BioNTech - Q3 2024

Transcript

Operator (participant)

Welcome to BioNTech's third quarter 2024 earnings call. I would like to hand the call over to Michael Horowitz, Director of Investor Relations. Please go ahead.

Michael Horowicz (Director of Investor Relations)

Thank you. Good morning and good afternoon. Thank you for joining BioNTech's third quarter 2024 earnings call. As a reminder, the slides we will be using during this call and the corresponding press release we issued this morning can be found in the Investor Relations sections of our website. On the next slide, you will see our forward-looking statements disclaimer. Additional information about these statements and other risks are described in our filings with the U.S. Securities and Exchange Commission. Forward-looking statements in this call are subject to significant risks and uncertainties and speak only as of the date of this conference call. We undertake no obligation to update or revise any of these statements. On slide three, you can find the agenda for today's call.

Today, I am joined by the following members of BioNTech's management team: Ugur Sahin, Chief Executive Officer and Co-founder, Özlem Türeci, Chief Medical Officer and Co-founder, Jens Holstein, Chief Financial Officer, and Ryan Richardson, Chief Strategy Officer. With this, I would like to hand it over to Ugur.

Ugur Sahin (CEO)

Thank you, Michael, and welcome to all those joining us today. I will be keeping my introduction very brief today. We made significant achievements during the third quarter, including advancements across our oncology pipeline and a strong start to the season for our COVID-19 vaccine franchise. Our progress in this quarter built on what has already been an impactful year. I would like to highlight achievements in three areas. First, with regard to our COVID-19 vaccine leadership, we have successfully launched updated vaccines targeting the latest variants, distribution now underway in multiple regions globally. In oncology, we have presented our progress in two strategic priority areas, namely our bispecific immunomodulator, BNT327, partnered with Biotheus, and our mRNA cancer vaccine portfolio. As part of our pipeline progress, we shared numerous clinical updates across our oncology pipeline at the ESMO Congress.

We and our partner Biotheus have kicked off the broad global development of BNT327, our bispecific antibody targeting PD-L1 and VEGFA. The datasets presented at ESMO and at conferences earlier this year support the pan-cancer potential of this priority asset and support our clinical development plans that we will touch on today and discuss in greater detail at our innovation series next week. We took significant steps forward in the execution of our clinical development plan this quarter and dosed the first patients in two optimization studies in small cell lung cancer and triple-negative breast cancer to inform the pivotal studies planned in both indications.

With regard to our mRNA vaccine portfolio, we announced earlier in the quarter that our off-the-shelf FixVac mRNA cancer vaccine candidate BNT111 met the primary endpoint in the ongoing randomized two-arm trial evaluating BNT111 in combination with Regeneron's anti-PD-1 agent cemiplimab in patients with stage III and stage IV cutaneous melanoma. This preliminary result underscores our belief in the transformative potential of our proprietary mRNA vaccine technology, which is a key pillar of our oncology strategy. Moreover, we are taking another step to broaden our personalized mRNA cancer vaccine development program. We and our partner Genentech have initiated a new randomized controlled phase II clinical trial evaluating our personalized cancer vaccine candidate in patients with bladder cancer in the adjuvant setting in combination with immune checkpoint inhibition. Our personalized vaccine program now includes four ongoing phase II clinical trials.

In addition, during Q3, we had our inaugural AI day, where we highlighted our in-house AI company, InstaDeep, and provided an overview of BioNTech's collective AI capabilities. This was an exciting event where we showcased our commitment to building state-of-the-art AI. Before turning over to Özlem for more detailed coverage of these achievements, let me remind you of our overarching strategy for oncology. BioNTech was established with the ambition to revolutionize cancer treatment through the development of mRNA-based immunotherapies, particularly through personalized cancer vaccines. This approach remains at the forefront of our efforts to pioneer the next wave of cancer treatments, aiming to tailor therapies to the individual genetic makeup of each patient's tumor. Building on this foundation, we have systematically assessed next-generation immune modulators with a focus on bispecific molecules that can engage more than one target.

BNT327, our bispecific antibody targeting PD-L1 and VEGFA, has emerged as a key molecule in our pipeline. We believe that BNT327 has the potential to serve as a foundational component in the treatment regimens for multiple cancer types, enhancing the effectiveness of our therapeutic mRNA cancer vaccines and other therapies through its dual targeting mechanism. Complementing these mechanisms of action, we have recently expanded our portfolio to include targeted immunotherapies such as antibody-drug conjugates and CAR T-cell therapies. These modalities offer precise mechanisms for attacking cancers, providing new avenues for combination therapies, particularly for fighting large metastatic tumors. Our integrated long-term approach will combine these synergistic therapeutic platforms to optimize cancer treatment. Our strategy aims not only to address the existing challenges in cancer care, but also to significantly improve long-term survival rates, even in patients with advanced disease states.

By continually evaluating the effectiveness of individual compounds and innovative combinations, we can better identify the most promising treatment strategies for specific patient populations. Today, Özlem will discuss in more detail our progress on BNT327 and our expanding efforts on our therapeutic mRNA cancer vaccine front, two proprietary key pillars of our strategy. Before handing over, I would like to thank you all for your ongoing support as we enter this truly exciting period for BioNTech and progress towards our founding vision. Thank you.

Özlem Türeci (CMO)

Thank you, Ugur. Glad to be speaking with everyone today. I will begin with our COVID-19 franchise. Ahead of this vaccination season, regulatory and public health authorities advised vaccine manufacturers to revise the antigen composition for the authorized COVID-19 vaccines in line with the latest epidemiologic data. The continuous evolution of SARS-CoV-2 and the emergence of variants have led to regionally different recommendations for this year's vaccine strain selection. We have been able to rapidly meet these different requirements due to the flexibility of our mRNA technology, which enables us to adapt our construct on relatively short notice. In Europe, less than three weeks after the regulatory authority recommended the use of a JN.1 spike antigen in the COVID-19 vaccine for the 24-25 season, we were able to submit our application to the European regulator, and we began rolling out our updated vaccine shortly after approval in early July.

Anticipating the regional differences, we followed up with the development and submission for a KP.2-adapted vaccine. In the U.K., the regulator approved our JN.1-adapted COVID-19 vaccine in July and our KP.2-adapted COVID-19 vaccine in early October. In the United States and Canada, regulatory authorities recommended the use of KP.2 as the preferred lineage for the present season. Less than two weeks after recommendation, we initiated our rolling submission with the U.S. FDA and received approval of our KP.2-adapted vaccine in August. In Japan, we received our JN.1 approval in early August. These early strain recommendations and approvals have allowed for the timely delivery and earlier availability of vaccines for the fall vaccination campaigns.

Execution at such speed was enabled by our continued surveillance and analysis of variants of concern, by the strength of our mRNA technology, which allows for scalable rapid production, and due to our expertise at navigating the regulatory landscape on a global scale. We will continue to monitor the evolving epidemiology of COVID-19 and remain prepared to develop vaccines with adapted antigenic compositions in line with regulatory recommendations. COVID-19 transitions to an endemic infection pattern. Data on weekly new hospital admissions due to infections caused by SARS-CoV-2 and by influenza show different patterns of seasonality. This past season, like in the prior year, COVID-19 disease-related hospitalization had two prominent peaks: one in the winter and an additional one in summer. In contrast, for influenza, we predominantly see increases in hospitalizations in the winter.

The emergence of new variants, coupled with the waning of both vaccine and infection-induced immunity, indicates that susceptibility to COVID-19 infection remains a concern after the winter vaccination season. These different patterns of seasonality of influenza and COVID-19 may have an impact on regulatory guidelines to facilitate protection throughout the year. Recently, U.S. authorities recommended older and immunocompromised individuals receive an additional COVID-19 vaccine dose. Administration of additional doses later this season could contribute to improved vaccine coverage over time, mitigating the risks associated with evolving COVID-19 variants. Given our current understanding of COVID-19 seasonality and its burden on healthcare systems, we are proud that our vaccine can contribute to mitigate severe infection and protect people around the world from COVID-19-related hospitalizations and deaths. Turning now to our oncology pipeline.

Our multi-platform immune oncology clinical pipeline is continuing to advance, and it is a rich source for the strategically planned novel combinations that we consider a key pillar of our vision for oncology. As you can see, two of our modalities, namely mRNA and immunomodulator IOs, are dominantly represented in our pipeline, and particularly so in the advanced clinical stages. This is a testament to our drive towards mid-to-late-stage trials as part of our ambition to achieve multiple product launches in oncology by 2030. As Ugur pointed out, we have a special focus on our mRNA cancer vaccine portfolio and our BNT327 central clinical development program, with the latter becoming our platform for unique combinations with several of our other assets, in particular our ADC. BNT327 is a bispecific antibody candidate that targets both PD-L1 and VEGFA, thus combining two complementary functions.

The binding of BNT327 to PD-L1 in tumors restores effector T-cell killing of tumor cells and enriches VEGFA neutralization within the tumor microenvironment to create a cycle of vascular normalization, improved blood flow, and reduced hypoxia within tumors. BNT327 also reverses the negative effect of VEGFA signaling on infiltration and activation of immune cells in the tumor microenvironment. By co-localizing the blockade of PD-L1 and VEGFA signaling to the tumor, BNT327 is designed to deliver superior anti-tumor effects compared to individual targeting of PD-L1 and VEGFA, with the potential to minimize adverse events associated with systemic anti-VEGFA therapy. With the anti-PD-L1 and VEGFA antagonistic mechanisms being validated across numerous tumor types and, in some cases, in combination, we have a roadmap for the development of BNT327.

We and our partner, Biotheus, have treated over 700 patients in clinical trials across a wide range of clinical indications with BNT327, either as monotherapy or in combination with various standards of care treatments. In these early studies, BNT327 demonstrated encouraging activity as mono and combo therapy with a favorable safety profile that was shown to be generally well manageable and in line with adverse events and immune-related adverse events observed with other therapies targeting PD-L1. The data also indicate robust single-agent activity for BNT327 and in combination with standard of care chemotherapy across tumor types and treatment lines. This extensive data collection provides us with a solid foundation for making data-driven decisions on potential indications and patient cohorts for future potentially registrational studies. One of the indications we have selected for further development is triple-negative breast cancer, TNBC, the type of breast cancer with the poorest outcomes.

In first-line metastatic TNBC, we have observed a high objective response rate with encouraging responses and long progression-free survival for BNT327 in combination with nab-paclitaxel. At ESMO this year, we presented updated efficacy and safety findings from the ongoing phase I-II study in this indication. Across the intent-to-treat population of 42 patients, we observed a confirmed objective response rate of 74%. Importantly, responses were shown to be clinically meaningful irrespective of PD-L1 status. In patients with PD-L1 combined positive scores or CPS smaller than 1, confirmed objective response rate was 76.9%. In patients with PD-L1 CPS between 1 and 10, the confirmed objective response was 56%, and in patients with PD-L1 CPS higher than 10, the confirmed objective response rate was 100%.

We also observed rapid tumor shrinkage with a median time to respond of 1.9 months and an encouraging median duration of response of 11.7 months in the intent-to-treat population. Treatment-related adverse events of grade 3 or above occurred in 57% of patients, leading to treatment discontinuation in 4.8% of them. In summary, we are encouraged by the potential of BNT327 in combination with chemotherapy to offer clinically meaningful anti-tumor activity regardless of PD-L1 status and by its manageable toxicity. We have prioritized the planning of global trials in TNBC where unmet needs remain high, particularly for those with PD-L1-negative tumors as they are not eligible for current anti-PD-1 treatments. We will be presenting additional data in first-line TNBC at the San Antonio Breast Cancer Symposium next month. We believe that BNT327 and this drug class at large are showing an increasingly validated mechanism of action.

The dose optimization trials in the U.S. initiated recently allow us to create a robust scientific data package to inform the global development of this asset and seek phase lll of focused development. We plan to execute quickly and move broadly into phase lll. First, we are investigating BNT327 combinations with standard of care chemotherapies as an intended fast-to-market approach. The data generated by our partner, Biotheus, have driven our decision to prioritize the planning of registrational trials in small cell lung cancer, TNBC, and non-small cell lung cancer due to start in the next few months. Second, we plan to evaluate BNT327 with our ADCs in some of these tumor types and additional key indications. The first exploratory trial evaluating novel BNT327 combinations was started earlier this year with our proprietary TROP2 ADC, BNT325. These novel combinations may open up new areas of activity for BNT327.

We plan to initiate additional trials evaluating novel proprietary combinations of BNT327 with ADCs before year-end and over the next 12 months. Lastly, we aim to expand with standard of care chemotherapy and novel combinations beyond ADCs across further indications and treatment settings. It is a strategic goal for us to explore BNT327 as part of novel-noble combinations. Given our experienced clinical development team, which has an increasingly global footprint, our strong financial position, and unique pipeline, we are confident that we are well positioned to efficiently execute on this comprehensive clinical development strategy. Now to the other cornerstone of our oncology portfolio, our mRNA cancer vaccine platform, iNeST and FixVac. iNeST targets neoantigens derived from somatic mutations in cancer cells that are unique to an individual's tumor.

iNeST vaccines are investigational vaccines that are being co-developed with our partner, Genentech, and are manufactured on demand and personalized to the individual patient. FixVac vaccines target multiple non-mutated tumor antigens shared by a majority of patients with a given tumor type and are offered shared cancer vaccine candidates. The computational approaches to discovering and selecting these two different types of target antigens are one of our core competencies. iNeST and FixVac both use the same vaccine and delivery technology, namely our proprietary mRNA LPX platform. Today, we have ongoing trials in multiple disease settings and indications across both vaccine platforms. We have reported translational and clinical data over the last couple of years, and future data updates from multiple trials shown on this slide outlined.

Aggregate data that we have reported in the past across iNeST and FixVac trials indicate that uridine mRNA LPX-based vaccines have a manageable and largely mild safety profile as single agents in combination with anti-PD-1, PD-L1 compounds, and in combination with chemotherapy. Our data also indicate that our uridine mRNA LPX-based vaccine platform is highly proficient in inducing and expanding high-magnitude functional and long-lived T-cell responses in the majority of patients, which is a prerequisite for clinical activity. Furthermore, our data from small sample-sized patient cohorts indicates clinical activity alone and in combination with anti-PD-1, PD-L1 treatment. In our FixVac program, I would like to highlight two vaccine candidates for which we had important updates during the quarter. For BNT113, our mRNA vaccine candidate against HPV16-positive cancers, we presented data from two trials at the ESMO Conference.

One data set was from the safety run-in cohort of our potentially registrational phase II randomized trial, AHEAD-MERIT. This trial evaluates BNT113 in combination with pembrolizumab, where the pembrolizumab alone in first-line HPV16-positive, PD-L1-positive, head and neck squamous cell carcinoma. The data supports the tolerability of BNT113 and clinical activity in combination with pembrolizumab and the induction of high-magnitude de novo T-cell responses against HPV16 antigens encoded in this vaccine. In summary, we are encouraged by the data of the safety cohort. The second data set from an investigator-initiated phase I-II trials exploring BNT113 as single agent in patients with localized and metastatic anal, head and neck, cervical, and other HPV16-driven carcinoma further confirmed positive safety and immunogenicity findings. We reported top-line findings for BNT111, which is being investigated in patients with anti-PD-1 relapsed or refractory melanoma.

BNT111 encodes four melanoma-associated antigens, which collectively cover more than 90% of melanoma patients and are highly immunogenic. In the randomized phase II clinical trial conducted in collaboration with Regeneron, BNT111 is being evaluated in combination with their anti-PD-1 compound, cemiplimab. The trial enrolled 184 patients with PD-L1 refractory, unresectable, stage three or four melanoma and comprises three arms, of which one evaluates the combination and the other to measure the activity of BNT111 alone or cemiplimab alone. The trial met its primary endpoint, achieving a statistically significant improvement in ORR, an objective response rate, in the BNT111 cemiplimab combination arm as compared to a historical control of anti-PD-1 monotherapy in relapsed refractory patients based on multiple late-stage clinical trials that established the expected ORR for monotherapy checkpoint inhibitors in this setting for this patient population.

The results we saw in the phase II study are consistent with results seen in the preceding phase I-II trial in patients with advanced melanoma who had exhausted treatment options. BNT111 alone or in combination with an anti-PD-1 compound induced high-magnitude T-cell responses against at least one targeted tumor-associated antigen in all analyzed patients, most of which were not detectable prior to using the vaccine. We plan to present the full data from the primary analysis at the medical conference. The various FixVac data updates provided in Q3 are a proof of concept in three dimensions. First, before our mRNA cancer vaccine technology that uses uridine mRNA chemistry, a non-coding vector backbone that is engineered for optimal translation performance, and our proprietary Lipoplex formulation for systemic delivery, which we are using in both iNeST and FixVac vaccines.

Secondly, for our computational approaches for selecting suitable tumor antigens and targets for our indication-specific FixVac program candidates. Lastly, a proof of concept for our strategy to combine synergistic modalities in the case of BNT111 and BNT113 with established immune checkpoint inhibitor treatments. Moving to autogene cevumeran, also known as BNT122, our individualized mRNA cancer vaccine candidate based on our iNeST platform in development with our partner, Genentech. We consider individualized cancer vaccines as a potential medical breakthrough in addressing the high unmet medical need of resectable cancers and in adjuvant or minimal residual disease treatment settings. We have demonstrated that our individualized vaccine candidate used in patients with adjuvant pancreatic cancer can induce de novo T-cell responses that are specific to the individual mutant tumor neoantigens and that the risk of recurrence of cancer for patients with vaccine-induced immune responses was reduced over a three-year follow-up period.

We have two active randomized phase II trials evaluating our individualized cancer vaccine in the adjuvant setting, namely in pancreatic ductal adenocarcinoma or PDAC and in colorectal cancer. The five-year survival rate in PDAC after resection is 10% and up to 75% of patients with PDAC relapse, even though they appear tumor-free within five years after adjuvant treatment. For high-risk colorectal cancer, about 35% of patients relapse within five years after resection and adjuvant therapy. To summarize, we aim to bring individualized cancer vaccines into the adjuvant treatment setting in tumor types where the unmet medical need is high. As such, we have expanded into a new indication with the start of a phase II trial evaluating our individualized cancer vaccine candidate in the adjuvant treatment of muscle-invasive urothelial carcinoma, which has started screening patients.

The current treatment includes neoadjuvant chemotherapy followed by cystectomy, and for eligible patients, this is followed by adjuvant treatment with an immune checkpoint inhibitor. The five-year survival among patients with metastatic bladder cancer is about 8%. Adjuvant treatment of muscle-invasive disease is an important opportunity to potentially avoid recurrent metastasis and improve overall survival. The randomized double-blind multi-site phase II clinical trial aims to evaluate autogene cevumeran as an adjuvant treatment with the immune checkpoint inhibitor and nivolumab in patients with high-risk disease. The trial is expected to enroll about 360 patients to evaluate the efficacy of BNT122 in combination with Nivo, compared to Nivo alone, the standard of care for this indication in the U.S. The primary endpoint for this study is investigator assessed disease-free survival. Secondary objectives include overall survival and safety.

Lastly, as a final note, I would like to invite you to our upcoming Innovation Series Day next week, where we will share additional details on these and other programs of our immunotherapy pipeline. With that, I will now pass the presentation to our CFO, Jens Holstein.

Jens Holstein (CFO)

Thank you, Özlem, and a warm welcome to everyone who has dialed in today's call. Let me start by reviewing our financial results for the three months ended September 30, 2024. The total revenues reported for the period were approximately EUR 1,245 million, mostly recorded in September, compared to approximately EUR 895 million for the third quarter of 2023. The increase compared to the same period last year can be largely attributed to earlier approvals of our variant-adapted COVID-19 vaccines this year versus last year.

Moving to cost of sales, cost of sales amounted to approximately EUR 179 million for the third quarter of 2024, compared to approximately EUR 162 million for the comparative prior year period. Research and development expenses were approximately EUR 550 million for the third quarter of 2024, compared to approximately EUR 498 million for the comparative prior year period. These expenses were mainly influenced by progressing clinical trials for our late-stage oncology pipeline candidates. Sales, general, and administrative expenses amounted to approximately EUR 151 million for the third quarter of 2024, compared to about EUR 154 million for the comparative prior year period. SG&A expenses were primarily driven by personnel expenses. The company's other operating results amounted to approximately EUR 355 million in the third quarter of 2024, compared to EUR 9 million for the comparative prior year period. The other operating result was primarily influenced by accruals for contractual disputes.

Income taxes were realized with an amount of about EUR 39 million in the third quarter of 2024, compared to approximately EUR 67 million of accrued tax expenses for the comparative prior year period. For the third quarter of 2024, we reported a net income of approximately EUR 198 million, compared to about EUR 161 million for the comparative prior year period. Our diluted earnings per share for the third quarter of 2024 amounted to €0.81, compared to EUR 0.66 for the comparative prior year period.

As of September 30, 2024, our cash and cash equivalents plus security investments reached approximately EUR 17.8 billion. Our strong balance sheet allows us to invest in future value creation. Consequently, we will continue to invest in maintaining a leading cash-generative COVID-19 vaccine business, in the development of our oncology therapies, and in our core capabilities to support additional late-stage trials and potential commercialization of our most encouraging oncology assets.

We will continue to assume a rigorous go-no-go decision-making across all development stages as part of our portfolio prioritization strategy. This allows us to maintain our focus on materializing the value in our pipeline. Turning to the next slide, where you see our financial guidance for the full year of 2024, we saw a strong quarter in terms of revenues, which included certain revenues that we previously anticipated in the last quarter of 2024. With this, we expect full 2024 financial year revenues to be at the low end of the guidance range provided in our outlook. Our guidance reflects some risk of write-downs and other charges by our collaboration partner, Pfizer, which we estimate to be approximately 10% of company revenues. We will continue to monitor the risk of potential write-downs to determine the full scope of charges related to the 2024-2025 vaccination season.

In line with our disclosure earlier in the year, we expect to report a loss for the 2024 financial year as we continue to invest in our most differentiating assets and technologies. We are committed to responsible and sustainable growth, and with this, are updating our full 2024 financial year expenses guidance to indicate a decrease in estimated SG&A expenses and capital expenditures. Reflecting our focus on continued investment in our pipeline, we are maintaining our R&D expense guidance. We have lowered the initial full 2024 financial year SG&A expense guidance by EUR 100 million from EUR 700 to EUR 800 million to now EUR 600 to EUR 700 million. We also reduced our capital expenditures guidance by EUR 100 million from the initial 2024 guidance range of between EUR 400 million and EUR 500 million to between EUR 300 million and EUR 400 million.

Please note that these guidance updates for SG&A expenses and CapEx do not reflect any M&A, collaboration, licensing transactions that we may enter into in the future, nor any potential payments resulting from the outcomes of ongoing and/or future legal disputes or related activities such as judgments or settlements or other extraordinary items, all of which may have a material effect on our results of operations and/or cash flows. In summary, we remain focused on executing the company strategy highlighted by the progress across our pipeline. We have advanced and started new dose optimization and potentially registrational trials and have shared encouraging data that demonstrate the potential of our product candidates. In our oncology portfolio, our focus remains on investing in our innovative technologies that we believe can have the greatest impact on medical practice while progressing our late-stage programs efficiently towards potential approvals.

Our cash position and financial discipline allows us to continue to invest in those assets with the highest disruptive potential and focus on generating value for patients and our shareholders. With that, I would like to turn the call over to our Chief Strategy Officer, Ryan Richardson, for our strategic outlook and concluding remarks. Thank you. Thank you, Jens. Starting with COVID-19, we continue to execute on our successful launch of this season's JN.1 and KP.2 variant-adapted vaccines in more than 40 countries and regions around the world. In September, we began distribution of our KP.2 variant-adapted vaccine in Europe, following the initial rollout of JN.1 vaccines in July. We expect additional markets, including the UK, that received initial shipments of JN.1 vaccine to transition to KP.2 deliveries in November.

In the United States, we continue to expect vaccination rates this year that are generally comparable to last year, with potential for slightly higher volumes due in part to the earlier approval and rollout of vaccines and supported by ACIP's recommendation in October for a second dose of COVID-19 vaccine for individuals who are 65 or older or immunocompromised. Internationally, we have seen the opening up of several private markets in countries like the U.K., Japan, Switzerland, Australia, South Korea, Singapore, and Brazil. This year, we have also increased our supply of prefilled syringes in a number of international markets. The epidemiology of COVID-19 over the last two years and the associated global demand for vaccination continue to support our view that COVID-19 vaccines will be a sustainable market for the foreseeable future.

We expect to maintain or even gain market share in a number of key markets this year versus last year and believe that we are likely to enter a period with improved visibility into vaccine demand. One of the unique features of our COVID-19 vaccine business is its lean cost structure. Our partnership with Pfizer allows us to leverage its manufacturing infrastructure and global commercial capabilities, which we expect will continue to enable us to limit the OpEx flowing through our P&L. These features create the potential for us to generate significant cash flow from our COVID-19 business, a feature we expect to benefit from in the future. Turning to the next slide, we are entering a catalyst-rich period for our company, in particular for our oncology portfolio. Today, we have more than 10 phase II and III trials ongoing across multiple tumor types.

In the next 18 months, we expect multiple clinical data updates from these trials and will initiate several additional trials with registrational potential. Data is expected in 2025 from both our mRNA cancer vaccine platforms, FixVac and iNeST. We also expect data updates for BNT327, our anti-PD-L1 VEGF bispecific antibody, and BNT323, our HER2 ADC. Before we conclude our planned remarks, I would like to invite everyone to watch our annual Innovation Series event on November 14. This event will include a deeper dive into our oncology strategy, including plans for BNT327 and our mRNA cancer vaccine candidates. We look forward to engaging with you later this month to share more on our plans to create value for patients, society, and shareholders. With that, we would like to open the floor for questions. Thank you.

Operator (participant)

To ask a question, please press star one on your telephone and wait for your name to be announced. To whisper your question, please press star one again. We kindly ask analysts to limit themselves to one question per person. We will now take the first question from the line of Tazeen Ahmad from Bank of America Securities. Please go ahead.

Tazeen Ahmad (Managing Director)

Thank you. Good morning, and I appreciate your time. I wanted to ask you about one of the data catalysts that you mentioned that's upcoming in 2025. Perhaps we'll talk about this more in detail next week. But for 323 specifically, I believe you've got data coming for endometrial cancer. Can you talk about the level of data you expect to show next year for that program and what you're looking for in order to move forward? Thanks.

Özlem Türeci (CMO)

Tazeen, thank you for this question. The question was about our endometrial cancer data with BNT323. And what I can tell you about that is that in 2025, we expect to share data from our single-arm trial in second-line endometrial cancer. We will be able to show efficacy data and safety data across different HER2 positivity populations, and this will be presented at one of the major cancer conferences. And also, what would be positive data in your mind for that program? Can you repeat?

Tazeen Ahmad (Managing Director)

What would be positive data for that study in your mind?

Özlem Türeci (CMO)

Positive data.

Tazeen Ahmad (Managing Director)

Yeah. What would justify moving forward?

Özlem Türeci (CMO)

What would justify to continue with the compound is a strong clinical activity profile and a favorable safety. And this is also what we see in the data, and we see this across different HER2 expression levels.

Operator (participant)

Thank you. We will now take the next question from the line of Daina Graybosch from Leerink Partners. Please go ahead.

Daina Graybosch (Senior Research Analyst)

Hi. Thank you for the question. I have one on the VEGF PD-L1 BNT327. I think we're all aware of a similar bispecific that has a PD-1 side, whereas you have a PD-L1 side. And in small trials in similar indications like triple-negative breast cancer, the two bispecifics look to have similar outcomes. Was that expected, and what does that tell you about the mechanism? And do you believe BNT327 could be differentiated in any indications? Thank you.

Özlem Türeci (CMO)

Hi, Daina. Thanks for the question. Yeah, this is a good question. And at the end of the day, both bispecifics link this activity of neutralizing VEGF and neutralizing PD-1, PD-L1 interaction. They have this in common.

The biggest difference is that BNT327 is directed against PD-L1, which comes with the potential advantage of being further enriched in the tumor microenvironment by binding to PD-L1 or vice versa, enabling or adding to the binding of VEGF in the tumor microenvironment. The data that we have so far, there are some overlapping clinical trials, as you mentioned, look similar, and we have to see whether this potential mechanistic difference could translate into a better response rate and better durability, particularly in PD-L1-positive tumors, so we have to see that there is a slight trend in this direction, but it's too early to validate that.

Operator (participant)

Thank you. We will now take the next question from the line of Akash Tewari from Jefferies. Please go ahead.

Hi. This is Kathy on for Akash.

For your VEGF PD-L1 bispecific BNT327, when do the AEs and dose reductions for hypertension and proteinuria show up in comparison to what we've seen historically for VEGF PD-L1 when co-administered as two separate drugs? And additionally, why aren't you going forward with it to first-line NSCLC in an all-comers population? And what's the rationale for going as a biomarker-selected population?

Özlem Türeci (CMO)

Thank you. Okay. I take both parts of the question. So the first question was the comparison with the historical safety profile, particularly with bevacizumab. So we have now more than 700 patients treated either as monotherapy or in combination. And the comparison to the historical safety profile clearly shows reduced side effect profile with regard to the key concerning side effects of bevacizumab: bleeding, hypertension, or the formation of fistulas.

We have not seen any significant increase of bleeding cases in this cohort, which goes beyond what is observed in this population, for example, for PD-1 antibodies, and hypertension rate is significantly lower than the historical comparison with bevacizumab. The mechanism for this can only be speculated that by linking the antibody, this VEGF part, to PD-L1, and the anti-VEGF interaction is more targeted to the tumor sites and less active in the PD-L1-negative areas, and this is, of course, encouraging and provides an additional argument beyond the so far increased clinical activity for this compound class. This was the first part, and the second part is why we prefer to go into an all-comer population. The response to that is that our bispecific has shown a clinical activity not only in PD-L1-positive and PD-L1-low populations, but also in populations which do not express PD-L1 or CPS.

So I would refer to our data sets that we generated in TNBC where the objective response rate in the TNBC all-comer population is extremely encouraging. We see something similar with a clear indication of a clinical activity in the PD-L1-negative population in the second-line non-small cell lung cancer and the other positive population. So the working hypothesis that we have is that this bispecific antibody truly overcomes the limitation of pure clinical activity in PD-L1-positive tumors and opens up the potential to bring checkpoint blockade plus VEGF activity into tumors that are also PD-L1-negative. So the clinical trial in non-small cell lung cancer is an all-comer trial, but we are documenting and collecting samples for PD-L1 evaluation, and we are stratifying patients according to PD-L1 positivity.

Daina Graybosch (Senior Research Analyst)

Thank you.

Operator (participant)

Thank you. We will now take the next question from the line of Suzanne van Voorthuizen from VLK. Please go ahead.

Hi, team. This is Suzanne. Thanks for taking my question. Maybe I missed it, but can you clarify what the exact amount is that you have taken as a provision for contractual disputes this year? Is this it, or will there be more? And can you indicate what this relates to, if this is the ongoing patent dispute with other mRNA players on the COVID vaccine, or if there are other contractual disagreements you are dealing with? Thank you.

Özlem Türeci (CMO)

Yeah. I'm happy, Suzanne, to take the question. So as you stated, the other operating result is reflecting these provisions that we have taken care of for contractual disputes with licensors and collaborators. At this point in time, given the legal situation that we're in, I cannot give precise messaging on for what this is.

There are a couple of disputes that are related, as I stated, with some of the players and collaborators that we're working with. In total, we have accrued around about EUR 600 million year-to-date for this, and this is the amount that we feel is accurate at this point in time.

Thanks.

Operator (participant)

Thank you. We will now take the next question coming from the line of Terence Flynn from Morgan Stanley. Please go ahead.

Terence Flynn (Managing Director and Equity Research Pharma & Biotech Analyst)

Great. Thanks so much for taking the question. I was just wondering if you can tell us what you think the relevant benchmark is for survival for the upcoming BNT327 TNBC data that we're going to see at the San Antonio conference in December. Thank you. Hi. Were you able to hear my question?

Michael Horowicz (Director of Investor Relations)

Yes. Can you just repeat that? Sorry. Yeah.

Terence Flynn (Managing Director and Equity Research Pharma & Biotech Analyst)

Survival benchmark is for the upcoming BNT327 TNBC data at the San Antonio conference in December. And then the second part of the question is, is it reasonable to expect some interim data from your global phase two lung cancer trial next year? Thank you.

Özlem Türeci (CMO)

Yeah. Okay. I can take the question. The trial will be randomized against chemotherapy standard of care. And the trial itself is powered for PFS and OS. The PFS is, in this indication, in the range of four to five months. OS, I can't recall at the moment. Yeah. Hazard ratio of 0.7. Yes. Right. I think we're going to provide an update at the 15- and 18-month OS mark in terms of percentage of patients reached.

And that's starting to get into a relevant zone, Terence, when you look at what Pembro has achieved in a similar indication, which is basically in the 15- to 23-month median OS, depending on the CPS patient population. Absolutely. And we have recently reported PFS data in the single-arm trial, reaching now above 13 months and still ongoing.

Operator (participant)

Thank you. We will now take the next question from the line of Yaron Werber from TD Cowen. Please go ahead.

Yaron Werber (Managing Director and Senior Biotechnology Analyst)

Great. Maybe just a follow-on on Terence's question. On TNBC, is the starting phase three to go for CPS less than 10 specifically in that cohort, or would you go across all CPS levels in phase three? And then secondly, on small cell, is the primary going to be head-to-head against chemo + Tecentriq, or is it going to be against chemo alone? Thank you so much.

So the first trial is intended in the patient population below 10%, and we'll be against chemotherapy alone. But we plan also further or we are in the evaluation of additional trials going to the above 10% population. And can you just repeat the second part of your question?

Terence Flynn (Managing Director and Equity Research Pharma & Biotech Analyst)

Yeah. Hey, Ryan. And just switching to small cell lung cancer, is the phase three going to be head-to-head against chemo or against chemo-Tecentriq? Thank you. In small cell lung cancer? Chemo-Tecentriq.

Operator (participant)

Thank you. We will now take the next question from the line of Jessica Fye from J.P. Morgan Chase. Please go ahead.

Jessica Fye (Managing Director and Equity Research Analyst)

Hey, guys. Good morning. Thanks for taking my questions. First, on guidance, of the various assumptions factoring into your guidance, what changed to lead you to guide to the low end of the range, even though Pfizer, I believe, maintained its Comirnaty guidance last week?

And then on the pipeline for BNT327, the VEGF PD-L1 bispecific, what do you see as the fastest-to-market indications? And what's the right way to think about R&D spend as the company expands trials for this product? Thank you.

Özlem Türeci (CMO)

Yeah. Jessica, let me take the first part of the question. So we've guided at the beginning of the year EUR 2.5 billion-EUR 3.1 billion based on, of course, certain scenarios. Year-to-date Q3 has been very, very good. And Q3 so far, or the year-to-date figures so far, have been generated dominantly by revenues that were generated in high-income countries. We have seen, though, low demand and also low pricing in some of the low and middle-income countries within the Pfizer territory. And therefore, we specified our guidance to the low end for this year. And then second question. I think your second question was speed to market.

Ugur Sahin (CEO)

What do we think would be the fastest-to-market for 327? Is that correct? Yep. So I think we're going to provide more details at our innovation series event next week in terms of the paths to market. But I think what we can say now is that we do think that small cell lung cancer could be one of the leading indications that we're looking at very closely. We initiated a phase two trial and believe that we can start a phase three trial. It's a phase two-three effectively, so a phase three portion of that trial in the coming months by first half next year. So that could represent one fast path to market. But of course, we're looking at others as well.

Operator (participant)

Thank you. We will now take the next question from the line of Cory Kasimov from Evercore ISI. Please go ahead.

Cory Kasimov (Senior Managing Director and Fundamental Research Analyst)

Hi. Thanks for taking the question. So your TROP2 ADC BNT325 looks like an important part of your emerging combination strategy with 327. Looking at the clinical trial posting shows that you're evaluating a variety of different dosing combinations. So wondering if you can add some color on the dosing strategies and your confidence level that all three mechanisms together will not compromise safety. Thank you.

Ugur Sahin (CEO)

Yeah. The current exploration of combinations is exactly also directed to explore the safety of the molecule in combination. So BNT325, the TROP2 ADC, comes with a safety profile that is characterized by stomatitis. And one of the questions that we want to ask is whether the combination with BNT327 would have an additive toxicity effect. That is something that we would like to understand. We do not expect any other overlapping toxicity since BNT327 has a very stable safety profile.

We will start with lower doses and then escalate to higher doses and assess then identify safe dose profile in an exploratory cohort for also determining the contribution of efficacy part.

Operator (participant)

Thank you. We will now take the next question from the line of Chris Shibutani from Goldman Sachs. Please go ahead.

Hi. This is Kevin on for Chris. Thanks for taking our question. Just wanted to ask another one on the PD-L1 VEGF 327. So you touched on potential mechanistic differences with Ivonescimab earlier. If we can assume that the clinical profiles remain relatively similar, do you believe this is a story more about clinical execution? And if so, how can you differentiate there? Thanks.

Jens Holstein (CFO)

Yeah. Thank you for the question, Kevin. I'll start, and then I'd like to also add to it.

I think that we do think that there's sufficient, actually, there's significant room for differentiation in clinical strategy. That's actually one of the main drivers that we're evaluating now because we do see applicability across many different tumor types, and as Ugur also alluded, across different patient segments within tumor types. I think one of the unique features of our portfolio in oncology is the combination agents that we could bring to bear with 327. I think we've talked about chemo combinations being likely the fastest path to market initially, and we've guided to a couple of early indications, but we're definitely thinking broader than that. We're thinking about ADC 327 combinations to follow shortly thereafter. Our current thoughts would be to initiate those trials already in 2025, the first combinations potentially in 2025, rather than waiting to do those in sequence.

And we're also going to be evaluating other combinations as well down the road. So I do think that that's a differentiation angle that we're well-positioned to exploit. So it really comes down to a combination strategy and also clinical execution indeed as potential differentiators for this large opportunity that we see. Great. Thank you. Thank you. We will now take the next question from the line of Etzer Darout from BMO Capital Markets. Please go ahead. Hi. This is Etzer Darout at BMO Capital Markets. Thanks for taking our question. So what are you learning about overall survival in advanced breast and lung cancer indications that you're looking at? And what's your level of confidence that you can beat standard of care given the importance of that endpoint to regulators? So I think we had a little bit of a buzz in the question.

I think you were asking about the importance of overall survival. Is that correct?

Yeah. So what have you learned for overall survival across breast and lung? And what level of confidence do you have given the importance of that endpoint to regulators?

Yeah. Yeah. So we completely understand the rationale of this question, particularly based on disappointing results coming with Bevacizumab, which in many indications had an improved PFS, but did not translate into an OS. And we are, of course, collecting our own in-house data. And we clearly see that this maturing OS data, unpublished OS data, we are getting more and more encouraged that the improved PFS is indeed translating also into an OS. I would like to remind you that the PFS improvement that we are seeing, for example, in TNBC is more than substantial.

It is not the pattern that is usually observed with Bevacizumab. Usually Bevacizumab added two-to-three months additional PFS. And then the drop in PFS was steep, following the pattern that is observed with chemotherapy alone. We are not seeing this pattern. We are seeing that particularly in indications where we combine BNT327 with chemotherapy, that there is a sustained PFS, and the PFS does not drop in the pattern like a steep curve but goes slowly down. And this is the best hint that we have so far that this can translate to OS. And I think we can definitely answer the question in the next few months for the first indications in which we are TNBC, small cell lung cancer, and in nine months small cell lung cancer.

Operator (participant)

Thank you. We will now take the next question from the line of Eliana Merle from UBS. Please go ahead.

Eliana Merle (Executive director and Biotech Equity Research)

Hey, guys. Thanks for taking the question. For the flu/COVID combo program, I guess, what's the latest on this program after the phase three missed one of the endpoints? And what's your latest thinking around the timelines for the second-gen program with the trivalent mRNA flu vaccine, just given Moderna expects to launch its combo next year? Curious the latest on your strategy with your combination. Thanks.

Ugur Sahin (CEO)

Yeah. Eliana, thanks for the question. So we're working with Pfizer now on our next-generation flu/COVID vaccine combination vaccine program. And I think it's a little too early to give you a precise roadmap, but we're hoping to give you and planning to give you updates over the course of 2025.

I think, needless to say, I think this is a program that has the full weight of Pfizer and BioNTech R&D teams behind it. And we do think that some of the problems that we've been seeing in that initial trial, that those can be addressed through further optimization of the construct. And we have early evidence that supports that. But I think before we can give you a definitive roadmap, I think we'd like to generate a little more data and hopefully come out with that next year.

Eliana Merle (Executive director and Biotech Equity Research)

Great. Thanks.

Operator (participant)

Thank you. We will now take the next question from the line of Yifeng Liu from HSBC Bank PLC. Please go ahead.

Yifeng Liu (Pharma and Biotech Equity Research Analyst)

Hello. Good morning. Thanks for taking my question. I have one on your oncology portfolio.

Just wondered, for the other assets apart from BNT327, BNT325, especially on the IO space, in the next 12 months, what are we going to hear your updates on, specifically things like BNT312 or BNT314, those early-stage, early-mid-stage assets? Thanks.

Jens Holstein (CFO)

So I think BNT312, of course, is the CD40 and 4-1BB program with Genmab. And that's in our ongoing trials right now. I think our intention is to bring data forward upon that trial's completion. We don't yet have dates for that, but it's likely going to be next year. And I think the other programs, generally speaking, our intention is to bring data out when we think we have something relevant to share. We tend to do that. And our preferred mode of data disclosure is in medical meetings.

And so, of course, that requires that you've got data in hand that is cleaned and been analyzed and is accepted by publication. So we can't always give precise guidance on when every program will read out. But I think those other programs are progressing. And I think we'll plan to update our pipeline disclosure schedule going into early next year.

Yifeng Liu (Pharma and Biotech Equity Research Analyst)

Thanks a lot.

Operator (participant)

Thank you. We will now take the next question from the line of Simon Baker from Redburn Atlantic. Please go ahead.

Simon Baker (Head of Global Biopharma Research)

Thank you for taking my question. Another one on BNT327. And going back to Terence's question, I just wanted to double-check that the comments you made with respect to trial design were related to triple-negative breast rather than the planned non-small cell lung cancer study.

If that is indeed the case, is there anything you can shed on the design of that upcoming first-line study in terms of geography comparator arm? I think you mentioned stratification already and interim results, but any detail would be much appreciated. Thank you.

Özlem Türeci (CMO)

Simon, I would like to refer you to our Innovation Day next week, where we will discuss in more detail a couple of study designs and benchmarks we are comparing against, also contextualized to our entire trial, where also questions around BNT327 pivotal trials we are planning will be disclosed.

Simon Baker (Head of Global Biopharma Research)

Thank you very much.

Operator (participant)

Thank you. We will now take the next question from the line of Emmanuel Papadakis from Deutsche Bank. Please go ahead.

Emmanuel Papadakis (Head of Biopharma)

Hello. Thank you very much since my question was stolen. Basically, just wanted to ask on your ongoing confidence on your TROP2 program, but also your iNeST melanoma program as well.

Özlem Türeci (CMO)

Thank you very much. So the first question was about TROP2 ADC. Did I get that right? So as you know, our TROP2 ADC BNT325 is at an early stage of testing. And in particular, we see potential in combination with BNT327, which we see as we have already discussed as a platform to combine with different ADCs. And the combination trial we just have started to explore, first of all, safe combination doses, is going into this direction and is exploring TNBC, non-small cell lung cancer, and ovarian cancer, and cervical cancer cohorts for our TROP2 ADC and our BNT327 combination. The second question was about our iNeST, our individualized vaccine platform. We are continuing to expand into the adjuvant space. As you might know, we have trials running in adjuvant colorectal cancer with an upcoming interim analysis end of next year.

We have started with our partner Genentech a trial in the adjuvant setting of pancreatic cancer, motivated and informed by small phase one trial with, however, exciting data, and we just have started a third trial in the adjuvant setting in muscle-invasive urothelial cancer, also a randomized, potentially pivotal trial. So these are the ongoing trials, and we are reading out our trial in first-line melanoma and will be able to disclose more about that in our upcoming Innovation Day next week, and I would just add to that that in summary, that we continue to believe that iNeST has disruptive potential, in particular in those adjuvant settings that Ozlem mentioned. And we're investing accordingly in the program.

Emmanuel Papadakis (Head of Biopharma)

Thank you.

Operator (participant)

Thank you. We will now take the last question from the line of Jay Olson from Oppenheimer. Please go ahead. Congrats on the progress.

Jay Olson (Managing Director and Senior Analyst)

Thank you for providing this update. Can you comment on the approximate level of R&D spending increase you expect in the next few years, considering how rapidly you're expanding the number of phase three programs in oncology? And is there an ideal number of phase three trials that would optimize your organizational and financial resources?

Ugur Sahin (CEO)

Thank you. Yeah. Yeah. Thanks for the question. I mean, it's a bit early for any guidances that we are not intending to give now in November. I think we feel comfortable with the EUR 2.4-EUR 2.6 that we currently have running. And on one hand, we want to control costs. On the other hand, of course, we want to invest wisely. If we talk about 327 and the potential, of course, it would be not very clever to not invest in that compound, to just use this example specifically.

But be assured that we control our costs going forward, be it SG&A expenses or be it R&D expenses. Yeah. And with regard to the target pipeline, I think it's a very good question. I would just note that with the current level of R&D spend that Jens has just alluded to, and we currently have 10 ongoing phase two or three trials. Some of those are with partners. Some of those are fully BioNTech self-funded. But I think it already shows you that we've already reached at this current R&D level pretty significant scale in the mid- and late-stage pipeline.

Jay Olson (Managing Director and Senior Analyst)

Great. Thank you.

Operator (participant)

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.