In the second dose escalation arm, patients with chemotherapy-naïve extensive-stage small cell lung cancer, will received BNT411, in combination with cytotoxic therapies and [chocolate] checkpoint inhibitors.

The dose escalation part will be followed by dose expansion cohorts. As of July 1, 2021, 11 heavily pretreated patients have received BNT411 monotherapy. Thus far, type of 8 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 a non-serious pyrexia and mytomoderate in India. 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 5 months of stable disease in a patient with anti-PD-1 pretreated squamous cell carcinoma (inaudible).

These data support the advancement of the trial into the dose escalation part in which patients receive BNT411 in combination with cytotoxic therapies and checkpoint inhibitors and recruitment into this 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 SITC 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.

Thank you, Ozlem, 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 EUR 6.1 billion for the third quarter of 2021 compared to EUR 67.5 million for the comparative period in 2020. For the period of 9 months ended September 30, 2021, we reported estimated total revenues of around EUR 13.4 billion compared to EUR 136.9 million 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 calibrations, 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 EUR 4.4 billion and respectively, EUR 10.2 billion for the first 3 quarters of 2021 that comprise our gross profit share generated by our collaboration partners in their respective territories as well as sales milestones. The sales milestones included in the figures I just mentioned amounted to EUR 17 million for the third quarter and EUR 432.8 million for the period of 9 months ended September 30, 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 adjustments 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 EUR 312.3 million in sales to our collaboration partners of products manufactured by us and EUR 1.4 billion of direct COVID-19 vaccine sales to customers in our territory which includes Germany and Turkey.

For the period of 9 months ended September 30, 2021, we had sales to our collaboration partners of EUR 514.3 million and approximately EUR 2.6 billion 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 EUR 1.2 billion for the third quarter of 2021 compared to EUR 6.8 million for the comparative period in 2020. For the 9 months ended September 30, 2021, total cost of sales were estimated to be around EUR 2.3 billion compared to EUR 18.3 million 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 EUR 260.4 million for the third quarter of 2021 compared to EUR 227.7 million for the comparative period in 2020. For the 9 months ended September 30, 2021, research and development expenses reached EUR 677.7 million compared to EUR 388 million for the comparative prior year period. The increase was mainly due to an increase in research and development 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 security expenses following an increase in head count.

The recognition of inventor compensation expenses as well as expenses incurred under share-based payment arrangements from the company. General and administrative expenses was EUR 68.2 million for the third quarter of 2021 compared to EUR 23.5 million for the comparative prior year period. For the 9 months ended September 30, 2021, general and administrative expenses reached EUR 154.9 million compared to EUR 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 arrangements, increase in expenses for purchased 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 EUR 1.5 billion for the third quarter of 2021, and around EUR 3.2 billion for the 9 months ended September 30, 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 EUR 3.2 billion compared to a net loss of EUR 210 million for the comparative prior year period. For the 9 months ended September 30, 2021, total net profit reached approximately EUR 7.1 billion compared to a total net loss of EUR 351.7 million for the comparative prior year period.

As of September 30, 2021, cash and cash equivalents totaled EUR 2.4 billion. Please note that the contractual settlement of the gross profit share under our COVID-19 calibration with Pfizer as temporal offset of more than 1 calendar quarter. As far as the fiscal quarter for subsidiaries outside the United States differs from ours, creates an additional time lag between the recognition of revenues and the payment receipt. Consequently, trade receivables, which were outstanding as of September 30, 2021, where we 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 the calendar year 2021, we're providing estimated COVID-19 vaccine revenues of approximately EUR 16 billion to EUR 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 the collaboration part of the 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 to low-income countries where prices are in line with income levels or at non-for-profit basis to serve the progress. We maintain our previous cost guidance for the fiscal year 2021 and expect to incur R&D expenses in a range of EUR 950 million to EUR 1.1 billion, 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 EUR 250 million to EUR 300 million.

Capital expenditures for the year 2021 are expected to be in the range of EUR 175 million to EUR 225 million. These figures have again been estimated at 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.

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 in silico therapeutics platform designed to enable the rapid production of recombinant natural license, which are optimized for potency, stability and manufacturing yield. The transaction, which closed in the third quarter included an upfront cash payment of approximately EUR 50 million in addition to potential future performance-based development milestones of up to EUR 100 million.

PhagoMed now operates as Biotech R&D Austria and will serve as Biotech'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 in 19 ongoing clinical trials across 4 drug classes. With the new trial initiation so far this year. We now have 4 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 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 Instructions)

And your first request is from the line of Cory Kasimov from JPMorgan.

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?

I can take this question.

I hope that you can hear me, I'm at the airport and there might be background noise. So the oral inhibitors, of course, provide the opportunity for treatment if the disease is established. The key question is indeed that this 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, that how much this all inhibitors will be available in 2022 at which percentage. And we have, of course, to understand whether the high efficacy, which was reported the last -- over a longer time. We know that single treatments with inhibitors in viral disease often results in development of resistance -- resistances and we have really to wait and see how this type of additional treatment, which is fantastic to have now in the market will complement or even compete with vaccines. I personally don't believe that this will have a huge impact on the vaccination rate in the future, but we have to monitor the field in the upcoming future.

Your next question is from the line of Chris Shibutani of Goldman Sachs.

Regarding the outlook for the Booster market, there are 2 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 address 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 2 issues: one, the broader population for booster recommendations; and two, the frequency of subsequent boosters longer term?

Yes. Yes, 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 sort of population who did not receive the booster vaccination in the range of 15 to 20 fold. And we have now evidence from our Phase III clinical trial where we compared the efficacy of the third dose -- of a booster dose in a randomized fashion and observed that an additional booster increases happen at an 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 infection rate.

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 overall population is not -- the vaccination rate is still not sufficient to control the delta variant. And with the increasing reining of vaccine responses, we will see also in the vaccinated population and increase of infection. 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 the 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 require -- which will probably require adaptation of the vaccine. But we can't say at the moment, when this is going to happen, that boosters are coming every 12 months or every 18 months or 24 months.

Our next question is from the line of Tazeen Ahmad from (inaudible).

Just a couple of points of clarification from me with regards to the SITC presentations. The first one for 111, 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 per the 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 do you expect there?

Yes. So for 111, we have now started the Phase II clinical testing and this trial will generate data earliest in 2023 from the Stage 2 clinical trial for 312. We will update on SITC about the clinical findings, of course, including the dose levels, yes. And we will certainly provide updates during ASCO -- ASCO and ESMO next year.

Your next question is from the line of Daina Graybosch of SVB Leering.

I wonder if you could give us an update on where you are with your partner, Fosun, in China on regulatory approval and potential distribution?

Yes, sure. I can take that one, Daina. So we have -- 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 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 response from the regulator and still engage with the regulator to open up the approval pathway in Mainland China.

Your next question is from the line of Akash Tewari from Jefferies.

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?

I could take the first part of the question. And so it is what regulators convinces is, of course, the overall data package at the time point and when we requested authorization of the booster doses, we had data from antibody responses, increase of 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 the third dose.

We believe that the increasing level of evidence for protection with -- from disease by booster doses is an increasingly good argument to enable also authorization of our vaccines in the overall population. My estimate is, even though we see a good protection against severe disease even after 8, 9 and 10 months, we will see also for protection from severe disease, a further decline, maybe in the direction of 80%. And if you calculate that the booster dose could increase the overall protection against the disease from 80% to 97% or 98% is 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 lead to overall authorization of booster doses for the broader population.

And thank you, 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've 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, 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.

Your next question is from the line of Daniel Wendorff of ODDO BHF.

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.

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

Yes. So in simple terms, will it be just mRNA vaccines being eligible for the booster shot? Or are there any new developments, other patients to other vaccines, which would also make them likely to be available booster shots.

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

Your next question is from the line of Arlinda Lee from Canaccord.

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 that maybe 1/10 and 1/3 of the original adult dose and then potentially emerge out of the pandemic control?

I'll take that one.

I think 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 consideration in how we calculate a future ex-pandemic price. With the pediatric, again, I think you have to look at -- you have to look at it from a value perspective and not a straight reduction in milligrams or micrograms and a kick in terms of the price that we would consider. Again, I would say that there will certainly be a ex-pandemic price. And of course, we're currently working on that. We're still very much in the pandemic.

And our last question today is from the line of Ali Merit from UBS.

Just on the business development strategy going forward. I guess just after the PhagoMed 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?

Yes, I can take that question. Thank you. So yes, I think you've seen us do 2 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 PhagoMed acquisition. And I do think you can expect to see more of these types of deals, and our key criteria will be to broaden our technology base. As with PhagoMed 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 has 2 key areas of focus.

Thank you. There are no further questions. Please continue.

Thank you. 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 the future. Thank you everyone.

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