Great. Good morning, everyone. My name is Jess Fye. I'm a senior biotech analyst at J.P. Morgan, and we're continuing the conference today with BioNTech. Joined by the company's CEO, Dr. Ugur Sahin. He's gonna give a presentation on the company, and then we're gonna move right into Q&A. If you have a question in the room, just raise your hand and someone will bring you a microphone. Or alternatively, if you want to submit questions on the portal, you can do that too, and I'll read them up here. So with that, let me turn it over to Ugur.
Yeah. Thank you, Jessica. Good morning, everyone, and welcome also on behalf of my colleague, Ryan Richardson, here. I wish everyone a happy New Year, healthy, prosperous, and with peace. So some statements. So let me start with introducing a slide, which is known for many of you. BioNTech was founded 15 years ago with the vision to harness the power of the immune system to fight human disease. We built the first COVID-19 vaccine, and this marks our first critical contribution to mankind, and we believe that we can do more and can build on this transformative achievement. And to do that, we have decided to focus on the next years, in the next years on three key objectives.
The first one is creating a sustainable respiratory infectious disease vaccine business based on the leverage of our Comirnaty vaccine business. The second goal is to continue to develop our precision pipeline with developing multiple late-stage products to ensure product approvals in the coming years. And ultimate goal is to establish a multi-product company based on our pioneering technologies and science to address medical needs worldwide. So let's summarize the key execution aspects in 2023. In the last years, we developed and approved the first mRNA vaccines. We shipped, in the meantime, 4.5 billion doses in more than 180 countries. And in 2023, we have been able to deliver 400 million total vaccine doses worldwide.
We introduced the single-dose vials and never frozen prefilled syringe in the U.S., and we maintained our market leadership in the main markets. So we have currently 27 programs in the clinical stage, 20 in oncology. From this, 11 in Phase II and Phase III setting. We have started in oncology seven new clinical trials and in-licensed six new clinical assets. In infectious disease, we started first in human trials for shingles, tuberculosis, and mpox, and have, at the moment, seven clinical programs. Most importantly, we have brought several assets into mid- and late-stage clinical trials, Phase II and Phase III clinical trials covering technologies like checkpoint molecules, ADCs, as well as mRNA vaccines.
In 2024, we aim to advance additional product candidates to late stage, and we expect to have in total 10+ potentially registrational trials running at the end of this year. What we also did is that we further built on our AI capabilities. BioNTech, from the early days, has had strong ties in computational medicine and data science, which are subsumed today in AI. With the acquisition of InstaDeep, we entered into the next level of AI by integrating world-class capabilities in supercomputing, AI research, and generative AI. And we are going to use this to further build our pipeline, identify optimized molecules, and speed up workflows, and at the end of the day, become a fully integrated, AI-integrated company.
In summary, the corporate execution in 2023 shows that the company has now 27 clinical programs. We are now on five continents with manufacturing and offices. We have 1,600 new employees who joined us in 2023. We accomplished to in-license six new clinical-stage candidates. And in addition, we have built a strong balance sheet with more than EUR 17 billion total cash, plus security investments, which is one of our strongest assets for the future. So now more details on the infectious disease programs.
We already stated in 2020 that COVID will become, will stay with us, and we continue to believe that seasonal vaccines will be of key importance to deal with the challenges coming with COVID-19. This is driven by the continuous evolution of the virus. This is driven by continued high risk for severe COVID-19 in vulnerable populations. This is driven by long-term health consequences of a COVID-19 infections, and this is also driven by the success of variant-adapted vaccines. What we believe is that seasonal vaccination will become more and more an approach combining vaccines, for example, COVID and other respiratory vaccines.
Together with our partner, Pfizer, we are developing and evaluating various combination vaccines for respiratory diseases. We have, based on data from Phase I and Phase II clinical trials, showing us the strong immunogenicity and tolerability of the combination of the flu and COVID-19 vaccine. We have started a Phase III clinical trial aiming to assess the safety, tolerability, and immunogenicity of a COVID-19 and flu vaccine in the population of 18-64-year-old adults. Other clinical trials in other age groups will be announced later this year.
So, summarizing, the COVID-19 franchise is. We are following the track in developing seasonal adapted vaccines, and the commercialization model will shift in key markets from the pandemic supply to supply into direct supply to the population. We expect also a shift to towards single dose vials and prefilled syringe in other regions. We have several clinical trials running to improve the combination profiles, for example, extend the shelf life and improve the immunogenicity. And from 2025 on, we expect, if we get approval for the combination vaccines, to deliver the first combination respiratory vaccines. In the vaccine field, we are engaged into other infectious diseases.
Infectious diseases are responsible for more than 14 billion deaths, 14 million deaths every year. We have selected the infectious diseases with a high mortality rate in to develop mRNA vaccines. This includes programs in HSV, malaria, tuberculosis, mpox, and shingles that are all in the clinical stage. In 2024, we are going to report for all of these clinical trials and data, immunogenicity and safety data, and some of these programs will enter Phase II. We are driven by healthcare and social responsibility. We have inaugurated our first mRNA manufacturing facility in Africa, in Kigali, in December 2023, aiming to manufacture up to 15 million doses of mRNA vaccines per year.
This manufacturing facility will also serve for some of the other mRNA vaccines that are currently in development, like our malaria and tuberculosis vaccines, once running. Now focusing on our oncology development. The key focus of our oncology program is driven by understanding the key challenges in cancer. Cancer is a highly personal disease with every patient and every individual having different type of tumor cells. This is driven by the sequential acquisition of mutations, and consequently, one consequence of that is that many treatments have an initial effect, but most of the treatments are not associated with definitive cure because of the evolution of cancer cells and the tumor heterogeneity.
What we want to accomplish with BioNTech is to address the continuum for cancer treatment. We want to bring novel therapies to cancer patients, starting from the disease onset after surgery, but also address diseases which are metastatic in their advanced stage. That means to address that, we are building a portfolio strategy covering compounds, different compound classes, which have synergistic mechanisms of action. These are immunomodulators, these are targeted therapies and personalized mRNA vaccines. Yeah. And our aim is to develop each of these classes on its own, but also enable combination of that. To visualize that in a more detailed way, we have created this Venn diagram showing how what are the key mechanistic function of these classes of treatments.
These are immune modulators, like, anti-PD-1, targeted therapies like our CAR T cell therapies, ADCs, but also T cell receptor therapies and mRNA vaccines. Yeah. Let me start to guide you through these classes. Immune modulators, we have built a disease-agnostic armamentarium of immune modulators, aiming to exploit different mechanisms, including mechanisms for checkpoint blockade like CTLA-4 and anti-PD-1 blockade, but a number of bispecific molecules allowing to combine, for example, two modalities, checkpoint blockade and immune agonistic approaches, or combine or target two molecules which are addressing established and clinically validated pathways. For example, our bispecific antibody, BNT327 , which combines anti-VEGF and anti-PD-L1 blockade.
So we have reported on results for several of these molecules in the last year. And here is one of the updates for PM8002, which is a bispecific molecule inhibiting the VEGF and PD-L1 pathway. This is a clinical trial in first-line triple-negative breast cancers patients, where this bispecific molecule was combined with chemotherapy. In the population of 42 patients, we saw an objective response rate of more than 75%, with a disease control rate of more than 95%. And this is in this entity the best-in-class result.
We expect by combining PM8002 also with our ADC programs, to further build on this mechanism of double mechanism of action. The second asset class is our target treatments like ADCs and CAR T cell therapies. We had a strong focus in 2023 in acquiring new assets in the ADC field. ADCs will become more or less the backbone treatments in cancer for advanced cancers in all indications. We understand that even though the ADC field is very broad, that small differences, for example, in linker, small differences in the toxin composition, the type of the antibody, the epitopes, will make a big difference with regard to the safety and efficacy profile.
So we in-license a number of molecules, and we are also using our own targets to develop new ADCs, which will come in 2025 and 2026. Our strategy for acquisition of these assets was based on differentiated profile, safety profile, and efficacy profile, and by the idea to cover as many as possible indications. The idea is very simple. For advanced cancers, ADCs will become the standard of care, and we can combine that with our immuno-oncology portfolio and personalized vaccines. To the personalized vaccines, our mRNA vaccines are one of our core immunotherapy group. We have here two programs. This is this. Oh, sorry. To go back.
This is our FixVac programs, where follow using multiple antigens, shared antigens for vaccination, for example, tumors like prostate cancer, tumors like melanoma or HPV-positive head and neck cancer. And then we have the fully individualized program, where we identify neoantigens and create fully individualized neoantigens mRNA vaccines. A few words on our individualized vaccine approach. We are focusing for our late-stage clinical trials in the adjuvant setting, and in the adjuvant setting, we are focusing currently on tumors with low mutational burden. These are the challenging tumors, but these are also the tumors with the highest medical need. Examples are colorectal cancer and pancreatic ductal adenocarcinoma. Both tumor types are not amenable for classical checkpoint treatment. Both tumor types have a high medical need.
The five-year survival rates of loco-regional disease in colorectal cancer is 70%. For pancreatic cancer, the five-year survival is around 10%. So these provide high medical need, and we started randomized Phase II clinical trials aiming to assess the safety and efficacy in these patient settings. So the key is having these assets give us the opportunity to go for combination therapies. And our strategy for that is assessing the single compound activity for each of the compounds, and then assessing synergism, and based on the synergism, defining classes, combination classes.
So the combination classes are, for example, CAR T cells plus cancer vaccines, IO plus cancer vaccines, or IO with ADCs, which have been recently validated by independent clinical trials, for example, in bladder cancer. I will give you an example how two innovations, both developed by BioNTech, can be combined to further increase the impact of the treatment approach. For this, we use Claudin 6 CAR. Claudin 6 is a target which is expressed on testicular cancer, ovarian cancer, but also in many other cancers, for example, in about 6%-8% of non-small cell lung cancers. Yeah.
We combined this CAR T cell treatment, adoptive CAR T cell treatment, with vaccination using our mRNA approach, to stimulate CAR T cells, with the question whether we can further enhance the CAR T cell function. What we have seen is in a study we have reported in 2022, that with a manual process, we have around 50% objective response rate. In 2023, we changed the process, have now automated process, giving us a higher scale, and we confirmed objective responses in ovarian cancer, testicular cancer, but also, for example, in patients with lung cancer. We plan to start a registrational trial in 2024 for this approach.
But what we have also seen is that combining CAR T cells with an mRNA vaccine improves the persistence of T cells. Yeah. This is the first demonstration that the persistence of CAR T cells in solid tumors can be enhanced by using an mRNA vaccine. And we have seen that this is visible not only with a higher increased CAR T cell numbers, but also longer duration of the CAR T cells. So summarizing now, our oncology business is the biggest goal for 2024 is to prioritize the molecules to identify those which are accelerated to the market.
We have a number of ongoing mid and late-stage clinical trials in multiple indications, and we aim to start additional registrational trials in 2024. By the end of this year, we want to have 10+ potential registrational trials running for at least six programs, and we will start combination trials for our other assets. We are now in the process of building a fully integrated global oncology organization to discover, develop, and commercialize a multi-product portfolio by the end of 2025, expecting our first oncology approvals in 2026. So this is a slide that we showed in a similar fashion three years ago, but we are on path with our vision. We have currently 27 programs running.
These programs will be selected to start registrational Phase II and Phase III clinical trials. We expect from 2025 to 2029, multiple product launches in oncology. We expect to launch our next-generation COVID-19 vaccines and combination, respiratory combination vaccines. And this should give us multiple product approvals in the timeframe of 2025 and 2029. And the long-term vision is as defined from the very beginning, to maintain and deepen our COVID-19 vaccine leadership, to have a broad oncology portfolio and infectious disease portfolio, and then engage into new disease areas. Thank you for your attention.
Great. Thanks for the presentation. So maybe starting with the pipeline, you know, with a company that's got capabilities in a number of modalities, I think are probably of varying degrees of risk, going after a number of different targets with varying degrees of risk, how do you, how do you kind of balance the R&D portfolio across modalities and targets?
Sure. Or do you? So indeed, we have different modalities. And at the end of the day, we believe that we can differentiate cancer into two boxes. The one type is cancer at the early stage after surgery. We know that a large number of patients will relapse in the coming years. I gave you some examples like colorectal cancer, pancreatic cancer, triple-negative breast cancer, all GI tumors, yeah? And even after surgery, they will relapse. And for this, we clearly see that our personalized vaccines either alone or in combination could make a difference. So this is the focus for the early stage. And then we have the advanced cancers.
For the advanced cancers, it is very clear that the field for advanced cancers are going to combination therapies, yeah? And as a company developing innovations, you have to get the pieces together to be able to do combination therapies. So that means having now the three asset classes, IO, yeah, ADCs, and personalized vaccines, gives us really the opportunity for each disease to identify the best combination. And before coming into the combinations, we are selecting those assets which could give us the opportunity for fast-to-market applications. For example, we have seen a strong signal in endometrial cancer for one of our ADCs.
We got a breakthrough signal in this indication, and now the clinical trial, a single-arm trial, is running in this indication to enable us a potential product launch at the end of 2025. So that means the combination of pragmatism and long-term vision is the way how we deal with that. Of course, at the end of the day, we have to ensure that we bring products which are sustainable and can compete against other developments from potential competitors.
You also talked about continuing to access external innovation. You know, thus far, the deals you've done haven't been at a huge scale relative to the company's financial firepower. So what's the right way to think about that going forward?
Yeah, so I can take that. So I think what you've seen us do in 2023 is bring in-house six different clinical stage assets, some of those we profiled here today. And the sweet spot for us has been to move on the back of Phase I data for novel technologies. You've seen us go after a couple of validated targets because we thought that the technology, improvement from the latest generation was sufficient to disrupt, even against known targets where there's established franchises in place. And we brought those six assets in-house with about EUR 500 million of spend in total.
So of course, there'll be more R&D investment behind those assets, but we think that's really the sweet spot for us because it allows us to really assess mechanism of action, technology, and really go deep on diligence, both preclinical, but also to have human data to base those decisions on. We've already seen two of those assets move into pivotal trials within six months of the deal being struck. We think that's really the sweet spot for us to move, you know, on the back of some data and to quickly progress into pivotal trials.
One important aspect, of course, is doing registrational clinical trials. The highest risk is achieving hazard ratio, yeah, in a safe fashion, yeah? Combination trials allow us really to get better hazard ratios, yeah. The new way in focusing in oncology, as we see it, is going for combination therapies, yeah? So I don't think that in oncology, any new treatment will have a lasting effect, yeah, in the advanced cancer setting, being as a standalone compound without a combination partner.
Maybe turning to some of the guidance you provided today. Is it possible to reconcile the top-line guidance you gave, I think, for about EUR 3 billion of revenue in 2024 with the Comirnaty guidance, I think $5 billion of sales in 2024 that Pfizer provided maybe a month ago?
Yeah. So I think, you know, we work very closely with Pfizer, of course. We have a joint commercialization arrangement where the two teams exchange notes and compare on a regular basis. But at the end of the day, we're two separate companies, and I think what you've seen us do here is try to give a sort of base assessment for the year. And you know, there are some differences between how Pfizer reports, how we report. We've got some slight differences in the booking of international sales, for example, late in the year, and there's also some other adjustments.
So we've tried to put out a base case view, and that EUR 3 billion essentially assumes similar vaccination rates to what we've seen in the second half and the fall season of 2023. So that's the underlying assumption.
I guess speaking of 2023, it looks like Comirnaty lost share in the U.S. relative to prior years. What happened there? Is there a way to reverse that?
Well, I think we have to take a broader perspective. I mean, COVID, Comirnaty is a global product business. We've distributed the product to over 180 countries and regions, as Ugur mentioned, since the onset of the pandemic, and we've actually gained share through 2023 in a number of geographies. Just to mention a few: Japan, Europe, we've maintained a very high share for two years plus, and building on our original sort of position in the early pandemic. You know, I think in the United States, there has been a sort of aggressive competition. There's been aggressive discounting in the U.S. market, but I think overall, we've maintained a market-leading position, even in the United States, above 50% by our account.
I think globally, our market position continues to be very strong.... I think we feel good about how we've defended the brand, and I think well-positioned to bring the next generation of innovations forward next year, and.
You also talked about a return to top-line growth in 2025 off of 2024. What's kind of baked in there for COVID versus, I guess, is that growth coming from other assets?
Yeah. So I think, so we're expecting COVID to continue to be a highly cash-generative, profitable product business for us well into the future. I think as was noted in the presentation, we actually have two potential drivers over the next two years that could start to add top-line growth potential. One is the COVID franchise, next-gen vaccines and combination vaccines, which we expect to move into pivotal trials this year with Pfizer. And the other is, of course, the oncology portfolio, which is now in pivotal trials. We talked about that and where we think there could be some opportunities if the data plays out as we expect it could, for accelerated approval. So I think on both fronts, infectious disease and oncology, we're expecting potential for top-line growth, from 25 onwards.
Maybe switching to the vaccine pipeline. I think one of the vaccines you're pursuing is for... Which is the one I wanted to ask about here? Oh, shingles. What, where do you think you could differentiate in shingles or kind of, you know, add value with the new shingles vaccine?
Sure. Yeah, I think, shingles is a great example of a highly efficacious vaccine. But we see really the opportunity to further improve that by a more tolerable application and also by providing the opportunity, for example, to have, instead of two vaccinations, a single vaccination.
Can you talk a bit about how you think about the market opportunity for the 4-1BB bispecifics?
So the 4-1BB bispecific, so we have two bispecific. One is 4-1BB PD-L1, and the second is 4-1BB CD40. They are both first-in-class molecules combining the one combining immune checkpoint blockade with immune agonism, and the second one combining two immune agonistic functions. And I give you an example for BNT312, which combines CD40 and 4-1BB. What we have seen in preclinical setting, and we are now seeing that the same data in the clinical setting, is that the combination of this molecule with an anti-PD-1 augments the PD-1 activity, yeah, resulting in a higher rate of response, and higher activation of the T cells.
We want to position this compound in combination with PD-1 in first-line patients treated with anti-PD-1 to further improve on the efficacy of PD-1. You know, in most indications, anti-PD-1 alone has a response profile, objective response profile in the range of 20%-40%. We have now signals in clinical trials indicating that this can be further improved by the combination.
Yeah, and I would just add in terms of end market as well, that, you know, we've got the two 4-1BB bispecifics with Genmab in about 15 expansion cohorts, and we've conducted a Phase II randomized trial. You know, we're looking at big solid tumor indications in many of these cases. Second line NSCLC, for example, you know, huge unmet need and, and you know, commercial prospect, you know, I think sizable if we're able to extend IO into the second line, just as an example.
I think historically there have been some liver signals with 4-1BB molecules. Do you think of that as kind of those were molecule-specific issues, or is that a kind of target-related signal to work out, and how tricky is that to solve?
Yeah. This is definitely target related. What we have engineered into this molecule is a conditional activation of the 4-1BB pathway. So that means the bispecific molecule only triggers signal if on the other side, the target is engaged. So that means in the PD-L1 pathway, engaging on PD-L1 positive tumor cells and on the CD40 on dendritic cells or and also on antigen-presenting cells. And what is important is to identify the right dose, yeah, and the right dosing schedule for this. And we believe that by combining this conditional activity with identifying the right dose gives us the opportunity to, yeah, to mitigate the risk for liver signals, which are class-specific factor of 4-1BB.
Maybe shifting to your CTLA-4, can you talk about what gives you confidence in the monotherapy potential of this asset in lung cancer and where you see clinical differentiation from Yervoy?
Which one is it?
The CTLA-4.
... The CTLA-4, yes, yes, we presented data at ASCO, showing that BNT316, a CTLA-4 molecule, which has a distinguished mode of action. So the mode of action is that even after blockade of CTLA-4, the CTLA-4 molecule can recycle to the cell surface, and thereby we expect a higher dosing interval, higher dosing of the molecule, with a better tolerability profile. And we have reported an objective response rate in second-line patients with non-small cell lung cancer in the range of 35%, yeah, which is the highest signal for CPI observed in this indication.
The clinical trial is running here in the second-line non-small cell lung cancer patients, and what we are now aiming is also to assess the combination of anti-CTLA-4 with some of our assets in the early lines, including first line and neoadjuvant setting.
Maybe switching to BNT323, the HER2 ADC. What's the data you think that's gonna convincingly demonstrate differentiation from Enhertu?
Start if you want.
Well, I'll just say that, you know, I think the data that we presented data at ASCO last year right after that we in-licensed the asset, and I think what we showed there was, you know, lower rates of certain side effects in the early data. And I think, you know, Ugur talked about greater therapeutic index, and of course, that when you have if you do have a greater therapeutic index, you have the ability to dose higher and actually get more efficacy or take advantage of the side effects. And I think so I think you've got more room to work with. But that signal, I don't know if you want to talk about the NHP data signal.
Yeah.
tox signal as well or?
Yes, in the preclinical setting, the molecule can be higher dose as the historical data reported for Enhertu. And actually, we now went into our pivotal trial with a dose of 8 milligram per kilogram, which is higher than Enhertu. We have data indicating a better linker stability of the molecule, yeah. And interestingly, this is early, I think we need to be cautious in defining that, but in the early setting, we see some side effects with a significantly lower frequency, for example, hair loss, yeah. Which is not a big thing for physicians, but it's a big thing for patients, yeah.
And we see, we have the indication that hair loss is significantly lower as compared to the reported data for Enhertu. So there, these are several factors, and we have to see at the end of the day, of course, having the data from the pivotal trial, whether these expectations match up.
Great. With the last moment here, your adjuvant trials for iNeST in colon cancer and pancreatic cancer, when should we expect updates there?
For pancreatic cancer, we can't say it at the moment. For colorectal cancer, we expect updates in 2025.
Great. Thank you.
Thank you.
Thanks, Jess.