BioNTech SE (BNTX) Earnings Call Transcript & Summary

Okay. I believe we are live right now. Good morning, everyone, and welcome to the 42nd Annual Goldman Sachs Global Healthcare Conference. My name is Chris Shibutani. I'm a member of the research team in the biotech group. Joined by my colleague, CJ Zopf, we're very pleased to kick off this year's conference with a presentation and discussion with BioNTech. Clearly one of the incredibly emerging stories from 2020, increasing relevant for global investors. Joining us today, we have Ryan Richardson, Chief Strategic Officer and Managing Director. Ryan, thank you so much for joining us today.

Thank you, Chris. Good to be with you.

Before we kick off, I am required, apparently, to read a series of disclosures. So we'll see if we can get through this. The disclosures in public appearances and Goldman Sachs' relationships with the companies that we discuss, the disclosures relate to investment banking relationships, compensation received or 1% more ownership. We're prepared to read aloud any disclosures for any issuer upon request, however, these are available on recent reports available to clients on the portals. Disclosures and updates are available on that website with gs.com. The views stated by non-Goldman personnel do not necessarily reflect of Goldman Sachs. Our discussion will only focus on public information. We don't want any confidential information discussed, and the call is strictly for clients of Goldman Sachs, not intended for media and is off the record. If you're not a client of Goldman Sachs and you have not received an invitation to this call, you should hang up now. Goodbye. So Ryan, thank you so much for joining us. It's been an incredible year. I think you've been very much the face for investors. But tell us a little bit about yourself and your journey in terms of how you joined the company and just -- I think that's helpful context for the discussion that we're going to have.

Absolutely, Chris. So I joined BioNTech about 2.5 years ago from JPMorgan. And as Chief Strategy Officer, my role encompasses both capital markets, but also strategic growth initiatives of the company, portfolio management and also strategic collaborations that we enter into. And so it's been busy on all those fronts, as you can imagine, over the past year, especially.

And when you joined the company, obviously, there was a unique circumstance and so much has changed. And if you had to sort of guess in terms of what has been some of the most surprising things about your role that have evolved, maybe you can sort of share some of that. Obviously, COVID has just been front and center, but just some of the things that you've had to navigate when you think about this company. Just a little bit of context here in terms of what you face every day, separate from asking -- answering questions from us.

Yes. I joined right before a Series B round. And we went quite quickly after that into IPO preparation mode and then, of course, went public in 2019. And the company's ambition, I think, from the time that I joined, the vision and the ambition of the company was clear, right? It was to build a multi-product global company. I think what's really changed with COVID is that, that vision has been accelerated by many years, even beyond my own expectations upon joining. And so with our first product now on the market in over 90 different countries, having distributed or shipped over 600 million doses, along with our partner, Pfizer, to countries around the world, and now, of course, with the cash flow that comes with that, I think that our ability to prosecute that broader vision of bringing immunotherapies to patients across oncology, solid tumors in particular, but also now infectious disease, has really been transformed, right? And so my role now, in addition to being very involved with the COVID-19 rollout and execution around the world is now even more focused on sort of the next wave of growth, and that involves looking at sort of geographic footprint. Where should we expand our business? How should we do that? In what sequence? How front-footed should we be, but also looking at new collaborations we might enter into, and how do we scale? How do we scale the company across functions? How do we scale R&D to redeploy the proceeds from the COVID vaccine to advance our pipeline on multiple fronts, right? And so that's -- it's no small task, and there's a lot of strategic decisions and questions that are embedded in that, that I'm deep into and that we're navigating now. But it really -- it truly has been a transformation over the past 12 months, both in terms of our capabilities, but also in terms of our prospects and what we might be able to achieve over the next -- the near, medium and long term.

Right. No, that's very helpful context. I think we use often on Wall Street words like transformative and acceleration, but you guys truly embody that to such an incredible extent. And you touched upon so many of the categories that are clearly relevant, very front and center and very topical and very obsessively in the minds of folks, obviously, about COVID-19 and Comirnaty. So we'll go into some detail there. But in the time that we have, we'll be sure to want to make sure to touch upon the potential applications across other infectious diseases as well as the oncology platform, which is where the company went public. Clearly, one of these, very important opportunities, incredibly complicated, complex, difficult, but I think as we'll discuss, something that the company is especially well-equipped for in terms of having kind of a technology-agnostic approach.

So let's dive into the COVID-19. My associate, CJ, has spent a great deal of time on this as well, focusing on the model. So we'll be kind of attacking you on both sides with some of the questions there. But as we sit here now and almost approaching the middle of June, the vaccination rates in the U.S., that's -- the rates have actually started to slow down. And so where do you see the coverage plateauing? What's the BioNTech view on that? And related to that, obviously, we have some additional subpopulations, the pediatric authorizations. Do you expect that to have a material impact? What do you think that will do to the level?

Yes. I think it's difficult to predict where different countries plateau. I think we've always assumed that there would be a sizable proportion of individuals in the U.S. and elsewhere who just choose not to get vaccinated. I think what we're focused on is trying to expand the label. As you mentioned, we've just recently been granted EUA approval for the adolescent group, so from 11 to 16 -- 15-year olds. And we're now studying children, going as low as sub-2-years old, actually, 6-months to 2-years old. And we expect to have data in the children -- in various different children age groups by the end of this year. And so you asked, how significant that is? It's significant because if you think about it, under 16-year olds account for almost 20% of the population. So it's a significant group in terms of size. And so what we're focused on then is driving use into new population subgroups, like children, but also trying to get the supply ramp-up so that supply no longer becomes a constraint, right? That's really critical. And we do think that as an industry, how we see things shaping out over the next couple of quarters, we think we should be in a position to at least be able to supply vaccine for the majority, if not all, of the adult population in a number of key markets already by the second half of this year, into Q3 and even Q4. So that's what we're focused on presently.

Beyond thinking about what kind of coverage we'll get amongst the folks who've gotten the vaccine, really, the important question is focused as well on durability of that immunity. And if we take an assumption that we're probably going to not get hold to that herd immunity threshold, I think there's always been a lot of discussions of whether it's the definition of that. Are we going to get there? I don't think that, because of the hesitancy and reluctance and whatnot, that we're expecting to necessarily get there. But talking about durability, data continue to emerge. Trying to get an understanding for what the latest understanding of at which immunity may wane, reflecting on a recent New York Times article, where they had a view a few weeks ago, suggesting that decreasing antibody titers should be expected as the B-cell population shifts more towards a memory compartment. So what should we expect, in your opinion, in terms of the waning of immunity? What might that look like? And how will we know when we're perhaps approaching a point or a threshold of insufficiency?

Right. I think it's already clear that -- and to be expected, frankly, that antibody titer levels will decline over time. We already see that at the sort of 6-month mark quite markedly. And I think it's also becoming increasingly clear that, that decline in antibody titers, while not the only predictor of protection, are proving to be a strong one, right? And so there's a number of papers that have been published recently, actually, just in the last couple of weeks, that show a strong, nonlinear, but strong relationship between neutralizing titers and protection rates. And so I think the picture that emerges, right, is that there will be a declining curve of protection, right? Rather than a black or white question, on or off, it's -- there will be declining protection over time. I think that's fair to assume. And so then the question becomes, at what point is it justified to administer an additional dose to get those titers back up, right? And that's exactly what we're trying to study in our current booster trials.

Right. And I'll shift it over to CJ, who has taken a look closely about understanding some of the framework and the trials that you've designed there. CJ?

Sure. Maybe before that, just on the point of durability waning, do you have a sense yet of the proportion of patients that sort of start then neutralizing titers on the bubble and what fraction are going to be at risk at 6 months or 12 months potentially?

Yes, it's a good question, CJ. The short answer is no, not really in terms of proportion. I think we see pretty consistent strong titers or high titers after the 2-dose regimen, right? And that's what we saw from the Phase III trial and even earlier Phase I studies we conducted. I think that it is probably fair to assume that different -- there will be differential rates in decay. But I think the picture that's emerging to us is already, there's going to be a very broad use case most likely for a third dose in the population. I think what's, certainly looks, less clear is the frequency thereafter and whether or not they're -- it becomes more of a subpopulation question over the longer term. But I think that, that initial decline is actually fairly consistent, even though there is heterogeneity at the -- within that.

Got it. So we're going to start to see some of that durability data coming from your own trials coming up next month or 2. So can you frame for us, what will the durability data look like that we're expecting from the long-term readout from the Phase I/II trial or the booster trial you have looking at both the original community as well as a South Africa or beta strain-specific vaccine?

Right. So fundamentally, the booster data is going to look at safety. Of course, we're going to evaluate whether or not a third dose is safe. We're going to look at reactogenicity to determine that. And then, of course, we're going to look at immunogenicity, right? And it's really the triangulation of those 2 factors that's going to be the core of the data set that we produce. Now I think what policymakers will need to do then, of course, is to look at the broader picture, look at correlates of protection data that's amassed at the time and then make a decision as to what's indicated or should be indicated for a third dose. But the trials that we're conducting, safety, immunogenicity.

And do you have a sense yet of how big that data cut is going to be? And what sort of context should we keep in mind in terms of goals for the reactogenicity readout?

Right. So I think I'll take the second one first. I mean the goals for reactogenicity -- and of course, we don't want to see a significant increase in reactogenicity versus the second dose. That would create an obstacle for the vaccination. We don't expect that to be the case. I mean we vaccinated much higher dose levels, much higher frequency in the cancer setting. So we have a sense for how humans tend to respond to these vaccines. There are some differences, of course, here with COVID, mainly we're going into healthy individuals, and we have a different dose level, we have a different mRNA format. So it will be important to see that data. But fundamentally, we're going to be looking at the range of key factors on the reactogenicity scales, right? So fever, we'll be looking at the chills, et cetera, et cetera. In the Phase III study that we conducted, those factors were all transient that were noted, right? So we're looking at transient factors, but ones where -- because we're going into healthy individuals, we have a low tolerance for tolerability issues. In terms of the size, so the first trial, the Phase I booster trial is going to be evaluated in 600 subjects. And we have an additional 600 in the Phase III follow-on study that you mentioned, 300 in the wild-type virus arm and 300 in the South African variant arm.

Okay. And we'll see the data from all of those in the next month or 2?

That's right. So I think that late summer, so by early Q3, we should have data from both of those. And I should also mention that actually, we will also evaluate up to 30 participants of fourth dose. That would come later over the 6- to 12-month time frame, right, 6 to 12 months post-second dose.

And you touched on policy as being important. It's not just a scientific question, right? So do you have a sense yet of what data are going to be needed from these trials for regulatory filing? And how do you expect the overall macro picture of the COVID pandemic to need to look in order for policymakers to be supportive of moving forward with the boosting?

So there's been guidance that's been put out by regulatory agencies, which we followed in designing these studies. But the regulatory pathway for approval of a booster shot has not been fully elucidated. So our plan is by late summer to submit the data that we've collected from these booster trials. And I think we would expect there to be further regulatory discussions then about how the regulators would respond to that and what -- hopefully, further clarity on what the regulatory pathway might be. One of the goals here, especially for the South African variant vaccine, is just to establish a regulatory pathway. Whether it be for South African variant vaccine or some other booster shot, variant-specific or not, we want to get the regulatory pathway established because we think that will be useful, of course, in the future and allow us to bring additional vaccines quickly to the market if needed.

There was such an exceptional level of urgency and responsiveness from regulators, especially in the U.S., as well as, I think, a lot of commentary about how kind of -- how much visibility was provided broadly as opposed to things happening behind closed doors, disclosure, panel discussions. How has that level of energy and urgency been sustained? Particularly with the change in administrations and transitions that are happening at the agency, we still don't have an FDA head. Has it kept up? Has it waned somewhat? Inevitably, there were things that were put in other disease categories on the back burner. And to a certain extent, those efforts have been harkening for attention. What's your sense about what the level of activity and urgency and visibility is of the regulatory agencies for these next phases, particularly with the boosters?

I think there's still a very high level of engagement from the regulatory authorities on the boosters, absolutely. And I think it's -- there's been a number of prominent health policymakers who have voiced concern about the boosters. I think that we're already seeing demand from governments for the boosters. And so I think it's -- level of engagement is high and the level of dialogue remains very high.

Okay. Great.

So obviously, one of the goals here, you mentioned, is to establish kind of a pathway for a variant-specific booster. Are you planning additional variant-specific work as new variants emerge like the India or delta strain or even the Brazil gamma strain? And what criteria would a variant of concern have to reach that would sort of trigger a need for a new version of the vaccine?

Yes. Yes, we continue this along for the new variants, actually. And we do extensive in vitro assay work. We also have a growing body of real-world evidence that sheds light on our vaccine's ability to protect against those different variants in question. So far, we haven't seen susceptibility to any particular variant. We have seen reduced neutralization against a couple of variants, namely the Indian variant and the South African. But we still see neutralization such that we believe that it's likely to translate into still a fairly high level of protection, right? And that's also backed up as well by some real-world evidence that's been collected. So again, it's more of a -- for us, we're going to continue to stay on top of that. We are going to look at additional variant-specific vaccines. We may bring some additional ones forward into the clinic. More to come on that. But so far, we don't see a pressing need to replace or substitute our current vaccine with a variant-specific one.

And multivalent vaccines combining with things like the seasonal flu have the potential to be an efficient way to drive coverage. It's something others in the space are looking at. What's your latest thinking on sort of that strategy?

Yes. So we're looking -- we're going to look at a number of combinations, potential combinations. I think it's fair to say flu could be a candidate for that. We do plan to bring up an RNA vaccine into the clinic in Q3 with Pfizer that targets seasonal flu. And so again, more to come on that point as well. I think that we will look at a number of different combination opportunities for COVID vaccine that may involve multiyear ongoing studies, looking at more repeated vaccination, either alone or in combination with other vaccines.

And how do you think about the relative roles of mRNA vaccines for COVID-19 versus other approaches like full and activated viruses and -- eliciting durable and broad immune responses? Where do you see the pros and cons of those as you think about different kind of regional and temporal dynamics for the pandemic?

So first, I would say that we believe we need many vaccines to address the pandemic. That continues to be our view. And actually, we think it's a positive, certainly, that when you look at it on an industry-wide basis that the current estimates would project that we should have the ability to produce as much as 80% -- vaccines for 80% of the world's adult population by the end of 2021, which is going be a stunning accomplishment. But we still believe there's going to be further need for booster shots and a longer-term need. But -- so we think we need multiple vaccines here in the first instance. I think in terms of mRNA, where it fits in, one of the reasons that we chose to work with mRNA initially was that we got and had a number of potential benefits. We think now that we have even more data under our belt, we see that that's the case. And those benefits include high potency, immunological specificity. We don't have a background immunological noise that come with some of the other approaches. We have a nice tolerability profile. And we have an ability to scale production that is advantageous, in particular, for highly mutative diseases or pandemics like we're in now. So we think that RNA is, and our vaccine in particular, is well placed to play a major role in addressing the pandemic phase, the booster phase and ultimately, the endemic phase that we think is likely to come.

Yes, which is a perfect transition for it is that debate, right? I mean what is the definition of when we get to an endemic? Is there suddenly a flag that goes up, a date on the calendar, an announcement that's made? Clearly, the World Health Organization has to think about this from the totality globally and where there are still very complicated difficult issues in many parts of the world, even if -- as the U.S. seems to be more transitioning to that. Maybe let's talk commercially in sort of, what should we expect the commercial dynamics to look like, particularly as we transition from pandemic to an endemic phase? I think, certainly, we've already seen and the companies have talked about how, outside the U.S., a lot of countries have already been establishing contracts, extending their purchases through government channels based upon their health systems that extend over the next few years. So maybe you could just highlight in terms of what the status is as far as your levels of orders through those channels and then would also love to be able to understand what you think will happen in the U.S. But maybe just start outside the U.S. first in terms of the -- beyond 2021.

Yes, I think it's going to -- I think the demand for the vaccine, both near term and longer term, medium term, let's say, is going to continue to be dynamic. We see that already. I mentioned before, we're already seeing demand for the booster phase of supply in markets that were already well contracted for and will be well-supplied for the pandemic phase. We're seeing increasing demand, of course, from countries outside of that initial group, including very large-scale demand from the developing world, which we intend to supply in high quantities. So I think, Chris, if you look at the current order book, 2021 order book is around 2 billion doses of signed demand near term, right? I expect that's going to continue to grow over time. There's still more contracting discussions taking place. And at the same time, you're going to see increased orders committed for 2022 and beyond, right? We've already had the European Union order for 900 million committed doses with an option for an additional 900 million we've done. And that's for deliveries starting in December of 2021 going through December of 2023. We've signed similar orders with a number of other countries, Canada, Israel, and there will be others. I think we're still at the early -- in the early stage of the booster demand contracting process. So I think both are going to move for a while here in parallel. And of course, we're still focused on trying to supply as much as we can this year and also carrying over our supply capacity into next year. And of course, alongside all of that, we're continuing to iterate on the vaccine, right? So we've got our next-gen formulation coming in the second half, we expect. We'll have data on that. I mentioned at the outset, the expansion of the label, right, and to broaden that out. And I also mentioned our intention to supply large quantities to the developing world. A lot of those contracts haven't yet been signed, but we're working to try to get that done and also open up supply there as well in the near and medium term. So I think that's what we're focused on near and medium term. Long term, I think, is yet the come. Endemic market is still kind of the third step, not yet there. We do believe that there will be an endemic market here. And we think we'll be well placed to continue to play a major role there. But for now, it's more of a near- and medium-term focus.

Some of these contracts that you've already established for beyond this year outside the U.S., what does the structure of the contract contemplate in terms of the changes in potential formulation that you'll have or if the predominant need is for a version of the vaccine that addresses more of the specific variant? Is there flexibility and, therefore, there's always some degree? I mean the manufacturing process is so efficient, the ability to adapt is quite quick. But nonetheless, is there some element of -- you have this massive batch and this is what you guys bought. I know that the next version is available. Talk a little bit about that in terms of how the contracts are structured to enable adaptations for things that, obviously, we can't quite predict yet.

It's safe to say that those booster contracts I mentioned for 2022 and beyond, that they account or allow for the next-gen formulations, right, to be delivered. And in some ways, maybe even expect that we're going to continue to innovate because we've been, I think, front-footed in sort of the next-gen development, both [ vaccines ], but also we talked about the boosters and just the subpopulations. The data that -- our data packages continue to grow, right? And obviously, that helps the confidence in the vaccine. It means we have a massive safety database, right, which is also important. So yes, I think that the contracts are structured in a way that it acknowledges there's some uncertainty as to exactly which -- what kind of vaccine one might be getting or ordering, but that's all kind of built into the contract structure to [ allow for it ].

And then in the U.S., as we think about going forward into the future, there's the element of possibility and probability that we will transition to more of a private sector payer mix. How should we be thinking about what kind of visibility you'll have in terms of what that order dynamic will be as we evolve and progress into that change where it's just not a single purchaser or the government, et cetera?

Yes, it's a good question. And I think that's going to vary widely by country, by region, right, so in terms of how that unfolds, right? In the United States, we have EUA approval right now. We've just submitted for BLA approval. We expect that BLA approval could happen in sometime in the second half of this year. It could be early 2022. We're expecting a sort of, let's say, regular process. So approximately 6 months, give or take, right, would be our expectation. Of course, we already have conditional authorization in Europe. So it's a little bit different scenario. So I think these things will be market by market. I think what we would assume is that with full BLA approval, of course, that opens up our ability to promote, to educate the market on the product more broadly, that we would expect that would open up the channels and that, that could lead to a more individual decision-making or preferences for specific vaccines over the other, which hasn't really played a big role so far. Certainly, we see some preferences in terms of demand, but it hasn't played as big of a role because we've been under such tight supply constraints as an industry so far, right? And we expect going into the second half of the year, that will start to change. And I think that with a full BLA approval, I would expect that would change even more. I think you'd start to see even more bifurcation in terms of vaccines that people prefer versus those that are less desirable.

Let's thread into the question of pricing. As we think about in the future, particularly as we transition towards further technological advances, convenience advantages from a presentation standpoint, as we shift over to the endemic phase, to what extent maybe should we be viewing the government contracts as kind of anchoring from a pricing standpoint? I think in the analyst community, we're sitting here speculating about all sorts of vaccines that have been available. And the price range is considerable, and that has considerable impact, a swing factor when we're talking about billions of doses. So maybe frame for us some thoughts that you have in terms of what the potential for pricing, particularly as you're getting into the multivalency, and in the context also of prospects of more competition coming down the line, just a broad topic about question -- about pricing.

Yes, it's a good question. I think that a couple of points, a couple of things are clear. Number one is that the current price or the pandemic price was far below what would be a normal market price for a highly efficacious, safe, innovative vaccine; the U.S. price, for example, of $19.50 that we've made public. Order of magnitude below what you would expect in a normal market, but it's also true that this isn't a normal market and probably won't be a normal market for a long time. And so I think from where we are today, we see some incremental price upside in the developed world by virtue of having such a low starting point. So in the booster phase and beyond, in the sort of medium term, there's some pricing upside. I'd say -- I'd call it incremental rather than order of magnitude difference. And I think over time, that could -- as volumes decline, I would expect that to increase the pricing upside, approaching somewhere closer to a normal market price, but maybe always deviating a little bit by virtue of the market dynamic here and the number of entrants. But I think what's also true is that developing world price is going to be lower. And we do intend to supply large quantities of vaccine as well to the developing world. So it's going to be a bit of a mix there, right? And I think it's hard to predict exactly how that mix -- what those mix effects mean for an average price. I won't predict the average price. But I think, hopefully, that gives you a little bit of sort of directional indication about what we see in the near, medium and potentially longer term.

Okay. That's a good first answer. We'll keep on asking you for sure. So COVID, COVID, COVID, that's all we ever talk about, and I'm sure that's all you talk about. And I tried to promise Sylke that we would address some of the other platforms. So with the remaining time, we'll try and see if we can get some questions in on both the infectious disease leveragability and oncology as well. So with the vaccine platform, obviously, it seems clearly validated for infectious diseases to a certain extent. What properties and performance characteristics of the technology should we expect will carry over to other infectious diseases and maybe where might be very relevant and important to make sure that we're studying in a differentiated way from a clinical basis?

Yes. So the class effects that we expect from mRNA vaccines that were on display with COVID include potency, immunological specificity, which we think translates into repeat dose ability and also a tolerability, a manageable and attractive tolerability side effect profile on the clinical side. And then on the industrial side, the benefits that we've seen in terms of ability to very rapidly develop new constructs, a flexibility in production in both the discovery and early testing, and an ability to scale production in an efficient manner and in a rapid manner. I think these factors, what we see is not being specific to COVID, but being potentially applicable to a range of different diseases. And that's why when we look at the infectious disease space, we see opportunity to bring this technology to diseases where there may be an approved vaccine, but the efficacy currently is low or production is limiting -- production challenges. But we also see opportunity to potentially take this technology into indications where there is no approved vaccine, right, and where this technology has a chance to establish a new standard of care and make a difference. So I think it's safe to say we've got both types of diseases reflected in our preclinical pipeline. We have 9 different preclinical programs in the infectious disease setting right now, one of which is the influenza program partner with Pfizer. And over the next 12, 24 months, we plan to accelerate our effort to bring more of those candidates into the clinic.

Great. Yes. And I think over the back end of this year, you probably are going to be sharing more broadly in terms of beyond COVID. And so we look forward to that, the analyst community to get educated. I'll switch it over to CJ, and let's talk about the oncology platform a little bit.

Yes. So coming straight to vascular, this past weekend, still ongoing, where there have been several companies now starting to present more data on immunomodulatory bispecifics. You guys have your Genmab collaboration bispecifics coming -- with more data coming later this year. Has anything stood out to you at all, particularly in general learnings for this field? Obviously, there's a lot of different potential combinations, a lot of different ways of going about binding 2 things and bringing them close together. What has the field learn so far about dual immunomodulation?

No, that's a great question, CJ. I think we're seeing increasing evidence and getting increasing indications that, especially for solid tumors, that some of these dual-acting or dual-mechanistic approaches could add to the standard checkpoint blockade, right? So LAG3 would be one example that I would point to from recent disclosures. And that's consistent with our strategy, right? We're building a multi-platform toolkit for immuno-oncology. And that's been the strategy from the beginning, right? We have RNA vaccines, which allow us to target tumors in new, innovative and multi-antigenic ways, right? We have RiboCytokines just now going into the clinic, which will allow us to modulate the immune response. We have a number of novel cell therapies going into the clinic to -- in particular, which we think can move the needle for refractory tumors. And then, of course, we have our next-generation checkpoint immunomodulators, which are these bispecific antibodies, namely, with Genmab. So it is precisely that multi -- that toolkit, that multimodal toolkit that we're building that we think is the right strategy for IO. And while it will take time to fully elucidate the benefits, we think with that toolkit, we're really uniquely placed to make a major impact in the solid tumor field, right? And a couple of the data readouts we have later this year will be important next steps in that thesis. And so by both bispecific antibodies, our PD-L1x4-1BB and our CD40x4-1BB, we'll have data readouts, data updates in the second half of the year. And those are 2 that we're very excited about.

And how do you think about the new FDA guidance for bispecifics suggesting that perhaps you might need to compare these things to monotherapies that target one arm of what your bispecific is targeting? How is that going to impact potential clinical development?

Yes, it's not surprising. It's consistent with what we've expected. And I think because so many of our IO product candidates are novel mechanisms or have novel -- or exploit novel targets, we already expect that in many cases, there was going to be -- that they were going to need to be paired with a PD-1 backbone. So for example, even in the fix -- with FixVac, that's already the kind of study design that we're following in our randomized Phase II trials, like, for example, in FixVac melanoma where we can -- we add FixVac plus PD-1. And we also have arms that will look at PD-1 alone as a benchmark. So that's not -- it's not surprising. And I think the question will be for the bispecifics is, to what extent and in which indications would we look at monotherapy versus combination therapy? Because there could be benefits as well to a combination approach, right, of course, even with the PD-L1x4-1BB or CD40x4-1BB, combining them with checkpoint blockade, standard mono, PD-1, PD-L1. And so I think to the extent that, that becomes the path forward or at least in some indications, of course, that has implications for how the trials are designed. So I think we would expect that -- as you start to get -- introduce more complexity, you have to, in some cases, benchmark versus the mono.

And maybe one last question from me. We're all very excited for all these readouts that are coming this year. And you're also starting a number of randomized Phase II trials. Which of those approaches are you guys most excited about? And in particular, for the colorectal cancer study that you're starting, how big is that opportunity in early-stage colorectal cancer with positive for circulating tumor DNA?

Well, so first, we're excited about all of them, of course, and I think for different reasons, right? They're targeting very different patient groups. I think that we're excited about the FixVac Phase II studies because those are kind of at the nice edge, let's say, of our oncology pipeline with more of a near-term market opportunity, both in the case of FixVac melanoma and FixVac HPV16 cancers, both of which will pair with PD-1. In the case of the iNeST, the individualized neoantigen targeting RNA vaccine, so you mentioned adjuvant colorectal cancer. We're going to be using a ctDNA test with that. And that's important because -- so adjuvant colorectal cancer is, first of all, the standard of care hasn't changed much in a long time, right? It's fundamentally it's chemotherapy. And -- but with ctDNA tests have -- can have a huge impact in terms of predicting who's going to have a recurrence. I think they have positive ctDNA tests. So recurrence rates can be 75%, 80%, right? If you're positive versus without a ctDNA positive reading, you're in the high single digits or low double digit, around 10%, right? So it's a massive difference. And so that -- we'll use that as one way to sort of identify patients that could be well suited for therapy. And we're excited to take the iNeST into the adjuvant setting, right? We have really strong data in melanoma, which we published a few years back, continue to follow those patients in melanoma, had multiyear disease-free or recurrence-free outcomes in the melanoma -- advanced melanoma setting. And so taking this now into adjuvant CRC, which is a big indication, right, high unmet need, and is an indication that's very well suited to the mechanism of action of these individualized cancer vaccines. And we're very excited about that. And hopefully, that's not the last adjuvant trial we'll initiate with iNeST.

Great. We are at over our time here, but I'll just close with 3 points. Number one, thank you to you and your management team and the scientists at BioNTech. Obviously, when we use, we're transformative, truly earned and so much of the impact is very appreciated worldwide. Number two, thank you to you, Ryan. You are the triple threat. You can talk the science, the business, the strategy. I appreciate having the discussion with you. And then finally, my effort to actually squeeze in oncology, but not really adequately address it is intentional. I need you to promise on air that we'll have other opportunities to discuss with investors and focus on non-COVID matters as we go forward. So we look forward to those opportunities, right?

Absolutely. Thanks, Chris.

Okay. Cool. Okay, great. Thank you very much, Ryan, and thanks, everyone, for joining us. Okay, are we off?

All right, guys. Thank you. I'm going to sign out. Appreciate it.