Moderna Aktie

Good morning, and good afternoon for those of you that are following us from overseas. Thank you so much for joining us today. On behalf of my colleagues and I, welcome to Moderna's Science Day 2026. Before I start, let me remind you that we'll be making forward-looking statements. You can find those online at your discretion. Moderna's mission is to deliver the greatest possible impact to people through mRNA medicine.

And since the beginning, we built an mRNA platform based on 3 key pillars of science: mRNA science, which is the mRNA molecule itself, delivery system, how we get the mRNA molecule into cells and very importantly, also manufacturing processes where there's a lot of know-how that we developed over the years. But because mRNA is an information molecule, what is very exciting about this platform is we can create modalities, families of medicine that use exactly the same technology features so that we can replicate very quickly.

As you can see on the pictogram on the right? We basically start with a leading product to go into the clinic as a sentinel programs to learn about the modalities. And when we have clinical signals, we can scale very quickly because we use exactly the same technology components. And that's what is exciting about the platform. And of course, you are all very familiar with 3 established modalities that we built over the years, an Infectious Disease Vaccine modality with approved products, products under review and also products that are in the clinic.

Intismeran modality going after cancer and a rare liver disease therapeutics modality, all coming from the same mRNA platform. That established modalities is what we consider horizon #1, is driving the business today and in the coming years. But of course, we're working hard with the team to invent the future. And today, we want to talk to you about Horizon 2, the modalities that are today in the clinic, dosing patients that we want to share with you some of those programs and what's coming next.

And the other piece we want to talk about as well is Horizon #3. The future modalities that the team is working hard at that we believe should be testing in human by the end of 2027 in the next 18 months. But we're not stopping there. David will also spend time talking to you later this morning about what we're doing with AI to keep learning faster and faster to invent the next generation and the next generation of modalities.

And our AI strategy in science is based on basically 2 vectors. One is an mRNA technology vector that we will describe and talk about. And of course, there's a biology vector where we can leverage models that exist outside in the industry. So in a minute, David and Rose will come up to talk to you about mRED. And then Kristine, Professor Church and Sarah will talk to you about the cancer-antigen therapy modality. We'll take a small break, and then we will come back. Lin will talk to you about our T-cell engager modality. Then Sumana will talk to you about our EBV therapeutics in multiple sclerosis.

Lin will come back to talk about in vivo CAR-T for autoimmune disease. And then David will try to wrap it up to talk about what are the exciting science he and his team are doing to invent the future modalities. I'll come back with a few slides to close and then David, Rose and I will take your questions.

So with this, let me turn over to David and Rose.

Thank you very much, Stephane. So I joined about 3 or 4 months ago. And I think today, you'll begin to see why I joined the company, why I'm really excited about the potentials here at Moderna. But first, why are we creating an mRED, Moderna Research Early Development? The riskiest stage in the drug development continuum is the early clinical phase. And why? It's because we need to adapt to data that emerges quickly, number one.

And number two, teams need to be able to stop drugs that are not going to work to accelerate drugs that have potential. And it's very hard in the traditional scheme for teams to do that on their own. And this is compounded when you have multiple layers of governance and levels between them and senior leadership. So based on my tenure of working at 4 companies, 2 large pharmas and now 2 biotechs, I think there are 2 major levers that can be done structurally to enhance rapid innovation.

And number one here is creating an mRED leadership team, which is comprised of research, development and CMC. And by the way, we include CMC because mRNA and lipid nanoparticle science is evolving as rapidly as our biology understanding, and we need to have CMC at the table as well. But we're having this mRED leadership team with no barriers or connections, the teams directly report into the senior leadership.

And what this will do, as you see here, is it connects the senior leaders to the data directly. It allows us to accelerate decision-making that is fast, data triggered, and very clear with no guesswork by the teams involved. It ensures that we have a dedicated focus on bringing innovation in this next generation and very importantly, it enables us to make science-driven decisions to accelerate where necessary, but also to stop drugs that are not going to be promising.

The second major structural element that should be done is to marry early clinical research, early clinical trial development with research. And I think there are 2 major reasons why it's important to do this. First, early clinical research is actually closer to basic science research. We're getting data based on patients. We need to interrogate the data, and we need to adapt based on what the data is telling us as well as external data.

In late phase, you don't want to do that. You design a Phase III trial and you do not want to react and change rapidly in a rapid fashion. The second reason, and I think this is inherent to the modality discussion that you heard is -- we have these modalities with sentinel programs. And these sentinel programs are in the clinic, and you'll hear about them today. And these sentinel programs inform the other programs that share the same modality, whether it's T-cell engagers, cancer-antigen therapy, you'll hear about it today.

And so it's very important to make sure that the science that the clinical insights we're making in early phase are rapidly translated into the research and vice versa. The new insights we're making in research are embedded into the early clinical stage. So I think this mRED structure, which we are now rolling out will help Moderna accelerate where necessary, but also stop programs that are not going to be promising.

And with that, I'd like to call up Rose, who will talk more about the mRED portfolio.

Thank you, David. So we wanted to share a little bit of insight into how we actually craft this early portfolio. And so the first thing to say is that we want every asset in our pipeline to start out with a competitive advantage. So we, as a portfolio strategy, look for applications where the use of mRNA and LNP platform technology offers a competitive advantage to start. That helps us advance differentiated programs. So for example, you'll see that we utilize multiplexing in our pipeline.

And we specifically say multiplexing and not combination because from a regulatory perspective, we are able to encode and deliver multiple proteins in one therapeutic, and it's not considered a combination. It's considered one potential drug product. You'll see this in the Infectious Disease vaccines that we already have licensed, and you'll see it in our early pipeline today in the form of our T-cell engagers. We also have an advantage in being able to express intracellular and transmembrane proteins, which, of course, are not truly accessible, for example, if you have a recombinant protein platform.

Now you'll see demonstration of this already in our rare disease pipeline, which has advanced all the way through pivotal studies, but you'll also see it applied today for our in vivo CAR-T program. And then, for example, on the T-cell response front, we know that our platform can generate very robust CD8 and CD4 T-cell responses. That's been well demonstrated through our INT, our individualized neoantigen therapy program.

And you'll also see it today in multiple applications, both in oncology and now in autoimmune therapeutic space. So that's the first pillar of how we think about crafting the portfolio. We also think about how we're going to get the most leverage out of the investment that we make in R&D. And so we look for modalities where we can see multiple follow-on programs where the learnings that David mentioned that we're generating in the clinic can help derisk those follow-on programs. That lets us get the best return on our investment.

So what you'll see is we'll start a modality. We'll bring an initial program into the clinic. We often use the term sentinel program for that first program. We learn about how our technology performs and whether the biology that we were hoping to access is performing the way we anticipated. When we see that, we feel like that modality is more derisked, and we're willing to advance more programs behind it at a faster pace.

And then finally, this is the pretty early part of the funnel for our pipeline. So we like to keep quite a bit of diversity and balance. So you'll notice that we have multiple different modalities that utilize different types of our platform technology and are also looking at different therapeutic applications. And this is somewhat intentional. We want the very early part of the pipeline to also have uncorrelated risk in many ways so that we have multiple independent shots on goal as we're building the pipeline through that funnel.

So we won't talk through all of these modalities today, but to give you a sense, Horizon 2, these are the modalities where we have a program already in the clinic, generating that clinical data and moving toward clinical proof of concept. Horizon 3 that you'll see here is earlier. These are the programs that we're looking to take to first in human by the end of next year. And then while we don't talk about programs that are earlier than that, you will hear some about the technology that we're continuing to advance, and that's critical to make sure that Horizon 3 stays robust and diverse. You can also see across Horizon 2 and Horizon 3, how we gate our investment.

So in Horizon 2, in some areas where we've seen early encouraging clinical signal, we're willing to advance multiple programs in that same strategy, whereas in Horizon 3, we're typically looking at one sentinel program to move into the clinic, generate data, give us that confidence, and then we will bring in more programs behind it. So with that, I'm going to hand it over to the brilliant, Dr. Kristine McKinney, who's going to talk about our cancer-antigen therapies.

Thank you so much, Rose. And yes, I'm delighted to be here today to share with you a little bit about the emerging cancer portfolio, including our Horizon 2 that are entering and in clinic. So yes, my name is Kristine McKinney. I lead the Cancer Vaccines and Bioinformatics Research team here. And I'm going to walk you through a few of these cancer-antigen therapies. Sarah will also walk you through another one. First 2 that we are developing in solid tumors, mRNA-4106 and mRNA-4200 as well as our first foray into the preventative space with mRNA-4194.

Okay. So as Rose has been highlighted, we're very excited about the data coming out of the Intismeran program. We were really happy to share those -- the 5-year update of the Phase II at ASCO recently as well as showcase some of the data demonstrating the depth and breadth of the immune response that this drug is able to inspire in the form of a translational poster.

And as Rose highlighted, this means that we've de-risked this concept, and we're investing very steadily behind it to make sure that we bring this technology to the greatest impact in patients. And so just to orient you to how we're thinking about developing the next-generation cancer antigen therapies, I wanted to highlight that there are different opportunities in different tumors in terms of targets.

And here in the red boxes are the ones we're going to talk about today. I'm going to first start with the tumor-associated antigens. And just to reinforce that these -- this class of antigens are actually non-mutated, they're shared, and they are either misexpressed or overexpressed in malignancies. And so yes, again, these constitute Horizon 2.

So to start off, let's talk about mRNA-4106 and mRNA-4200. And you'll see these design principles flowing through the entire portfolio. So I wanted to take a second to double-click on those, how we're designing these cancer antigen therapies. So first of all, we are optimizing for population as well as individual level efficacy. Here, we're leaning into the aforementioned ability of our platform to multiplex. This really allows us to inspire the broadest immune response across broad populations.

Second of all, we're managing the biology risk. As I highlighted, there are different classes of tumor antigens, and we're really thinking about prioritizing validated antigens and optimizing for immunogenicity. Third, of course, safety is first and foremost in our mind. We're making sure that we're safely exploring that design space, again, in a data-driven manner. And fourth, in order to enable the portfolio strategy that Rose walked through, we are enabling optionality. So we are including targets that are also expressed -- that are expressed in a wide variety of tumors that allows us the ability to expand into different malignancies should the data indicate that would be wise.

Okay. So now -- sorry. Okay. So just to talk again about the design and mechanism of action for mRNA-4106 and mRNA-4200. On the left, you'll see the hypothesized mechanism of action, which is the mRNA encoding the antigens that we select, these are multiplexed, are formulated into LNPs, which are then administered intramuscularly just like in intismeran. Those LNPs are taken up by antigen-presenting cells, translated, processed and presented on MHC Class Is, which you see the little Y-shaped molecule that's sitting on the surface of the APC there. That serves as a signal to activate T cells in an antigen-specific way.

So those are now armed to go find and kill tumor cells anywhere in the body. Okay. So in particular, how do those design principles I just highlighted play out in mRNA-4106, so and mRNA-4200. So the targets are validated across many human tumors, as well as we look at both expression in tumor tissues and normal tissues in humans. That is RNA protein as well as peptide presentation using immunopeptidomics mass spectroscopy technology.

In addition, we generate preclinical data that confirm successful antigen processing and HLA presentation as well as immunogenicity in the particular -- once the antigen is formatted. And we -- and just to reinforce that we're using whole antigens here. So these are entire protein sequences that gives us many, many possible peptides that can bind across many HLAs across populations. Also, these are multiplexed products. So we -- this, again, reduces the risk of tumor escape through single antigen loss as well as improves the coverage in case of intratumoral and/or inter-patient heterogeneity, really trying to cover a really broad space here.

In addition, they are applicable across multiple tumor types. So we have selected targets that are expressed in multiple tumor types. Again, as we de-risk and prove immunogenicity in humans as well as efficacy, we will be able to expand these rapidly into other histotypes. So to show you how we're entering clinic with these. So mRNA-4106 entered clinic last year in a single monotherapy dose escalation. It's been progressing very well and without any safety findings.

And mRNA-4200 is coming close behind. We are developing these 2 in tandem. So mRNA-4200 will enter and importantly, we'll leverage the data that we've generated in mRNA-4106 to start the monotherapy dose at a safe and efficacious dose. So we don't have to go through the whole dose escalation. After the first dose, we will then combine with pembrolizumab in cycle 2 and continue dosing the combination. And of course, as all Phase I, safety and tolerability are first and foremost, but we will also be exploring, of course, efficacy as well as immunogenicity in these studies.

Okay. Now to switch gears and talk a little bit about mRNA-4194, which again is our first foray into the prevention space. And in this case, these antigens are actually exquisitely tumor-specific, very much like Intismeran, but they are derived from frame shift mutations. And I'm going to talk a little bit more about the provenance of those antigens and why they come into play in the following slides, maybe.

Okay. And like mRNA-4106 and mRNA-4200, this has a similar mechanism of action. So the only difference here is that the mRNA is encoding frame shift antigens, right? So that the T cells that it activates are then activated to kill any cell that expresses a frame shift peptide. So that could be a tumor cell or importantly, a premalignant cell. And that really is the biggest difference for mRNA-4106, right? Is that it's opening up the prevention setting.

So in order to help you understand the context of Lynch syndrome as well as the patient journey and what patients live through, we have the opportunity to hear Dr. Church explain that to you all. David Church is an esteemed collaborator. We're so lucky to have him on this program. He's really a world-renowned expert in this field. He's a physician scientist with numerous titles at Oxford, which you can see listed here. But I think I really want to reinforce that he is a person who's not only pushing the technology and the science, but he's also making sure that those are integrated into clinical practice in NHS and has multiple appointments to do that in a regional way. So without further ado...

Thank you, Kristine, for the kind introduction and the invitation to present on Lynch syndrome. My name is David Church. I'm a Professor of Precision Oncology at the University of Oxford, and I'm a Cancer Research U.K. senior Cancer Research fellow. In the next several minutes, what I'd like to do is talk you through Lynch syndrome, give you an overview, update you on epidemiology, how we diagnose it in the U.K. and its management and then cover the trial that we're really excited to be starting in partnership with Moderna.

So Lynch syndrome, is a condition that many of us have not heard of, but in fact, is a common condition. It affects more than 300 people globally. That's 175,000 people in the U.K., more than 1 million people in the U.S. And at the molecular level, Lynch syndrome is caused by germline defects and inherited defects in one of several genes which are responsible for DNA mismatch repair. This is a process that ensures our DNA is copied accurately when our cells divide.

And the failure of that due to the defects in Lynch syndrome causes error-prone DNA replication. And errors in genes that regulate cell growth, cell death can lead to cancer. And so people with Lynch syndrome have a grossly increased risk of colorectal, endometrial, and other cancers, as you see in the schematic here on the right. And also, as a consequence of that error-prone DNA replication, they're also prone to getting these stereotypical frame shift mutations. So mutations that change the sequence cause insertion of [indiscernible] encoding DNA and cause a frameshift and novel open reading frame, which is important as we'll come to in a second.

Management for Lynch syndrome relies primarily on surveillance with aspirin used by some people after the CAPP2 study to reduce the risk of colorectal cancer and possibly other cancers. But coming back to those frame shift mutations, these are important, particularly as we talk about the clinical trial that we're starting because they can create potentially targetable source of cancer-specific antigens. These are predictable alterations, which are present only in pre-cancers and cancers and people with Lynch syndrome other mismatch repair deficient tumors.

So to focus on the epidemiology of Lynch syndrome, there are 4 main mismatch repair genes that are defective causing Lynch syndrome, MLH1, MSH2, MSH6, and to a lesser extent, PMS2 and then rarely deletions in EPCAM, which cause silencing of MSH2. The cancer risk varies according to gene. As you see here, the risk of cancer is highest in MLH1 and MSH2 carriers. This is reflected in surveillance guidelines. MSH6 carriers have a lower risk of these tumors and overall, but a particularly high risk of endometrial cancers for women that carry these variants.

And you see here at the bottom, the takeaway, the lifetime risk of cancer very high in these individuals. And clearly, despite surveillance, despite aspirin, a huge unmet need for reducing cancer burden in this at-risk and common population. So recognizing the need to identify Lynch syndrome to reduce that cancer burden in this population over the last decade, we've put a number of steps in place in the U.K. to identify Lynch syndrome from cancer diagnosis and then more broadly.

Going back to 2017, NICE, the National Institute for Health and Care Excellence in the U.K. recommended that all colorectal cancers were tested for Lynch syndrome using either immunohistochemistry, so protein staining for the proteins where the genes are defective in Lynch syndrome, or microsatellite instability. This is a genomic readout of mismatch repair deficiency and consequently potentially of Lynch syndrome. And so we've been doing that to identify the 4% of colorectal and endometrial cancers or colorectal cancers that are caused by Lynch syndrome.

In 2020, the guidelines were updated to also cover endometrial cancer. So here, the testing is only immunohistochemistry because mismatch repair deficiency caused by Lynch syndrome doesn't always cause microsatellite instability in endometrial cancer. And in 2021, NHS England published guidelines to help clinicians streamline Lynch syndrome testing pathways as follows: So we do reflex testing on all colorectal and endometrial cancers where the testing suggests that it could be caused by Lynch syndrome. The follow-on step is to do germline testing to see if there's a pathogenic variant present in the germline.

And then if that's confirmed, the index case is managed by putting them on a national registry. We now have more than 13,000 people on our U.K. registry of Lynch syndrome. They're registered for surveillance to reduce their colorectal cancer risk. And then after discussion with the index case, a cascade testing of at-risk family members with the intention of identifying them, hopefully before they ever get a cancer and preventing cancer in these at-risk family members.

Management of Lynch syndrome, we've covered some of it already, covers both colorectal and extracolonic cancers. It should be noted that at the moment, there's no evidence -- high-level evidence for screening for extracolonic cancers for people with Lynch syndrome. So we focus on colonoscopy, reflecting the different risk of cancer, colorectal cancer, MLH1, MSH2 carriers compared to MSH6 carriers have a different age of onset or recommend starting surveillance.

But the recommendation in the U.K. is it's done every 2 years. Aspirin based on John Burn's CAPP2 data shows that high-dose aspirin reduces the risk of colorectal cancer. The unpublished CAPP3 study, which is just about to be published, shows that actually the reduction in cancer risk is the same as low-dose aspirin, so opening up to more people with Lynch syndrome to take this and reduce their cancer burden.

For some people, risk-reducing surgery, both colorectal, both the colon and also women who have completed their family may consider removal of the uterus tubes and ovaries. H. pylori eradication reduces the risk of gastric cancer and also lifestyle changes to reduce cancer-causing dietary and lifestyle factors. So despite all of those steps, as we said, there's a huge unmet need to reduce cancer risk and cancer burden in people with Lynch syndrome. It's a common condition.

And so we're delighted to be able to announce that in partnership with Moderna, we've developed and about to start this INTERCEPT-Lynch study. So a Phase I/II study of novel Moderna vaccine for Lynch syndrome. This vaccine leverages the fact that Lynch syndrome causes predictable frameshift mutations, which are recurrent across cancers, colorectal, endometrial, gastric, ovarian cancers caused by Lynch syndrome share these potential vaccine targets.

So Moderna developed a vaccine and was going to be opening the study to test it. The study is divided into 2 parts. First part will test safety, tolerability, and define immunogenicity of the vaccine to identify 2 doses to take forward into the second part, which will focus on identifying whether the vaccine has evidence of activity in the tissues in which we want to see it. So just to look at the first part in a little bit more detail. This is a fairly standard dose escalation study with endpoints of safety and tolerability. It will define 2 doses to take forward into Part 2.

And then Part 2, people with Lynch syndrome who are scheduled for colonoscopies will be identified. And the final stage of the screening is to do the colonoscopy. And what we're going to do here is we're going to leave small polyps, adenomatous polyps, which we know are the subtype of polyps that become microsatellite unstable and develop the target frameshift that we're looking to target with the vaccine. We'll be leaving those in situ, measuring them very carefully at baseline and then vaccinating at 2 doses defined by Part 1.

And after 28 weeks, we repeat the colonoscopy, we remeasure the polyps to see if there's evidence of response to the vaccine and then the polyps are removed. And then the standard of care colonoscopy at 2 years will be done, and we'll also be looking for polyp burden at that time point. So endpoint of the study, safety, and tolerability and then the secondary endpoint in Part 2 of the study is a percentage change in the MSI-high, the microsatellite-unstable adenomatous polyps post-vaccination.

We'll be looking at immunology, both circulating and in tissue. And we're really excited to be starting the study imminently in Oxford with the second part of the study recruiting from additional U.K. sites. And what's really motivating about this is not just the clinician engagement. We've had a huge interest from clinicians, but also directly from patients. I've presented the work leading up this study over the last 3 years to Lynch syndrome carriers at Lynch syndrome U.K. Annual Meeting.

And since we released the press release putting out the study, there's been a huge amount of interest and had many e-mails from people keen to recruit, keen to participate in the study and also just commending us on the effort that we're making to reduce the cancer burden in this common condition. So thank you very much for your attention. I'm really excited to take this study forward and look forward to updating you at a future meeting.

Okay. So David, obviously, I would just like to underscore a couple of different pieces that he mentioned as well as tell you a little bit about the design of this vaccine. So as we've discussed and David highlighted, Lynch syndrome carriers have polyps over time. And those polyps over the course of their lifetime can develop into microsatellite unstable cancer. So to design this product, what we did was take precancerous polyps and look with all of the same technologies I already highlighted. So protein expression all the way through presentation at the MHC level of the peptides from the frameshifts.

And we've also looked at MSI-high cancers from sporadic cases. So as the same genes that cause the germline defect and the germline sensitivity to developing frameshift mutations. Those mutations can be acquired sporadically as well. And so we do find them in cancers that have no -- like did not have any germline susceptibility here. Those have a lot more samples. So a lot more samples from the MSI-high cancers across different malignancies and across broad populations. And we compared the frames shift peptides that we saw expressed and presented in those cases.

And we were able to find many, many that overlapped. We selected specifically from that overlap to make sure that the cancer -- sorry, that the -- that mRNA-4194 would address all the relevant stages of disease, everything from polyp to frank malignancy. And in particular, we actually were able to incorporate 194, hence, the name, mRNA-4194, 194 different frameshift peptides into this vaccine. So we really have extremely broad coverage, again, not only intertumoral heterogeneity across disease, across histologies, and across populations.

Yes, I think that's -- and then I also just wanted to take a second to pause. I know Dr. Church reviewed the Part 2 of the Phase I and how it's constructed in great detail. So I won't take you through all of the steps. But I just want to highlight that this is quite an innovative design. And the goal here is really to make sure that we are learning fast, right? And that we are de-risking upstream of pivotal investments and that we can iterate in data-driven ways.

This sort of mindset is taken through all of the [indiscernible] trials, and we're leveraging these ideas across the [indiscernible] trials more and more leaning into the translational data because we know that if we can get this to patients, as Dr. Church said, they're hungry for it and they -- and this could transform their lives.

So with that, I'm going to pass off to Sarah, who's going to walk you through mRNA-4359. Thank you.

Hello. My name is Dr. Sarah Keidel. I'm the program lead for mRNA-4359. And it's my pleasure today to walk you through our program, including the exciting data that we presented over the last year at ESMO and earlier this year at AACR. So going back to this cancer-antigen therapy schema that Kristine talked us through earlier, we're now going to be focused on the top right-hand side of the figure at the tumor-associated antigen therapies. So mRNA-4359 employs the same mRNA and LNP technology base as the other cancer antigen therapies, but applies it to immune evasion proteins.

And importantly, mRNA-4359 is the first of our cancer antigen therapies for which we'll have the opportunity to really unpick that product concept, looking at the scientific and clinical data as they emerge. So what is mRNA-4359? It is a lipid encapsulated mRNA-based cancer antigen therapy, encoding antigens of PD-L1 and IDO1. And these are proteins that are intimately involved with immune invasion by tumor. And we know that PD-L1 and IDO1 can be expressed by tumor cells, but importantly, they can also be expressed by immunosuppressive cells.

And this gives mRNA-4359 a dual concept. So not only can it have the potential to induce T cell responses to direct tumor cell killing, but it can also direct immunodepletion of the immunosuppressive cells that are protecting the tumor. And because this immune evasion mechanism is common to many solid tumors, it is possible that this product can be applicable across multiple tumor types, although we're starting with melanoma as a very rational first place to test the mechanism given the intended backbone of IO.

So you'll recognize this schema, this mechanism of action from the talk that Kristine gave earlier on the cancer-antigen therapies. And broadly, we have the same mechanism, but there is one point of difference due to the specific antigens that are encoded by the mRNA, the PD-L1 and IDO. So kind of skipping through, you know that the protein is translated and they get expressed. The T cells that are specific to IDO1 and PD-L1 then get activated.

These mature, they expand, they go into the circulation and then they enter the tumor microenvironment. And it's at this point where you get that potential of that dual mechanism. So those T cell -- those tumor antigen-directed T cells will then look to destroy the tumor cells expressing these antigens and also those immunosuppressive cells also expressing these antigens. And so over time, we would expect a rebalancing of that tumor microenvironment to a more immune-permissive state.

Now this also gives us that impetus for the idea of the backbone of the checkpoint inhibition. So the idea of mRNA-4359 is that it really works as a target to induce those target-directed T cells. However, the idea of the checkpoint backbone is to release further brakes on the immune system to maximize the potential of the mRNA-encoded product. So now to the data. On this slide, you've got our Phase I/II study design.

We started off pretty typically with dose escalation and confirmation cohorts. And at the moment, we're in the Phase II portion of the study at dose expansion. We'll come back to that in a minute because what I'd like to focus on the next few slides is on arm 1b, which is our dose confirmation cohort in patients who are treated with mRNA-4359 in combination with pembrolizumab and who had checkpoint refractory advanced melanoma. So starting with the ESMO presentation here.

We've got here listed the patient disposition and the baseline characteristics for the 29 patients who are included in this cohort. They were treated at 2 different doses, but the main takeaway from this slide is that these were refractory patients. All of them were checkpoint refractory, and there's a median of 3 prior therapies with a maximum of 8 prior therapies in this group of patients. Now first and foremost, in this Phase I study, safety. So mRNA-4359 in combination with pembrolizumab demonstrated a manageable safety profile.

The majority of adverse events considered related to mRNA-4359 by the investigator were low grade, and they comprise of injection site reactions and localized self-limited systemic adverse events such as fever, fatigue and also chills. There were no dose-limiting toxicities or grade 4 or 5 adverse events considered related to mRNA-4359. Now switching to the pembro-related adverse events. These were very typical for the adverse events seen in the checkpoint inhibitors with irAEs.

But the overall, what we saw from this cohort is that it looks possible to combine mRNA-4359 plus pembrolizumab without getting unexpected safety signals. And this is something that, of course, we're watching out for as we expand our Phase I/II study. So here, we have the efficacy, and this is the part that really started to get us very excited. So what you'll see here on the left side of the slide is the efficacy table, and we're going to focus on all patients pooled across the dose levels. So you'll see that we had 25 patients who are valuable for their tumor responses and 6 of these patients responded, giving us an objective response rate of 24%.

We even had one complete response. The median duration of response was not reached for these patients, and our disease control rate was 60%. So we're encouraged by these results already. As we mentioned, this is a heavily pretreated population, but we were really interested in understanding, are there any signals or any biomarkers that could help us point to which patients have a higher chance of response. So on this slide, you'll see the spider plot looking at the tumor responses over time.

And what we've done here is color through the patients by their tumor PD-L1 expression. So in the red, we've got the PD-L1-positive and in the blue, we've got the PD-L1-negatives. And what you can see really clearly here is that all the responses occurred in patients who were PD-L1-positive. And indeed, these responses were enriched in that PD-L1-expressing population. So 6 out of our 9 patients responded, giving us an ORR in this subgroup of 67%, which we were very encouraged by.

But of course, we wanted to understand a little bit more who are these patients? Are they on the lighter end of the treatment spectrum? What's going on with them and what treatments have they had before? So on this slide, we've got the 6 patients treated who responded on the -- in each row. And we've got their prior treatments listed in chronological order and including the disease setting as well as their best overall response to that drug. In addition, on the right for reference, you'll also see the results that they had on our drug in the combination of mRNA-4359 plus pembrolizumab once they came on to our study.

But I'd really like to focus on the middle part of this slide because looking at it to me, what I take from this is that these were a heavily pretreated group of patients genuinely. So almost all of the patients were treated previously with anti-PD-L1 monotherapy as well as IO combinations with nivo/rela or nivo/ipi. And half of them had prior exposure to TILs or TCR therapies.

In addition, when you look at the best overall response to each of these therapies, the majority of patients had the best response of disease progression to the majority of these prior therapies. And so again, these are patients that in the real world would have exceptionally poor prognosis and see any responses in this group of patients to us was encouraging, but particularly important when you look back at that spider plot that we had in the previous slide of the durability of those responses that we saw. So for us, again, very, very promising.

Last but not least, for this checkpoint-refractory cohort, we have the translational data. We are very interested in understanding, is there a proof of biology for this drug based on its mechanism of action. So on the left-hand side there, you'll see some ELISpot analysis looking at for the development of antigen-specific T cell responses between baseline and after treatment. And what you'll see here is that indeed, there was an increase in the PD-L1 and IDO-specific T cell responses in the periphery for the evaluated patients and that this was seen across best overall response categories.

On the right, we are then interested in looking at whether the patients develop novel expanded TCR clones once they're exposed to therapy. So again, looking from baseline and across the treatment cycles and as we go through the diagram, you can see that there, again, there is an increase in these novel expanded TCR clones after starting mRNA-4359 and pembrolizumab. And this does seem to be directionally higher in those patients with responses versus those patients with either stable disease or progressive disease.

So together, these data were important for us because it really helps to underpin mechanism of action. We see that proof of biology, and it helps us to understand some of the data that we're seeing clinically as well. So based on these data, we expanded into another multiple treatment expansion cohorts. And so we're looking at a couple of first-line melanoma cohorts with combinations of checkpoint inhibitors. We have further expanded our second-line and beyond melanoma cohort, looking at those patients specifically for good reason, who are PD-L1-positive.

We've also added a first-line non-small cell lung cohort in high PD-L1 expressers. But I'm going to focus at the top at our Arm 1/2a. And this was a small cohort treated with mRNA-4359 in combination with pembrolizumab in the first-line melanoma setting. And this is fully enrolled. We had results and these results were presented at the oral plenary for AACR a couple of months ago. So here, we have treatment disposition at a median follow-up of 54 weeks. 7 of the 12 patients had discontinued treatment by that point, 2 because of progressive disease and 4 because of adverse events.

Five patients continued on therapy at this point, 4 had completed their mRNA-4359, but continued their pembrolizumab. One patient remained on the combination side of the therapy because they were pretty early in these treatment cycles. Here, we have the baseline characteristics, nothing particularly unexpected. The majority of patients had an ECOG performance status of 0. The disease stage of the majority of patients was 4. About half of the patients had BRAF-mutated disease. And this is a small, but important clinically relevant cohort for us, which we'll come back to in a few slides' time.

We had 4 patients who had prior exposure to neoadjuvant therapies, 3 of whom had immunotherapy exposure in the form of nivolumab. So again, first, the safety. Here, you'll find nothing unexpected. These are, I think a slide has gone missing, but yes, needless to say, the mRNA-4359 related adverse events, they were all low grade in these 12 patients. The most common were those fevers, chills, pyrexia and fatigue, as you'd expect from innate immune activation after administration of an mRNA product.

Pembrolizumab-related adverse events, as determined by the investigators, were predominantly low grade. Most common -- I think that's just going to -- I'm so sorry. It looks like that's pembrolizumab, but that's the mRNA-4359. This is now the pembrolizumab. So the majority of the most common adverse events were fatigue, nausea, increased amylase, diarrhea and pruritus as expected for anti-PD-1 monotherapies.

About 1/3 of patients had high-grade events, and these were pretty typical for immune-related adverse events that occur with checkpoint inhibitors. So again, based on a small number of patients, we're not seeing any signals that there are unexpected safety events occurring with the combination. But again, we continue to monitor carefully. Now to the efficacy. Here on this efficacy table, we've got all the participants on the right-hand side. And in the middle, we've also looked at the subgroups by PD-L1 expression because based on the checkpoint-refractory data, we were very interested in understanding what happened by PD-L1.

So looking at all participants first, you'll see that 10 out of those 12 patients responded, including 2 patients with CRs, Median duration of response was not yet reached. Now looking at the small subgroup of patients with PD-L1 positive and negative expression, you'll see that we were very encouraged to see that there were responses across PD-L1 expression. So we had 2 out of the 3 patients who are PD-L1 negative who responded to therapy.

On this slide, we've got the swimmer plot showing the patient journey as they came on to the study. So we've got those 12 patients on the Y-axis. And just to orient you a little bit to the plot, the blue, dark shade is the treatment duration. The lighter shade is the period of follow-up. The blue and white triangles are the complete and partial responses the patients had and the red circles are the progression events.

And what you'll see here visually is that the majority of patients remain disease-free and in follow-up on the study at the time of the data cutoff. We had 3 progression events, 2 of which contributed to the PFS results because one of them, per the prespecified statistical analysis plan, was censored because of multiple missing tumor scans. The median duration -- the median PFS was not reached. Now going back to that important small subgroup of patients who had prior neoadjuvant therapies.

And these are the patients that are denoted by the asterisks on the right-hand side of the swimmer plot. There's those 4 patients. So what you'll see here is that 3 of those 4 patients had a response of either CR or PR, and these patients remain progression-free through the duration of the follow-up. Now the reason this is important despite the fact that it is a small cohort is it starts to give us a sense that it may be possible to give mRNA-4359 in combination with pembrolizumab in the first-line setting with efficacy despite prior exposure to IO.

Now on this slide, it looks, in some ways, very similar to the one we saw in the checkpoint refractory disease with that spider plot. We've got the reduction in tumor target lesions over time. On the right-hand side and on the left, we've got the waterfall plot, again, colored by PD-L1 expression with the positives being in red. But the main point of difference that is quite striking on that spider plot compared to the one we saw earlier is just that the majority of patients here are responding. And again, that you do see those responses in the patients with PD-L1 negative disease.

What looks similar is the translational data. So here, we have the translational data from the first-line cohort. And again, we see biological activity demonstrated both by the development of IDO1 and PD-L1 specific T cell responses as well as the novo clonal expansion of those T cells. So again, very nice to see this based on the mechanism of action of the drug. So in conclusion, we were very heartened by these data. We now have data that the combination of mRNA-4359 plus pembrolizumab may have a manageable safety profile and also may have evidence of biological activity in these patients with both refractory melanoma as well as treatment-naive advanced melanoma.

In terms of efficacy, we saw durable responses in both. Of course, it was higher in the first-line setting, where we actually saw that it was regardless of PD-L1 expression, while the responses were enriched in the PD-L1 positive patients in our checkpoint-refractory disease. So based on these data, as we mentioned, our Phase II expansion cohorts are ongoing, and they should help us to elucidate our strategy in terms of ideal treatment setting, in terms of our preferred combination partner and also in terms of our biomarker strategy. And we also are eagerly anticipating the results in the non-small cell lung cohort.

So with that, you've bear with me through a lot of data, but thank you so much for your attention, and we now break. Thank you.

[Break]

Hi, everyone. Welcome back. I have the distinct pleasure of telling you about a new modality we are creating within Horizon 2, specifically mRNA-encoded T-cell engagers against surface antigens. And so T-cell engagers, as you know, are a well-established class of medicines with 10 FDA-approved products. T-cell engagers are a great demonstration of how we use mRED principles to build modalities.

And so I'm going to walk you through our platform differentiation within those modalities, walk you through also about how we think about our sentinel, our first application and how that de-risks follow-on programs. And then also about how we think about the depth of the well, follow-on programs and diversification of the follow-on programs thereof. Now unlike cancer vaccines, cancer antigen therapies, therapeutic vaccines, where we use our platform technology to train the immune system, specifically T cells to go and hunt their target.

T-cell engagers, as you know, are bispecific antibodies that physically direct T cells to tumor cells to unleash killing activity of those T cells on tumor cells. Now you probably know that T-cell engagers are conventionally recombinant antibodies. And you're probably wondering, well, what's our differentiation there. And so I'm going to come back to a point Rose and Kristine made, which is on multiplexing. And so here for T-cell engagers, we really lean into our ability to multiplex. So in a single drug product, we have multiple messenger RNAs encapsulated in lipid nanoparticles.

Again, that is considered a single-drug product. And we can encode, we can produce multiple T-cell engagers all at the same time. Why that becomes advantageous is because we can go after multiple tumor targets and thereby overcome some known resistance mechanisms for given histotypes. So inter- and intratumor heterogeneity specifically and also antigen escape, which is a well-described phenomenon for certain histotypes.

On top of that, for T-cell engagers, we can think about tumor biology and really, again, resistance mechanisms and also include T-cell engagers that encode co-stimulatory molecules. So not only directing T cells to kill tumors, but also providing molecules to improve the fitness of T cells. Now we're going to talk about the modality with respect to surface antigens, but we also are working on this modality beyond surface antigens against intracellular antigens as well.

So for our Sentinel application, we always try to minimize biology risk because this is the first time we're taking our platform technology into a new area. And so when we looked at T-cell engagers, the optimal sentinel application from our perspective was going after multiple myeloma, where you already have a bunch of clinically approved T-cell engagers and other T-cell engagers showing great antitumor activity in clinical development.

And so there, the thesis was we could encode multiple T-cell engagers all at the same time against clinically validated tumor-associated antigens, we use our technology. So we use our systemic lipid nanoparticle where we had a ton of repeat dosing clinical experience in patients with devastating rare diseases over 80-plus patient years. And we leverage that technology for oncology. And I'm going to walk you through that sentinel application momentarily. Beyond that, once we get an encouraging clinical signal from our Sentinel application, we can learn and we've ungated and de-risked follow-on programs.

And so here, our follow-on program, we wanted to move from multiple myeloma, a hematologic malignancy and really go towards solid tumors. You probably know that the 10 FDA-approved T-cell engagers 8 of them are for heme malignancies and 2 are for solids. Solids have certainly been far more challenging. And we're up to that challenge. And we're excited about using our technology to encode not only the kill T-cell engager, but also provide that co-stimulatory signal to enhance T-cell function to have greater antitumor activity against solid tumors.

Now coming back to diversification within a modality and then broadly across the portfolio. I already touched upon our first application, we go after kind of what we know the signal should look like in myeloma in a liquid tumor and then venturing into ovarian cancer, where there are clinically validated tumor-associated antigens, and we understand some of the tumor biology resistance mechanisms, particularly around the tumor microenvironment and its hostile immunosuppressive environment.

Okay. So the Sentinel application is mRNA-2808. And this sentinel application is a multiplex product. It encapsulates 4 different messenger RNAs that encodes 3 distinct T-cell engagers against clinically validated tumor-associated antigens. You recognize those antigens, I'm sure, BCMA, GPRC5D, and FcRH5. Now our differentiation with respect to multiplexing also is because it's a single drug product, we don't have to show contribution of components for each of the T-cell engagers.

And so if we were working on this with recombinant antibodies, we would have to follow a more traditional drug development path where for each specific recombinant bispecific antibody, we would have to conduct a nonclinical program, manufacturability assessment, clinical development program for each T-cell engager and then combine them. Because mRNA-2808 is a single drug product, we can advance this as a multiplex product, as Rose was saying, it's not a combination. It's a multiplex product, and we can advance it through preclinical, nonclinical, and currently, we're dosing in Phase I/II.

By the way, we haven't been asked a single question about contribution of components from the FDA. And I think that's incredibly exciting as you think about the multiplexing potential for T-cell engagers as a class of medicines for messenger RNA. Now as I said, by multiplexing, we can overcome known disease biology and resistance mechanisms. And so for myeloma, we know that there is significant both inter-and intra-tumor heterogeneity. But also very importantly, we know that these antigens upon treatment can escape. They'll mutate and they will escape patients will stop responding.

And so by going after multiple targets, we should be able to overcome both the tumor heterogeneity, but also the antigen escape. And in fact, the investigators that we're working with are really excited about the potential here of going after these clinically validated tumor-associated antigens all at the same time. Okay. So as you know, the first generation of T-cell engagers are really focused on what we call monoplex. So single target, single T-cell engagers. Of course, you have actually approved BCMA T-cell engagers and approved GPRC5D T-cell engager for multiple myeloma, and they are effective.

The second generation companies are starting to combine those T-cell engagers together. Sometimes they are separate T-cell engagers. Sometimes they are novel multi-specific antibody formats that can be difficult to manufacture. And you have a variety in clinical development and also preclinical development, mRNA-2808 to our knowledge, represents the first time any drug product encodes 3 T-cell engagers all at the same time. And so the multispecifics that others are working on typically are focused on 2 tumor-associated antigens.

Here, we don't have to resort to a fancy multi-specific antibody format. We can use actually an antibody format that we designed specifically for ourselves, for our technology, and we multiplex. We can include multiple messenger RNAs so that we can encode very functional, very well-behaved molecules, all at the same time. And so I'm going to walk you through some of the preclinical data that we showed at ASH about 1.5 years ago.

First showing you that the mRNA-2808 encoded T-cell engager proteins are all incredibly potent. And so what I'm showing you here is in vitro data when we look at binding of the T-cell engagers to their respective targets. They are in nanomolar binding affinity. So these are very potent binders. When we look at killing activity, cytotoxicity against the respective tumor cells that express their respective targets, we are in the picomolar range, so very, very potent.

And then when we do a mix and match of the various tumor cells that have their respective tumor targets, as you can imagine, by multiplexing, by including multiple of these T-cell engagers, we achieved greater killing than simply going after one of these targets by itself. Now importantly, for us, monkeys represent a highly translationally relevant species. And that's based on all of our platform experience in advancing different medicines from preclinical from monkeys to patients.

And what we showed in monkeys was definitively preclinical proof of concept. where we took mRNA-2808 and we evaluated both single and repeat dose administration studies in monkeys, both to assess pharmacology, but also we conducted repeat-dose GLP toxicology studies as well. And what we're showing you on the left-hand side is that after a single dose administration, both intravenous administration and subcutaneous administration that we see really nice dose-dependent expression of the T-cell engager protein.

Now I'm just showing you one of the exemplary T-cell engagers. This is against GPRC5D. By the way, you can note the EC50 dashed line, that's from the cytotoxicity. That's how potent the molecule is. So we are well above what is therapeutically relevant even at these very, very low doses. But what you'll notice from the protein expression kinetics is we actually don't hit the Cmax until about 1 to 2 days later.

And that's exciting for us because if you think about how the T-cell engager field has evolved, as you probably know, they have shifted from IV administration to subcu. And that really was to flatten out the protein exposure curve because you were having CRS cytokine release syndrome that was a Cmax-driven event. So they flatten out the curve. Well, we're excited because actually, our IV administration looks much more like a subcu curve from a recombinant protein.

We're also excited because you can see from this plot, we can subcu administer mRNA-2808 as well. And in fact, we actually included subcu administration as part of our nonclinical program, and we intend to evaluate subcu administration in the ongoing Phase I/II study. Okay. So on the left is we can make TCE protein at very therapeutically relevant levels. Now we know it's functional also because when we look at on-target pharmacology, specifically depletion of target expressing cells, specifically we're showing you here memory B cells.

Again, these T-cell engagers are very, very potent. And so what you'll see is after a single dose administration, we have very significant depletion of target cells. This is only a single dose and the rebound is approximately 2 weeks later. And so in monkeys, we've shown that we achieved good tolerability to enable the first-in-human study. We actually had a massive safety margin heading into the first-in-human study, that we can encode functional and therapeutically relevant levels of T-cell engager proteins of all 3 of them. And we've demonstrated on-target pharmacology.

And so with that, we have an ongoing Phase I/II study in advanced multiple myeloma. And so the patient population is relapsed and refractory multiple myeloma. They're triple-class-refractory, and so they've been exposed to proteasome inhibitors, immunomodulatories and anti-CD38. We are currently in dose escalation, where the primary endpoint, of course, is safety and tolerability. And our secondary endpoints include PK, pharmacodynamics and also antitumor activity, specifically response, duration of response, and progression-free survival.

And so we are really encouraged with the ongoing Phase I/II study, and we look forward to presenting findings and results at an upcoming medical conference. So with that, based on the encouraging signal that we've seen to date in mRNA-2808, we've actually ungated advancing our follow-on program, which is mRNA-2151 for ovarian cancer. And here, again, we diversify, we take more biology risk as we advance the follow-on program. And actually, the follow-on program, mRNA-2151, uses the same T-cell engager antibody format is mRNA-2808.

And so with mRNA-2808 having that encouraging signal and being able to show repeat visibility, et cetera, safety, we can apply those learnings to mRNA-2151. For mRNA-2151 is a similar idea to mRNA-2808. So it's a multiplex T-cell engager product, single-drug product. It encodes in this case, 2 T-cell engagers that kill the so-called Signal 1. And these are against 2 clinically validated tumor-associated antigens for ovarian cancer.

Now when we looked at ovarian and solids in general, we thought it would be a good idea to include a co-stimulatory molecule as well, again, because of the hostile, immunosuppressive tumor microenvironment and also that many of these patients, unfortunately, as a consequence of that tumor microenvironment can have poor T-cell fitness and function. And so in the drug product, we also included for the first time ever, a T-cell engager, a co-stimulatory signal, a Signal 2. And so mRNA-2151 combines the Signal 1, the kill, but also includes the Signal 2, the co-stimulatory.

And I'm going to show you some preclinical proof-of-concept data that gets us really excited about the addition of the co-stimulatory molecule to enhance antitumor activity. Now finally, I'll just note that by design, the antibody format, the molecules we're encoding, of course, messenger RNA being an information molecule. It's a very plug-and-play format. And so we're excited because we actually have a whole host of binders against other high unmet medical need tumor types where we can envision different Signal 1 and Signal 2 combinations going into higher unmet medical need tumor types and overcoming known resistance mechanisms and tumor biology.

Okay. So I'm going to show you some of the in vitro data first. So similar to mRNA-2808, these T-cell engagers for Signal 1, the kill T-cell engager are very, very potent. So we're talking about picomolar, killing activity, cytotoxicity, and this has been shown in a variety of tumor cells that express high antigen levels, mid and low. Importantly, the green is the Signal 2. And the Signal 2 molecule similarly is incredibly potent.

So here, I'm showing you sub-nanomolar affinity for T-cell activation. Now in vitro, when we look at both the Signal 1 cell and the Signal 2 co-stimulatory T-cell engager, we see enhancement of killing activity. And so the EC50 for the Signal 1 alone is shown on that dashed line on the upper right-hand side. And as we add concentrations of the Signal 2 co-stimulatory molecule, we can improve the potency, we can improve the killing activity for the drug product.

Now importantly, when we look in vitro, and we do repeat simulation studies of the T cells with tumor cells. So we stimulate the tumor cells day after day. If you focus on the blue line there, that's just a Signal 1 T-cell engager. And day after day, stimulating those T cells, those T cells get more tired, more exhausted, more terminally differentiated, and they lose their ability to kill, which is what you see in the blue. When we add the co-stimulatory Signal 2 molecule, you can see that we retain its ability to kill over time upon repeat stimulation. And that's because what we're showing on the other 2 plots is that those T cells have enhanced function.

And so they proliferate better, they have better survival markers. They're just overall more happy. And so we're excited with that in vitro data, but of course, we've taken this in vivo to various humanized xenograft tumor-bearing mice. Here, I'm showing you the OVCAR-3 model, which is one of the kind of workhorses in the field. The black line shows you just vehicle control. You can appreciate that these tumors grow out of control if these mice are not treated. The blue lines show you Signal 1 T-cell engager that kill T-cell engager alone.

And so you have significant control of the tumor with the Signal 1 T-cell engager alone. But when we add Signal 2 in addition to Signal 1, that's exemplified in the pink and red there, that's when we start to see complete responses and really significant and durable control of tumor. And so similar to mRNA-2808, we are administering this product intravenously, but we're excited about enabling subcutaneous administration as well. And so for mRNA-2151, the next steps are to complete the IND-enabling studies and also to initiate a Phase I study in 2027.

We've had excellent pre-IND meetings to date, and we're excited to advance this to patients. And so as I said, this is our T-cell engager modality against surface antigens. As part of Horizon 3, we're actually working on T-cell engagers against intracellular antigens. So these are antigens I get to that process and displayed on the surface of tumor cells with little parts, and they are HLA restricted. But there, again, we lean into our platform differentiation to multiplex. And we're excited because we should achieve broader patient coverage and also enhanced antitumor activity for that class of targets as well.

Okay. So with that, Sumana is going to walk you through our EBV therapeutic vaccine for MS.

Good morning, everyone. It's a pleasure to be here. My name is Sumana Chandramouli, and I'll be walking you through our mRNA-1195 EBV therapeutic for multiple sclerosis. Epstein-Barr virus or EBV is a very prevalent human herpes virus. It is associated with many serious diseases. And this starts with infectious mononucleosis when EBV is contracted in early adolescents or young adulthood.

And then it can -- it is -- EBV is one of the first human oncogenic viruses that was identified. So it is positively linked to several cancers such as lymphomas Hodgkin's, Burkitt lymphoma, nasopharyngeal carcinoma, and also certain forms of gastric cancer. On top of that, there is emerging evidence and strong evidence that links EBV to several autoimmune conditions, including multiple sclerosis or MS. That will be the focus of the talk today. And in immunocompromised patients and persons, it can also cause several diseases such as post-transplant lymphoproliferative disorder or PTLD, in transplant patients and chronic active EBV.

The underlying complexity of the virus and these diseases and the diversity of the biological mechanisms require not only prophylactic intervention, but also therapeutic intervention to address all of these. And we believe that the unique advantages and attributes of the mRNA platform allow us to address these from all angles. So taking a deeper look at EBV and multiple sclerosis. Multiple sclerosis or MS is a devastating neurodegenerative disease that affects predominantly women in the prime of their life. It can then lead to decades of progressive physical and cognitive disability that can be crippling in every sense of the world.

For many, many decades, people have been looking at the causative agents behind MS. There's nearly 1 million people with MS living in the U.S. today and many millions more worldwide. And the emerging evidence from looking at the data over many decades is that EBV seropositivity and a prior infection with EBV seem to be very strongly linked to a risk of developing MS later in life. This translates to an almost negligible risk of developing MS if someone is not ever exposed to EBV.

All of this was recently summarized in a landmark study that was published a few years ago now in science that showed that quantified this risk to be a staggering 26 to 32-fold increase in risk of developing MS following EBV exposure. That is shown in the graph on the left. The graph on the right shows something additionally interesting, which is that on top of the risk that comes from just having EBV infection, there is an additional two to threefold increase in risk of developing MS if there is a history of infectious model.

So this indicates that the virus starts manipulating the immune system quite early on as soon as it encounters -- so EBV is a tricky virus. It's a herpes virus. So as soon as it enters the body, it stays there for the rest of the life of the host. It bounces between forming active viral particles, which is known as lytic replication and going into a very quiet immune evasive state known as latency. And it goes into a latent state in the B cells of the immune system.

So what we understand from seeing healthy people because EBV is so seroprevalent around the world and most of the exposed people are still healthy is that the immune system uses both arms and antibody response that actively prevents EBV replication and infection of new cells and a very strong T cell control to maintain control over the latently infected EBV cells. So from that was born the concept of mRNA-1195. The composition of mRNA-1195 consists of 6 mRNAs 4 of them, gHgL, gp42, and gp220 are glycoproteins that are known to be the primary targets of neutralizing antibodies on the surface of the virus. These will prevent the virus from infecting naive B cells and epithelial cells.

Then we've also added in engineered forms of 2 latent antigens. These are a group of proteins that the virus uses to maintain its latency and to remain latent in the B cell compartment of the body. So we've included engineered forms of EBNA3A and LMP2B, which are key latent proteins that the virus uses to propagate latency. We are starting out with testing this in multiple sclerosis because we believe that immune dysregulation, often by EBV, may be one of the underlying mechanisms that EBV uses to not only trigger the disease, but also to drive it forward.

We also envision that other conditions like PTLD that might require a combination of antibody and T cell responses in order to prevent the condition from occurring might also benefit from this composition. So we started out by testing mRNA-1195 in healthy seropositive adults, and we wanted to de-risk the immunogenicity of the product before going into the vulnerable patient population.

So the Phase I Part A was designed as a randomized observer-blind, placebo-controlled study. We tested different ratios of the antigens in order to get the ratio right. So we have 2 different compositions of mRNA-1195 in this trial. We also included our mRNA-1189, which is a prophylactic vaccine for EBV against infectious mono that we are developing. We use that as a comparator to understand the interplay between the different antigens between the latent and the lytic antigens we've added in, and there was a placebo group as well.

We -- of course, the primary objective of the study was to look at the safety and the reactogenicity of this candidate. And then we were also going -- we also looked at the humoral and cell-mediated immunity and the impact on EBV shedding. So to share some of the early data we have here, this is the reactogenicity profile of mRNA-1195. As we can see from -- as we can see, the top panels show the local reactogenicity and the bottom panels show systemic reactogenicity. The shades of blue are grade 1 and grade 2, very fast resolving reactive symptoms and very, very low levels of grade 3 were detected.

So overall, mRNA-1195 was well tolerated with an acceptable safety profile. We then looked at the immunogenicity of this candidate. So here, we are looking at the binding antibodies to the glycoprotein components in the -- in this composition. So that's gHgL, gp42, and gp220. Just to orient ourselves, the gray bars that go through the middle of these graphs are the baseline responses to natural infections seen in these seropositive individuals as they come into the trial.

The line in black is the comparator mRNA-1189 that contains these glycoprotein antigens as well. And then in the shades of yellow and red are the different dose levels of mRNA-1195. So a few things are immediately obvious when you look at the curves here. The first is that compared to the placebo, there is a significant boost in the binding antibodies following just a single or 2 doses of mRNA-1195 in this population. This is then sustained by the third dose, and we can see these responses maintained well above baseline out to 6 months after the last dose, which is the last time point in the study.

There was no pronounced dose response as we can see all of the yellow curve -- yellow and red curves are overlapping with each other as well. They're looking at the functional antibodies. So the B cell neutralizing antibodies would be preventing the infection of EBV into B cells and the epithelial neutralizing antibodies are doing the same, protecting epithelial cells from incoming EBV. So here, what we see is that both -- all of the tested dose levels of mRNA-1195 and mRNA-1189 are able to boost significantly the neutralizing antibody response to both B cells and to epithelial cells.

The B cell nABs are considered the more relevant ones here because we are primarily studying B-cell biology-related diseases. And we did measure that all the way out to Day 337, which is 6 months after the last dose, and we can see that the neutralizing response is well sustained above baseline. This is an exciting piece of data we would -- we are also excited to share here, which is looking at EBV shedding and saliva of these seropositive individuals.

So as EBV bounces between lytic and latent replication over a lifetime, any given moment, multiple -- majority of the EBV-infected people will be shedding EBV in their saliva. And this is shown in the gray bars in the top panel that is the average -- the genome copies of EBV DNA in saliva in placebo recipients. And what becomes apparent is that as soon as a single dose of mRNA-1195 is given, we can see that this drops in that group and is sustained all the way through the end of the study.

This is similar to what we had presented previously with mRNA-1189 as well, where we see this rapid and sustained suppression of EBV shedding in saliva. The bottom graph is a different way to look at the data, which is to look at, at any given time, what is the percentage of individuals with detectable DNA in their saliva. This gray bar is, again, represents the placebo group and the black and the orange are mRNA-1189 and mRNA-1195. And again, we can see that as soon as either of the mRNA compositions is given, there is a rapid and sustained reduction in the frequency of individuals that are shedding over time.

As we mentioned earlier, the T cell responses are just as important in this case because the surveilling T cells are what keeps the latently infected B cells in check. So we looked at 2 different types of T cell responses induced by mRNA-1195. These are the CD8 T cell responses. And what we observed is that unlike the placebo group, we can see a nice boost and sustained increase in CD8 T cell responses to the 2 latent antigens, which are shown in the top panels, EBNA3A and LMP2B. And in the bottom, we also observed that there were very strong CD8 T cell responses to the glycoprotein antigens -- antigen gH.

Again, we didn't see much of a dose-specific response, and we also see that these responses were sustained through the end of the study. This panel here now shows the other type of helper T cells, CD8 T cells -- sorry, CD4 positive T cells. And again, we observed a nice boost in sustained response to both EBNA3A and gH following mRNA-1195. And this is sustained through the last time point in the study.

We are now continuing our Phase I, knowing what we know about mRNA-1195. We are now continuing with a second part to the Phase I. Now we are testing it both in seropositives with additional dose levels and also in seronegatives, trying to plan for the future for indication expansion as we go forward. And we also have mRNA-1195 now actively dosing in our proof-of-concept multiple sclerosis study, P201. This is a randomized, observer-blind, placebo-controlled study, where we are again looking at the potential impact that mRNA-1195 might have in people that are living with MS -- and we are looking at various time points.

In addition to safety and reactogenicity, we are also looking at the impact of mRNA-1195 on MRI markers of MS disease activity and other clinical markers as well and also looking at the humoral and cell-mediated immunogenicity in this population. I'm very happy to share an update on this study, which is that we fully enrolled our sentinel cohort of 12 patients. And the DSMB has reviewed the safety data and has given the recommendation to proceed with the dose escalation phase in this study.

So in conclusion, we have learned through our Phase I data so far that mRNA-1195 is generally well tolerated and we are continuing with our Phase I and Phase II studies. In the immunogenicity realm, we see that mRNA-1195 is able to strongly boost both B-cell and epithelial cell neutralizing antibodies, binding antibodies, CD8 positive and CD4 positive T cells. We find this very encouraging and the immune responses are sustained for well over 6 months after the last dose.

And we also, again, were able to demonstrate that mRNA-1195 is able to reduce measurable viral shedding in saliva, similar to our mRNA-1189 composition. We are continuing with our Phase I data. We expect data -- sorry, we are continuing with our Phase I trial. We expect data coming up soon, and we'll also have data from our proof-of-concept MS study in the future.

With that, I'll hand back to Lin to talk through our in vivo CAR-T program.

Thanks so much, Sumana. So I have the pleasure of walking us through an emerging modality we are advancing as part of Horizon 3, which is in vivo CAR-T more broadly in vivo T cell therapy. And so in contrast to the modalities that you've heard about today with our therapeutic vaccines, again, intravascular administration, we encode in antigen-presenting cells, and we train the immune system to go and hunt and find their target.

In contrast to T-cell engagers, where we encode multiple T-cell engagers to physically direct T cells to their tumor targets and also provide co-stimulatory signals. Here, we are directly engineering T cells in a person's body in vivo. And so the technology here, our messenger RNA encapsulated in targeted LNPs targeted to direct preferential uptake into those T cells. And the sentinel application here is focused on deep B-cell immunity reset for autoimmune diseases.

And so you probably know that many autoimmune diseases have B cells playing a central and pathophysiologic role with respect to pathogenesis. And the unmet medical need remains high. And so you often have patients cycling through various standard of care, broad immunosuppressants, sometimes targeted biologics, specifically anti-CD20 monoclonal antibodies as an example. Those targeted biologics, as you probably know, do not deplete B cells in tissues as well as they do certainly in the blood.

And the emerging ex vivo CAR-T, autologous CAR-T experience for various late autoimmune conditions has been incredibly exciting, showing that those patients can achieve durable remission and deep B-cell depletion along with an immune reset. And so the ex vivo autologous CAR-T field for autoimmune is emerging with over 400 patients dosed to date and about 270 total years of clinical experience. What we're really excited about for ex vivo CAR-T as well is by going after deep B-cell depletion in blood and tissues to achieve that immune reset, what we deem are encouraging signals across a variety of autoimmune conditions.

So you can see here for lupus, for myasthenia gravis, for scleroderma, myositis and so on and really encouraging rates of durable remission. Now the durability in particular, remains to be seen. The data is still emerging. But so far, it appears that the results are quite durable, about half year to a year plus. And importantly, the dose, as you probably know, is lower than what is typically required for oncology ex vivo CAR-T. The persistence of those T cells, in particular, seem drastically shorter for autoimmune patients than what's observed for oncology.

And so in autoimmune patients, they typically persist for several weeks versus in oncology, you will typically see them last for months up to several years and correlated with clinical outcomes. Now what's been incredibly exciting as well as the tolerability with low-grade CRS and neurotoxicity observed across patients and really manageable tolerability, particularly with respect to infection risk, which is an on-target pharmacology consequence.

Now for ex vivo CAR-T, as you know, that whole process is complicated and costly. And so the manufacturing is incredibly complex. You have to take blood out of a person's body, engineer them ex vivo with a virus. And then to get them back in, you have to make space with harsh preconditioning. There are only specialized academic centers that can really realize this entire process for patients and the entire process is not scalable and quite costly.

Compare and contrast that to in vivo, which is an off-the-shelf approach to engineer T cells directly in a person's body. You do not need to lymphodeplete. You do not need to do the harsh preconditioning regimen. The field has been showing that quite definitively, which is really exciting. And because it is off-the-shelf, you're doing this in a person's body, it is scalable. And additionally, it is transient, which confers tolerability aspects, attributes for this drug product.

And so in vivo CAR-T, in contrast to ex vivo CAR-T, where you have a single dose administration and those T cells kind of persist for several weeks. We think with in vivo CAR-T with transient expression of those CARs in T cells, we can give a limited number of repeat dose administrations. And with a concomitant deep B-cell depletion in blood and tissues, we should see a concomitant decrease in disease activity, hopefully resulting in durable remission.

Now when those B cells reconstitute or rebound, as you know, the immune system has been reset, and so they will reconstitute with a naive phenotype. And so this modality exemplifies another area in which we take mRED principles to build not only the sentinel application, which has huge value for patients across many different autoimmune conditions, as I just showed you, but also take the same technology and apply it in other aspects that we can go into such as oncology and T cell reprogramming.

So we are advancing our lead nominated candidate, mRNA-6007 that we affectionately call 007. And we selected this based on comprehensive screening of various targeted LNPs, optimization, and preclinical evaluation. It's built on the foundation of our platform, which we have extensive experience, both from a clinical perspective and manufacturing. And the LNP, the base particle that we use for the targeted LNP is actually the same LNP that we use for T-cell engagers for our rare disease programs as well.

Now we actually had screened multiple base particles to evaluate them actually in monkeys before selecting this base particle. But just to reiterate, this is an LNP where we have 80-plus patient years of repeat dose clinical experience in patients. We understand the safety profile. We understand the repeat disability. And importantly, we know how to manufacture and scale this particle. Now the LNP has to be decorated with a targeting moiety to really facilitate and preferentially drive its uptake into T cells.

And here, the targeting moiety is a single domain antibody binder that was internally discovered and humanized, and it is decorated on the surface of the particle using a validated linker chemistry. The payload itself, we lean here again into our platform differentiation to multiplex. So we have a dual CAR approach, but we use clinically validated CAR architecture. And here again, we can encapsulate multiple mRNAs without having to show contribution of components.

Now 007 is our sentinel application, as I said, I'll walk you through some of our really encouraging preclinical data, and we are advancing this rapidly into the clinic, where we will evaluate a basket of B-cell-mediated autoimmune conditions, including lupus, but other autoimmune conditions as well. But beyond that, we're taking the same targeted LNP because it gets into T cells, and we want to explore applications for oncology as well, using both mRNA transient payload, but also working on gene insertion so that we can have integrating technology as well.

Beyond that, the team is kicking around clever ideas with respect to T cell reprogramming and what we can do broader with this targeted lipid nanoparticle. Now our points on differentiation for in vivo CAR-T are twofold. Number one is on the platform in manufacturing; and number two is on the product. On the product -- on the platform in manufacturing, the platform is built on validated technology. So we have extensive experience, of course, with the messenger RNA.

I will note that the messenger RNA includes a chemical modification on the 3 prime ends of the molecule to extend the half-life of messenger RNA. So we have greater exposure, greater half-life of the encoded CAR. The base particles, as I already mentioned, has tons of clinical repeat dose experience, and we have extensive manufacturing experience of that base particle. We have a proven global health authority regulatory strategy where we know how to take platform nonclinical studies and apply them across the board for our portfolio, including this program.

And as I already highlighted, we have extensive know-how and knowledge on manufacturing. And this includes both scale-up processes, phase appropriate control strategies and an infrastructure that enables end-to-end manufacturing with the long game with getting this to patients in mind. Okay. So that was point number one on differentiation with respect to platform and manufacturing. Point number two on differentiation of the product. And so 007 actually targets CD7 on T cells.

Now the rest of the field really primarily focuses on getting into CD8 T cells. We think we're differentiated because CD7 gets you into CD8s. They get you into CD4 T cells, which we know are important for oncology, and they also get you into NK cells, which have cytolytic potential. And so we think because CD8s are not necessarily a sync for us, we can get into CD8. I'm going to show you that data momentarily, but we also get into other immune effectors. We think that is advantageous for this product.

The other differentiation on the product, again, comes back to multiplexing, where we are not encoding a single CAR, we are encoding 2 CARs. And so it's a dual-CAR approach. And by targeting 2 different antigens, we can cover not only the entire B-cell lineage, but also plasma cells, which are implicated in many autoimmune conditions. Specifically, they are responsible for the generation of pathogenic autoantibodies for many of these diseases.

And so -- but we think by targeting a broader immune effector cell population, in addition to the dual-CAR strategy, we should achieve greater biological performance, greater reset and hopefully, durable remission in patients. Okay. I'm going to walk you through some of our preclinical data, starting with humanized mice. And so this is a CD19 CAR messenger RNA encapsulated in that targeted LNP. Here, we are doing IV administration once every few days, 3 times.

And I'm showing you data in spleen after the second dose, but the data are very similar after the third dose. And what you'll see on the left-hand side is we see really nice dose-dependent expression of the CAR in both CD8 T cells, but also CD4 T cells. And we know those CAR-Ts are functional because if you look at the B cells on the right-hand side, they're completely gone. And they're completely gone at all dose levels evaluated.

Now importantly, we have taken the product into monkey studies, several monkey studies, where for us, again, monkeys are a highly translationally relevant species. Again, that's based on our experience in advancing different medicines from monkeys to patients. But also the field has shown translatability as well using monkeys. Here, we do use a surrogate CAR CD20 and not simply because the binder is cross-reactive with monkeys. And we have demonstrated reproducibility and consistency across lots in these monkey studies.

And so what I'm showing you here is first, the safety and tolerability of the CD20 CAR messenger RNA packaged in the targeted LNP. These monkeys received 3 IV dose administrations every 3 days and importantly, received no pre-treatment. So no dexamethasone, no diphenhydramine. We wanted to understand the safety and tolerability profile of the targeted LNP by itself. And the dose levels we evaluated were 0.5 and 1 milligram per kilogram. And so with respect to safety and tolerability, we've been really encouraged.

As you can see here by the liver enzymes, the gray shows you what's normal for monkeys. So we are well within normal. By the way, we have 2 controls, a vehicle and another messenger RNA control, which is simply a reporter messenger RNA control. Beyond that, the clinical pathology also looks very clean, uneventful, clinical observations great. Again, these monkeys were not pretreated. So again, happy with the safety and tolerability profile.

Let's come to delivery. So we focus on our reporter messenger RNA here, which is Green Lantern -- it's essentially GFP. And I'm showing you data from Green Lantern versus the CAR because Green Lantern is a more stable protein, and with CAR, you have trafficking and kind of the kinetics of CAR pharmacology. And what I hope you can appreciate from all these immune effector populations is we get great delivery. This is 2 days after the last dose administration in blood and various lymphoid tissues. You can see in blood, we are in the approximate 80% plus range in CD7-positive immune cells.

And in the various lymphoid tissues, we see really great uptake in various immune effectors in these lymphoid tissues as well. Now when we look at pharmacology, so first, I'm going to show you blood, but then I'll show you B-cell depletion in lymphoid tissues. When we look at blood, I hope you can appreciate, so the vertical gray lines show you the dose administrations. We see rapid depletion of B cells in blood in comparison to the control groups that you can see in gray and green.

And we wanted to show you exemplary flow cytometry plots here just to show you how comprehensive the gating is for capturing the B cells. And I hope you can appreciate the CAR-treated animals, again, in the pink and red, B cells are completely gone, not detectable in the FACS plots, and when we look at counts completely gone and remain gone after each dose administration. Now as we talked about, okay, blood is great, but it's all about lymphoid tissues. So 2 days after the last dose administration, we look at lymphoid tissues.

So starting with spleen, I'm going to show you immunohistochemistry against CD20 in these various tissues. And you can see in the control arms, you see really nice staining of CD20. You see nice follicles, you see really pronounced staining. And in all of the treated animals at both dose levels of 0.5 and 1 milligram per kilogram, in spleen, we see complete B-cell depletion. So not detectable at all, no brown spots whatsoever. In lymph nodes and here, we looked at a variety of lymph nodes. In the control again, really nice staining of CD20.

And in the treated animals, we see substantial B-cell depletion across the various animals across the various lymph nodes. In bone marrow, similarly, we see CD20 staining and upon treatment, complete B-cell depletion in bone marrow. And so with that, we've demonstrated proof of concept, pronounced B-cell depletion in blood, lymphoid tissues, excellent delivery and uptake into NK cells and T cells, and acceptable safety and tolerability to advance this asset forward.

Now I'm also going to show you some cytokine data as well. So we evaluated really the full cytokine and chemokine panel. And what you can see here is the usual suspects for CAR-mediated cytokine induction do spike up transiently after the first dose that is on-target pharmacology that attenuates upon subsequent doses. And just to remind you, these monkeys are not pretreated. And so interferon-gamma, IL-6, TNF-alpha definitely spike as a result of on-target pharmacology.

Again, we looked at the full panel of cytokines and chemokines, saw nothing concerning, very consistent with our platform, data and knowledge of repeat dosing LNPs.

And so again, we get really excited when we see data like this in monkeys because of our experience in translating these products from monkeys to patients. And we're also really excited here because that binder that I told you about that decorates the base particle, our anti-CD7 single-domain VHH binder is actually a very weak binder for monkeys.

And so actually, by monovalent format, it is not detectable for binding to monkey CD7. We can only detect it weak binding when it's in a multivalent format. It has been optimized and was selected for human performance. And so it is a very tight binder to human CD7. It binds at sub-nanomolar binding affinity. And when we look at T cell uptake in vitro, so in PBMCs from human versus [indiscernible] , we see an 18-fold increase in the potency and the uptake into T cells in humans versus humans.

Moreover, when we look at the expression pattern of CD7 on sino immune cells versus human immune cells, we see far greater expression of CD7 on normal healthy donors in addition to PBMCs from autoimmune patients as well.

And finally, as you probably know, monkeys tend to be more CD8 skewed than patients. And so with our targeting approach getting into CD8, CD4s and NK cells, we are excited about the potential of the pharmacology we may observe in human patients that have been likely underestimated from our monkey studies.

And so with that, we are completing our IND-enabling studies. We are conducting a series of pre-submission health authority engagements, and we plan to advance this program into the clinic in 2027. And we're super excited about this modality. So with that, I'm going to pass it over to David Huss, Chief Technology Officer of Research, who's going to walk through platform innovation.

Thank you very much, Lin. As Lin mentioned, my name is David Huss. I am responsible for our platform science organization. So I hope that you can appreciate through all of the talks we heard this morning on our therapeutic programs that there's really a common thread that goes through all of them.

And that is that they are each built on a unique combination of Moderna's platform technologies. Now one of the reasons that I'm standing in front of you today is because I firmly believe that our best technological innovations are still ahead of us. And so one of the things that we think about is how can we really innovate the technologies of the future to build the medicines of the future.

And today, I'm actually really excited to be able to give you the first glimpse into Moderna's scientific intelligence engine and where we are taking the future of our platform technologies. So I think it's safe to say that we are truly entering a completely new era of scientific exploration. If you think back to the days of scientists in the lab doing an experiment, looking at the data, reformulating their hypothesis, going back and performing another experiment, this serial way of experimentation, while incredibly important can be very slow at generating data that can be scaled.

And so we're now in an era where the advance of new AI technologies and automation are really eliminating this slow traditional limit on hypothesis generation and experimentation. And so we truly believe that now scientific advantage really belongs to those that can learn the fastest. And so how do we set ourselves up to be that company that can learn the fastest. This really requires fundamentally changing the way that we do experimentation and also the data infrastructure that is required to take the data in and make it usable for all of our modern AI tools.

And so what I'm going to share with you is how we really think about this concept of learning at scale and positioning ourselves to be able to do that better than anyone. And so today, I'm really excited to introduce Lucy. So Lucy is at the heart of Moderna's scientific intelligence engine. Lucy connects everything that we've built in AI, automation, experimentation and data into a continuously improving learning system.

So if we think now that experimentation is no longer done one experiment at a time, we really are conducting iterative learning cycles. And these learning cycles allow us to find that next discovery in a faster, smarter and more predictable way. Now importantly, if we think about all of the data that exists in people's lab notebooks, it's very disconnected. And so the way that we use Lucy is to be able to pull that all into connected data sets and so over time, with every learning cycle, Lucy becomes a strategic advantage that compounds across all of Moderna.

Now one of the really important elements is how do we teach Lucy. So a number of years ago, we made a really important investment into a digital-first automation platform that is able to teach Lucy. And so if you think about being able to do experimentation in a closed-loop cycle where we can go from mRNA synthesis, LNP formulation, we can look at the biophysical properties of that LNP.

We can then take that LNP and put it into a cell-based assay so that we can learn about its biological performance. And then imagine being able to take all of the data that's generated at every step along the way and without needing human intervention, we can go back to the next round of experimentation based on what Lucy has learned from that first round of experimentation. And this isn't done with one mRNA or one LNP at a time.

This is done in a scalable format so that we can be testing hundreds to thousands of iterations with every single iterative learning cycle. And so this takes that concept of a single scientist in the lab doing an experiment and really just expands it to a level that we've never before seen possible.

And what we're looking at in the video here is an example of our automation platform that is running right now up in our labs where we're able to really generate data at scale, importantly, that is connected from the initial mRNA design all the way through how that LNP mRNA performs in a biological system. So this combination of the automation that we looked at and Lucy really creates this ultimate scientific flywheel.

And the way we think about this is we're transforming the data that we generate truly into intelligence. And so I talked a little bit about this concept, but it's really allowing us to go from an AI-driven hypothesis generation. We can go through mRNA production, formulation of that mRNA into our lipid nanoparticles.

We learn from about the biophysical properties of those LNPs, going through a series of in vitro based assays and that is what we do within a closed-loop platform. And you can envision that why this matters is because if I want to test 1,000 different LNP formulations or one LNP formulation and 1,000 different mRNA designs or I can do a combinatorial approach.

And so you just start to generate data at a scale that we've never been able to do before. And now that we have the AI tools available to make sense of that, it really is able to generate new hypotheses to learn in a faster way and to make better decisions about the candidates that we move forward. Now importantly, we don't stop just at primary human cell data. We've built platforms that allow us to do in vivo multiplex screening in mice and in nonhuman primates.

And what I mean by that is instead of taking one candidate into one animal, we are able to use current barcoding systems so we can take 100 or 1,000 different candidates into a single animal and then deconvolute on the back end to understand the performance of each individual candidate.

Now of course, we view human clinical data as our ultimate ground truth. And it's probably fair to say that Moderna has more human clinical data than anybody else on the planet. And so important in our scientific flywheel is the incorporation of the volumes of human clinical data that we already have and all of the data that's emerging from our ongoing clinical trials.

So when we think about the totality here, I always think about Lucy as kind of the heart of the scientific intelligence engine. But it's not just the data that we're generating today or our internal data that we've generated over the last 15 years. We also have an ability now to look at the public domain. And with our collaboration with OpenAI, with other large language models, with emerging AI tools that are coming today, we are able to pull in publicly available data sets.

And so that allows us to kind of supercharge our existing proprietary internal data that we have and that we are generating to ultimately allow us to make better, faster decisions, not just about the therapeutic candidates that we move forward, but the diseases that are applicable if we think about the biology and pulling that in. And it allows us to continually do this cycle where we learn, make better decisions and are able to create better drugs. So with that, I'm going to turn it over to Stephane.

Thank you, David. Before I close, I would like just to thank my colleagues, not only those that presented today, but the literally hundreds and hundreds of colleagues that are working within the Emirates world trying to invent the future of medicine.

So just to close, I think you've got a good sense today of how we are trying to make sure that we both deliver for the short term through Horizon 1 initiatives, but also how we prepare the future and how we have a dedicated team within the [indiscernible] community within Moderna, working on Horizon 2 and Horizon 3.

And you just saw for David, we think we're just getting started, and we're very excited about what we can do in the future by investing in science to invent even newer modalities. As we shared at Analyst Day in November of '25, for the next few years, the plan is very clear. We're going to grow through diversification of geography, as you already saw in Q1 and through diversification of products. We are very excited with the launch across the world of mNEXSPIKE happening this year.

It was a start last year, as you know. We're very encouraged by the [indiscernible] meeting both last week, give us good hope about the approval of flu moving forward. And of course, the other products that are on the slide that we talked about.

If you look at this year, it's going to be a very exciting year because not only we're getting back into sales growth, we continue to make progress on the cost structure of the company, a lot of products approval across geographies. We are very, very pleased and proud with mCOMBRIAX to get the first approval in the world of a flu and COVID combo.

And as you know, the COVID component is actually mNEXSPIKE with much higher performance than Spikevax as we totally reengineered the product. It's a totally different product.

And so with flu, you saw the data, it was published in New England Journal of Medicine recently, showing great performance, especially for people at high risk. And those 2 products are in single dose. It's already approved in Europe and many more countries are going to follow.

Of course, we have very important clinical data ahead of us with intismeran. We had very good reception at ASCO of the 5-year data, not only the data and how all the subgroups look really strong, but also the transactional medicine that we understand the mechanism of action. That is how we decide intismeran and it is doing as advertise in terms of T cells, both expansion and programming of de novo T cells.

You heard today from the team about 459. We are also expecting norovirus data, of course, depending on case accruals and PA because it's a time-based pivotal study should read out this year as well.

So it could be very, very exciting in 2026. But as you saw today through a few examples of a few modalities, we don't have time to show you everything. Just looking at the cancer antigen therapy, looking at the T cell engagers, looking at [ 007 ], just getting a sense of all the exciting new medicines that are either in the clinic for which we are waiting for human proof-of-concept data and the new medicines that are entering the clinic in the next 6, 12 to 18 months to basically expand and expand the possibility of what we do with mRNA.

And as you just saw with David, what is so exciting is we have been doing mRNA for 15 years, and we feel that we're just getting started. The ability that we have to just change totally the pace of our learning is so exciting. We've always said as a motor of a company that we don't have to be the smartest, but we have to learn the fastest. We used to do it one experiment at a time, one lipid at a time, one chemistry at a time.

But as David showed you, the team is really changing the scale of what we are doing. And what is really exciting for me is we're really best positioned, I believe, in the world to do that. If you look at the scale that we have in science, in process engineering, in early clinical, the capability we're putting together on mRNA, the AI, the automation, all those pieces coming together.

I don't believe there's a company in the world that has the scale that we have in mRNA. And that is exciting for what we can do for patients. So if you think about where we stand today, I truly believe that we have not invented our best molecule yet. I'm very proud of what the team has accomplished.

During the pandemic, obviously, the mNEXSPIKE, [indiscernible] , the flu product, cannot wait to see the NRO data. [ Intismeran ] is looking very exciting, what we can do in rare disease.

But what we're doing also now with mRNA-1195, EBV and MS, 007 with autoimmune disease. If you think about it, we're really expanding the domain of what we can do for patients in infectious disease, in oncology, in autoimmune disease and in rare disease, which is why I'm really excited about the future. I'm so thankful for our team and all of our partners around the world, including the clinical trial sites, the participants in the studies.

And I really look forward for the next few years, it's going to be really exciting. So with this, I would love to ask Rose and David to join me, and we'll be happy to take your questions. And Lavina, you'll be moderating online and in the room. Thank you.

Please introduce yourself before your question.

This is Ted Tenthoff from Piper Sandler. So firstly, just recent things. Congrats on the flu AdCom, excited for [ intismeran ] data, really cool new in vivo CAR-T program. I have 2 quick ones.

First one is kind of high level. So when it comes to really evaluating all these different new oncology products, how do you sort of prioritize and/or sequence, obviously, data-driven, but there's some overlap between [ intismeran ] and some of the shared or tumor-associated antigen products. So how are you going to really kind of select when one is appropriate or maybe better than another one?

Yes, happy to take that. So I think it's a scientific question and a strategic question. I think the [ intismeran ] represents probably the defining clinical trial on whether cancer vaccines can work or not. It's been tested in the ideal population in the adjuvant setting.

And so we are planning for that to be a success, obviously. And that's why we are moving forward the off-the-shelf cancer antigen therapies that you heard about before.

So those are moving in parallel behind intismeran, but intismeran will be the gatekeeper for those trials because the cancer antigen therapies, the cancer vaccines will probably require randomized trials, large investments and we don't want to do that until we know that intismeran is positive, which I expect it to be, but I think that's the defining moment.

I think just to your other question about how do we prioritize, part of what I've seen successful over my career is a rigorous application of does the science work? Does the drug do what pharmacodynamically intended to do? And then does it clinically have a strong enough impact to be developed? And I think both of those questions need to be answered separately for us to move something forward.

Andrew Tsai, Jefferies. Thank you for sharing your vision today. Bigger picture question as well is that as you're developing these Horizon 2, Horizon 3 products and should they succeed in the clinic and so forth, can you maybe remind us the latest and greatest about your cash breakeven guidance for 2028? Does that incorporate an increased R&D spending over the next couple of years? And then maybe a second follow-up question is there's a lot of things going on. Would it be possible to give us a brief summary of the time lines of the data readouts actually for your Horizon 2 and 3 products that you've guided to today?

Sure. Thanks for the question. So in terms of cash guidance, there is no change. Those budgets have been all along through our long-range planning and annual budgeting process. We have not just set them apart in terms of disclosure, but those investments are in the budget. What we'll have to do as we see in human proof of concept is to figure out what's the best strategy for the product. And we'll be looking at this on an asset-by-asset basis based on the asset performance, but also where the portfolio is, what makes sense for the company. Some assets we're going to develop ourselves, some assets might be better in the hands of partners. So we'll just do what is practical and for the portfolio of the company, both upside and risk.

And for your second question in terms of the horizon for data readout. So 4359 was data we just shared at ASCO and at AACR. So we're now in the confirmation stage of that signal. We have a larger expansion. And so that should be data, I imagine, next year to be shared. 2808, which is the myeloma program that you heard about, we hope to share initial data later this year on that. And then I think the other two -- the other programs, the cancer antigen therapy and the multiple sclerosis 1195, 1195 will probably have data not until '28 just because it's a randomized trial. The cancer antigen therapy could be data next year.

Mark Allen of Goldman Sachs. A couple of mechanistic questions for the in vivo CAR-T. I was just wondering, because you're targeting T and NK cells and you're combining, I guess, both B cell and plasma cell targeting, is there any risk for a greater toxicity profile? Maybe these patients be at greater risk for infection? And also, would you -- do you plan to reimmunize patients afterwards?

I can take that one. Sure. So I think a lot of these things have to be done empirically. Obviously, we're pretty comfortable with the results that we have in NHP, but you have to use surrogate programs for some of those studies. And so we're also building off our understanding of those potential targets from oncology where they've been used extensively. So we're pretty comfortable proceeding with the plan that we have today. If the depth of depletion is such that patients do need to be revaccinated for your like standard vaccination routines, that's certainly an option, and we would look to provide that for them certainly.

I think -- I'd just add, I think part of the advantages of our RNA platform is we can hit the B cells extremely hard with CD19 and BCMA, but do it in a pulsatile short-term fashion without the need for gene integration and potential risk down the line there.

This is Greg representing Tyler Van Buren from TD Cowen. So on 4106 and 4200, how should we think about the undisclosed antigen targets? Are these well characterized from existing literature? Or does their novelty represent a key differentiator? And following on that, in the absence of robust in vivo data, what underpins your confidence that these will translate into meaningful efficacy, particularly in advanced solid tumors where the biology is more challenging than the adjuvant setting?

Yes. I'm happy to take both of those. So these are antigens that are known. So that's, I think, question number one. Question number two is a great question. I mean it's probably one of the -- it's the biggest cancer vaccine scientific question, which is cancer vaccines actually work. It's been decades, as you know, where they haven't worked. And we think mostly that's because they've been tried in late-stage patients. And I think also the vaccine technology was not the ideal one.

I think the RNP -- the RNA LNP is probably the best vaccine technology. So we don't know whether it will work. We will need to do randomized trials, but we are set up. I mean this is the company that's set up to answer that question. So if intismeran is positive, if neoantigen cancer vaccines do work, we are poised to have an off-the-shelf version. And it could be complementary. It could be in adjuvant setting, and it could also be in -- we'll try it in the metastatic setting. I think that's a question which we don't yet know.

And I might just add on the validation of antigens. This has actually been an important part of our collaboration with Immatics, where, as you mentioned, in vivo models are not particularly relevant for many cancer vaccines, but we can actually access patient samples and look at what antigens were both present in those tumor types and presented on those cancer cells.

This is Matt for Mike Yee from UBS. Maybe on the ovarian cancer program, could you talk a little bit about the target you chose, how it maybe fits into the standard of care already in ovarian cancer into the competitive landscape, the TCE modality, especially? And would this be a novel target relative to the other ADCs out there? I'm just going to speak to how you see this fitting in the landscape here.

I'll handle the landscape and you can address the target. So obviously, ovarian cancer is becoming incredibly complex and crowded and it's generally divided into the platinum-resistant setting where response rate is very important and where, of course, the ADC landscape -- the ADCs are really radically transforming the landscape. The other setting is the platinum-sensitive setting.

And here, probably the maintenance setting is the right place. And this is where probably you don't want -- this is after patients have a response to platinum-based therapy. They're in the intervening period. They probably don't want to have chronic toxicity with chemotherapies or ADCs. And this is the ideal setting for where a T cell engager can work. It's also an earlier setting where the T cell fitness is better.

So the general approach would need to be study this initially in platinum-resistant setting because those -- that's where the biggest unmet need is, and we can demonstrate, hopefully, as a monotherapy signal and then decide whether it can be developed as a monotherapy approach and then study it in a platinum-sensitive maintenance, which would be a longer trial and which you would do once you validate it in the PROC setting.

I would just add that mRNA-2151, much like 2808 is actually multiplex. So it's pursuing multiple targets for Signal 1 and also includes a targeting moiety for Signal 2 co-stimulation. So that is part of our strategy for, yes, using clinically validated targets, but being able to add on to anyone who might have been exposed to a treatment targeted at one of those same proteins.

This is [ Tejas ] from Ellie Merle's team at Barclays. Maybe I'll ask on your program in multiple myeloma. Can you expand on your target product profile in terms of safety and ease of administration as T cell engagers start to move out of the academic and community settings?

Yes. So the current formulation is administered intravenously, but we have the ability and plans to also test it subcutaneously. In terms of the safety profile, it's actually potentially better. And for the reasons that you heard, that when you administer a biologic T cell engager immediately, there's very rapid high Cmax that occurs very rapidly, and that results in very -- in high cytokine release syndrome. When you use an RNA approach, the RNA has to be first translated into protein and then secreted. And so you get a gentle ramp-up in the T cell engager release.

And what we know from the field is that there is a tachyphylaxis that occurs with repeated dosing or repeated exposure. And so we hypothesized actually that the safety might be better because you get a delayed and a blunted Cmax. Of course, that needs to be validated. I believe, especially in myeloma, that T cell engagers are going to be able to be moved into the community setting. And I think our three targets we have will be acceptable for a community setting. So right now, we're focused on demonstrating, of course, activity in heavily pretreated patients, and we'll be sharing that with safety later this year.

Alexandria Hammond from Bank of America. Thanks for hosting us here in your headquarters. A couple of pricing questions. ICER is holding a meeting today to talk about cost effectiveness of COVID-19 vaccines. I guess, do you anticipate any price changes for your COVID products this fall? When might we hear about the price that gets set? And how do you expect price will feed into coverage and availability this season? I guess a related follow-up, when you think about pricing for the flu/COVID combo opportunity, how do you expect this could shake out maybe using your early discussions in the EU as an indicator?

Yes. So we're having discussions with payers like we always do. We are following what's going on, but we are not commenting on pricing at this stage.

Myles Minter from William Blair. Two for me, one on the science. Just for 1195, the EBV vaccine, great healthy volunteer seropositive data that you showed there. My question is, as you move into an MS patient population that's going to be treated, I would think with CD20 therapy prior. How does the latent portion of that vaccine work in patients that theoretically have B-cell depletion? That's the first one.

Second one, just to confirm on capital allocation, is the potential trial that you have to run if you do get approval for your flu vaccine, that, I think, was 800,000 patients over two seasons, is that in the budget? And if you do have to run that trial, that won't impact anything that we're seeing from Horizon 2 and 3 today?

I'm happy to take the 1185 (sic) [ 1195 ]. So the initial proof-of-concept trial that you heard about today is going to be run in recently diagnosed patients who are not on any biologics. So that's the proof-of-concept trial. After that, we'll determine based on the strength of the data, do we need to add on to an anti-CD20 or can we try and replace it, of course. And then finally, anti-CD20s, of course, work well, but they don't completely reset the B-cell immunity because they probably don't eliminate all those residual B cells. And so I think that's where our approach can help.

And on your second question, yes, the discussion that we had with the FDA that was discussed are in the budget.

This is Shelby here for Luca Issi from RBC. Maybe on the 1L metastatic melanoma data that you shared earlier, do you think that 33% Grade 3/4 AEs are attributed to just pembro? Or do you see some kind of additive toxicity since that rate does seem higher than pembro alone? And then maybe on Lynch syndrome, how should we think about the TAM? I think you said 1 million patients in the U.S., but I guess, what proportion of those patients do you plan on targeting initially? And then do you expect that number to kind of increase going forward?

It's a really great observation. It's something that's occurred to us as well. And when we -- it's a small number to begin with. But when we spoke with investigators on the trial, they said potentially, it might be slightly higher than what we would expect, that they are traditional immune-mediated adverse events. Some pointed out that this is using the 600 milligram, so -- which they sometimes feel does have a slightly higher toxicity profile than the every 3-week version. But on the other hand, I wouldn't be surprised or necessarily upset if there is a higher rate of severe immune-mediated because it means that we are activating T cells.

Yes. And on the Lynch syndrome, I mean, as we said, it's around 1 in 300 people. As you know, genetic tests are available for blood work today. A lot of people are not aware of Lynch syndrome. There are some geographies where there's a bit more awareness and a bit more advocacy. So definitely, this is not the right time to do anything about it for us. But as we get more data, if we think we have a product and we have in situ approval, you will see us engaging with payers, with patient associations, with governments and so on because that will be a beautiful thing to do in terms of preventing cancer and also, of course, reducing health care costs. So we will do all that if we have a product.

This is [ Adam ] on for Jess, JPMorgan. I apologize if I missed this. But for the in vivo CAR-T, how did you decide to pursue autoimmune? And should we expect Moderna to advance in vivo CAR-T for oncology?

Okay. So the ex vivo CAR-T results that have emerged over the last few years in the autoimmune space have been really eye-opening and started to tease out some of the important biology that some of these very rare B-cell populations are bringing to autoimmune diseases, including autoimmune diseases that we would have previously characterized as more T cell driven. These are showing responses to those ex vivo cell therapies.

Now, we think as you're going forward and thinking about patients and accessibility of that therapy, that in vivo CAR-T is the way to go. So from that perspective, with the ability with a few doses to truly put an autoimmune patient into remission, we think the platform is actually the ideal approach there. We are pretty excited about continuing down the road into oncology, either thinking about CAR-T or TCR-T, which is similar to CAR-T, but lets you also pursue intracellular antigens.

Yes. And I just add one other reason I think, is important in that if you think about autoimmune diseases, the confirmatory trials and Phase III trials are, of course, going to be very large. The commercial opportunity is very large. And there's no other company in the world who can really manufacture on that scale than Moderna for mRNA-LNP. So it makes sense scientifically and it makes sense also commercially for us.

Chris Yu from Morgan Stanley on behalf of Terence Flynn. We have two questions. One is, do you have any update on the pace of event accrual for the Phase III INT adjuvant melanoma study? And the second question is, the treatment landscape for multiple myeloma is rapidly shifting due to bispecifics and CAR-Ts, and you have presented multiple programs here on multiple myeloma. Just how do you think about your approaches and how that fit into the treatment landscape?

Yes. So for intismeran, we have not disclosed events, and so we're not going to start today, but we are confirming again that 2026 is the right time frame.

Yes. In terms of multiple myeloma, it's great for patients. I started working in myeloma 15 years ago, before all of the recent changes were available. It really is phenomenal. From a drug developer standpoint, it makes it extremely hard, as you point out, because the bar keeps on getting raised. For us, it made sense for this to be our initial pilot of a modality because it is derisked biologically, and we can do it. And so the question is, can we generate sufficient response rates and a differentiated product, right? This is the first time ever three T cell engager targets have ever been administered to a patient. So we'll generate the data to see if this platform works.

And number two, is it clinically differentiated enough to develop into earlier lines? I think for us, it provides also important positive control for our modality system. You heard about the ovarian cancer T cell engagers that we're going to be moving into clinic. But behind there as well, this is a company, I think, that could be on the forefront of not only multiplexing different targets for T cell engagers, but also figuring out how to manipulate the tumor microenvironment because, as you know, T cell engagers have had a difficult time or more difficult time in solid tumors and hematologic cancers. And I think the science is beginning to catch up to where we have the technical ability to multiplex. And so that's sort of the background here.

Lili Nsongo from Leerink Partners. Thanks for the great overview of the pipeline. I just wanted to backtrack a little bit. So we talked about how Horizon 2 and 3 fit into the R&D guidance. And then on the other side of that, could you maybe give us a little more color in terms of the commercial performance assumptions that kind of support the development of the second and third wave of assets?

So obviously, a lot of the Horizon 2 assets are currently in early clinical stage and then a couple of INDs are expected in 2027. So how should we think about the revenue mix that supports it in terms of the contribution from the COVID vaccine, the flu vaccine, the combo, as well as the rare disease and the oncology pipeline?

Sure. So what we're doing at this stage is developing those assets to get to human proof of concept to validate both the assets and the modality, because that's really how we've scaled the company historically. And then we will look at where the company is at that stage in terms of what do we do for the assets moving forward of the modality in terms of does it become something that we commercialize ourselves worldwide, in the U.S., and we have a partner? Does it go through a partner for global rights? So we just look at the portfolio. So what we've always done with the company is to look at how do we maximize the value of a portfolio of products and manage risk at the same time.

So it will depend on when some of those products get launched, what is their ramp. So we don't have to make those decisions now. The Horizon 2, Horizon 3 right now generate the human data to know do we have a new modality or not? If we have a new modality, then we'll assess at that time the entire portfolio. And it doesn't necessarily have to be Moderna alone. Look at intismeran, it was a great example. Years ago, when intismeran was a great scientific idea, it was clear to us at the time that doing it alone was going to be very expensive and much harder than partnering with best-in-class company in oncology, which is why we partnered with Merck.

We're very happy about that partnership. I think being with Merck, we're able to execute things we could not have done alone. So you always see us being very pragmatic. But where is the company at the time we have to make a decision? We will always look at how to maximize the value of the asset. And sometimes it might not be in our hands, sometimes it will be in our hands.

Great. I'll take some questions from the webcast. The first question is you've previously spoken about the intention to out-license or find a partner for EBV. Is this, first, still in play? And what demonstration of data do you think a partnership becomes more relevant for that asset?

I'm happy to take it. So 1195, as David said and the team presented, we are running the clinical studies to figure out the signal we have. And again, as I just answered right now, when we have the data, we look at the totality of the Moderna portfolio, the investment opportunities, the portfolio upside, the risk, and then we'll make a decision at that time.

Great. Similar question on the CAR-T assets in oncology potentially also likely to be partnered? Or what is the strategy with Horizon 2 and Horizon 3 assets?

So those assets, initially, is really to get a confirmation in the clinic, do we have a modality or not? And you're going to see us being very consistent like we've done historically with infectious disease vaccine and we're doing [indiscernible] and then we're doing with rare disease. You're going to see us doing the same thing, which is we think we have a very interesting way to address medical need using mRNA as a platform. Let's take it to the clinic. Let's look out through one or two or three programs, do we have a modality or not? And at that time, it will graduate out of MRD, and we have to figure out, as I just described, what's the best home for that modality, either internally or externally.

Okay. With that, it looks like we have exhausted questions. Thank you very much to everyone who came in person and to all our presenters.

Thank you. Have a great day.

Thank you.

Good afternoon, everyone. Thank you so much for joining us. It's my pleasure to introduce Moderna. And with us, we have Jamey Mock, CFO. Jamey, thanks for joining us.

Thanks for having me.

So to start here, maybe frame for us how you see the company positioned today. There's been an evolution, I think, with regard to the growth outlook for the commercial business with COVID and combination flu plus COVID vaccines, where you've gone to the point, I think, here of kind of returning to this positive revenue growth cycle and you have an opportunity set with your late-stage pipeline. So what are you most focused on when you look at this from a strategy and execution standpoint as we head into second half and beyond?

Yes. Great. Well, again, thanks for having me. Good to see you, Salveen. So yes, we're super excited. The last 3 years have been hard, but we've been hard at work, really trying to build the next chapter of Moderna. And so that chapter, I think, is defined by growth, diversification and really an improving financial profile as well. And so from the growth and diversity perspective, if you look at -- we're going to have market expansion across the globe with our commercial products, as you just mentioned. We will grow from a product diversity perspective, and I'll kind of walk through some of these. So I think we're really set up, and I -- we think we started that at the beginning of this year. And I'm sure we'll get into some of the financials and that kind of thing. But we laid out 10 growth drivers a handful of months ago, and over the course of 2026 through 2028, we think could be pretty substantial.

And so in 2026, we think that mNEXSPIKE, which is more -- have better relative vaccine efficacy versus Spikevax had tremendous share last year for its first year, was approved in June, had 24% share in retail. So we were excited by that, and we hope to grow on that. And then our international partnerships in the U.K., Canada, Australia, in 2027, and we can talk about it more. Europe opens up for us. We have a flu PDUFA date this year that we hope to sell in 2027. We've announced some other market expansion opportunities, particularly in Latin America, but we're working across the globe as well.

And then 2028, additional product expansion, hopefully, with norovirus, which I'm sure we'll get into, as well as the combination vaccine in the U.S. And that's just infectious disease. Then we have INT, which I'm sure we'll talk about, 4359 as well as rare disease. So we're really set up for growth.

I think underpinning that really, though, is really financial -- is disciplined execution. And that's commercial, that's R&D, that's CMC. And I think that's really starting to show up in the financial profile, and I'll just mention a couple of things. So first, over the last 2 years, we took out nearly $5 billion in cost and investment. So in 2023, we were at $8.9 billion. Last year, we were $4.3 billion, so over 50%. And we've been trying to really make sure we navigate this so that we can grow in this next chapter that we still are investing. So that's the tricky balance. Of course, you can find efficiencies, but we also wanted to make sure we were making the right investments for this next chapter, which is here, which is what we're so excited about.

And we ended the year with $9 billion in cash and liquidity, which was ahead of our profile. So I think the execution has been terrific. We've set up this next chapter. We're in the midst of it right now. So -- and I think big picture strategy, what we're trying to do is build an infectious disease business that is leading in its space with various vaccines that is a cash cow, generates a lot of cash and has a lot of growth over the next few years and then invest that into oncology. And so we hope to diversify and have additional therapeutic areas in the next couple of years and really a vastly improving financial profile. So that is what we are focused on. That's what we've been focused on for the last [ 3 ] years, and we're in the midst of it.

Great. On the 1Q earnings report, you reiterated expectations for up to 10% year-over-year revenue growth on the -- with guidance accounting for potential decline in U.S. COVID vaccinations. Now that the winter respiratory virus season has ended, do you have any more granularity on expectations around next season? And what are the puts and takes on the revenue guidance and where there could be upside?

Yes. So I think it's important to start with 2025. And in 2025, we had $1.2 billion of revenue in the U.S. and $700 million of revenue in OUS. And we said we were going to grow -- we will grow up to 10%. We hope to beat that, but that's what our guidance is, so that's $2 billion to $2.1 billion. And we said that we are going to be 50-50 geographically split U.S. versus OUS. So roughly $1 billion each. And [Technical Difficulty] thinking in the U.S. and then what are we thinking outside the United States.

So in the United States [Technical Difficulty] $1 billion this year at some kind of midpoint here. That really takes into account a couple of things. One is vaccination rate decline. And so you were just mentioning what happened in the winter season. So if you look at fall last year, it was down 27%, but fall was a wild time. There was many different reasons, I'm sure we can get into them if we want to. But -- if you look at the spring booster, it's actually improved quite a bit. So it's encouraging the trend in terms, but it's a small sample size. But -- so nonetheless, we've provided for vaccination rate declines again in the fall of 2026 and winter of 2027. So we kind of sized that in to be prudent.

What could offset that though is everything I talked about in terms of mNEXSPIKE. So if we can grow share, particularly in retail, we were 24% share overall last year. If we can grow that, that's great, number one. Number two, it comes at a higher value. So that's the U.S. dynamics. If it really comes down to the upside question, what happens to vaccination rates? We plan for a sizable decline relatively speaking. And what happens to mNEXSPIKE share and how much penetration can we have?

Outside the United States, we were $700 million last year. And you really -- and I talked about these international strategic partnerships. And you saw that in the first half already this year. So in the first quarter, we had $400 million in revenue. We said there was $200 million in the U.K. That's just for the spring booster. We're going to have another fall campaign as well that we'll supply for. So that's substantial growth. Last year, we had next to no revenue in the U.K. and now all of a sudden, we have $200 million in the first half alone.

So when you step back, if we -- if I just -- I just want to really simplify the math for people. So we guided to $450 million to $500 million in the first half. And last year, we did $250 million. So that's up $200 million to $250 million. On $1.9 billion, that's 10% plus by itself, if we're just flat in the second half. So if you're just flat in the second half and how do you get to flat, that's if the U.S. comes down a couple of hundred million dollars and U.K. backfills [indiscernible] really simplify it. That's why we're so confident in growth this year, of up to 10%, and we hope to do better.

Great. You're also still guiding to cash flow breakeven in 2028. Can you walk through what's needed from an OpEx and revenue standpoint to achieve it. Moderna's ability to be flexible on the spend side and your confidence in meeting this goal?

Yes. So I've always -- we -- I've always said that this is both a revenue increase story and a cost decline story. And so I'll start with revenue. I already kind of laid out all the variables. But just to maybe emphasize just how big these are because I said substantial. I mean there's 10 variables for several hundred million dollars each. So if we have a 50% hit rate, it's a couple of hundred million each, that's a $3 billion-plus business. And so that's kind of the revenue side. You have to assume what do you think these 10 things are going to do. If you got a 50% hit rate, you can be at least a $3 billion business. If you hit on all of them, it could be much more than that. And that's kind of the revenue side. We've kind of got to obviously got to grow over the next 2 years.

On the cost side, we've already guided to 2027 because we have such clarity of what we want to do, and we guided to $3.5 billion to $3.9 billion of cash cost. So that's down another $400 million to $800 million from last year ending point. And so we're trying to manage what is that growth line and what is that cost line. And let me say one more thing about 2027, we know what we're going to take out. There's efficiencies that we were going to go have. There's Phase III trials that are going to run off. So that's obvious to us.

Then it comes down to this choice of, okay, how are we growing? How much are we going to invest? We're building the next chapter? How are the readouts happening? What investment level do you want to make? And of course, you can always drive efficiency to some degree. But that becomes more of a choice come 2028, and that's why we haven't guided 2028, which is let's see where the revenue line is. Let's do the things that we know will happen on the cost side. And then let's make a choice based upon the data that we're seeing on readouts, the execution on commercial sales. So that kind of paints the picture of what has to happen on both sides.

Perfect. Perhaps we can pivot over to your pipeline. So Intismeran data, you recently presented 5-year follow-up data in adjuvant melanoma at ASCO. Just to level set, remind us the high-level takeaways here and the importance of the translational data that was presented.

Yes, I'm glad, yes. It's quite an exciting year for Intismeran -- for both Merck and Moderna this year. And so I think the key -- there's two punch lines, but the headline, I would say, is that Intismeran continues to be a strong benefit, a meaningful benefit, a durable benefit. So we've now have 5 years data that we're seeing the same recurrence-free survival rate at 49% improvement. We saw it at 3 years. We saw it at 5 years. So we're really encouraged by the consistency of that, point number one.

You mentioned translational data, point number two. So now this is the first time we actually try to show what is the underlying biology and how is it affecting the clinical outcome here that we're seeing. And what we saw is that tumor-targeted immune responses are better with Intismeran versus KEYTRUDA alone. And that's largely due to T cell clonal expansion as well as the number of T cell clonal types that you have. And we saw like a 2x fold improvement on those patients that survive until 5 years or recurrence free to survive for 5 years versus just KEYTRUDA alone. So that gives us a lot of confidence in the underlying mechanism of action behind this overall program. And that's why Merck and ourselves have invested so much behind this program in various indications, and we're pretty excited about it.

Great. What is your confidence level for success on the Phase III interim study that's reading out in the second half? And maybe in the context of the Phase II results translating to Phase III, but being able to get it on an interim versus the final analysis?

Yes. I won't assign a probability to it. I'll just say a few things. One is, obviously, we're super encouraged by the Phase II results. We're super encouraged by seeing some amount of translational data that supports the program. And I think this isn't a transient response now. This is now 5 years that we're seeing this kind of impact. That's a very long time. So it's a Phase II. It's 107 patients on the -- on INT versus just KEYTRUDA alone. But that gives us a lot of confidence in what's going on. And again, we've continued to invest -- both Merck and ourselves have continued to invest. So I won't assign a probability to it, but we are quite encouraged.

On the interim point, I mean we've set up the Phase III to have numerous readouts. So I don't want to dwell on just the first interim analysis. Of course, we are hopeful and optimistic that it will be just as successful as what we've seen on the Phase II. But there will be other data points, and we will look at the totality of the data in terms of DMFS and RFS and how long from a durability standpoint. So there's other things to look at, but hopefully, the first interim analysis will be strong as well.

If you had to speculate what are the key risks here to the first interim the Phase III not working?

I'm probably not the best person to speculate on the risk of why it wouldn't read out well. But I mean, we always talk about it that you never know in clinical development until you actually get the data. So -- what we've seen is very strong, very durable and very consistent. And so that gives us a lot of confidence, but you never know. So clinical development being one. And then -- it's the first interim, like I just said. But if I step back, this trial was enrolled in very quickly. So I think that speaks to investigators and patients and just how encouraged they are and optimistic they are by this therapy. So -- but we'll see when it comes out.

Can you frame for us the commercial opportunity here for this drug in adjuvant melanoma, but also lung and RCC or where we have the best sight, I guess, line of sight to data this so far?

Sure. So all three of those are going to be multibillion-dollar opportunities. Merck and ourselves have not yet released what we think the addressable size will be, but they're quite sizable, and we're really excited. And so we think, overall, if this works across a lot of indications, it can be a very large product and a platform that is and very meaningful from a revenue standpoint, but we haven't given specific estimates yet.

How are you accounting for this asset with Merck? Will you recognize it as top line revenue? And how will commercialization expenses be split?

Yes, it's a great question. So -- first, yes, it will be top line revenue for us. I'll come back to that because that's a little bit more complicated. But broadly, it is an overall, we shared the economics 50-50 split down the middle. So at the end of the day, the cash is reconciled to make sure that both partners are in on it or benefiting from it from a 50-50 standpoint. So the expenses -- commercialization expenses are actually much easier. It will be 50% on Merck's P&L, 50% on our P&L. The reason why revenue and gross profit is a little bit more complicated is because we're manufacturing the products. We are selling it to Merck because they are the market authorization holder, and then they will sell it on to the end customer. And so we'll recognize whatever our COGS are with revenue because Merck will pay us for the COGS. And then that gross profit split, split 50-50 will be added on top of our COGS and revenue for extra revenue. So it won't be 100% of the revenue on behalf of Moderna. Merck will recognize 100% of the revenue. We will not recognize 100% of the revenue. We will have something in between, and we will recognize the full COGS as well.

Is there any commercialization effort from your side? Or is the sales force fully on the Merck side here?

There's an agreement to jointly commercialize in some areas to a small degree. But I would say the lion's share is certainly on the Merck side.

Got it. At your Analyst Day, you discussed a line-by-line expansion strategy for manufacturing. Can you touch on what this means and how it leads to efficiencies over time?

Yes. We're super excited and the team did an amazing job. We have a facility just outside of Boston in Marlboro, Massachusetts, that is a stand-alone facility only for INT and it was purchased and built in a matter of 2 years. It's just incredible. And what -- to your point, we said it's a line-by-line strategy. So the facility has the ability to have 7 lines. We have only built one of those lines, and that was very intentional for two reasons.

The first reason is why invest if you don't have -- if you don't have the demand for the second, third, fourth, fifth, sixth line, don't spend the money yet. So that makes sense. It just keeps our overall cost down and a better return. But then more importantly is the ability to drive additional productivity. So we are continuously -- we already have 3 phases of how we are going to manufacture this product from inception that we've been doing for our clinical trials. We have a second phase that is already in Marlboro right now, and then we already have a vision for a third phase. And what do I mean by that? So what I mean by that is think the footprint of the boxes to manufacture these are much more automated, so therefore, less labor and much smaller footprint. So you can get a lot more throughput through the lines, and therefore, your cost comes down as well.

So as we have the demand, hopefully, for a second, third, fourth line, we'll be able to put in the latest technology. And therefore, the overall cost of goods sold will come down because it will be the latest technology on the second line. And we have already started to envision a fourth line, frankly. And so that's the key to making this as efficient as possible and most importantly, to give it as much market access as possible across the globe to drive our COGS down.

And could you discuss the cost component here of manufacturing, noting it's a personalized product. How should we think about margins initially and longer term?

Yes. So we're very confident that the initial margins will be solid, and the long-term margins we have -- based on what I just said, we have a lot of productivity roadway here. And I think that's natural in a product like this, and I've seen it in other industries as well that you will continuously automate, take labor out, make it simpler, make it smaller. And so therefore, the cost of goods sold should go down.

To step back and just think on behalf of Moderna, in terms of margins, they will start on from a rate perspective, smaller but a revenue perspective higher because you're selling at a cost of goods sold that's higher. So if you have to do that and then you split the gross profit on top of that, you actually have more revenue but less margin. Then as costs come down, you don't sell as much from that initial transaction with Merck, but then you get a greater portion of the gross profit split so your margin rate goes up, but the revenue per patient comes down a little bit over time. So that's the way to think about it. But as the patient ramp goes up, that will more than offset the small decline on a revenue per patient basis, and the margins will improve over time.

What is the view from Moderna at this point on the read-through from INT in adjuvant melanoma to other distal tumors, like lung, among others. And the confidence that this is going to translate beyond?

Yes, we get that question a lot, rightfully so. So INT wasn't really made just for melanoma. So that's how we think about it. It wasn't designed for melanoma. It was designed for cancer, and it was designed to target specific neoantigens on a tumor cell and train the immune system to attack it. And so we're hopefully seeing that already in our Phase II with melanoma. Should that work and if the biology is different to some degree, but at the same premise should be there for other indications, albeit that biology can change and maybe you have different neoantigens and that kind of thing. But -- so we are optimistic that, that mechanism of action and what we just showed in terms of translational data at ASCO can apply to numerous indications. And again, that's why I think we have 10 trials going on right now [indiscernible] and maybe 5 Phase IIs [indiscernible] and us are confident that this could work and starting to invest aggressively behind it.

And we're on track to see Phase II data in renal cell carcinoma and non-muscle invasive bladder cancer this year, too?

I don't think we've given an exact date. There is a chance, I mean, if you look at events and that kind of thing, but we have not said that specifically that we would have renal cell data in 2026.

Got it. Perfect. Norovirus here. So -- can you discuss the commercial opportunity for the Phase III asset here and when -- where you'll likely have data this year and your confidence here that this could be successful?

Yes. This is an important product for us. And so as we -- as I said earlier in my prepared remarks or my initial remarks, we want to build a leading vaccine franchise in infectious disease, and we want to have various products to bring to patients and customers. And so having two COVID products, one RSV flu hopefully later this year, our combination vaccine was approved in Europe. Adding norovirus to it, where there is no other vaccine is really a competitive advantage. And so we're quite encouraged by that. So maybe to speak to the commercial opportunity. The burden is pretty severe with norovirus. And I think there's 20 million cases a year. There's nearly 1,000 deaths. There's maybe 100,000 hospitalization. So it's severe and anybody that's had it, I think, knows that. And so the burden is obviously substantial. We think the patient population that we would target is a little over 150 million individuals in the United States.

I think older adults that get dehydrated and it really impacts -- if you're in a hospital, it really impacts you even further. So older adults think occupational therapy, health care workers, where it might spread. So -- but if we even got a fraction of that, a fraction of $150 million from a vaccination perspective, that would be a very sizable opportunity to which there is no competition. So I say it's an important product. I think it's very meaningful from a revenue perspective. And so that's that. The second part was on the trial and our confidence around it. So we'll see. We'll see this year. We've -- we know that. We believe it will happen this year that there will be enough events that it will read out. And from an approval perspective, what we see is where there is no other standard of care, anything that has relative vaccine efficacy of 50% above versus placebo normally is encouraged and approved. So that's kind of the limit that we're looking for is to be above that, and we hope to bring it to market in the not-too-distant future and we've said, hopefully, by 2028.

On the forward trajectory here for the COVID vaccine, given Pfizer's pandemic era contract in the EU will expire this year, that geography could meaningfully contribute to your growth in 2027 plus, as you mentioned. Can you discuss the size of the market and your strategy here to gain greater share and what steps you can take now for success?

For sure. There is a lot of active work going on right there. So to size the market, the flu market is about $1 billion. These are our estimates in Europe in the year 2027. COVID market, again, in the year 2027, from an actual demand perspective, there might be greater sales going into it right now, but we think it's a $700 million market and RSV is like a $100 million market. So a $1.8 billion market, pretty substantial to which we have less than $100 million is what we've said. So even 20%, 30% share across that would be pretty substantial for us. So that's kind of the market size.

In terms of where we are, so number one, I mentioned earlier, we got our flu plus COVID vaccine approved in Europe. So we're excited to bring that to market next year. We got mNEXSPIKE approved as well. So we're kind of ready to go. And so what are the actions we're taking now? Europe is normally a single payer system where you go tender by tender with countries that are the decision-makers, so we are working with them right now to shape tenders. The second thing is you need to work with health authorities and NITAGs to make sure that you have the right recommendation as well as reimbursement. So we're working with various countries across Europe to make sure that when the tenders come out at the beginning of 2027 or maybe even some of them come out late 2026, we are -- we have market access, and we have two products approved that we can go compete in.

So -- yes, I mean, 20%, $360 million versus less than $100 million, it's another couple of hundred million dollar growth, maybe $300 million growth driver for us. So that's why I keep going back to you have to believe that if we get 50% of these hits, we could be about $3 billion, and we've already mentioned that where our cost could go at least in 2027.

And your flu, COVID combo vaccine mCOMBRIAX was approved in April by the European Commission as the first COVID/flu combination, while not included in revenue guidance for '26. Can you speak to the commercial launch preparation underway, the kind of education and patient access efforts needed and your expectations for top line contribution in 2027 plus and expectations on timing for approval in the U.S.

Yes. I kind of size the market in Europe already, flu being $1 billion, COVID being $700 million, so call it $1.7 billion. So first, you got to shape tenders to actually allow for a combination vaccine as opposed to discretely COVID or discretely flu. So whether that is large in the first year or it takes time to develop and maybe have additional competitors also, we'll see, but that's number one. And then it's the same things I just talked about in terms reimbursement and getting recommendations and that kind of thing. So that's kind of the size and the tender process.

I think what's unique though and what we're trying to educate on is it brings a lot of simplicity. It brings simplicity to the health care system because they don't have to run 2 campaigns. They don't have to run a flu and a COVID campaign. You can run one campaign so that should simplify things and increase compliance, frankly, as well. And it's better for patients as well. So that instead of going and having two vaccination appointments, you can have one vaccination. So that's really what we're trying to educate every country and every health authority in Europe right now. And I think it's resonating well. We'll see how much it can grow over time, but it could be a very substantial opportunity over time.

Great. And for flu itself, you have an August PDUFA date for the seasonal flu monotherapy vaccine. Would you expect to start contributing to revenue in 2027? How big is the U.S. market for an mRNA flu vaccine? We know how big the flu market is, but what is the willingness to take an mRNA version?

Well, that remains to be seen. Yes. So it's a sizable enhanced dose market. That's where we'll play. What we think we're bringing is a lot of innovation to this space. And I think actually, we got quite a bit of education on that over the recent history because of everything that transpired around this. So the fact that -- and why do I say we're bringing innovation to the space. So we're bringing innovation to the space because the current flu vaccines take a long time to produce. And since they take a long time to produce, you have to pick the strain well in advance of the actual season. Whereas with mRNA, the innovation is you can be ready in 60 days. And so you can pick a strain that is more likely to circulate during the actual season and perhaps have a better impact and a better clinically meaningful impact to patients because it could be more effective.

So I don't know exactly the consumer angle on that. But I mean, I think people recognize that a better strain matched vaccine, if allowed could be much more effective. And the burden of flu is still in the tens of millions of people in the United States. The hospitalizations are in the hundreds of thousands. The deaths are in the tens of thousands. So it's very meaningful. And so -- but we have to continue to educate on what that can mean, and we're excited to bring the innovation to the flu market.

On the education front, in the context of just the use of mRNA during COVID. And to the period now, how much education do you need to do on side effects and safety just to have people recalibrated to real-world data as it exists today?

Yes. So we've done a lot of that. We publish everything. We're super transparent on our website to make sure every single, in our view, myth that is out there. [indiscernible] I think there is [indiscernible] I say, look, last year, we had 40% to 45% market share. So that tells you 40% to 45% of the people that are willing to get vaccinated are willing to get our vaccine, I get that our competitors also mRNA. But maybe then the better metric is look at COVID to flu. I mean there's still over 30 million people that are getting a COVID vaccine that is mRNA right now.

So hard to say we try to debunk, it what will come with that. It's a journey, I would say, but we're -- we stand tall behind our science, and we put it out there transparently. And there's still at least 30 million individuals that are willing to get an mRNA vaccine at this point. And hopefully, if the flu vaccine is better or a combination vaccine is more effective, then maybe that will grow over time and maybe the sentiment will change over time in the country and the world.

Jamey, as the last question, anything we didn't touch on that you want to highlight?

I think we touched on all the really pertinent stuff for the next 3 years, which is our next chapter, and that is what I know is on investors' mind. And rightfully so, particularly since the journey we've been through. That said, there is a lot going on behind the scenes for the chapter after that, so to speak, which is why we are having a Science Day on June 25. But there's been a conscious and disciplined investment around our science, around our platform and around programs. We announced one this morning or last night, I think. So there's more to come beyond this chapter, but we got to get this chapter right, for sure. That's what we're focused on. The only thing we didn't touch on is there still is a lot of great work going on for the next chapter as well.

Great. Well, with that, thank you so much. We appreciate the time.

Yes. Thank you, Salveen.

Hi, I'm David Berman, and I'd like to welcome you to the Moderna ASCO Oncology event. Here are forward-looking statements, and you can read them at your leisure.

Here's the agenda for today. I'm going to review the -- give you an overview of intismeran, then Michelle Brown from Moderna is going to highlight the neoantigen selection and the mechanistic foundations of intismeran.

We're very honored to be a jointed by Dr. Matt Carlino, who will give a reprise of the Phase II KEYNOTE-942 study that he presented today. Dr. Ryan Sullivan will then join us. He presented translational data on intismeran yesterday at ASCO and say we'll be sharing that data. And then I'll conclude and we'll have some questions and answers.

So for those of you I haven't met, I'm the Chief Development Officer, and I joined Moderna about 3 months ago. About 20 years ago, I had the honor to participate in the world's first checkpoint antibody for cancer that was ipilimumab. And over the past 7 years, I've had the honor to participate in the world's first TCR therapy for cancer. And I joined Moderna 3 months ago because I believe intismeran has the potential to be the world's first RNA immunotherapy for cancer. And you'll see why I'm so enthusiastic today.

Intismeran is the most advanced individualized neoantigen therapy in development. And in brief, a tumor and blood samples are taken. They are sent to a lab for sequencing to identify neoantigen mutations. These neoantigen mutations are then designed into a neutralized mRNA. We manufacture 1 lot per patient individualized. This is then shipped back to the investigator and the investigator then administer this. And you'll hear more about this from Michelle in a few minutes.

We've begun to develop a stepwise experimental framework for understanding how intismeran works. First, of course, is the production of intismeran. And as mentioned, Michelle will walk you through this in detail.

Once intismeran is produced and injected into the muscle, the lipid nanoparticle and intismeran migrates to the regional lymph node where it's picked up by dendritic cells, converted into peptides, which are presented on the surface of the dendritic cells and then the dendritic cells activate neoantigen reactive T cells. So T cells that are specific for the neoantigens encoded by intismeran.

These neoantigen T cells then circulate in the blood and hence, there is an increased clonality in the blood. And the T cells then migrate to where the tumor is and identify those neoantigens and kill the tumor. This is the theoretical framework.

Now personalized or individualized vaccines have been studied for several decades, predominantly as peptide adjuvanted peptides and as DNA. And it has been shown that novel T-cell clones in the blood can be produced or induced as a result of personalized vaccine. However, until intismeran, no one has ever demonstrated efficacy and especially not in a randomized trial. And so today, as mentioned, Dr. Carlino will present the 5-year updated efficacy of RFS, DMFS overall survival, from our randomized Phase II trial.

Now he will also take a step to the left and show you that we do see an increased level of novel clones in the blood. And he will show that on the intismeran randomized arm that patients who are relapse-free who don't relapse have higher levels of T-cell clones in the blood than patients who do relapse. So this provides a link between intismeran and the efficacy.

Now the outstanding question to date has been what are these novel T-cell clones you'll see in Dr. Carlino's presentation. What exactly are they? And this is where Dr. Sullivan's presentation will come in, and he will complete this loop showing that these novel that appear in the blood are in fact, T cells that react to specific neoantigens encoded by the intismeran product. Therefore, we have this complete circle. And to me, someone who has worked in immunotherapy for several decades, this is the strongest proof of confidence for any immunotherapy, of course, prior to a randomized Phase III trial.

Now why have prior therapies not worked? Why have prior individualized vaccines not produce the results? And why do we -- do I think intismeran works? First, of course, is the intismeran drug product. It's a modified mRNA in a lipid nanoparticle. And we know that this type of product is highly [indiscernible] to induced T cells. We've known this for COVID, for flu and for RSV, and we now know it as well for intismeran.

But the second is where intismeran was studied. If you think about it, prior studies were in heavily pretreated patients with metastases, usually multiple lesions and 1 lesion of many is usually biopsy to make the individualized product. However, in this late stage, there's probably intralesional variability. So producing a neoantigen vaccine from 1 tumor may not represent other tumors in the patient. Second, of course, the T-cell fitness in heavily pretreated patients is not good. And finally, patients with metastatic disease usually have somewhat rapid progression and this limits the time for the vaccine to take effect.

All of these are eliminated in the adjuvant setting. There is 1 single dominant lesion that is sequenced for the vaccine. That's removed allowing maximal T-cell fitness as good as you're going to get, and there's enough of a runway to produce the intismeran drug product.

Even, in the successful -- despite the successful development of anti-PD-1s in the high-risk adjuvant setting, there is an unmet need. For example, bladder cancer, 64% of patients treated with anti-PD-1 will still recur. And up to half of patients with adjuvant high-risk melanoma will also recur. And you can see even in other tumors, there is a significant high risk of recurrence. So unmet need still remains. Pancreatic cancer is here in gray because, of course, anti-PD-1s are not approved here, but this remains in the adjuvant setting, an area of high unmet need. And this is why intismeran was initially focused in the adjuvant setting, and in tumors that are known to be IO sensitive because IO sensitive means that checkpoints work here and checkpoints unleash he sells to target neoantigens. And therefore, it makes sense to study intismeran in adjuvant settings that are IO-sensitive melanoma, lung and genitourinary tumors.

We also have trials recently initiated, for example, the Stage 1 Phase III non-small cell lung cancer, which is the first time that we're actually getting a intismeran arm that's monotherapy, and then we have our Phase II non-muscle invasive bladder cancer. We decided to also study this in the metastatic setting. Now this is a higher risk for the reasons I articulated, but it is certainly worth studying in a Phase II trial.

We have also decided to explore intismeran in tumors that are generally less sensitive to immune therapy, gastric cancer and pancreatic cancer as well. And these are single-arm trials that we hope to share results for soon.

I'm now going to call Michelle up to talk about neoantigen selection and the development, how we make intismeran..

Thank you, David. So hi, everyone. It is nice to see you on feedback Okay. It is nice to see you at the end of ASCO, and we're really excited to have this as one of our third type of conference events around an intismeran dataset. And so we're very excited to see Dr. Carlino and Dr. Sullivan showcase the data that was planned over the weekend.

As David alluded to, he highlighted the unmet need that still remains in adjuvant melanoma and the adjuvant setting and tumors overall and also the basic principle behind why we think intismeran can be extended into the type of clinical portfolio we have today. But one of the things that we think about, and I think it's important to highlight with intismeran is that it is not just a traditional clinical product. It really is a process, and it's a process that sits at the culmination of mRNA LNP advancements on genomic medicine, next generations with next-generation sequencing, digital [indiscernible] small scale manufacturing, and really, it is because of all of that, that we're able to generate a personalized approach that we think has brought applicability to a number of tumor types.

So my intent here is to double click on some of the technologies that funnel in to intismeran to be able to make it as applicable and where we're advancing and making learnings. So as you see here, one of the starting point, as David alluded to, is that with intismeran, it starts and ends with the patient. And so this is very true with the leverage of the patient's tumor tissue and their blood sample and then the use of next-generation sequencing to understand the wide variety of mutations that are actually present in a patient's tumor.

And using that litany of information, we can understand what mutations that tumor is using to generate these neoantigens. And what neoantigens are, are those aberrant tumor mutations that are recognized by the immune system. But it's not enough for a mutation just to be present. It also has to be expressed. And so we use RNA seq to understand or pick the expression profile of these mutations and then also HLA typing to understand how the immune system is going to recognize these aberrant proteins.

So then when we take all of the genomic information, the RNA seq information and the data analysis, we leverage all of that data inputs into integration and interpretation with our bioinformatics algorithm to actually manufacture intismeran. So it's a different way of looking at the little cycle that you guys are used to seeing. But as you see here, one of the foundations building on all of the inputs for the next-generation sequencing is the algorithm itself.

And the algorithm, you have to think about it as a node for this technology. Because what it does is it takes all of that input, we use the litany of mutations that are present and basically says, which out of these are going to be the ones that are most able to mobilize the immune system. It then rank orders the amount of neoantigens and puts them in and selects the top 34 that we think will activate the immune system to generate de novo T-cell clones and increase endogenous T-cell responses. And this type of mechanistic hypothesis is the foundation of what Dr. Sullivan will be presenting today.

So if you believe this, what it means is that right now, the current algorithm is well controlled, and is essentially applying the same basic rules and principles for every intismeran patient that we have. But what we know is that science advances and technology advances, and we have a litany of clinical studies, as David alluded to, that are going to drive learnings. And so while the algorithm itself right now is fixed, it doesn't mean that we don't have an approach where we could adapt to those learnings and have it iterate on itself. And in fact, we're in conversations with the agencies to understand how we could adapt the algorithm based off of learnings today.

Now a lot of you ask, this seems like a relatively complicated process. There's a lot of steps, there's a lot of arrows. Do we really have to do this? And the answer was presented back in SITC in '24 where we essentially looked at the patients in KEYNOTE-942, so the Phase II study that Dr. Carlino will be discussing and looked at their intismeran antigen cassette. And what we found in that was that the majority of intismeran plus pembrolizumab patients had a full 34 cassette. So 91% of the patients that were treated had 34 neoantigens, but you can see that there's a span. It goes from 9 up to the 34. And that's not surprising because melanoma tends to have a lot of tumor mutations and so we have a lot to choose from and select from.

But what was interesting was that 99.1%, so over 99% of the neoantigens that were selected were unique. So they did not overlap between patients. And for that, less than 1% of patients that did have overlapping neoantigens, these were BRAF mutations and NRAS mutations. So what we know is that the algorithm is actually accounting for your traditional biological relevant mutations and then selecting hotspots that are relevant for those specific patients.

But it's important to note that even though some of these were overlapping neoantigens, the actual neoantigen itself, like the cassette frame, was different because it's based off the patient's biology, it's based off their HLA type, and it's based off the specific sequence for themselves. So even though they're targeting, let's say, BRAF, it's different parts of that BRAF that are tailored to that patient. So really, what this tells you is that we do have to go through all of the steps to generate an individualized neoantigen therapy because no 2 patients and now 2 tumors are the same.

So that funnels into the mechanism, which I think you've seen before. But the idea here, as David alluded to, is that we use all of the digital infrastructure in the next-generation sequencing to program and select these 34 neoantigens, which then integrate seamlessly to our manufacturing site to generate an mRNA cassette and encapsulate that into an LNP, which is then administered IM. Once the intismeran enters into the body, it tends to go to the lymph node, where it uses natural cellular processing to generate peptides that are expressed on MHC I and MHC II to activate CD8, CD4 cells, which then generate effector immune memory phenotypes.

So essentially, this was our hypothesis for how intismeran should work. And it's essentially saying that we're training and activating the immune system in a targeted way. And then the thought was that if we combine this with a PD-1 inhibitor, you're essentially taking the brakes off the immune system and mobilizing and maintaining activity of these targeted T cells. And again, one of the things we've been so excited about is not only the clinical data that's being presented, but the translational story that's following this mechanism.

And I think it's important to double-click on that translational story because, what we talk about a lot of the time is the clinical data set, the clinical portfolio. But one of the foundations with this type of technology is, again, the amount of learning that we are going to be able to have. So it is important to note that because of the litany of clinical studies we have in collaboration with Merck, we do have a lot of translational learnings to guide our future states. So we do have across the studies, multiple sample collections basically from every patient that comes on. We have a tumor sample for sequencing. We have a blood sample, and this gives us baselines, but it also can give us baseline about their biology, their sort of biological state in the blood.

And then within each study, we have a number of samples that are being collected to generate additional earnings. So that can teach us on the mechanisms of recurrence or progression. It can also to us about the use of ctDNA or really how the neoantigen and the immune system are interacting and interfacing. And all of these learnings can then be put back into the platform to help us with either future clinical trial designs or again, future intismeran design.

And right now, if you take a look at the totality of the clinical seats that we have, what it would mean is that we would have a repository of over 5,000 patients that we would have samples for to help us learn, which represents the largest portfolio that for a neoantigen approach to really drive those learnings.

And I think it's important to know, as David alluded to, that we do have a very large portfolio of studies, and each one is addressing different questions, where we started in this immune-sensitive foundational tumor, as Dr. Carlino will talk about with adjuvant melanoma for the highest probability of success. We then expanded to tumor types that had biological adjacencies that would make sense with the mechanism that we talked about. But after that, we started exploring the bookends because really, this type of approach is tumor specific. So we wanted to test how early can we go, especially with the safety profile we see, and that's one of the reasons we're so excited for the Stage 1 study but also for the NMIBC study. And then how late can we go because maybe we really do have the ability to activate that immune system in a metastatic way.

And then lastly, we're able to do this with multiple combinations. So we aren't just combining with the PD-1. We are combining with standard of care where it makes sense because, again, the mechanism is distinct and the safety profile is distinct.

And all of this really started with the Phase II P201 study that we presented back in '23 at AACR with the primary analysis and what Dr. Carlino is going to talk about today with the 5-year analysis, which represents the longest duration we have for follow-up for this type of technology. Thank you.

Thanks, Michelle. So if I [indiscernible]. It was exciting then and to sort of think about the concept, but the last few weeks have sort of closed the loop both presenting this data, but also visiting the production facility at Moderna and seeing the change from a trial that we were, I think, we put 15 or 20 patients on at our site and 107 patients collectively to now an infrastructure that's ready to make thousands, hopefully, for commercial products very, very soon.

So this is a slide deck I presented this morning. I'm happy for people to interrupt. Also presented slightly differently, given that some of the information overlaps with David and Michelle and maybe have some commentary as I go.

So ASCO makes you do your key findings first. And the key finding of the study was intis and pembrolizumab really works. So it reduces the risk of recurrence by 49% or 59% for distant metastasis-free survival.

To put those numbers in perspective, I think the benefit of pembrolizumab over placebo is smaller than that. And one of the things I was taught when I was reading papers as a trainee was the easiest study to do was when your study is of an active drug versus nothing or an active drug versus an inactive drug, right? So a study of placebo versus an active drug, placebo versus pembro or an active drug versus an inactive drug dacarbazine versus nivolumab. It's actually harder to get a big benefit when you're comparing yourself again something that's effective. So I think those numbers are more effective when you -- when the comparators actually pembro, not placebo or we weren't silly enough to give adjuvant to dacarbazine.

The second point is the safety profile. I'll touch on when I get to the safety slide. But I think when it comes to adjuvant treatments, there's really important safety factors that this does that other adjuvant trials hasn't done. And the last point I'll come to David and Michelle touched on, is the translational data that really links how intismeran is designed to what we're seeing. So this is clearly on-target benefit in these patients. So I think the translational data that's sort of, for want of a better word, a little bit superficial from this that I'll show you to the really deep dive that Ryan will show you. It closes the loop of the story.

So this is -- I'm sure you saw my slide or maybe I saw your slide. Anyway, so look, just reminding you of the mechanism of action, the goal is to expand existing and create new T-cell clones, targeting those up to 34 neoantigens that's in the intismeran. And we'll show you that, that's actually what's happened. And the theory is by giving the pembrolizumab, you're potentiating that response. So you're, if you like, getting that response and then driving it forward with the pembro.

So as I said, background, nivo and pembro both work. In the adjuvant setting in stage 2, stage 3 and stage 4, they reduce the risk of recurrence by 40% to 50%. So that's how I -- and I'm sure Ryan's the same describer of patients. If your risk of recurrence started at 60% roughly, we're making at 30% with pembro.

But that means whatever we're doing a significant proportion of patients still develop metastatic disease and still die. So an improvement on this matters because someone who gets adjuvant pembro or nivo and subsequently occurs has a very high chance of coming from their disease.

I think the other thing to remember is no trial has improved on this. And there's been -- I've been involved in 4 studies that have tried to improve on pembro or nivo. One of them stopped early. The drug was so bad. 3 of them were negative, including 2 agents that were positive in the metastatic setting. So the addition of ipilimumab and the addition of [indiscernible] don't improve nivo. I think the other thing about those 2 studies is both of those agents increased tox. So in the adjuvant setting, the thing I don't like is permanent toxicity. And so pembrolizumab, relation ipilimumab, all drive permanent toxicity, and the one that bothers me the most is patients who make diabetic or patients that give quarters old efficiency, too.

So I guess the alternative trials that we filed and failed had the added negative causing the toxicities we don't want in the adjuvant setting. And the previous analysis were positive. So the job today was to update the 5-year data and then give that beginning of translation data.

So here's the study design. There was a question today from the audience or maybe a comment from the audience, which was a compliment to me, but really a compliment to Moderna and a slap in the face to everyone else. So Jeff Soman is the most famous question ask in melanoma. And he made the point that this study was so important to be a randomized Phase II. And the other 2 people I shared the stage we've had single-arm studies. So I think that's right.

So if Moderna had done 200 patients with intismeran and pembro, and then try to compare it to some historical control. Rightly, we wouldn't -- we would be more skeptical or you should be more skeptical -- you should be most acceptable than a randomized Phase II. So I think this is a perfect example of the power of randomized Phase II trials, not to get a drug approved but to say it's worth and it's likely to win in Phase III, it's worth going forward with.

It was quite a high-risk population, which I also think was another smart move. Although we enrolled stage IIIb patients, they had to have recurred first. And actually, there's no stage IIIb patients in the study. So by going for a high-risk population, you can get away with a 150-patient study, and you get an answer early. There's nothing biologically different between stage II melanoma and Stage III. It's just you can get an answer with a small study, and I guess from a major point of view, a quick answer with a relatively small investment.

Patients needed to have tissue available to make or design a intismeran. That's something we were really worried about early on. We are -- the investigators thought, "Gee, we're going to need large chunks of tumor to get to make this thing," but we learned in this study in the subsequent Phase III study, that's not necessarily the case. 1/3 of the patients on this study actually had micrometastatic disease. So they didn't have big lungs of tumor. It was microscopic.

And certainly, when we all see the results from the Phase III study, probably 2/3 of patients had microscopic stage 3 disease. So you don't need big lumps, but you do need tissue but patients have tissue, easing 2 patients will have blocks of tissue available. Am I going too slow?

Okay. So this was a primary endpoint, relapse-free survival. A couple of things what I touched on before, a hazard ratio of 0.51 is really impressive against an active drug. So I imagine -- and I like to do this, so I'll do it. But if you put the placebo curve from the 054 study down there, and you looked at the equivalent patients. So not the whole 054 study, the 054 is pembro versus placebo. If you put in the placebo curve, I think I calculated that it probably sits at about 30. So you're going from 30 to 50 to 72. And so that really -- it's an additive benefit. And not many drugs do this.

So I was going talk when we developed on it, it was well before my time. But when people got hormone therapy for breast cancer, tamoxifen versus nothing, tamoxifen nothing was really impressive, but arimidex versus tamoxifen wasn't that much better. Same with Herceptin. Herceptin versus nothing is fantastic. Adding in Perjeta, a small benefit. So this tells you unlimmab, unlike relatlimab, this is a new class of drug and that's why you're getting that significant delta.

The other thing to say is a delta of 23%, so an absolute benefit of 23%. Or if you put the placebo curve in an absolute benefit above 40%, 40% absolute is kind of huge.

This slide really just shows that the benefit is durable and maintained. So first analysis, the hazard ratio actually gets better. Often with trials that have transient the first ASCO presentation, the hazard ratio is as good as it's going to get, and then it gets worse. So typically, what happens is ASCO presentation, one, best data you'll get post #2 because you don't get a second oral presentation, the hazard ratio gets worse. And then you don't even bother with the third presentation. This is the opposite, improves and then maintain benefit in terms of relapse.

Acknowledging this is a small study. I think this gives us confidence that it's not just 1 small group of patients we're helping. So, the collection was better if you had stage III disease, stage IV disease, PD-L1 status, BRAF status, left-handed, right-handed, high tumor mutation burden, et cetera. And so I think it's really promising going into the Phase III study that we're unlikely, I think, to have a population of melanoma patients that aren't going to benefit from the incremental benefit of intismeran, pembro.

Just a metastasis-free survival. So this has a ratio of 0.41. Got a lot of talk, I think, probably the first presentation. So another thing that you often see if you look at an adjuvant study, the relapse-free survival hazard ratio is typically better than the distant metastasis-free survival ratio. So there aren't many studies where distant metastasis-free survival is better. And in some ways, if it's a patient, what do you want, right? You said you can -- you have to have a recurrence, Certainly, I choose a local one.

So a drug that shows a bit a great benefit when it comes to the stuff that matters liver mets, brain mets, lung mets in some ways. So I'm really interested to see if this pans out. And certainly, biologically, there's an argument why this immune surveillance may be helping with distant metastasis. And once again, an absolute benefit of, I think this is 18% is huge in terms of distant metastasis-free survival. And incrementally, that's bigger than the benefit of pembro over nothing.

Overall survival is a really high benchmark. So to give you an idea, KEYNOTE-054, pembro versus nothing, there's still no overall survival available. It's at 9 years, right? So to see even a hint of an improvement in overall survival hazard ratio of 0.47, the reason this crosses one is the lack of events. But if this pans out, we may be getting an improvement of overall survival with intismeran versus pembro when pembro versus placebo has done, which will kind of be interesting for -- we won't be allowed to use pembro unless it's given with intismeran.

Okay, side effects. So A couple of things about side effects for me. So I'm not particularly concerned that any treatment-related AE in some ways there's an incremental slightly higher number with the combination versus a single agent. That doesn't bother me in the slides. So these incremental increases relate to pretty predictable side effects, and these will be better manageable today than they were on the study.

Remember, when we were enrolling these patients, it was either no patient had ever been an mRNA vaccine because it was pre-COVID or it was post-COVID, everyone who got febrile made us panic and we had to lock them up if they were febrile. So I think having slightly higher treatment-related is not a lot of consequence, particularly when we know what they are.

The most important point to me is this, the red box, immune-related AEs being equal or at least numerically, potentially lower. So give adjuvant treatment, how I describe it to patients in the wording I use is if you get in certain side effect here and it makes you run well for a week, but your melanoma doesn't come back, you should still thank me.

If I give you type 1 diabetes, if I give you cortisol deficiency, you still have to thank me, but you're allowed to be angry at me. And there's no increase in those type of immune toxicities with this. So this, in some ways, for us, it's a relief that we're not talking about giving adjuvant ipi/nivo and giving people a 10% to 15% chance of cortisol deficiency because when this is approved, we'll be able to say a risk of quarter efficiency remains 1% to 2%.

The intismeran side effects are pretty predictable. It's interesting now that we've got a placebo control trial. I've got two. We're currently running the metastatic trial of pembro plus intismeran for Stage IV melanoma, and either I'm very lucky at getting my patients randomized to the combination or a lot of my patients/myself have the placebo effect because everyone gets chills and a sore arm, but it doesn't seem to be too bad. So they are really manageable. And I don't think of, now that we know what we're doing with the current trial in the previous Phase III trial, it was responsive really to NSAIDs, paracetamol, a little bit of fluids.

So this is the translational data that Michelle touched on, which I actually think was the best part of this presentation rather than the uptake. So I'll just talk you through it and because this took me a while, and I think Moderna immunologists had to slow it down for me.

So what this is [indiscernible] clonality. And so clonality means have you got a large amount of T cells attacking 1 clone and up is more clonality and down is more diversity. So a spread T cells targeting lots of different targets or not targeting for that matter. And they're sort of inverse relation, the more clonality, the less diversity. And the more diversity, the less clonality.

So at baseline, and the time point to baseline. So this is before they get the drug. We have sign consent. Moderna is busily making the product. They haven't yet got any pembro. We give everyone 2 doses of pembro, and they haven't yet got the intismeran, which is often given with the third dose. This is after 2 potentially with the third intismeran at this time, point. And this, for most patients, is a year after starting, but importantly, 6 months after the intismeran dose for the vast majority.

And so I'm going to talk this backwards to what I did today. I'm going to talk about the blue line first. So pembro alone does not increase clonality. And the way I think about that is pembro is activating your immune system, but it's not specific to any one thing really because otherwise, if it was specific to certain targets, you would expect clones to could have come out. And that's certainly how I describe pembro tox to patients. I say I'm trying to activate your immune system to attack melanoma because I'm not smart enough to point it towards the melanoma, you're going to get a side effect that ataxia thyroid. What intismeran is the opposite. We're getting an increase in clonality, right? So we're getting our immune response directed. This does not tell us -- well, this curve doesn't tell us that we're directing the immune response towards those 34 neoantigens. But the question is, well, if it's not directing it to those 3 neoantigens, what are you directing it to? But also, Ryan is going to show you that we are, in fact, directing it towards those 34 neoantigens.

But this also tells you why you don't get immune-related toxicities additively because your immune response from intismeran is directed at those 34 neoantigens. And hopefully, the algorithm is choosing neoantigens that are novel to the tumor, not host neoantigens.

Similarly, this is the new clones now. So the -- what they've done here is forget about any line that existed before the patient walked into the study. Same thing. We are getting new clones coming out. And at the early time point, because the 2 arms of the study are identical, as many new clone pembro as you get for pembro because both arms are getting pembro. But you get a greater number of clones with intismeran. And once again, the suggestion or the hypothesis confirmed by Ryan or whoever did the work Ryan presents is this delta, this extra number of clones is due to clones directed at those 34 neoantigens in the product.

Okay. closing the loop is this. So just for a moment, forget about that curve, this is now just the patients who got combination. So intismeran, pembrolizumab, everyone in this curve, it's the same time point. Red patients did not recur. So these are the patients who, if you like, can't hasn't come back [indiscernible] patients, unfortunately, did recur. And it's really linking the mechanism to outcome, the patients who didn't recur got more novel clones than the patients who did recur.

Closing the loop. That association between novel clones and outcome wasn't seen with pembro alone. So once again, really strongly suggesting a mechanistic link between intismeran and the improved outcome. So as I said, I think the support for this data that Ryan's data gives is huge [indiscernible]. So I think the ratios of 0.41, hard to look aside, but when you see the data that proves how it happened really does close that loop, even based on 157 patients.

So this is essentially a return to the things. It works. It reduces the risk of staff coming back a lot. The safety and tolerability is fantastic. Really, the side effects you see are pembro side effects. So there, I don't -- I cannot think of a patient that I am willing to give adjuvant pembrolizumab to that I'm not willing to give adjuvant intismeran and pembrolizumab. There are many patients I could consider giving intismeran to that perhaps wouldn't have pembro, but it's that good a safety profile.

The translational data, yes, the superficial translational data I showed to you really does, I guess, suggest the link metastatically. And Ryan's data is going to take that suggested link to a kind of uncertainty in a moment.

I think like always, I think finding so much information from a randomized phase to is a positive, not a negative. But ASCO e-mail me said I had to have some study limitations. So I actually think the ability to make such a strong scientific argument based on a randomized Phase II is a strength, not a weakness. But the job of this study, and it did it in Spain, not only to lead to a registration Phase III in melanoma but to lead to multiple registration studies. So I think when we -- I'm glad that the first registration positive study will be melanoma and like always, all the other cancer types can follow. I think when we see the study -- the registration study soon, I think, at least I'll remember and it kind of started with 157 patients 5 years ago. Okay. Thank you.

Okay. So I get to take us home. So one of the joys I've had with working with Moderna and with Matt and the other investigators is having the opportunity to present some of the translational data with this study over a few years. And when we were presenting that data that Matt just showed with the expanded clones, people said, well, are they, what are they against, and he said, "I don't know."

And we just, there was initial collection of large numbers of patients with leukapheresis to do very sophisticated analysis, and to type these T-cell clones and see if they were neoantigen specific. And we've ultimately gone to the point where we have some of that analysis. And so that's what I'm going to share.

We've seen much of this. I will say that KEYNOTE-603, which is the Phase II study of intismeran did show in their -- in the publication that came out last year that all of the patients that they had T cells collected and analyzed, they could show that there was neoantigen-specific T-cell clonal generation. 30% of those neoantigens elicited immune responses, and you could see both expansion of CD8 and CD4 positive T cells.

At KEYNOTE-942, again, intismeran shows higher new clonality. And those were sustained over the course of the study, in fact, in those patients that didn't recur, it seemed to be going up. And the novel T-cell clonal type expansion associated with better outcomes.

So what I'm going to do over the next few minutes is talk to you about how the efforts that have been done to link the de novo T-cell clonotypes to intismeran-encoded neoantigens and to characterize the resulting neoantigen-specific T-cell responses in patients who received the combination.

So importantly, this study looked at some patients worth samples. Samples were collected. I wish I had that little the figure that had each of the time points. But baseline after starting pembrolizumab after starting intismeran and then a long-term follow-up, which is usually a year after therapy started, in about 6 months after intismeran ended.

From these 7 patients, 3 were actually from the Phase I study and 4 were from the 942 study. And what this figure shows is that using a really cool assay where you can essentially load the peptide and have a reporter assay that has a T-cell receptor that can recognize that peptide, you can begin to see -- or you have the T-cell receptor that are on these T cells, you can see whether or not there was a target agent which essentially means that it was a neoepitope-specific TCR.

So this is a patient, and just showing the example that you can identify a number of different TCRs against the same neoantigen. So remember, up to 34 neoantigens are in the cassette. So this was looking at neoantigen 14. And so these were all generated for neoantigen 14 in [indiscernible]. These happen to only be CD8. So this patient generated CD8 T-cell clonal clones against neoantigen 14, against neoantigen 27 and 28 similarly, just CD8, but also CD4. And so proving the sort of proving the point that when you create a neoantigen therapy, you may get both CD4 and CD8, and we think that's probably a good thing.

Now this is taking that same patient and then looking at all the T-cell clones that were generated against those specific neoepitopes. So again, 14, 27, 28. So this is only CD8 positive T cells against 14, but as I mentioned, CD4 and CD8 against 27 and 28.

And the ones that are in color are the ones that have been characterized to date. It turns out it takes a lot of time to do this. And really, the point of doing this was just to show, yes, we can do this, we can follow this, but there's a ton more that were generated. And I think it's important to note this straight line is when patients are getting pembro. And then the steep upward sloping lines are after intismeran. So dozens of different neoepitopes for specific TCRs were mapped to each neoantigen.

And the other point to make is that, some of these are going down, but most of these are sticking around. And it's been 6 months since this person received intismeran and yet they still have at least the same, if not higher, numbers of T-cell clones against, for example, neoantigen 14.

When we look at all 7 patients, we were able to identify at least 1 T-cell clone that are T-cell neoantigen-specific T cell. This was this patient. The highest of the 7 was 18 out of the 34. Importantly, and I think it was mentioned earlier that there is rare shared neoantigens, but those that are shared are either BRAF or NRAS neoantigens. And that intismeran, again, elicits CD4 positive and CD8 positive and combined CD4 and CD8 positive to different neoepitopes.

When you begin to look and say, okay, that's cool. You have T cells that can recognize the neoepitope, what are those T cells doing? And so in this, we're looking at staining of the T cells. What you can see when these T cells are engaging the antigen is that they're making granzyme B, which is a good thing if you want T cells to kill things, and they're making interferon gamma. And so this is different patient still patient 3 and looking at the responses against neoantigen 14 and neoantigen 27. So not only are they there and we can identify them, but they seem to be acting like the type of T-cell we want to generate cancer cells.

In addition, you can then begin to look and say, okay, what type sort of bucket would you put these T cells in? Are these the cytotoxic T cells that are terminally differentiated and killing and then dying are these memory cells that may not be as close to the action, but can stick around a while? Or they T effector memory cells. And you can characterize that, what's happening here is you're doing a [indiscernible] stain of the neoepitope, and then you can see which actually buy into the [indiscernible] and then you can see where they are. So this is a control against viral antigens.

And so what you're seeing that these T cells when exposed to viral antigens are terminally differentiated. These are ready to go. They're trying to get rid of those virally infected cells that they thought they got exposed to. And when we look at the intismeran-treated T cells, these are falling more into the T effector memory. So they functionally active. They're positioned to do rapid surveillance and they can also potentially leave and go to other sales, other areas of the body.

So to conclude, we saw durable dovo neoantigen-specific T-cell responses in patients who are treated with intismeran and pembrolizumab. The team at Moderna was able to functionally validate and directly map the intismeran encoded individualized neoantigens. They've validated the neoantigen-specific TCR clonotypes and expanded during intismeran therapy. And most importantly, they persist over time. We could see both CD4 and CD8 T-cell responses.

And the nice thing about this is if I'm standing in front of somebody talking about intismeran and they say that was [indiscernible] you showed about those TCR clones, but do you even know that those things are going after neoepitopes? I can say, yes, I think we do know, what's next, Dave?

Okay. Thank you very, very much. Wonderful presentations. We appreciate you both taking time out from your busy schedules. So today, you heard about intismeran, and that's frankly, why I came to the company. But since joining the company, I have also discovered quite an exciting oncology pipeline, including our 4359, which we presented, we had an oral presentation at AACR, 4106 and 4200, which are off-the-shelf cancer antigen therapies. A T-cell engager, in vivo T-cell engager program, which is really, really interesting, 2808 and then cell -- in vivo cell therapy enhancers. These 3 programs as well as our emerging oncology research programs, which will enter the clinic will be highlighted at our Moderna Science Day later this month, and I encourage you to attend that.

So now I'd like to invite up our speakers, and we're happy to take questions and answers. So guys -- if Michelle.

Great. Thank you, everyone, for fantastic presentations. We're going to start the Q&A session. When you do take the mic, please introduce yourself and then ask your question.

Ted Tenthoff from Piper Solar. If I may, I have two for Michelle. And if you permit me, I have one for Ryan. So it was very interesting to see in melanoma that a small percentage of the antigens albeit unique to the patient were kind of what I would call shared or known driver mutation, i.e, respin. In other cancers, are you seeing more of these shared ones? And the one that jumps to mind right away would maybe be a Phase II for CRC. Are you seeing more KRAS or things like that? So are you seeing different patients depending on the tumor type, a different flavor and/or number of these shared antigens?

And kind of the second part where the question is going is, how do we know these neoantigens are actually better than shared antigens? And I guess it's kind of impossible to prove that out until maybe we do like intismeran versus one of your shared antigen [indiscernible], I don't know. But how do we actually know that these are better?

Yes. So maybe I'll start and then phone a friend if anyone else wants to answer. So I think the key is that in the bioinformatics algorithm, all it weighs out all the mutations and that includes hotspot mutation irrespective of the tumor type we're going into, which is why you see the type of clinical trial portfolio we have. So in melanoma, you would expect BRAF and RAS mutations pop up and be within the ranking system. For non-small cell lung cancer, I would expect EGFR, ALK, ROS. The question becomes when we rank them based off HLA presentation, expression level and sort of a prediction to engage the immune system, do those shared mutations actually link to the way the neoantigens or the novel clones? And in some patients, that's the case where you see it for the less than 1% in some patients, you don't see it. So the answer is in all tumor types that we have, there is the potential to have some of those shared incorporated into the neoantigen asset.

Now the question becomes, do we have data yet across the rest of the studies to start showing this? And the answer is, we did see this the P101 study back from some of the older papers where we were mapping the different neoantigens, but we haven't accessed the Phase II studies yet that are ongoing or any of the new Phase III studies and the rest of the tumor type. So that is one of the things that we are really looking forward to as the data sets there to see exactly how those neoantigens map. Do you want to add.

Yes. I was going to add, it's highly likely. The answer is going to be yes. And that's, there's a long literature on this, going back to Steve Rosenberg's interrogation, that shared neoantigens are just not a, and that probably has to do with the fact that there's evolutionary immune pressure, even in hotspot mutations, they tend not to be presented or they're presented at very low levels. So I think that's to be the case. And then the answer to your second question, which was -- what was the...

How do you compare the share?

Oh, yes. Yes. So shared antigens versus neoantigen, of course, we won't know but scientifically neoantigens have not gone through thymic selection. And so there are T cells that are going to recognize it with sufficient [indiscernible], whereas shared antigens by definition, have gone even shared antigens, such cancer tests that are not usually present in adult tissues, they're present in the testes or the placenta, so they have gone through some timing selection, that's the scientific hypothesis, but of course, we won't know until we test.

That's a great point. And I really do appreciate the comment that you're making, but it's really about how the patient is going to respond to these neoantigens. And my quick question for Ryan was, and maybe I misunderstood this really cool presentation. But on Slide 39, where you showed the 3 antigens that were activated in expanding the T-cells, does this mean that only 3 of the neoantigens were kind of taken up and activated that way? Or were these just the top 3 that you had across analyzed.

Yes. So when characterized each of the 7 patients were characterized and they were tested against each of their 34 new epitopes, and the range was 1 TCR expanded 1 TCR expansion against the 1 neoepitope to 18, neoepitopes that generated TCR expansion. So I think it's why does 1 happen or 18 happen, why do you get a dozen or 2 dozen or 3 dozen against TCRs against 1 neoepitope, I think these are questions that are hard to answer from a small data set. But maybe areas of study is particularly if we can, I mean, all these patients that I showed, none of them had recurrence. So it's not like I can say, "Oh, the 1 had 1 recurred, but the one 18 that had a gain didn't recur." And of course, because it's an adjuvant study, you can't look at response or PFS or other endpoints that sort of make you feel more certain about what's clinically happening from an anticancer standpoint.

I think the other thing with the one, my understanding is that, that patient had 1 neoantigen with a response. It wasn't 1 TCR.

Correct, [indiscernible] TCR.

Even for a given HLA, you may have more of the CR, some neoantiwill be presented in different HLA. So I think there was an illustration when one of them had multiple T-cell clones against 1 antigen. That was the norm rather than exception. The norm is multiple different T-cell clones against 1 antigen.

And what we didn't show here showed in the poster, there was an example of a patient who had across HLA and HLAB that would generate against the same neoantigen.

It sort of gives this sort of innate biological redundancy. So it's not HLA 02, 01 limited or the -- and so I think I was surprised by the number of different T-cell loans against a given neoantigen.

Yes, that was clearly the most interesting, what I would not have guessed before seeing the day.

Particular when you go, we've chosen that clone because it binds well to HLA. And in your head, the carton new drawers student was 1 T-cell finds that HLA with that neon.But clearly, there is so much redundancy in the immune response.

Alec Stranahan from Bank of America. Really great discussion. Just two questions from me. Maybe first, I believe that the Phase III is enrolling Stage II disease as well. I guess what percent this sort of within the Phase III data set? And I think we saw, I guess, directionally higher hazard ratio in the Stage IIIc versus the Stage IV in the 5-year follow-up, small end, but how does that maybe bode for even earlier patients?

And then maybe one quick one for Dr. Sullivan, in the poster yesterday, it looked like there was maybe some variability in terms of the number of immunogenic neoantigens sort of within that 34% total delivered between patients. Could you maybe speak to the variability and if there's maybe a minimum threshold of truly immunogenic neoantigens?

So I'll take the first one, which is we wouldn't disclose the number right now, but an ongoing trial. But I would say it's likely to be sufficient labeling negotiations. And in terms of efficacy, I think you're right. I think the lesson we're learning is that the earlier you go, the more likely you're going to have a treatment effect. Of course, that's balanced the early go the less treatment events or the less events you're going to have. So it will be a balance between that.

So my feet that is that the benefit the same. But I think there's some chance the benefit will be greater. So when you look at -- so when you develop a hazard ratio of a curve, the hazard ratio is a reference to the whole curve compared to the whole curve with sound intuitive, the higher risk of your population, the earlier you get recurrences. So in adjuvant studies, you get a group of patients who recur within weeks. And they're the absolute highest risk patients. So if a treatment starts at week 6, I predict the hazard ratio in the slightly lower risk patients, not the risk because Stage IIc is still a high-risk population, but they're less likely to recur 3 weeks after you start the pembro.

So if the hazard ratio instead of being 0.51 is 0.45, my hypothesis is it's that by having a more, if you like, typical adjuvant population, paradoxically, we get a better hazard ratio because when the curves run together, that feeds into the hazard ratio of the whole curve. So I actually think it's going to be a positive that we've balanced the population because really, we have -- this has got an artificially early recurrence population, not necessarily a risk, but microscopies has those early recurrences, whereas the IIIbs, the Ias and the IIcs, IIbs, don't get that, they recurred at first scan often, so I predict we might get a better number, a typical population.

And then your question about the number of neoantigens that you get T-cell responses to -- we said again, we can't answer that in this population because it's, one, we don't have enough patients and we don't have a splay between patients who recurred in patients who didn't recur. There is 2 pieces of information that speak to this, both is with a competitor called autogene [indiscernible]. One is in the pancreatic cancer data set, the initial data set that came out of MSKCC where they treat patients in the adjuvant setting with their new epitope and new epitope therapy.

The patients that generated responses against the neoepitopes didn't recur in the patients who didn't generate new epitope responses did recur. And that's very clean data. In another trial with that drug, we did a Phase II randomized study in frontline melanoma, previously untreated. This actually was launched around the same time. So weren't a lot of patients who got adjuvant therapy on that study was mostly just first time of being exposed to checkpoint inhibitors. And very similarly to that, we could see that patients who generated more new epitope and more responses to more neoepitopes had better outcomes than the patients who didn't. So it's not a specific answer to intismeran, but presumably, these things work together, and that biology is biology if you're having sort of an immune responsiveness to a therapy like this.

The one other piece I'd add on to what Dr. Sullivan saying is, at least in the poster, right? So you had that splay between 1 and 18. So we know one can be sufficient, at least for disease control in that 1 patient. And this is one of the reasons we're so excited for the 5,000-plus samples that I highlighted because these are the types of sizes. I think we're going to need to understand how many neoantigens do you need, what makes features of a neoantigen, how do we start parsing that out, I don't think we can do it with just the.

Yes. You basically need all the samples from all the patients or nearly all samples from all the patients that you can really get a good look at how core it outcomes.

Cory Kasimov with Evercore ISI. Probably for Dr. Carlino, but anybody can chime in. Curious as to your thoughts about how the upstream migration of immunotherapy to the neoadjuvant setting could impact -- eventually impact intismeran? And once available, how would you choose which patients get neoadjuvant therapy versus an intismeran-based adjuvant therapy.

Yes. So that's a good question. So, the one question I asked expecting to that get that question this morning, but not getting it was on this study, even though they're IIIc, remember, a lot of IIIc patients are microscopic IIIc, so even on this study, 1/3 of patients have micrometastatic disease, right? So by definition, those people can't get neoadjuvant.

When you look at the registration trial, the prediction or the estimation is 2/3 of those patients have micrometastatic disease. So the micrometastatic population is a significant proportion of the Stage II. And by definition, the Stage II, despite the presentation this morning, Stage II don't really have an option of neoadjuvant because the definite the biopsy removes all the tumor. So you've got all the Stage IIs. And most of the Stage IIIs, neoadjuvant isn't even on the cards for us. So I think that's the first thing. So this is the dominant much, if you will.

I think clearly, I guess the question, the provocative is at the moment, if someone walks in with macroscopic nodal disease, they're getting neoadjuvant, not adjuvant, right? And I think that will remain the standard unless the hazard ratio on the registration trial is so good where you'd actually say to someone, look, I could give you neoadjuvant pembro, same toxicity. I think intismeran outdoes the neoadjuvant benefit hypothetically. But when you're saying I'm going to give you neoadjuvant, ipi/nivo, a different question. So I think the short answer is there's a huge market or a huge group of patients that need adjuvant and can't have neoadjuvant. That's the easy population.

If the hazard ratio is spectacular, it becomes quite a complex discussion because the lack of increased tax compared to adena because adena right adds permanent tox. And then I think the most interesting question and the next study is for the can intismeran add to the neoadjuvant therapy, so if you give intismeran presurgery, can you improve on the adena or the SWOG result, and that's an important study to do. So we have to do that study. We start SWOG or start adena and you start intismeran before the operation. But the easier group patients to study is the patients to get neoadjuvant whichever one. And then post neoadjuvant if they don't have a complete response, they get their adjuvant would be typically nivo or pembro plus intismeran. So that's a very easy study to run.

Some may argue you don't need the study. But certainly, once you've got the positive Phase III study, I've just given you an idea of 2 other studies and the post-neoadjuvant one, I'm confident we could design a study with 200 patients because those patients have such a high risk of recurrence. They're technically already on label. So we could do another quick study with 200 patients and get that answer relatively quickly expanding the population.

So I think my main answer in summary is that the microscopic population is still the bulk of the patient/Stage II. And this will be tested in the adjuvant. Those 2 studies have to happen. The lung cancer guys have already got those studies going on. So we saw on that first slide, the neo -- post-neoadjuvant study already happening in the equivalent lung cancer, and we, lung cancer is not allowed to beat melanoma, so we'll get there quickly.

Myles Minter from William Blair. Congrats on running a controlled study here if you deserve that comment earlier today. My question is actually very much coming from investors and that is Dr. Carlino, I was interested you were kind of inferring where the placebo curve would be on the RFS that 5-year data, investors bring up where the pembro curve from 054 would have fitted on that. Do you think that pembro performed as expected in this trial? Did it underperform?

Exactly. So I think I think, so if you go to the 054 papers right, you can't use the whole 054 population. So the best way to capture the prediction is just look at the IIIc group. So that one of the 054 papers, we sort of update 054 every 2 years, but one of the 054 has the IIIa, IIIbs and IIIc. And that IIIc group is the best approximation to this. And I think it's smack on 50 at 4 years. So it's very, very close. And so that's what I was using in my head. I was remembering that. I think it's actually, there's 1 figure because there's, or these III, it's a, b, c in the middle. I can't remember which paper it is, but it's, I'm pretty confident it's smack on.

This is Greg Torres representing Tyler from TD Cowen. So how confident are you that the high rate of INT manufacturing you've achieved in clinical trials will be replicable in the real world? And are there any considerations related to feasibility of this in the Stage II and III versus Stage IV patients?

Yes. So maybe I'll take that one. So I'll start with the Stage II and III. So obviously, we've done it for the 001 study. And then on top of it, one of the things that we're so excited about with some of the other studies is that, especially for like NMIBC, the amount of tumor is actually even smaller than what you could get into the Stage II. So not only are we expanding the hypotheses within the clinical studies, but we're also testing the bounds for the tissue requirements as well. So for that, I think we've been able to showcase that based off the enrollment that we've had.

And then as far as the global expansion, you have to remember that this study for KEYNOTE-942 ran from 2017 to 2019. And in that time frame, we manufactured the 157 right or 107 intismeran doses over a 3-year span. The 001 study started in '23. And since then, we have the litany of the pipeline. And to date, we've dosed over 2,000 intismeran patients. So you're talking a tenfold range in the past 3 years.

So again, that ability to scale that we saw with the COVID era is what we are able to scale with intismeran, actually, a miniaturization of the process and then a scale out across the globe. So what we saw with KEYNOTE-942 was that we had a U.S. and Australia footprint. And now our global studies with Merck are in over 46 countries. And again, that turnaround time is really maintained [indiscernible]. So even with that up of the tenfold that scale out globally, we're still able to actually maintain the distribution time in the manufacturing chain. And that gives us confidence that if we enter into the commercial sphere, that we'll be able to deliver the way we expect.

When we visited, I visited the Moderna plant. And I think you really got the feel having visited that it was set up to do 50,000, and it almost felt like if it wasn't doing tens of thousands you could see the sort of the exponential of the processes where it felt very impressive to see how it's sort of this process had turned down to one thing and then you can -- it would just repeat it. And if you wanted to double it, your times it by 4. So I think probably of the ASCO week, the visit to that plant was up there with the sort of how much thought have been put into the scalability. I think as a none -- someone doesn't make things, but it seemed to be ready and raring where it's almost felt like it was built and sitting there ready to go.

Lili Nsongo from Leerink Partners. So maybe a quick question going back to the piping and then linking that to the epitope selection. So up to 34 neoantigen [indiscernible] selection, I think it was down to 9, between 9 and 34. And then 1 to 18 that are immunogenic. Can you maybe give us a sense of how much do we know in terms of whether there is any correlation between any baseline characteristic of those patients, namely P1 status stage and what you're able to do in terms of [indiscernible] selection and then what you see in the context?

Yes, I think, I mean it's an excellent question and an important one. I think with 7 patients across 2 trials we don't have -- it doesn't matter what they were in terms of like the PD-L1 status or TMB and things like that. I think we need to look at more patients and to be able to answer that question with any certainty.

But I guess, intuitively, it's unlikely to be a simple thing like stage in my mind. It's the biology of both the immune response and the tumor. And if we look at TMB, we don't have a huge difference in TMB between Stage IIIc and Stage II melanoma. Certainly, actually in Australia, you probably had a higher TMB in Stage II because they're slightly older and we get these group of patients who have Stage II melanoma and older people, which goes with chronic sun damage and TMB. But I don't think it's going to be something like stage or PD-L1 or something simple.

I guess the only thing, and I think this is where this could only get better is hypothetically, you could imagine an analysis in 5,000 patients where you run the algorithm and say, actually, this type of neoantigens isn't as good, so you no longer make the cut of the 34. And so I think the exciting thing for me is you're choosing the 34 best, right? So I think it's impressive that they chose the 34 best not having ever treated a patient, and that's worked out pretty good.

If you can feed the positive and negative feedback into the algorithm, could you improve it? I guess the question is, do you need to improve it? Until the curve is flat, you can always try. And so I actually think that if there was an opportunity to evolve the algorithm. And I know that's complicated and we'll need discussions. But certainly, the algorithm is pretty impressive. But theoretically, I think that was where the difference might come not something about the stage of the patients or...

True. But who knows, right? Like somebody with a big bulky tumor may be different than somebody with microscopic disease. So I think it's valid to look into that, but we also have to just get many more, need to get data from many more patients.

Matt Hagood for Mike Yee from UBS. Maybe one for Dr. Carlino. I just wanted to ask if you could expand a bit on the safety profile here. Compared to IO, I'm curious your thoughts on whether this kind of expands the population of patients who would get treated in the adjuvant setting with an agent.

And then if I can just squeeze one more in on the earlier stage pipeline, I wanted to ask when we might start seeing some days on updates from those programs, too?

So look, a couple of things about the safety. So I think the decision to use intismeran and pembro from a safety point of view is completely driven by the toxicity, right? So am I using intismeran and pembro and soon with a kidney transplant adjuvantly? No, but nothing to do with intismeran. It's because of pembro.

The only area, I guess, that may expand the population theoretically is I gave a second talk at ASCO this afternoon about tox. And my first slide was about risk benefit, right? So every patient has a risk profile, which can alter based on their comorbidities, and every patient has a risk appetite, right? So as a patient, a Stage II patient may say, look, for an absolute benefit of 10%, I'm unwilling to take the risk of a 1% risk of cortisol deficiency. Whether you would make that decision or I would make that division, that individual patient may decide not to take a given risk. Because intismeran doubles the benefit, right, and does nothing to the tox the risk/benefit discussion in some ways becomes easier. And so certainly, that's how I discuss adjuvant, risk/benefit, ex benefit, ex risk and you as an individual have to decide, but we're not touching the risk side of that equation. But if we're doubling the benefit side of the equation, you may expand the population.

The thing that we haven't touched on in melanoma, but the lung cancer guys get to is single-agent intismeran completely different conversation because it's probably safe to give a kidney transplant patient in single agent intismeran or a person with rheumatoid arthritis or ulcerative colitis, et cetera. So I think the summary answer to me is the combination, you probably have a slightly bigger population because of the risk benefit, but if the population was going to expand hugely, it would be single agent.

I guess a question for Ryan, when the drug is approved, if you had a patient who was contraindicated to pembro, theoretically, you could. There would be a temptation to use intismeran.

Probably wouldn't do it, but that's generally because I like some data before I make a decision. I don't need all the data. I do want to come back to your point, Matt, I think not only is the risk/benefit -- I mean, ultimately, the decision is to patients', but the way that the physician talks to the patient really can influence the decision. And right now, I don't know about you, Matt, but if somebody has a Stage IIIa melanoma. They have a 1.1 millimeter thick melanoma on their leg, and they have microscopic deposits in their node. I'm not going to recommend pembrolizumab for that patient. I'll talk to them about it. I'd say absolutely like to say, I have to have this, otherwise, I'm not going to be live. I'll entertain it. It's on label, but it's -- I think, to Matt's point about what a patient's threshold might be our threshold, just kind of our biases about how we think about risks and benefits, we might actually be more supportive of making such a recommendation.

Just to answer your second question. The 4359 we just updated at AACR, and we now are expanding the data set to confirm the signal. So that's ongoing. And I would estimate probably next year would be an update 4359. For the other 3 or 4 clinical programs, they're still mostly in dose escalation. And so we will share when we plan to update, I think, as we get closer. And then I'll just put plug in for the Science Day we have later this month.

And then the only one other part since we're talking ASCO is we did have the 2808 tip actually as a poster session here. So it does showcase that we're beginning to actually One, have the trials in progress and two, there's some preclinical papers that are out for that one as well as 4106 and 4200.

Ellie Merle at Barclays. Maybe first just for the physicians. Obviously, really impressive hazard ratio on Phase II. What would be the minimum effect size that you would want to see in Phase III to adopt this and say, widely added on to all your PD-1 adjuvant patients, given the risk-benefit comment that you make around the safety?

And then just a question for the company. obviously, really impressive hazard ratio in Phase II. As we think about the interim analysis, any color on sort of what the minimum hazard ratio would be needed to be successful on the first interim? And then just based on the curves that we've seen in the IO trials, how we should think about the likelihood that if it misses the first interim, it could be successful at the final analysis.

So just quickly on the statistics, we have we've said nothing on the interim analysis on the statistics. And with that, I'll hand it over to one of the physicians, please, to speak to what they consider a good hazard ratio in the Phase III.

Yes. I guess the first thing is that there, in my mind, is in Australia, I think there are 2 thresholds. So as a patient, as a clinician, because there's no, so when I think of tox, all I care is serious to permanent tox is the big one for me. There's permanent tox or tox that bothers the patient's quality of life is what we don't want.

So because the cost from the patient perspective, not financial, the cost from the patient's perspective is negligible, the benefit to consider doing it is lower in my mind. So hypothetically, if I had 2 trials that had the same hazard ratio, intismeran/pembro versus pembro or ipi/pembro versus pembro in the adjuvant setting, and they were identical hazard ratios, ipi doesn't meet the bar intismeran does. So from a patient and a clinician, I think the bar actually is quite low.

Acknowledging that there's another part to cost, right? And so the hazard ratio that is required to make it financially worth and it's hard as a clinician, we're not great making financial decisions, me personally. I'm also Australian, so therefore, I've come from a health system that has a central payer and has those complexities. So I don't know what number.

I think certainly -- and the other way to look at it is actually not hazard ratio, it's absolute benefits and numbers needed to treat. So we've got an absolute benefit in that study of 22%. So a number needed to treat of 25. Would I do this for a number needed to treat of 10? Yes. The pay a bit is something I don't think I'm don't have the knowledge to answer on. But from the patient point of view, the benefit could be really tiny because the patient's cost is not measured in dollars and cents. The patient cost is measured in tox. So with the calculation being tox versus benefit, the benefit could be smaller than.

Yes. And I think the answer to your question about what hazard ratio, whatever the hazard ratio where the p-value is significant and the FDA can approve it, I'll use it.

Okay. And we'll take our last question.

This is Morgan Lamberti, representing Salveen Richter at Goldman Sachs. For the physicians, how does the translational clonality data impact how you think about success in non-small cell lung cancer and indications beyond this?

I'll just start and then I don't know, I mean, if you didn't have the translational data, but you had an amazingly positive Phase III trial, it doesn't matter that you had, didn't have the translational data. it kind of matters and from a sort of scientific interest standpoint, like did it actually do what we think it can do. But I think from a proof-of-concept and as you're also rolling out potential ways that you can monitor patients. It's way easier and cheaper to do TCR sequencing than it is to do all of that really sophisticated experiments to get that reporter assay and characterize all the TCRs.

So on some level, I think seeing that there is a likely explanation of that in TCR clonality that correlates with actual expansion of neoepitope-specific clones, it will make us feel better about any of the trials if we just followed TCR clonality instead of through TCR sequencing instead of doing these deep characterizations of all these. As a scientist, it also makes me feel good that we are saying, we designed something to do something. We did it, and then we've actually shown that we were able to do the thing that we were trying to do. There's a lot of dos in there.

But ultimately, I think it feels good when you can say this works and we actually are doing what we think the drug is supposed to do, and we might even have a surrogate biomarker that can be reflective of the more sophisticated TCR characterization that can be rolled out into all of the trials.

Yes. So look, I agree Ryan. I think when you've got a randomized Phase III trial that's positive, it almost doesn't matter what the drug does, right? And by the same token, if I can give you the coolest drug ever and the best preclinical data, if properly designed and run Phase III trial is negative, it doesn't matter how cool, the net -- the science is, it's negative. So the Phase III trial thing.

I think the big thing this does for me is, one, it gives you huge confidence that the Phase II data is real certainly. So when you've got less than Phase III evidence, predicting your drug works because of x and then showing that it actually happened gives you confidence I think with the reference to non-small cell lung cancer.

The other positive is this mechanism of immune response is not melanoma specific. So it actually gives you the confidence that this is likely not just to be a melanoma, right? And so I think at the point now where we're going, what's the likelihood of the register melanoma study being positive, the translational data increases that of the scale. To be honest, once you've got the Phase III data and you just get Phase III positive trial after Phase III positive trial, the translational data is really important about working out if there is a subgroup of patients you're not helping, what do we have to tweak to have them and what's next? But it's more about the confidence today about what's coming next year, really, which is, that's the most important thing. Yes, it's cool, but it makes us way more confident than we otherwise would be.

Yes. Maybe I'll just add in the final minutes is the most validated immune therapy, of course, are anti-PD-1s. And we know that anti-PD-1s work by releasing the brake carb reversing exhaustion on tumor reactive T cells which then go on to kill the cancer. That's the most validated clinically immune therapy. We know now that our therapy roughly does the same thing. We give the intismeran. It activates neoantigen-specific T cells. And from the randomized data, we see evidence in this Phase II that the T-cell are doing their job. I think to me, that's the reason that gives me reason to believe that this is not just a melanoma specific melanoma because anti-PD-1s are not just melanoma drugs. Of course, we'll have to wait for the randomized trial, to find out.

But with that, let me thank our investigators who joined us, and thank you all for joining us tonight. Thank you, guys. Appreciate you. Thank you so much for spending the evening.

My pleasure. Thank you, guys.

Welcome, everyone. Thank you so much for joining us for this conversation about Moderna. My name is Courtney Breen. I am the U.S. pharma analyst here at Bernstein. And it is my privilege to have Stéphane Bancel here with me, the CEO and Chairman of Moderna. He's been in this role for a decent amount of time as well and has seen Moderna through the ages and through the different areas of the company. So I'm really excited to kind of have an opportunity to dive into kind of Moderna today, where Moderna has come from and where Moderna might be going in the future.

I also know that AI is a super important topic for all investors these days. So we'll be hoping to touch on kind of the impact and potential of AI and drug discovery and kind of in operating some of these businesses. But I do also want to remind you that if there are other topics that I'm not planning on covering that you'd love to have covered in this conversation, please do send them through the Pigeonhole app. You'll find a QR code to be able to send them through. I'll receive them up here and can integrate them into the conversation. So we want to make this as relevant and as impactful for everyone's here.

But without further ado, Stéphane, again, thank you so much for joining us here today. As I mentioned, you've been leading Moderna for a while, I think, since 2011. It was back kind of before there were any products in the market. Before we knew about COVID. Back before then we had the COVID vaccine. A lot has changed between then and now. What has fundamentally changed in how you're thinking about the opportunity for Moderna and how you're running the business of Moderna today?

That's a great question. Good morning, everybody. Thank you, Courtney and the team for having us here today. So yes, I've been CEO since the beginning. I was employee #2 technically. There was a scientist at Flagship VC whom the founders had recruited and I joined and we started to have the team. So of course, the job has changed a lot.

If I look maybe pre-pandemic, we were really a research and early development company. We have quite a number of products in the clinic.

I think my belief in mRNA has increased tremendously for a few reasons. First, nobody has got the mRNA product approved in 2018. If we take the IPO time frame, pre-pandemic, whereas now we have four products that have been approved by FDA, another one being under review right now and a lot of readouts for Phase III in cancer and in rare disease this year. So it's kind of quite a different world.

And the team keeps on pushing the boundaries of the science of the platform. And so I think we're still in the very early days of what mRNA can do for patients. I've always taken a very long view on things, which is when we started the company, I used the biotech technology as kind of what I was trying to achieve with mRNA, which is if you think about Amgen and Genentech when they started in the '70s, which is like more than 50 years ago now. They had no idea they could do antibodies. They're working on human protein. And it was not working well in the early days, and then they made the first growth hormone insulin and then they made more and then made first antibodies. And if you look at the biggest set of products as we know in pharma today, it's mostly antibodies and proteins, right?

And so we've always taken that arch to say, okay, if we invest in science, if you can scale the company, you can be the true platform we should be able to get a lot of medicine over time into many therapeutic areas. And so I used to spend a lot of my time before COVID on just research and early development because that's where we were. If you look at where we are today, we are very different companies present around the world. So I would say spend maybe 25% of my time on the commercial business. Which is sales, marketing, manufacturing, cost of goods, scalability, prelaunch of products like Intismeran, right now in the thick of Intismeran pre-launch activity, marketing, medical, pricing, sales. Same thing for PA, we record that on rare disease because the Phase IIIs are reading this year.

That's maybe around 1/4 of my time on research and early development because, again, as I just said, I believe we're still in the early days of mRNA. I believe we are the only company at scale today because the landscape has changed a lot. CureVac used to be an independent company. It was the first mRNA company. They're gone. They have been acquired by BioNtech. BioNtech is spitting in two. They just announced as closing down their manufacturing facilities in Germany. And so Sanofi bought Translate Bio. Translate Bio, they just announced they're not working on the flu program anymore, Sanofi on mRNA. So the world has changed a lot. And I think we are the only company today at scale to be able to keep inventing new technologies. So I need to spend a lot of time helping the team find the next IND.

And then I spend around maybe 25% of my time on AI today because I think it's an amazing opportunity to reinvent the business of its science or it's just how we do work. And then the rest is around talent and a bit of time with investors.

Fantastic. Super helpful. You touched on so many things that we're going to dive into in this conversation. Perhaps one thing that didn't necessarily come up as where you're spending time with some of the policy pressures.

Last year was a year where I think every single biotech and pharma company perhaps spent an inordinate amount of time kind of dealing with the potential risks, policy risks that might have landed at the doorsteps of the sector. We're still seeing changes play out of the FDA, particularly. We no longer have an FDA Director of Commissioner. We've got an acting individual in that role. He's come from the food side.

How are you thinking about the changes occurring in the regulator kind of impact of vaccine skepticism, but also is there going to be consistency? And therefore, how does that influence how you're making decisions in R&D and kind of the choices you have to make upfront that perhaps then don't land in front of the regulator for a couple of years?

Sure. That's a big question. So I would say, obviously, for the industry, it is really important to have predictability. I mean, every CEO said the same thing over the last couple of years because of a very long life cycle of our industry in terms of investment and returns, we need predictability. We need to know when we invest in something, is that what's going to be reviewed ? Is it going to be reviewed in the right way and so on. So that's, of course, really important.

The good news, I would say, is that most of the teams do the work. So I think it's important to differentiate at an agency like the FDA, what the commissioner and the head of the divisions do, which is around the policy about the future. So of course, that is really important for the agency to prepare for the future. So not having roles filled is, of course, a problem for the country, for Americans and the health, if you think about 5, 10 years from now.

But if you look at the product reviews we're having, whether it's a vaccine, whether it's a rare disease or Intismeran. It's a working team that are in constant discussion with our working team. And those teams are pretty stable. There's been a bit of changes early last year. But thankfully, for our programs, they have not been really impacted. The key players in all our key programs have stayed through since early 2025.

And so I'm, of course, like anybody else anxious to see stability in the agency. To be able to have people in a leadership position to talk about for example AI. How do we use AI to file for approval? How do we use AI to do science? How do we use AI to enroll clinical trial faster, to get site faster? There's a lot of things that we can decide ourselves as how we run the business. But because we are a regulated industry, there are a lot of things we need the regulatory approval, and so we need policy clarity on those topics.

So I'm hopeful because I'm not optimistic. I'm an entrepreneur also. I have to be optimistic. or I will be in different lines of business. I think those things are going to get resolved. And again, they don't impact us short term, they impact us on more long term.

Yes, absolutely. So per super helpful. I do want to get back to AI, but maybe I'll dive into some important data, particularly as we've got ASCO on the horizon and a big oncology conference and more data anticipated later this year for your Intismeran program. And just for those in the audience that don't know, this is what previously might have been called a personalized vaccine is now being turned over as an individualized neoantigen therapy that can be used to reduce the likelihood of progression or disease in cancer states.

You've obviously got programs ongoing for melanoma. We've seen some very long-term Phase II data. Demonstrating durability of the outcomes and outperformance relative to standards of care like KEYTRUDA, which previously were big step-ups. How do you think about kind of what we might see later this year? What is the goal in terms of what could be demonstrated for this product? How different might it be to what we've seen in the Phase II for the product so far? And perhaps just a broader question, what could be the potential future for something like Intismeran, if you were we're thinking a few years further out?

Wow, that's a lot of questions. So I would take them in order. If I forget anything I'm sure you keep me honest. So we shared the top line of the 5-year data in January of this year with a hazard ratio of around 0.5, which we are very pleased about because it was the same as what we saw at 3 years.

And so as you said, the durability of a response was extremely exciting to us, what it can mean for patients and what it can mean for the company. And what also was really exciting to us as we looked at the data in detail is the p-value. The p-value improved as well. Which when you see a study where you have duration in oncology and improvement in p-value, this is really a good sign. Again, does that mean it's going to be a great outcome, but it's a really, really important key enablers to a great outcome in Phase III.

We're excited about this weekend. So there are two things that ASCOs, of course, the full data set of the 5-year data Monday morning, scheduled as a plenary session oral session at ASCO. We have an Investor Day at the end of the day to walk people through the data. We don't have direct access to ASCO. And this weekend, against public information, there is a poster about the translational medicine of Intismeran, which is really at the cell level, a very detailed work is being presented this weekend ahead of the clinical data to explain how Intismeran works.

We've already shared a little bit at ASCO before including, I remember in 2018, showing in lung cancer, how we could take the blood from people -- from patients, sorry, before we inject them the product, we had sequenced the DNA of the tumor cell. So we knew exactly what antigen we coded in our product. But we took the blood before we had the first injection of Intismeran. We look at the T-cell for those new antigen. And then we do the same thing after [ four ] those, and we show that T-cells we are starting to recognize the new antigen that we knew we coded in our product. Yes we knew the patient T-cell did not recognized before starting Intismeran. So that's a great proof of mechanism. The question we all had, which is when we saw the clinical data 2 years, 3 years and now 5 years, we are very pleased to say, do you have any clinical impact because you could have T-cell activation, but have no clinical impact, and that's not the drug.

But we saw the mechanism, you're going to get more detail on Saturday, and then we saw the data and now the duration of the data. So like anybody else, I'm binded to the data, when we have the data, you have unit of data pretty quickly. As we always do at Moderna, we never keep data wrapped that are important for obvious reasons. And so we're looking forward to the data.

I think the piece that is exciting is that we just announced recently with Merck, a new Phase III study in lung disease. It's our second one, Phase III in lung, just to tell you, Merck's and our beliefs in the science and the mechanism. It's in Stage I lung cancer patients. If you're diagnosed with lung cancer in stage I you do not get a checkpoint today because of a side effect of checkpoints. As you know the checkpoints when they work are wonderful medicine, but they come with a heavy side effect profile. And so the standard of care today is surgery. Sometimes chemo, sometimes no chemo and monitoring the situation. But here, the idea is to try Intismeran as a monotherapy because whether in the study, we're also going to try Intismeran plus KEYTRUDA. But we are very, very excited. Personally, I'm very excited about trying Intismeran on monotherapy because we know from the Phase I study of Intismeran, we showed had at ASCO several years ago that we had response in several tumor types, including lung, because of what we understand the mechanism, partly was going to be presented on Saturday at ASCO on melanoma.

We really believe that if you go earlier in disease, you have first less burden of disease. And two, you have a stronger immune system. And what is very clear to us is that this drug works by teaching your immune system, what to look for or your T-cell to go eat your cancer. And so we believe that having a very healthy immune system is very important. Earlier in disease, we believe, is going to increase the odds of our medicines working well.

Fantastic. That's super exciting. And I think the there's one question of, does it work in melanoma? And then the next question immediately is how well is it going to work in other cancer? And do they have to be highly immune-sensitive cancers? Or can they be kind of a broader set of heading towards your gastrics and other cancers and other immune sensitive.

Yes. So like in science, we have to run the experiment because you cannot know a priority. But we are deploying a lot of capital and so is Merck. Again, for those of you that are not close to the partnership, it's a 50-50 cost share now and profit share. So every time you see a study going, you know that Merck is paying half of it and the capital allocation they're making compared to a lot of other assets we have in the pipeline, of course.

Look, as I just shared, we have shown earlier response of Intismeran as a monotherapy without even KEYTRUDA in melanoma, lung, head and neck. So with what we know of melanoma and the mechanism of action, we believe, I personally believe -- strongly believe. It's not the we don't deploy capital either that where KEYTRUDA works, Intismeran should help improve the response from KEYTRUDA.

How much is it? Is it a 0.5 hazard ratio like melanoma? I don't know. We have to run the clinical experiment to know. Could it be better in some, worse in other, most probably. The piece that I'm excited about, as I said a minute ago, with our lung Stage1 disease is to go earlier in disease. For example, I learn talking to key opinion leaders, world key opinion leaders in melanoma that some patient Stage 2 melanoma do not want a checkpoint because of the side effect. So could 1 day we go earlier in disease, assuming the Phase III is successful of melanoma later this year, do we want to go earlier in disease because that could be interesting and could Intismeran monotherapy. We actually could become standard of care because you don't have a safety profile. I think what most people are missing about it is Intismeran, and you have to do the work because it's a different asset, it's different technology. Its the safety profile.

The safety profile of Intismeran is similar as an infectious disease vaccine. So I think if you have a cancer and you're diagnosed by cancer or a loved one, and you are told you can try this drug, and it's like you might spike a fever tonight or you might have chills tonight and that's it. If you have a cancer and that's a side effect profile, like yes, sign me in.

We've said it several times, but -- the Phase III Intismeran plus KEYTRUDA drug melanoma study was a fastest study Phase III of KEYTRUDA that Merck ever enrolled. And I cannot say we did it better than Merck. It's not true. Merck run the study. And they are pretty good at running clinical study in oncology last time I checked. And this was a fastest study ever enroll in Phase III. And you asked the investigators why, and I have done that myself, and they tell you Stéphane was an easy call. We had very exciting data in Phase II, 0.5 hazard ratio, one in two people benefiting and the safety profile is like our vaccine.

Every patient that I told that, that they have one in two chance that this is better than what I'm going to give them anyway, KEYTRUDA. And there's no downside in safety in the like mine, which is why the PIs sometimes will tell me, I signed up everybody. Because I recommend it to everybody and when I explain it to them, they all signed up. So that's I think the interesting thing about Intismeran is its safety profile. It's unlike anything I think we have seen as a field in oncology.

Absolutely because you usually in some ways trying to...

It's always the trade-off. And when you see sometimes a lot of time, you have two checkpoints together and then you have a lot of talks.

Absolutely. So the core of your business today, though, is still very vaccines, very COVID oriented. And we've obviously been through a lot of evolutions of the COVID market. It seems like we're getting to perhaps a more stable level, predictable level of what does cover vaccine utilization look like going forward? Perhaps you can make a comment on that, but also norovirus, this is different to COVID in so many ways as you think about this opportunity. Can you talk about the market opportunity here? And what will it take for this to become a really meaningful contributor to Moderna's revenue profile?

Sure. So again, a lot of good questions, Courtney, as I want to try to unpack everything. So yes, today, we're [indiscernible] vaccine business. We have now four vaccine approved around the world. We should get through this year. And if Noro Phase III is positive later this year, we'll file it very quickly, and it could be approved next year.

And if that happens, we'll be, I believe, with the largest respiratory portfolio of any company, which will be very helpful to us as we negotiate with customers because in the U.S., most people want to realize, we sell directly to pharmacies whether it's a CVS or Walmart local pharmacies. And there's no PBM in the middle. So we are direct in a B2B setting and be able to bundle product is really important. And for one of the reason we have struggled with RSV, in my opinion, is two things. One has been the market has decreased in size tremendously. Because of a lack of a recommendation by [indiscernible] for boosting people. So basically you got the first class of people who all went in. He was a great first year for GSK and Pfizer with the [indiscernible] year 2 and year 3 with no recombination yet. I believe there will be a vaccination recommendation because if you look at the epidemiology, natural infection after a couple of years, you start to be infected and seek again.

And so what we've done over the last capital years is a few things. First, we've become much better at predicting the business because it was tough to model coming down from the pandemic. Because if you think about Moderna, we went from too big roller coaster, [indiscernible]. One was first going up from $0 to $18 billion of sales in the year. I don't think the company has ever done that before. That's at least what [indiscernible], let's say at a time. And then we went down from $18 billion to around $1.9 billion last year. So it's down 90%. No pharma company has ever done that because when they lose patent expiry on one product, it's one product. This was the company.

So we did everything we have to do in terms of processing manufacturing. We sign the company and so on. So I think that we're in a very good place. We still have work to on costs and opportunities that I think we're in a very good place. And so what is interesting for me is last year, we were in our guidance of sales for the first time because the year before were not.

And this year, we're predicting growth. And if you look at how good our Q1 was based on our outside the U.S. strategy, especially U.K. was a big driver in Q1. Even if we are flat in Q2, Q3, Q4, you will have sales growth compared to last year as you can run the math.

So I'm quite excited about where we're going. I think we stabilized. We're going to back this year and sales growth and with a very diversified product portfolio now. So four products approved, maybe five by customers, maybe six by next year. and a great geographic diversification, which is, of course, very helpful.

So I'm very excited about Noro because Noro has no vaccine on the market. Everybody in the room, I'm sure, knows of Noro from personal experience, it's not a fun experience to go through. I know doctors that have told me, when you have a Noro vaccine, I'm sure you're going to get every year, even though I don't get through every year, and I know I should. I get no way very because I would rather have a flow that we can be having no from doctors working hospitals, protecting all of us.

And so if you think about Noro the market is clearly people at high risk, age, obviously, comorbidity, usual, cancer, cardiac comorbidity, autoimmune disease, allergy and other things that I would know those infections are very bad for.

Development is going to be interesting is health care workers. Like I just mentioned the doctor to have heard it from nurses, nursing home with the elderly and then teachers, because same go talk to kindergarten teachers or lower school teachers, and they tell you, yes, I would like a Noro virus vaccine. They might not be at the full shot of a COVID shot, they take the Noro vaccine because they get Noro regularly because of just all the little kids that take off every year. And that's how we parents get Noro going back from school.

So I think Noro was going to be quite an interesting opportunity from a marine standpoint. I think is going to be very interesting opportunity for product building with customers because if you look at the margin the retailers are making on vaccines.

Again, for people who don't know they make profit from a discount they get from us and our competitors compared to list price. They get reimbursed by the payers, but to get an administration fee. So when you add those two numbers, it's actually a very large number. And if you do the math, you need to sell a lot of [ Kitkats ] to the same EBIT margin are selling one vaccine, which is where you get text from CVS and Walmart over time to get more vaccines and so on, that's why. So when you go to a pharmacy, pharmacist will ask you, are you here for food, you want COVID, are you for COVID, you want RSV or you on [indiscernible] because they get cash bonus, the pharmacist. So I think the bit to bundle products is really important for us in terms of share.

And if you think about the growth of our customers, we arcane for product. We are the only one with combo approved at IDS, but Phase III data in the U.S., Noro. So we're going to be at a stage that was really handicapping us before where we didn't have a lot of unique products. Moderna is literally in '26, '27, '28 going to flip to a company that has not one, but several products that you're going to want for your growth, that I'm going to be the only one we're able to provide to you.

So it's going to be quite interesting what happens to us in the next couple of years. The good news for us from a P&L standpoint is I don't need to add on a rep. So think about the cost leverage because I still have the same team going to CVS and the same team going to Walmart. I don't need to get the ones crop in U.S. and the manufacturing is all [ gravy ] because it's volume. I have a platform company able to spend $1 of CapEx to launch Noro or the combo. It's the same manufacturing equipment, the same people in the same factory. So what we're going to see -- and by the way, the cost of good infectious disease -- sorry, the R&D cost of infectious disease is going to come down because those Phase III studies, sunset. And so I'm going to have a very interesting P&L leverage at every line because of good R&D and SG&A.

So a I love the vaccine business. And by the way, I love a [ tale ] as well of a vaccine business. Those products last forever. I mean, you used to work for Merck, those products are in the market forever. Because the buy to entry is a $1 billion Phase III.

Absolutely. And some of those products can grow for 40 years.

And plus, as we update them all the time because the COVID is different from core last year and core 2 years ago. And so there's also that aspect to it. So I love [indiscernible]. I know what everybody does, I love it.

You touched some a few things that sparked my interest and I do want to get to cut some of the cost cutting you've been through and where there still is areas to cut in, I think you made some comments about not needing to add to generate some of this revenue, which I think is interesting as well.

There's also a question that's come in from the audience that builds on some of the vaccines topics. So I'll hit that first. which is we've seen an announcement on Tuesday this week that [ Eli Lilly ] has become a vaccines company again three acquisitions in one morning. Can you perhaps tell us how does this sit with your strategy? How does -- how do you see them now as a competitive set?

I think there was actually some commentary from Lilly that actually echo some of the things that Moderna commented on in terms of EBV and the potential for [ Sequele ] and long-term health impacts. But it would be great to hear how are you internalizing kind of this new news.

So I think it's great news. I think first, it's a great news for the world because we need more vaccines. They are more than hardware barriers that helps human. There is vaccine for less than [ 30 ]. So having a couple of serious vaccine players is a good thing for humanity, number one. Number two, I think for everybody was running away from vaccine 2 years ago and we stuck to it because we believe there's a medical need. If you add just the depth of COVID RSV, flu and Noro, it stacks in the top 5 deaths in this country. Will you take a vaccine to not have cancer. We will take a vaccine to not a hard attack. Yes and yes, I'll take both. We see why every year, I take my true shot, my COVID shot, I got in my first [indiscernible] because I'm more than 50 in the fall.

Like table stake, you want to go for sleep and run and it's healthy and you don't think of vaccines at rally. Okay. And then as you said on EBV, we believe so deeply about EBV. We believe EBV is one of the nastiest virus that hurts human. Of course, we know it mononucleosis. But it's most probably the #1 cause of [ MS ]. Many cancers are caused by EBV.

A virus that stays in your body forever. It is not a good thing. It is not a good thing. Look at the new data coming on [ Shingrix ] with [indiscernible] and potentially slowing down dementia. It's only observational now. GSK is running a study, a prospective study. It's not surprising that virus stays in your brain. It inflames your brand. It's a piece of the. It was a DNA virus. It's a piece of DNA in your human cells. We does it do it creates inflammation. If anybody likes inflammation, I don't think you're feeling hard about biology.

And so the one is an EBV vaccine. We have one right now. Actually, we have two, sorry. When in Phase II has a [ prophylactic ] vaccine, we're going to necrosis. And hopefully, we'll have to prove when they proven [ MS ]. Think about the nickel impact of that. And then we have an EBV vaccine as a treatment for MS patients. It's in the clinic right now in MS patients as we speak, and it's trying to manage the viral load of EBV, the quantity of copy of EBV virus, like people have managed beautifully HIV. If you think about HIV, you try to manage your copies of the viral load of HIV to keep it undetectable. So the virus doesn't do damage in your body, same EBV.

And so I'm delighted that Lilly is going after EBV. And I think Lilly coming at this moment after what has happened over the last couple of years around the vaccine hesitancy post-COVID and what has happened around some vaccine misinformation the biggest pharma company in the world that is saying, "I want to deploy capital, not in one, not in two, not in three companies, I want to be a vaccine business, like, alleluia.

And I'm waiting for [indiscernible] for the patients are on the product.

Absolutely. Absolutely. Prevention is one of the best interventions that we can have. Perhaps diving into that kind of costs and scaling side of the equation. I think in 2025, you took something like $2.2 billion of costs out of your business year-on-year. You're tracking to, I think, $4.2 billion in cash costs for this year.

And kind of laid out a target for that even being lower by 2027, somewhere, I think [ $3.5 billion to $3.9 billion ] is the goal. Can you talk a little bit about where have you taken out cash costs? Where are you planning to continue to take out cash costs? And most importantly, where are you cautious when it comes to risking cutting too close to the bone ensuring that, that revenue content.

A lot of questions in one, Courtney. I am going to take them in pieces. So first, we came from $9 billion of cash cost. Last year, we had [ $4.3 billion ]So the first wave was really cutting down manufacturing because we need less volume. So we've had built a very large partner networks for filling. We closed most -- we stopped most of them, but [ Rovi ] in Spain now. And we had a big partnership with [ Lonza ], which did roughly half of the drug substance for the mRNA and the lipid product during the pandemic, and we also ended up a partnership with a big write-off for all those costs. And the raw material that we had purchased because we didn't know the shape of the curve, we want to make sure we can provide vaccine to protect people.

And then it went down to prioritization of a portfolio of R&D. So we cut in R&D. What also helped us is some of the, as I say, infectiously studies tailed off because a lot of people don't appreciate that for regulatory reason our Phase III study in infectious disease failed, last longer than the end of your Phase III. Because for safety reason, and it's a good thing for the world, we have to monitor people in the studies several years after launch. But when those costs are to tail off, of course, it helps you in terms of R&D cost.

And then we took cost across the business. We restructure the whole business to rightsize it for the work, which was a streamlined portfolio. And then -- so we worked a lot with suppliers on cost because during the pandemic, as you can imagine, given we had no time, we didn't go every time we throw an [ RFP ] process because in process takes time. And sometimes suppliers will tell you, yes, if you on this, you to sign now, this needs to sign now for 3 years or you don't get product because I want to go to say to AstraZeneca, [ Myviles ] or to Lilly to somebody else.

And so we knew as we went into the pandemic that there's a lot of work that unwind that cost structure that made no sense, but was the pandemic price of doing business. Because nobody of a supplier, I'm not trying too many rocks at the suppliers just for.

But nobody if you are running a supplier company, whether you make vials or anything else, you add in your business plan for 2020 that there was going to be a pandemic. So of course, in no manufacturing infrastructure, you have not -- do not have people, you own the raw material to make those products. So it was ready. That's what I can do and the capital system, right? And so we structured a lot of that cost and we're still doing it because I was just with the procurement team a couple of years ago, and they're looking at the work they are doing for '26 savings into '27 for contracts that are expiring in '26. So we still have contracts that we have work to do to improve the construction.

I say cost across the whole P&L, whether it's material cost or with some consultant or other things. So cost across the whole P&L, the R&D cost, as we talked about as our RSV comes out. So this will help as well. And then the AI impact is going to be very profound because like most companies, we still have a lot of what we call AI gaps, meaning base data in e-mails and in PowerPoint and our smart sheet and in an [ ERP ] system. Sometimes it's not the same data and sometimes humans have to check out what's true.

It's happening in every company I worked for. And it's even more acute in Moderna because we built the company so fast. If you think about Moderna in 2020, January 2020, we had no late-stage clinical capability 0. We had 0 commercial employees, 0. So what we have to build in 2020 is all those functions, and we build them a lot in stacks parallel to each other right? Because I heard the head of safety of Merck Rose as a safety system in 3 months. So just through one body is, great expertise, we went to still to the industry, hired those people. We paid some suppliers for some [ ITSM ] we needed that we didn't have, [indiscernible] and other companies.

And so all that now we are using actually AI to go and to fit if you could start everything from scratch and do it with today's technology, even last year technology or 2 years ago technology, how will you design the business process? And we're doing it in business process by business sales. I'm personally sponsoring several business process in the company. And we are a business process across the enterprise and some business process within functions for [ Jamie ] in finance, our CFO, he is working with his finance team on things within finance, how can they use technology to streamline how they do work in finance.

I'm also challenging a lot of people about how we organize across functions. So moving things also between functions, consolidating work. So there's still work to be done. I would not surprise if there's still a couple of years of work to be done. I'm not thinking you're going to see everything in cost because I'm going to reinvest some of it into product of science that you will not see at the P&L level because this work reinvention that we're doing right now is, of course, massively enabled by AI and by vibe coding, obviously.

And it's going to impact every business process of the company. Like I cannot think of a business process, and you think about, please, [indiscernible], that is not going to be impacted by our ability to reinvent it with much more digital capabilities, not only AI, I mean software that we can write ourselves with an LLM for vibe coding, that we can plug to our system like SAP and so on. And then if we need a layer of LLM [indiscernible] it to use AI on that data. But to do things even in accounting. I think we can improve accounting tremendously. I think we can improve [indiscernible] in, we can improve [indiscernible]. There's not one business process at I cannot think of I've not spent time with the team that I think we can improve in the next 2 or 4 years.

So because I want to pace things because if I do everything at the same time, we're not going to get a good outcome. And we need a good outcome because we're launching so many products. And we have so many good things happening at the company. So we are just doing waves of business process, and we are very senior people sponsoring them, including me, as I said, for some of them to make sure that the work gets done and that we really challenge more junior people about what really drives the value.

Because like in any company, I still have people doing work that is interesting. That doesn't drive value. So I'm using that also as the moment was okay. Let's really think about everything to build more than half or tomorrow because we have a platform company in terms of the science, the manufacturing. I don't think yet I have platformized the company in all the functions of the company. That's what we are doing there.

And to that point, I mean, just continuing this AI part of the conversation, you're obviously embedding kind of this way of working and perhaps this operational lens to deployment of AI, how can we do things more efficiently. There's also a lot of talk around drug discovery and kind of can we kind of crack new problems in biology. Can we design targets or interventions that are much more likely to succeed in Phase II and Phase III? What's your kind of philosophy or thesis when it comes to the potential for the industry at large, but especially from Moderna comes to?

I want to talk about Moderna because I think the industry will depend how quickly people adopt it, how we are able to change how we do business. So can you talk about the industry with [indiscernible].

I'm extremely excited about AI for science, but I want to be realistic, investors want it next year in the sales, right? Because when the business we need to do our product and take it to [indiscernible] so for context, we have done machine learning in biology since 2016, '17. So this is not new to Moderna. We have actually invented enzymes, which are protein enzymes that we use in our factory, in our reactors that came out of silicon. And when this happened, the first time I remember vividly, the team put it. You're okay in the computer covenant we have not thought about there's going to be better than the one that exists in nature. Somebody was crazy enough to make it with their bare hands and tested. And he was doing exactly as advertised by the computer and he was optimizing the feature that the scientist that coded in the machine learning system.

We've had the time data scientists because my scientist is had no ability to write the machine on algorithm. And but they had achieve what they wanted. They have improved enzyme that exist in today by basically in my own view accelerating time. In just mutating amino acid on the enzyme solving for the chemistry they were looking for, while preserving a part of the enzyme that was doing the job they need to evolving another part of the enzyme that was doing something that didn't want happening in the reactors.

And that was a huge AHA moment for me because then as an engineer, I have heard about AI since encouraged, which is a long time ago. And it was this type of thing will never happen always later. And that moment was a huge AHA moment for me. I was lucky it happened before, COVID because at the time I set up on a academy with in Moderna to start earth one. Half my team for that was nuts.

Then, of course, COVID was a bit of a distraction to us. And then, of course, OpenAI happened, with Chat GPT. And when Chat GPT came out, I read about it a little bit, but a good friend of mine with a software guy, told me early December, you have to try the thing. [indiscernible], you have to try this thing. So as Christmas calmly we had a bit of time. I went hiding somewhere of a computer for a couple hours and [indiscernible] because I was doing science and biology and then physics and then engineering and then [ French ] port tree and then in [indiscernible], this is insane.

And again, I think led the story of Moderna, where I leave the S curve of mRNA technology from day 1. And the piece that shocked me and it was a use so for me because I've read in business book when I went to business school, I read about S curve. But I never lived the one because when I was at Lilly or at [ Boer ] that year, I was on the top of the S curve. So 3% improvement per year was great.

But I've never leave the steep curve myself. I've read [indiscernible] in books. But I was a modern and my scientist will come and say, we have a 5x improvement. Like what? You have what? A 5x improvement. You really show me the data, go redo the experiment, take back 5x, I said, okay.

And then after another team will come, we have 2x improvement. But that's uncorrelated to the 5x. No, it's not. So that's an exit those 2 pieces of science. So we have AHA [indiscernible]. And this had never seen before. And the piece for me about AI, and now we know because we're a bit of a few years behind us, if you talk to people the hyperscalers and so on and people at OpenAI or Entropic or [ DeepMind ], they'll tell you, as you've read doubling of compute every 6 months. Well, I can do math. You guys can do math, right, you can compound on your computer, right? So I have that moment that December when Chat GPT came out, oh geez, this is going to be a big deal. Not necessarily now, but this is the worst version I will ever see in my lifetime. And it has been true every time I've got a new version.

And so when we did that, I reached out to some Sam Altman say, "We need your thing, but I cannot teach everybody else with my data". So we did something which basically we've got a license for our product on AWS, but only for more than I use. And then we help them develop GPT Enterprise, which is now the product we use for all the employees of the company.

And in science now, I think it's going to change two big things for us. One is, let's talk about the field. I think we are going to accelerate the pace of learning about biology. Keeping about immunotherapy that changed the life of so many created so much value but what we do with Intismeran and so many of the biology insights, we have -- we are accelerating as a field, the pace of biology insights. And we can now do because barges very complex systems with negative feedback loop in very complex biology.

If you knit the biology we have done a human so far in the last 50-plus years is one gene, one target. Most of the biology in our bodies don't work like that. Which is why I'm excited about MRNA-2808, one of our products in the clinic, multiple myeloma, for mRNA in the drug going after full target in one chart. That's the future of medicine. You cannot do that if we're not [indiscernible]. But you can know that by mRNA. We've done already the mRNA with 11 mRNA in monkeys.

So I think the [indiscernible] tailwind we're all going to get is going to be amazing. And those are going to be able to catch it, which will go back to comment but the industry, the company is going to be able to catch it. And change how they work and have the workforce to change how they work and be humble to sometimes say to stop this job it will structure a job differently. I need a different skill, I need to upgrade people. So it's going to be a very painful process to adapt the workforce it's really like when you work into the factory when you went from people looking at from by hand and having machines 100 years ago. It was a huge change. It's a huge change management test. So people are going to have the courage to do it and the skills to do it are going to benefit it tremendously.

The second piece that's unique to Moderna is mRNA technology know-how. So what we're building now is a huge flywheel where AI generated hypothesis on M&E technology. I'm not talking biology, mRNA technology, build the mRNA, build the lipid, we can do fazed at the same time, a fatality time, we take me several years before. [indiscernible] in 1 run. Do the in vitro testing, go in animals, go in humans, feedback learn and keep going.

I would argue there's no company in the world that has -- or public institution that has as much human data as Moderna. Same thing for monkeys. Why not scale Moderna to go run a 100 monkey experiment when we have to. With six or seven arms in the study too long. We're obsessed about learning about mRNA. It's one thing that has been since day 1. We believe this is a very long game over several days. We want to be the company we know the most about the mRNA on the planet. And we want to use data we have now an AI to learn even faster because I want nobody to be able to catch up with us.

And to bring that accelerated learning to patients from new medicine. And my goal is to be able to combine two things. So we're developing internal AI machine learning on mRNA, partnering with the best on the biology, whether it's Anthropic or an OpenAI or DeepMind, Google, the best biology and access to all the platforms, I'm not abated to any platform in biology on the best platform. And within the platform of changing each other. We have already processing in a company where you ask the system, the same questions, and you haven't debate the same question in front of your eyes. It's fascinating. About very complex biology and sometimes scientists I didn't think about it.

A bit like remember we [indiscernible] came and people are protonated you, the competitor made a move had no human that they were recorded, we [indiscernible] in biology. We sent to see insights that no human scientists that we're aware of published on or documented.

And so combining those two things to design drugs. So the scientist of Moderna starting today because I have pieces of those two vectors. I don't have the full vectors yet. But getting those two vectors to be able to design your medicine is going to be fascinating.

So then, of course, we have to take them to a clinic. The piece I think the development process will be accelerated is like all my peers from GLP talks to filing an IND to Phase I and Phase II, Phase III data BLA, it's all a business process, sorry. It's all hundreds of business poses all of them, you can apply AI vibe coding to shrink and shrink and shrink.

The ultimate thing which most will take here is, can you start doing some clinical trial simulation in silicon I think it's for tomorrow, we need the FDA stability as described and so on. But given there's a finalized number of cells in the human body, given we have 20,000 genes, given we have 40,000 metabolites. It's a very big math problem. -- but it's not an infinite math problem.

That's why you see us partnering with IBM in quantum 2 or 4 years ago? Because quantum is going to happen. I don't know precisely, it's happened in '29, in '30, '40, it doesn't change anything for our trajectory. But when it starts working, when I can buy compute IBM or Google or Amazon on quantum, I want my team to know about quantum to understand quantum to have very for how do we use quantum that we're doing. We've already had several problems that the team solved with quantum that we couldn't absorb before -- that has really happened. But I want to be ready for when we do run with quantum because I don't want to discover, we need to do quantum now. It's not how we think about technology. I told you AI 2018, AI academy at Moderna for all the employees, 2016, first machine learning. So I'll do the same thing on quantum because I cannot even understand but my brain cannot understand what quantum and will do together. Put on compute quantum I want to be able to solve a very big science for. So I think 1 day will look clinical trial, not necessarily a full thing, but we do negotiate in [indiscernible].

Much better prediction.

Yes. You can predict all the biology. It's just -- it's all science and math. What happened in our body is not black magic. A lot of things we don't happen, but it's not black market. It's chemical interaction. It's molecule binding to which, it's all physics and chemistry.

Sometimes it's quantum physics. We've done quantum Moderna to sort some problems. Sometimes you have to go there science bigger is solvable. You just need enough compute. That is why I am more excited.

It's a very exciting future and kind of particularly when you sit here and think, and I think others have said maybe it's 1%, maybe it's 5% of biology that we understand the amount of potential unlocks that exist in the future.

And maybe just a side note because it's public information. I'm on the board of General Bio. General Bio has a Phase III drug that came out of a computer. The team designed it with some features they wanted on half-life. The computer design the antibodies. You went into the clinic. It's in Phase III now, and it's working in patients in Phase II as advertised. It's in Phase III now. So the notion that can we make a drug using AI, I think, is a question already answered, yes. The question is what type of innovative drug, but you cannot even think about today, you can make with that.

I mean we had a town hall after an earning call, and I told the team because I spent 2 days deep in science before that, as [ Levina ] was preparing the call and everything. And that's sort I'm convinced we have not invented our best drug yet. I'm deeply convinced, I believe in this brand should be amazing for patients. [ PA ] already the patient stories we're getting from parents for where these are unbelievable the Christmas stories and so on that they never had a Christmas story like this. All the isolation and deaths were preventing with vaccines, but I'm convinced in every set in my body, we have not yet invented besides.

That's an amazing place to end this conversation, perfect timing and a very exciting kind of path towards innovation for the industry as a whole, but also kind of Moderna's journey within that industry. So thank you so much.

And today, they're a great privilege to have Moderna as part of our 2026 Global Healthcare Conference. Representing the company, we have Lavina Talukdar as Head of Investor Relationship here. Lavina, thanks so much for joining us. How are you doing today?

Great. Thank you so much for having us.

That's awesome. Yes. We have a long list of questions here. But maybe before we go into the individual programs, let's start big picture. Can you maybe talk about what progress has Moderna made over the last few months? And maybe most importantly, what's ahead here for Moderna?

Sure. Great question. So I'll start with like the foundations that have been laid in 2025. So we entered that year with a little bit of uncertainty given the change in administration and the transition that was taking place. However, we try to control what we can control and costs came out of the infrastructure pretty significantly. We set a goal to take out $1 billion in cash costs, and we took out $2 billion.

And we also ended the year at the high end of our revenue guidance of $1.9 billion in sales, which I think, again, makes a really good foundation or establishes what we did in the first quarter of this year, also continuing on cost containment and beating sales expectations, mainly driven by where we see growth drivers this year, the ex U.S. strategic partnerships as well as mNEXSPIKE later in the fall to be continuing to drive growth for us.

Got you. Got you. Super helpful. Maybe given this is obviously been some headlines around Hantavirus, -- we continue to see those headlines kind of daily. However, it looks like the risk to the general public remains relatively low. What has Moderna disclosed around what kind of effort you guys are doing around Hantavirus?

So we do have preclinical programs that we're working on with the U.S. Army Medical Research as well as a program that we've had with the Korean Institute of Innovation at Korea University. But again, it's preclinical data, preclinical efforts that are going on there. But as you said, we're watching Hantavirus. It doesn't seem to be posing too much of a risk at this point in time. But the good news is with mRNA technology, should there be an issue, we can spring into action pretty quickly.

Yes. That's helpful. Let's pivot to INT. You're going to obviously have some data at ASCO. Maybe just walk us through -- this is the Phase II data, melanoma. I think you're going to have the 5-year data. I think we already have seen the hazard ratio for progression-free survival. However, I'm assuming you're going to present some data for OS. What should be the expectations for OS into ASCO?

Again, I think you presented data a couple of years ago. There was only 9 events at that time. I'm assuming we have more events now. But do we have enough events to have a meaningful OS Kaplan-Meier curve here? Or how should we think about that?

So you're right, we will be presenting data at ASCO, and it is the 5-year follow-up data to the Phase II study where we're testing intismeran plus KEYTRUDA versus KEYTRUDA alone. And the big news is really that the recurrence-free survival hazard ratio has remained the same. So we're really seeing a durable effect there.

And -- good question on OS. I do want to talk about the significance of recurrence-free survival as well as OS. And so with recurrence-free survival, it is a higher bar than OS is, in terms of you're asking 2 questions with recurrence-free survival, you're asking, did the cancer come back? And is the patient alive?

And so that bar is a little bit more stringent and higher, which is why recurrence-free survival is the gold standard. And as you just mentioned, the fact that it held at a hazard ratio of 0.51 is very impressive. On OS, we are following OS as well. It still may be immature data. However, we will potentially have a full data set at ASCO, which will include OS as well as DMFS.

Got you. Got you. That's helpful. Maybe just a quick follow-up on recurrence-free survival, which to your point is obviously the primary endpoint in the Phase III trial, right? So are you going to show us the p-value, both one-sided and 2-sided? I think in the press release, you have showed the p-value of one-sided. Is there -- are we going to share both at ASCO or still TBD?

I think you'll see the p-value and the one-sided versus 2-sided is literally, you can just multiply it by 2.

Okay. Okay. That's helpful. Maybe let's talk about the Phase III interim for melanoma. The company is obviously not committing to whether data is going to come this year or next year. It's possible this year, obviously it depends on the number of events and how those events will accumulate. Just maybe walk us through what's your latest thinking there? And how are you spending the alpha between the Phase III versus the Phase II?

So in a scenario where the trial failed the interim look at Phase III, does that mean that the data is worse than the Phase II? Or are you spending the alpha differently so we can't compare one to the other? Any thoughts there?

So we -- you are correct that this study is event-driven. And we do expect that 2026 is a pretty good estimate of when we will see that data set. However, we haven't commented at all on any of the statistics. So I'm afraid I can't answer any of the questions around the statistics.

Got you. But the 2 scenario at this point is that either the trial continues to the next interim or it hits on efficacy. Is that the way to think about it?

If there was an interim analysis, yes, the SMB will be looking at the results of that analysis, and it can either go on to the next analysis or we can stop the study for efficacy.

Is there a look for futility as well? Or is it just for efficacy for Phase II?

The Phase II study was very strong, as we just talked about. And so there isn't just a futility analysis.

Got you. Got you. That's helpful. We've seen this move in oncology over and over again with some time the standard of care evolves when you're kind of mid-trial, if you will. And obviously, the NADINA trial suggests that maybe PD-1 and CTLA-4 should be used in the neoadjuvant settings instead of the adjuvant settings of your trial is in the adjuvant setting.

So is there a scenario where by the time you read out your trial, maybe the standard of care has moved and everybody has moved to the neoadjuvant setting and your trial is less relevant? Or is that maybe not the right way to think about it?

So my understanding is that the NADINA study was an investigator-run study and the results were impressive. It may take some time for it to actually become more of a standard of care. In any case, having an armamentarium of medicines and products that physicians can prescribe for their patients is important. And the other thing that I'd like to point out around the combination so far with intismeran and KEYTRUDA is the remarkable safety profile there. We don't see any overlapping safety, which makes it a pretty powerful offering should this be a positive Phase III trial and make it to market.

Got it. Got it. That's actually helpful. Moderna commented on price should that drug ultimately become a reality? We're all obviously rooting for patients here. How should we think about pricing in the context of where IO is today, in the context of where CAR-T is today? Like any big picture thoughts on that side?

So it's a little premature to talk about price. We'd like to see the data first. And so unfortunately, we won't have any comments on price. But as you pointed out, there are IO-IO programs and products on the market that can give you somewhat of a proxy of what pricing may look like, but it will also be data dependent as well.

Okay. That makes sense. You also have 2 additional Phase II trials that are fully enrolled for INT, obviously, both renal cell carcinoma as well as bladder. Maybe just talk about timing of when those data sets could come out. Again, my understanding is that the melanoma Phase III trial enrolled, finished enrollment before the renal cell carcinoma trial. And I think if I look at the Kaplan-Meier curve for the PD-1 monotherapy, it looks like events are accumulating faster in melanoma than RCC. So would it be fair for us to assume that no matter what, the melanoma trial will come before RCC?

A couple of points for you. You're right that the melanoma study was fully enrolled in September of 2024. So there has been more time with that study being fully enrolled and events accruing. The RCC trial was fully enrolled as of the second quarter of 2025. So less time with that study being fully enrolled.

And if you were to compare the Kaplan-Meier curves of IO programs or checkpoint inhibitors by themselves, you would probably see that melanoma patients recover quicker than RCC. So when we say that 2026, we feel pretty good about the melanoma readout despite it still being event-driven, there is a possibility maybe RCC could read out, but it is event-driven, but we haven't committed to a readout in 2026 at all.

Got you. Got you. That's helpful. We also have seen some interesting data published in Nature Biotech, where essentially patients that received -- that were on PD-1 and actually received COVID actually had better responses than patients that did not receive COVID. So in your Phase III for melanoma, are you stratifying in any capacity, the number of patients that are going to receive COVID on both arms? Should we -- or is there a scenario where maybe you have more patients that receive COVID in one arm versus the other and that imbalance can kind of skew the statistics, if you will? How should we think about that?

So we -- I don't believe we are stratifying for COVID vaccination. What I can say is that we are very keen on seeing the mechanism of action really shine through in intismeran with intismeran plus KEYTRUDA. And there is some data that's been presented on the neoantigen selection at AACR earlier this year. We hope to have additional data on the neoantigens in our intismeran product, where we're seeing an effect of the selected neoantigens and recurrence.

And so very much in line with the mechanism of action that we expect to see. Whereas with the COVID vaccine, it's really hard to pinpoint what exactly is happening there. That study that was published, I believe, in Nature, also could have many confounding issues there in terms of the type of patients that would get COVID vaccines are likely to be more healthier. So a lot to be kind of still serrated out from that study. But we will have our data, the Phase III data, hopefully, at some point in the future that should give us a good answer on the mechanism of action that's happening with intismeran plus KEYTRUDA.

Got you. Got you. That's very helpful. What about the metastatic settings? I mean, so far, obviously, the data that we've seen is primarily in the adjuvant setting. We have seen some data in the metastatic settings from basket studies from back in the days, ASCO, I think maybe 18 or something.

Just however, I believe that you and Merck have yet to commit to run a registrational trial in the metastatic settings. What's holding you back? Is there anything in the biology that makes you believe that this is much more likely to work in the adjuvant settings versus the metastatic settings?

So we do have a study, a Phase II study that's running in metastatic frontline melanoma as well as metastatic squamous cell carcinoma of the lung, so non-small cell lung cancer squamous. And those studies have just recently been up and running. And so we are eager to see what the data there looks like. But you're right, the vast majority of the program with partner Merck has been really focused on the earlier settings in the adjuvant setting as well as potentially going even earlier as we just announced our non-small cell lung cancer study in Stage 1 patients.

So yet to be determined if it is something the mechanism of action is really the driver of that selection. We want to see the data both in the metastatic setting as well as the adjuvant setting before we rule out any area where intismeran plus KEYTRUDA doesn't show a benefit.

Got you. Got you. That's helpful. I think in non-small cell lung cancer, which is obviously the largest potential commercial opportunity in the metastatic settings, I think the only trial that you have started is actually in the squamous histology, not in the non-squamous histology.

In the metastatic setting.

Metastatic setting, the squamous histology, not non-squamous. Can you just maybe talk about why that's the case? Is that because squamous is more driven by smoking? And so patients have higher tumor mutational burden. And so this mechanism of action is more likely to respond in that histology or what?

I'm sure there's multiple reasons why we selected going into the squamous cell setting. I'll just remind you that there is a joint steering committee with both the Merck scientists and the Moderna scientists when we agree and move forward in the development and in the different areas of development. So there are probably multiple reasons why they decided to go with squamous in the metastatic setting.

Got you. Got you. That's helpful. Maybe pivoting to flu, never a boring day with the FDA these days, right? Maybe at a high level, is the fact that Makary and Prasad are no longer at the FDA, a good thing or a bad thing for Moderna?

I would just really think about how Moderna has worked with the FDA and the review staff, the scientific -- career scientists that are there all throughout 2025 and remind folks that the relationship that we've built with the FDA based on the science and the products that we take through is a really strong one. And that's really evidenced in 3 different programs that were approved by the FDA last year.

And that includes our new COVID vaccine, an expansion of the RSV label for high-risk individuals 18 to 59 years old as well as the pediatric vaccine that was approved, a full approval on the pediatric vaccine. And we are the only ones that have a COVID pediatric vaccine in the setting of 6 months to 5 years old. And so I think that shows that strong relationship rooted in the science, and we expect that to continue given that it's really started and it is with the review staff and the career scientists that are at the FDA.

Sure. That's helpful. I think PDUFA date for flu is the upcoming, right, August 5, if I recall it correctly. What's the latest thinking there? Have you had any back and forth with the FDA? Are you already in label discussions? Like how should we think about that?

So that review is ongoing. And you're right, August 5 is our PDUFA date. We typically don't talk about back and forth with FDA, but we are looking forward to a decision on that date.

Got you. Got you. That's helpful. How should we think about the commercial opportunity for flu? Obviously, it's an established market. There's a lot of players out there. Probably the most intuitive competitor here will be Fluzone HD from Sanofi, which is obviously doing pretty well commercially. Like just walk us through how should we think about the ramp of the flu vaccine from here in the United States? And are there any lessons learned from RSV? Obviously, the launch of RSV hasn't been maybe what some of us were hoping for. So what are some of the key lessons learned from RSV that you're hoping to apply here for flu? And how should we think about the trajectory of this market going forward?

Sure. So the flu market versus the RSV market, there are some marked differences there. Flu is a very established market with players competitive. But RSV was a relatively new market when we entered that market. And it also had a number of recommendations that actually didn't happen for that RSV market.

So I would characterize RSV as a competitive market. And so we entered a very competitive market where the market wasn't established as well as the lack of having a revaccination schedule that really impacted the market. Whereas with flu, again, a very established market, we'll be entering that market with a strong product profile should we get approved. And I'll just remind you that the head-to-head study that we did with standard flu vaccine showed a 27% relative vaccine efficacy. And so we think we're entering that market with a very strong profile despite the fact that it's a competitive market. We would like to position it as one for that enhanced market that Sanofi is in as well, as you mentioned, for the older adult population.

Got it. Helpful. What about the combo? Obviously, you filed in Europe, and hopefully, there will be a combination of flu and COVID available in Europe soon. However, what's the latest thinking on filing in the U.S.? It's my understanding that for a period of time, you guys were hoping to file them together versus now the FDA has come back and says like, hey, we want to first approve flu before we consider the combo. Where do we stand in the conversations with the regulators to get the combo over the finish line here?

All right. So a couple of corrections there in your question. We are approved in Europe with mCombriax. That approval came through pretty recently in this past quarter. So we're looking forward to starting discussions with NITAGs and getting it ready for the fall of 2027. In the U.S., we first filed for the combination last year, and we were asked to withdraw that filing so that we can add in the flu filing. And now that the flu filing is on track, we're still awaiting guidance from the FDA for the next steps on the combination in the U.S.

Okay. Okay. That's helpful. Maybe COVID and the guide for the year. Again, you're still guiding for potential revenues up to 10% for the year. Obviously, your competitor, Pfizer, has a little bit of a different outlook, they're actually guiding, I think, their COVID franchise more broadly. This is both the vaccine as well as their therapeutics approach, I think, down 23%.

So like what's kind of the best way to rationalize that dichotomy? And maybe just talk us through what are your expectations for vaccination rate in the U.S. I know you guys have guided that vaccination rate is expected to further decline. However, there's got to be some other dynamics that are more than offsetting that vaccination rate coming down. You already mentioned ex U.S. But yes, how should we think about the outlook for COVID for the rest of the year?

Sure. So you're right, we guided to up to 10% growth for 2026. And that growth is going to be driven by our strategic partnerships that are outside of the U.S. in the U.K., Canada and Australia as well as growth of mNEXSPIKE, our new COVID vaccine, which also showed a better relative vaccine efficacy, so higher vaccine efficacy by 13% versus Spikevax. Those 2 drivers are what will be contributing to that growth. And so while I can speak to our growth coming predominantly from the ex-U.S. strategic partnerships as well as continued growth of mNEXSPIKE, it's hard for me to say what Pfizer was thinking about their own guidance.

The visibility we have with those strategic partnerships is pretty strong. And so most of our growth is coming from that -- the international markets. In the U.S., as you pointed out, our guide of up to 10% growth, if you took the midpoint of that instead 5% off of the $1.94 billion of sales last year, you get to roughly $2 billion. And we said that ex U.S. versus U.S. would be a 50-50 split. which would then mean that our U.S. outlook would look for a 20% decline. And there could be multiple factors that go into why we see that U.S. declining.

One of them is vaccination rates, anticipating another potential decline in the number of people getting vaccinations, but it could also be additional competition, for instance. We wanted to be -- take that into account just in case, but still we see growth. And so if we are flat on vaccination rates or flat to the U.S. versus last year, then we would see growth closer to the high end of that up to 10%.

Got you. Got you. That's helpful. Maybe related to it, how should we think about the long-term floor for COVID? Obviously, numbers have come down. And however, there is now some stability, especially ex U.S., to your point. However, again, the timing of the ex U.S. orders and whatnot can be lumpy, and it's kind of hard to fully model that. So what do you think is the floor here? Is it fair for us to think that maybe $1 billion to $1.5 billion floor going forward is the right number here? Or would you guide us against that?

So COVID specifically, last year was, again, on access was a pretty tough year with the transition in leadership at HHS, for instance. And so last year could serve as a pretty good proxy in terms of what we're looking for on the go forward, particularly since those folks who wanted to get their COVID vaccine showed up and got their COVID vaccine. But as you know, we'll just have to kind of go through the years to see if, in fact, last year's rate of vaccination is somewhere in the floor.

But again, these strategic partnerships that we have that do give us visibility into international markets does provide a good sense and visibility on what the COVID and vaccines market will look like, which just gives us confidence in our projections going forward.

Got it. Super helpful. Last question. I know we're already out of time here. But what's the latest on the IP dispute with Roivant and Genevant. Obviously, you settled for a big chunk of money upfront. However, you're still in the hook for $1.3 billion potentially. You're obviously appealing that decision. Maybe just remind us what are the timelines? And I think in your press release, you mentioned that you believe that, that $1.3 billion additional payment is not probable. Why did the legal team concluded that, that $1.3 billion was not probable?

Yes. So a couple of points there. On the appealing, this is actually -- it's going to the court. We do not believe it is probable, and there isn't much more than I can say other than it is not probable in the eyes of our legal team, which is why there isn't a reservation or any kind of reserve on the cash.

Got you. Lavina, I have a lot more questions, but no more time. So I appreciate you joining us here at RBC. Thanks, everyone, for joining, and we'll talk soon. Thanks again.

Thank you.

All right. I guess it's quiet, so we'll probably get going then. Thanks for joining the session with Moderna Therapeutics, and thanks for attending the 2026 Bank of America Healthcare Conference. My name is Alex Stranahan. I'm a senior biotech analyst at Bank of America covering Moderna. And I'm pleased to be joined by Lavina Talukdar, Head of Investor Relations. Lavina, thanks for being here.

Thank you so much for having me. That was the best pronunciation of my last name.

Been practicing. But just for this.

But maybe just to start, you've got 4 approved products. You've guided to revenue growth for 2026. You've already beaten your own reduction targets ahead of schedule. I guess, is 2028 still the breakeven target? And is this now maybe conservative? And I guess what are the key variables that could accelerate or delay this?

Yes, great question. Thank you for asking it. we did guide to up to 10% growth in 2026. And there are 2 contributors to that growth that I would focus you guys on. There's increased growth of mNEXSPIKE, which was approved last year and participated in the fall 2026 -- 2025, 2026 season as well as our strategic partnerships in the U.K., Canada and Australia, where we have very good visibility to the growth coming from those 3 markets, owing to the fact that we've built facilities there, and those facilities have been online since 2025.

So the full year effect of those contracts or those strategic partnerships come into play in 2026. We've also, as you just highlighted, beaten our cost guidance that we gave for 2025. The beginning of the year, we guided to taking $1 billion out of our infrastructure costs within Moderna, and we came in at taking out $2 billion in cash costs. So already ahead of the game. 1Q we are on track to meet our cash cost guidance of $4.3 billion for the remainder all of 2026. And so what we can control, we've been really controlling. And there are factors that aren't necessarily fully under our control that will contribute to growth in '27 and '28 to ultimately get us to that breakeven. Those include approvals. I mean we do have a flu PDUFA date coming up later this year, which I'm sure we're going to talk about.

The data there looks great. We're working very well with the FDA, so there are approvals that will also play into that growth, reaching that growth as well as continued cost containment. So for 2027, we've guided to $3.5 billion to $3.9 billion in cash costs, so another reduction in 2027. So those are the things we'll control and make sure that we do get to that breakeven in 2028.

Okay. And I believe intismeran is not contemplated in the breakeven. That would be an additive.

Intismeran, we're expecting to hopefully see data from the Phase III study there are approval time lines that go into effect as well, as you know. We do think there's a possibility we'll see the approval there in 2027, but the first year of launch won't be a meaningful contributor in '27 to get us to the '28 breakeven. But there will be -- hopefully will be some sales from intismeran as well.

Okay. Maybe circling back on flu that you mentioned. So you've got your PDUFA date later this summer. It got an RTF and then that was pulled back. Now Makary is resigning not saying that there's a direct line to be drawn there, but it did create, I guess, some uncertainty around the U.S. revenue build here. I guess what are your expectations around when this could become available in the U.S.? And how do you sort of see this playing out in terms of approval sequentially thinking about a combo in the U.S. as well?

So you're right, there was some uncertainty with a change in administration every year. Any time there is a change in administration and changes at regulatory bodies, one should expect some uncertainty. And I think 2025, when we entered 2025, there was a tremendous amount of uncertainty that we had to deal with, and yet we got through 2025 pretty well. We have 3 products that were approved, and we came in at the higher end of our guidance that we gave on the third quarter earnings call. So I would characterize that as Moderna really having a strong collaboration with reviewers and scientists at the FDA, including higher -- those that are higher up as well.

And so to see some more of that continue in 2026 is something that we will try and stay ahead of, but going back to that very strong relationship with FDA, the career FDA folks that are there, I think, is testament to us navigating through some of this uncertainty. Coming back to flu, as you mentioned, we do have an August 5 PDUFA date. We're on track to hopefully see what that result is in terms of a thumbs up or thumbs down on the approval. The data speaks for itself. We showed 27% better vaccine efficacy versus the standard of care there, so we're hopeful that August 5 is when we'll see that PDUFA date go positively for us. And that will be another data point that suggests that our relationship with the regulator is pretty strong.

Okay. I guess how have your interactions with the agency evolved over the past year? And I guess, are there any near-term PDUFA time lines or review interactions that are being affected in practice?

So as I just mentioned, it's been a pretty collaborative 2-way street with the FDA. And other than to say that we have that PDUFA date on August 5, will -- there isn't much more to say on that. I think the collaboration is something that I just talked about is one that we're pretty proud of.

Okay. And in terms of, I guess, sentiment, and this is going to be a Hantavirus question, Moderna's technology has always been or has had the capabilities to be kind of first mover for any emerging pandemic. I feel like that's just being reiterated with Hantavirus. Obviously, you had something in the works, I think since 2024 I believe. Maybe you can just speak about that program and sort of what we're seeing, understanding that it's still sort of an evolving situation.

Yes. So you're right. We do have an early program. It's preclinical and that's in collaboration with the U.S. Army Medical Research as well as through our mRNA access program, we've allowed for access to our technology to major institutions around the world. In the case of Hantavirus, it's with the University of Korea, they have an innovation center. And Hantavirus is one of those viruses that the WHO ranks as potential for becoming an epidemic pandemic. So the whole realm of pandemic preparedness is what mRNA access is also trying to accomplish through that program. And so this early stage program that we have, I think, could be something that gives us a leg up should Hantavirus turn into something a little bit more serious than what we're all reading about in the headlines.

I mean we see a lot of things in the headlines about Hantavirus. Is this another COVID? I mean it's a fundamentally different virus in terms of the RNA and spreadability and how it's transmitted. I guess, how are you thinking about this as being a potential public disaster like COVID was? Or is it maybe something that's a little bit more isolated?

So that's a great question. I think we're still learning a lot about Hantavirus. There is some speculation that there is human-to-human transmission once somebody does have or is infected with Hantavirus. It is particularly from rodents is my understanding because they are the carriers of the virus. And once you have exposure to their experiment, then it could be something that you have to worry about. But then we have heard from the recent headlines that there is a possibility of human-to-human transmission. So all of those things, I think, are going to be what regulators and health agencies around the world monitor, and we'll continue to monitor that as well. But the key point you brought up, which is being ready for something like this is what the -- where the world is today, owing to what happened with COVID. And having a technology like mRNA technology as well as an early program in development, again, preclinical that gives the world a leg up on potentially avoiding something like a major pandemic in COVID.

Well put. I want to circle back sort of on the European combo approval. That was a recent positive update for the company. And the European market does have the potential to be a large growth driver with the pandemic era contracts expiring. I guess with mNEXSPIKE and mCOMBRIAX approved in the EU, how are you sort of seeing the European market evolving in terms of your up to 10% revenue guidance this year? And then when does the combo kind of add to that top line growth?

Yes. Great question again. So for 2026, we do not have mCOMBRIAX contributing to -- or even mNEXSPIKE from the EU contributing to the 2026 top line. And so you shouldn't expect any contribution from the EU for 2026 growth, that up to 0%. You did mention the competitor contract that lapses later this year. And so it will make 2027 an open opportunity for us. And it's a fairly large respiratory vaccines market in the EU. So based off of demand, we believe the COVID market is $700 million in sales for the EU, $1 billion for flu and roughly $100 million or so for RSV. We'll be entering 2027.

As you just mentioned, mNEXSPIKE is approved in the EU and mCOMBRIAX, the first approval in the world for a combination flu plus COVID vaccine is also approved in the EU. We have RSV approved. And the flu standalone program is actually being reviewed by the EU regulators. So we may be in a position to have that product approved as well, and that would be our fifth product that's approved globally. And so it gives us 2 things. One, the competitor contract lapses, so the market opens up for us. And then we'll have a full portfolio to offer the EU territories. And so we're looking forward to competing in that market. As of the end of 2025, sales from the EU was less than $100 million. So even if you assumed a fairly modest penetration or market share in the EU, you would see still meaningful growth coming from the EU once 2027 hits, and we're competing in that respiratory market.

Okay. Great. And I appreciate the color on the timing piece. I guess when we think about the launch preparedness in flu, this feels like kind of bread and butter for you guys, but it's is kind of an established market, right, whereas RSV was like you're building that out. COVID was like the pandemic funneling into an established market, but flu feels kind of like the first established market launch. How should we sort of think about the trajectory there? And how does this get positioned versus, say, some of the approved flu vaccines?

Yes. So you're right, flu is a competitive market. We feel we're entering that market with a very strong profile in our vaccine. So I'll remind everyone, we showed roughly a 27% relative vaccine efficacy relative to standard flu vaccines that are on the market. So that already positions us pretty well for that enhanced market for that highly vulnerable population, older adults and people who have medical issues that might want a little bit better coverage in their flu vaccines. And so we'll be entering that market, which wouldn't include the standard flu vaccines and so a little bit more limited in terms of who's competing there.

And given the profile of this vaccine, plus having it be part of a portfolio of vaccines that we'll be selling to our customers, I think, will position us well for that market. It's a fairly large market, the flu vaccine market. It's $6 billion worldwide with the U.S. making up roughly half of that. And so we look forward to the launch. But you're right, it's competitive. So we'll see what we can do there.

Okay. Okay. Great. I do want to shift gears and ask about oncology now. We're all eagerly awaiting the intismeran adjuvant melanoma update. The 5-year data look pretty compelling, roughly a 50% reduction in relapse or death. I think this is kind of the context for the ASCO presentation later this month. For the Phase III interim expected later this year, I guess, what is the sort of statistical framework? What are the hazard ratios that give you early success versus continued finding?

Yes. So our partners, Merck and Moderna have not discussed the statistical plan for the trial. So unfortunately, I'm not going to be able to say anything about that. We do think on timing, it's going to be in 2026, and that's been the guidance all along. So we look forward. We're just as anticipatory and anxious about that data and want to see that data as all of our investors are as well.

Okay. And I think the Phase IIb showed a median RFS of like 19.4 months, if I'm remembering correctly. Would that be kind of a win?

The Phase II data was an absolute home run. And so that would definitely be a win. Is it the hurdle you need to have in a product that could be successful on the market at the end of the day, probably not. And so I would like say, if you looked in the sea of other oncology products that are approved, you'd often find hazard ratios of 0.8 as products that are approved. And that's oftentimes in relation or with a control arm with a placebo. So not an active comparator, which hazard 0.8 means there's a 20% reduction in an event or death happening.

And in the case of our Phase III at the end of the day, if we had a 0.8 hazard ratio, would it still be a meaningful clinical impact for patients, we believe so because it's on top of a very good active comparator in KEYTRUDA. So that would still be a meaningful result for patients.

Okay. That's helpful. I guess, in a few weeks at ASCO you'll have, like I said, a 5-year data, I believe. Anything specifically that you think bodes well or sort of informs what we should be looking at from the Phase III.

So we've already released the top line data of RFS, and we said the hazard ratio was sustained at the 5-year mark as well. So a 49% reduction in having a recurrence or dying if you get the combination of intismeran and KEYTRUDA. So that already kind of tells you. When I get that question, Alec, I often think to myself, other than the durability now out to 5 years, continuing to see that hazard ratio, which we all know and it is going to be presented at ASCO as well. Do you -- can you glean any more from that Phase II? I feel like the Phase II results in of itself at 3 years and the top line at 5 years kind of tells you a lot of why we're and our partners, Merck, are excited about potentially having that Phase III readout.

Is there anything more you'll learn? I know that outside of the Kaplan-Meier curves, and this has already been released with the abstracts, there will be some translational data. So this is speaking to the mechanism we've announced is fully enrolled and has been now fully enrolled since the second quarter of 2025. And it is one, as you mentioned, where KEYTRUDA also works. So a lot of the development programs that are under this broad development program within intismeran is to really exploit that synergy, if you will, with INT plus KEYTRUDA because we do believe there's that synergism in terms of how the 2 act together or behave together. And so KEYTRUDA has shown positive results in RCC as well. So it felt low risk to go after that type of a tumor because KEYTRUDA has shown a benefit already.

And if this is true synergism with intismeran, then we would expect to see that follow through in RCC and all the other cancers that we're developing this intismeran program in. And so despite being less tumor mutation -- having less tumor mutational burden, we do think that's one that could be interesting. It's a Phase II randomized study, as you pointed out, an end that is nearly twice the end of the Phase II in adjuvant melanoma. In terms of whether or not it serves as a registrational study depends on the strength of the data and also conversations we have with regulators. But we're looking forward to that data readout as well at some point in the future.

Okay. And on your 1Q call, you disclosed that your partner, Merck recently launched a new study in Stage I lung cancer. That's basically the very earliest population in combination with KEYTRUDA. I guess does this, in your view, kind of signal confidence from Merck in the program or continued confidence? Obviously, they've been confident in it. But how should we be thinking about this new study start in the context of all the other studies you have ongoing?

Definitely continued confidence because it already was a very broad development program. As you know, we have -- this is our third non-small cell lung cancer study that we've started. I think it does speak to how committed Merck is to this intismeran program. It is a 50-50 joint venture with Moderna. And so they're splitting the costs and resources, all of that evenly with us. The other thing I'd say from -- personally, I'm actually super excited about this study because it gives intismeran 2 opportunities to win. And so what do I mean by that? This is a 3-arm study where you've got in one arm, intismeran plus KEYTRUDA, in arm intismeran monotherapy and then the final arm, the control arm of placebo because in Stage 1 nonsmall cell lung cancer, the standard of care is watchful waiting.

So after you've resected the cancer, you're just waiting for a recurrence -- hopefully, it doesn't happen, but if it does happen. And so you've got now 2 active arms with intismeran in it. So 2 opportunities to win in that study. So I'm super excited to have the ability through this study to offer patients active and proven through at least the Phase II studies that we've conducted in adjuvant melanoma to show meaningful clinical benefit with intismeran plus KEYTRUDA as well as intismeran by itself. And it also speaks to another thing that both Merck and ourselves have been pointing out, which is the safety profile of intismeran and the combination of the 2, intismeran and KEYTRUDA.

There isn't any overlapping toxicity that you see oftentimes with other IO/IO combinations. You just don't see that with intismeran plus KEYTRUDA. And so that offers us this ability to move earlier into the earliest stages of disease in the case of non-small cell lung cancer in Stage 1 setting. And so the risk benefit there is something also that I think is another reason why Merck and ourselves felt very comfortable moving as early as we did.

Okay. That's helpful. I want to ask about mRNA-4359. This is your 100% owned cancer antigen therapy going after IDO and PD-L1. The IDO component of that, we haven't seen for a little while, but it showed some pretty encouraging, I guess, initial activity at AACR earlier this year. I guess, -- maybe you could walk us through sort of the emerging profile for that therapy. And I guess what sort of efficacy signal would be sufficient to move this into pivotal study?

Yes. Great question. So you're right. This is wholly owned by Moderna, off-the-shelf antigen therapy, cancer antigen therapy. And we are targeting epitopes of both PD-L1 protein as well as epitopes of IDO1. So the mechanism that we're using, I know when I speak to investors about IDO, they recall the small molecule approach back several years ago that did not actually have a successful readout. Here, we are teaching your T cells to look for epitopes of IDO1 as well as PD-L1. And we've learned a lot from INT and how we can teach your T cells to look for neoantigens in the case of INT, here it's epitopes of those 2 proteins.

And so the data we've seen so far, and we've now turned over the cards from the Phase I study at ESMO last year, we showed some pretty compelling early -- still early data in highly refractory patients. So people who have had multiple rounds of therapy, some 3 lines plus. And there, we were able to show close to 2/3 overall response rates in a highly refractory patient population. Most recently at AACR, which is what you asked about, in the Phase II portion of that study in frontline melanoma patients, we've seen the ORR now of 83%. So 11 out of the 12 patients or 10 out of the 12 patients have now had a meaningful response rate.

So again, very encouraging. But this is still a handful of patients of data. I think if David Berman, who just joined us here at Moderna were here, he'd say he'd want to see a little bit more quantum of data in a few more -- many more patients to actually then move this forward. And so we're running the Phase II. So let's see if this data consistently holds up as we've been finding with this program, then it will be ripe to move into the later stages.

Okay. Great. And maybe in the last minute that we have, I want to ask -- in terms of the burn vis-a-vis investing today in the Moderna of the future, do you feel like you've rounded a corner on that kind of seesaw of trimming expenses to a point where now you feel confident in building out the pipeline further, doing external BD or additional partnerships? I guess, what are sort of -- where are we in that continuum leading up to 2028? And I guess what are the investments that you're comfortable making today to build Moderna for the future?

Yes. What a great question, and I'm going to probably take more than a minute to even answer it. But the key thing to note that on that kind of rounding out on the cost side, many of the Phase IIIs that we ran up until the last one that we'll be doing in the infectious disease arena is the norovirus vaccine study that also has a readout in 2026, by the way. Once those Phase IIIs are done, that cost is largely behind you because the maintenance cost for infectious disease vaccines is probably 10%, maybe 15% of sales. And so a lot more manageable. And that large cost that you needed to make in order to get the product on the market is behind you.

In oncology, the cost of a late-stage development program pales in comparison to infectious disease vaccines, Phase III studies costs. And that's largely driven by the end, the number of people you have to have in your studies. In infectious diseases is tens of thousands of patients. A Phase III in INT is 1,000 patients. So even though the cost per patient might be a little bit higher, the number of the N in those Phase III studies are so much lower that you can handle the cost. And so if the future for us is now going into cancer as a big therapeutic area and other therapeutic areas that don't require large clinical studies like infectious diseases do, and now we have this commercial portfolio that's coming to market, all of the R&D costs associated with that is behind us. And so we still can now invest without the quantum of investing being as large as it should be for infectious diseases and have a plethora of opportunity from oncology and other therapeutic areas going forward.

Okay. Very good. Well, with that, I know we're over time. So I really want to thank you, Lavina, for the great conversation, and thanks, everyone, for attending.

Thank you.

Good day, and thank you for standing by. Welcome to Moderna's First Quarter 2026 Conference Call. [Operator Instructions] Please be advised, today's conference is being recorded. I would now like to hand the conference over to your speaker today, Lavina Talukdar, Head of IR. Please go ahead.

Thank you, Kevin. Good morning, everyone, and thank you for joining us today. to discuss Moderna's First Quarter 2026 Financial Results and Business Update. You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the Investors section of our website.

On today's call are Stephane Bancel, our Chief Executive Officer; Stephen Hoge, our President; and Jamie Mock, our Chief Financial Officer.

Please note that this conference call will include forward-looking statements made pursuant to the safe harbor provisions Securities Litigation Reform Act of 1995. Please see Slide 2 of the accompanying presentation and our SEC filings for important risk factors that could cause our performance and results to differ materially from those expressed or implied in these forward-looking statements.

With that, I will turn the call over to Stephane.

Thank you, Lavina. Good morning or good afternoon, everyone. Thank you for joining us today. I will start with a review of our first quarter, jimmy will then cover our financial results and outlook, followed by Stephen on commercial and clinical progress. I will close by discussing our value drivers before we take your questions.

The Moderna team delivered a great quarter all around. In the first quarter, we grew year-over-year revenues significantly to $0.4 billion, driven primarily by execution of our long-term strategic partnership in -- with the U.K. government. With a strong Q1, we are reiterating up to 10% growth in 2026.

We reported a net loss of $0.5 billion, excluding the previously announced Arbutus litigation settlement or $1.3 billion on a GAAP basis. We ended the quarter with $7.5 billion in cash and investments, maintaining a strong balance sheet as a result of continued financial discipline.

Our cost reduction efforts continued in the first quarter, building on actions taken in 2025 and resulting in a 26% year-over-year reduction in adjusted cash cost in the first quarter, excluding the litigation settlement. This performance keeps us on track with our full year objective of approximately $4.2 billion in adjusted cash costs.

We also advanced our commercial portfolio and our pipeline. In our respiratory portfolio, we achieved an important milestone with the approval of [indiscernible] in the European Union. [indiscernible] was known before as amounted 1083 of flu plus COVID combo vaccine. This is the first flu plus COVID combo vaccine approved in the world, and this marks Moderna a fourth approved product. I am very proud of the team for bringing this innovation to patients. This is exactly what Moderna stands for. We also secured approval for [indiscernible] in the European Union. These 2 new approved products in Europe will be important growth drivers in the EU in 2027, and when we anticipate COVID market reopening for Moderna.

In the U.S., our seasonal flu vaccine mRNA-1010, was assigned a pot of August 5. In oncology, for Intismeran, we initiated a new Phase III clinical trial in non-small cell lung cancer for patients with Stage 1 disease. It's our first Phase III clinical trial evaluating Intismeran in a monotherapy arm in patients with early-stage disease. I am very excited about this new clinical development because Stage 1 lung cancer is mainly treated with surgery alone today.

Additionally, we look ahead to our upcoming ASCO oral presentation, where we'll report a 5-year update of our Intismeran in adjuvant melanoma.

We were also pleased to recently present at AACR the new clinical data for mRNA-4359, which is currently in Phase II for patients in Stage IV disease, metastatic disease in melanoma and lung cancer.

Lastly, with support from [indiscernible], our Pandemic flu program, mRNA-1018 has now initiated its Phase III study. I'm very pleased with the company's strong performance in Q1 and very thankful for our team that executive across the board.

With that, I'll turn it over to Jamie.

Thanks, Stephane, and hello, everyone. Today, I'll cover our first quarter financial results and then review our 2026 financial framework. Let me start with our commercial performance on Slide 7.

For the first quarter, total revenue was $400 million, coming in above our guidance and represents a $300 million increase versus the prior year. Our geographic mix was approximately 80% from international markets and 20% from the United States. This strong international revenue performance was primarily driven from deliveries under our long-term strategic partnerships.

For the second quarter, we are expecting revenue of between $50 million and $100 million, evenly split between U.S. and international markets, which would bring our first half revenue to approximately $440 million to $490 million.

Our strong revenue performance year-to-date puts us on a solid path to achieve our full year revenue growth target of up to 10%, which we are reiterating today.

Now I'll round out our full first quarter financial performance on Slide 8. As I just mentioned, revenue was $400 million in the quarter. Cost of sales for the quarter was $955 million. This includes $878 million related to our previously disclosed litigation settlement. Excluding this item, cost of sales was $77 million, a 14% year-over-year decline on a non-GAAP basis, driven by reduced unutilized capacity costs, losses on purchase commitments and inventory write-downs, partially offset by higher sales volume.

Regarding the litigation settlement in March, we announced that we entered into a settlement agreement with [indiscernible], resolving all litigation with them worldwide. Under the deal terms, we will make a lump sum payment of $950 million in the third quarter of 2026, of which $878 million was recognized in cost of sales during the first quarter of 2026, and the remaining $72 million is being amortized over the next 3 years. Under the agreement, Moderna will appeal to the Federal Circuit to argue its government contractor immunity defense, which limits its liability under federal statute 1498. If Moderna ultimately prevails on that issue, no further payments will be due. If, however, the Federal Circuit of firms liability under Section 1498, Moderna has agreed to make an additional payment of up to $1.3 billion. We have concluded that a loss related to this pending Section 1498 proceeding is not probable.

And accordingly, no charge has been recorded. R&D expenses for the quarter were $649 million, a 24% decrease compared to last year, driven by lower clinical development and manufacturing costs as we wind down large Phase III respiratory programs, and our CMV Phase III study, partially offset by higher post-marketing commitments from our COVID products.

SG&A expenses for the quarter were $173 million, an 18% decrease compared to last year, driven by lower spend across all functions, reflecting continued cost discipline while supporting the business.

Our income tax provision was immaterial in both periods as we continue to maintain a global valuation allowance, which limits our ability to recognize tax benefits from losses.

Net loss for the quarter was $1.3 billion or $3.40 per share compared to a net loss of $1 billion or $2.52 per share last year, primarily driven by the litigation settlement. Excluding this item, the net loss would have been $0.5 billion or $1.18 per share, down over 50% versus the prior year.

We ended the first quarter with cash and investments of $7.5 billion compared to $8.1 billion at the end of 2025. The decrease was primarily driven by operating losses as we continue to invest in R&D and advance our pipeline. The litigation settlement did not impact cash in the first quarter as the $950 million payment is due in the third quarter of 2026.

Now let's turn to our financial framework for 2026. As mentioned earlier, we expect total revenue to grow up to 10% in 2026, with a geographic mix of roughly 50% from the U.S. market, and 50% from international markets. Our 2026 revenue guidance factors in potential future declines in COVID vaccination rates, offset by increased penetration of mNEXSPIKE and revenue from our long-term strategic partnerships. As a reminder, this guidance assumes no revenue from our flu vaccine or [indiscernible].

Our cost of sales projection has increased from $0.9 billion to $1.8 billion, and now includes the $0.9 billion litigation settlement charge. Without the litigation charge, our cost of sales projection would have been unchanged versus our previous guidance and reflects our expectation of gross margin improvement from manufacturing efficiency gains and volume leverage. R&D expenses are still anticipated to be approximately $3 billion as we continue to invest in our pipeline while maintaining financial discipline. We now expect the timing of our R&D spend to be slightly weighted more to the second half of the year.

SG&A expenses are still expected to be approximately $1 billion, flat versus the prior year. Similar to 2025, our commercial spend will be more heavily weighted to the second half of the year due to the seasonality of our commercial business.

In aggregate, excluding the $0.9 billion litigation charge, we are expecting total GAAP operating expenses of $4.9 billion and cash costs of $4.2 billion, which excludes stock-based compensation, depreciation and amortization.

Additionally, we do not see any material impacts from the ongoing conflict in the Middle East to our 2026 financial outlook, but we'll continue to monitor geopolitical developments.

We expect taxes to be negligible in 2026. Capital expenditures are still projected to be between $0.2 billion and $0.3 billion, and we expect to end 2026 with between $4.5 billion to $5 billion of cash and investments. Our cash guidance does not assume any additional drawdown from our remaining $0.9 billion undrawn credit facility.

Overall, we are encouraged by the strong start to the year and remain focused on executing in Q2 and beyond.

With that, I will now turn the call over to Stephen, who will walk through the commercial outlook in more detail.

Thank you, Jamie, and good morning or good afternoon, everyone. Today, I'll review our commercial outlook as well as progress across our pipeline. Slide 11 outlines our multiyear revenue growth strategy, anchored in both geographic expansion and continued advancement of our product pipeline. In 2026, as Jamie mentioned, we expect a 10% revenue growth driven by our long-term strategic partnerships in the United Kingdom, Canada and Australia, and supported by the continued growth of mNEXSPIKE.

Looking across the 3-year horizon, we are building a diversified portfolio, adding a flu vaccine, a combination vaccine and a norovirus vaccine as well as late-stage assets in oncology and rare diseases, and all while expanding our global footprint into new markets. We made good progress against this strategy in the quarter. We delivered our first shipment under a strategic partnership in the United Kingdom. We secured key regulatory approvals in the European Union, including mNEXSPIKE for individuals 12 and older, and [indiscernible] for adults 50 and above. positioning us well in the large $1.8 billion annual European respiratory vaccines market. We expect both products to contribute to revenue growth starting in 2027 and in the U.S., our flu program continues to advance with a PDUFA date for set for August 5, 2026. Stepping back, our execution in the quarter gives us confidence in our ability to deliver in the near term and to grow over the long term.

Slide 12 highlights our approved products within the infectious disease portfolio. With the recent EU approval of mComvriax, we now have 4 approved products, a remarkable milestone for our commercial portfolio. Starting with our COVID vaccines. We plan to submit annual strain updates across all approved geographies shortly. More than 30 countries for Spike Fax and in the United States, Canada and Australia and now the European Union for mNEXSPIKE. mNEXSPIKE also remains under review in Taiwan, Japan and Switzerland, with additional filings planned for the second half of 2026 to further expand global access to this important vaccine.

Turning to RSV. mRESVIA is approved in the United States, European Union and Canada. Most recently, the European Commission also extended that approval to expanded indications to include adult age 18 and older, broadening the eligible population. For our flu plus COVID combination vaccine, mCOMBRIAX, we recently received approval in the European Union for adults 50 and older. The product is also under review in Canada and Australia, and we are awaiting further guidance from the FDA on the next steps for resuming filing in the United States.

Finally, at ESCMID, we presented new data supporting heterologous vaccination with mRESVIA as well as results from a Japanese cohort from our Phase III mCOMBRIAX studies. Links to both presentations are included on this slide.

Our late-stage infectious disease pipeline also continues to progress. Following with -- starting with flu, mRNA-1010 is under review in the United States, Europe, Canada and Australia, and the U.S. FDA PDUFA date is set for August 5. We recently presented revaccination data for mRNA-1010 at SMED, with a link to the presentation included on this slide. And for our norovirus vaccine, our ongoing Phase III study is now fully enrolled in its second Northern Hemisphere season. Based on case accrual to date, we continue to expect data from this study in 2026.

Turning to oncology, starting with Intismeran, our individualized cancer therapy developed in partnership with Merck. This trial program continues to expand with 9 ongoing Phase II and Phase III studies. As Stephane previously mentioned, we have initiated another Phase III study in non-small cell lung cancer, our third Phase III in lung cancer. This one is in high-risk Stage 1 disease, expanding us to the earliest stage of the disease. The trial includes an evaluation of Intismeran as a monotherapy. This is our second monotherapy study following our non-muscle invasive bladder cancer study announced previously and highlighting Intismeran's safety and tolerability profile as we move into earlier stage disease.

Across the portfolio, we now have multiple late-stage studies fully enrolled, including Phase III adjuvant melanoma as well as Phase II studies in renal cell carcinoma and muscle invasive bladder cancer, all of which are accruing events towards their interim readouts.

We continue to make progress towards completing enrollment in our other Phase III and Phase II trials, including in non-small cell lung cancer, bladder cancer and metastatic melanoma. This broad late-stage portfolio is supported by the strong clinical data including robust 5-year results from our Phase II adjuvant melanoma study, which will be presented at ASCO.

Beyond late-stage programs, our Phase I studies in pancreatic and gastric cancers are also fully enrolled, and we look forward to providing updates on those trials later this year.

Now outside of Intismeran, we continue to advance additional oncology programs. For mRNA-4359, our cancer antigen therapy, Phase II cohorts are enrolling across first-line metastatic melanoma and first-line metastatic non-small cell lung cancer. We recently presented new data in first-line metastatic melanoma setting at AACR with a link to the presentation included on this slide.

And finally, our early stage pipeline includes -- continues to progress, including our T cell engager, mRNA-2808 in a Phase I/II study, a cancer antigen therapy mRNA-4106 and cell therapy enhancer mRNA-4203 in Phase I studies in patients actively dosing. Now in rare diseases, our propionic acidemia or PA program is fully enrolled in its potentially registrational study. We continue to expect pivotal data from this study later in 2026. For our methylmalonic acidemia or MMA program, we have decided to defer the start of a registrational trial for that program until after we receive the pivotal readout from the PA or propionic acidemia program later this year.

With that review, I will hand over the rest of the call over to Stephane.

Thank you, Stephen and Jamie. Looking ahead to 2026, we see multiple value drivers across our company in commercial, in new product approvals and in [indiscernible] pipeline. On the commercial side, we continue to expect up to 10% revenue growth and remain focused on delivering our adjusted cash cost target of approximately $4.2 billion. We'll continue to invest in AI with a number of cross enterprise projects to reinvent work with AI. We will, of course, continue to drive increased personnel productivity across the company.

We also expect potential approvals across the respiratory portfolio in additional geographies. We could, later this year, see our fifth product approved with mRNA-1010 for flu. From a pipeline perspective, oncology remains a key focus with upcoming data for Intismeran and mRNA-4359. We're also waiting for a Phase III data for norovirus, subject to case approvals, and of our PA programs, which should read out this year.

The team remains focused on disciplined execution across these priorities. Over the coming months, we also look forward to engaging with the investment in medical communities at several upcoming events. This includes our investor event on June 1 at ASCO. But also, we would like to invite you in person to Cambridge or via webcast for our Science Day on June 25, where we'll provide a deeper look into our early stage pipeline, also how we're using AI and robotics to accelerate our ability to discover new technology to expand the use of mRNA to new drug modalities.

On November 12, we also hosted our Annual Analyst Day, where we plan to focus on commercial priorities, product launches and expanding late-stage pipeline.

In closing, I want to thank our teams around the world for the progress we've delivered this quarter. We have been executing consistently over the past 1.5 years, and I'm very excited of what is to come in 2016 and beyond. We are advancing our science, expanding our portfolio and continuing to translate mRNA into innovative medicines for patients. Each milestone achieved as important momentum and reconfirms our commitment to deliver [indiscernible] impact to people for mRNA medicine. With this, operator, we'll be happy to take questions.

[Operator Instructions] Our first question comes from Salveen Richter with Goldman Sachs.

So you newly disclosed initiation of a Phase III study for Intismeran as monotherapy and in combination with KEYTRUDA subcu for the treatment of high-risk Stage 1 small cell lung. Can you just -- and you spoke to it a little bit, but could you discuss your strategy to pursue this line and where it fits into the treatment landscape and why pursue a monotherapy here in addition to the combination?

Yes. Thank you for the question, Salveen. We and our partner, Merck, have been really excited by the clinical data that we've seen with Intismeran to date, including the Phase II. And it's important to highlight that the 2 pieces of that, one is obviously the efficacy signal we see, but the second is the remarkable safety profile associated with that efficacy, really no significant increase in serious or Grade 3 events when you get combination IO-IO like benefit. So the real question for us has been could we get that benefit risk profile in a monotherapy context? Could Intismeran provide IO-like protection against a relapse or recurrence of disease with a profile that really looks like a vaccine? And the best opportunity for us to do that, we and Merck have decided is it's across a couple of studies. Now the first I previously discussed was in bladder cancer, but we ultimately decided that in lung cancer, given the incredibly high burden of disease, the right approach there was to go into a Phase III potentially pivotal study.

In that context, as Stephane mentioned, as you referenced, standard of care, more often than not a surgery and then watchful waiting. And so essentially, there is no other intervention. And we're looking at, therefore, INT as monotherapy as opposed to just surgery and watchful waiting for high-risk Stage 1 disease.

Now we're also going to look at whether or not there's an incremental benefit of combining INT with KEYTRUDA in that setting because obviously, the best way to address cancer is to have it never occur after Stage 1. Unfortunately, what happened in the treatment landscape is many of those Stage I patients will recur, sometimes even recur as Stage IV or metastatic disease, and that is when we're fighting very late to try and control a quite progressed cancer. And so our goal, simply put, is to intervene early, prevent the relapse or recurrence from ever happening and in so doing, try and achieve cures in the earliest stages of disease.

Benefit risk there needs to have a very good safety profile, and we really do think that the monotherapy safety profile of INT will be really strongly supportive if we can see in that Phase III study a strong efficacy signal.

So we and Merck have been talking about this one for a while. Our strategy has been to focus on the adjuvant settings, but we have -- and we have started, as you know, some metastatic studies, but we have always wanted to move earlier, signaled that from the beginning because of that benefit/risk profile of INT and we are really excited to see the potential now in Stage 1 disease in a Phase III lung cancer trial.

Our next question comes from Jessica Fye with JPMorgan.

With a significant amount of international sales this quarter, I remember the -- I think the U.K. order from last year got pushed into early '26. I'm just trying to think about those contracts and the right way to think about what more could come from the U.K. for the remainder of '26? Like is it possible this is a double order year? And maybe you could just elaborate on how that works?

Yes, sure, I'll take that. And so the delivery that happened in the first quarter is for their spring campaign. And so for -- in the United Kingdom, there's a recommendation for both spring and fall booster for the targeted population does over the age of 75 or with significant risk factors. And so a second campaign is planned for the fall, and so the third and fourth quarter of this year, and that would be an additional delivery later this year.

Our next question comes from Terence Flynn with Morgan Stanley.

Great. Just wondering if you can be any more specific about the timing of the interim Phase III of the INT and adjuvant melanoma. I know you said 2026, but can you refine that at all at this point? And then maybe talk to the range of potential outcomes there? Are there only 2 outcomes, either the trial hits at the interim and continues as planned? Or is futility also a potential outcome on this interim?

Yes. Thank you for both questions. So I will disappoint in the sense that we won't refine that guidance. We have said we are confident based on the event accrual that we will see interim analysis conducted in 2026. I shouldn't say more, except that, that confidence should indicate where we think we are. On the question of the outcomes, there is not a built-in futility assessment. The interim analysis is either to declare early success or to continue to accrue events in the trial towards a subsequent interim analysis or final analysis both of which could happen in the years ahead. The study is very well powered and has been balanced in terms of its accrual. And so we have continued to accrue events in a way that we would expect, and therefore, we're optimistic about that interim analysis. But obviously, if we have not yet hit the critical hazard ratio to declare early success, we will have the benefit of continuing to look at more events afterwards, but futility is not a part of the current plan.

Our next question comes from Luca Issi with RBC.

Great. Maybe, Jamie, on IP, can you just walk us through why the legal team deemed the additional $1.3 billion charge on 1498 is not probable. I guess the question is what gives you confidence that you will ultimately prevail there? And then maybe just kind of bigger picture, remind us that time line of when the final ruling could come? And then maybe quickly, Stephen, what's the latest thinking on flu in the U.S. ahead of PDUFA? We obviously now have a new acting director [indiscernible]. So I wonder if you have had any interactions with her, and whether you think that having her need is incrementally positive or incrementally negative for you? So any color there, much appreciated.

Yes. Thanks for the question, Luca, I think I may disappoint as well because we're not really going to comment too much on the merits of the trial. So all I can say is our legal team and ourselves, we are confident, and therefore, we believe it improbable that we would lose and therefore, have not recorded anything. From a time line perspective, it's always difficult to exactly read, but we think that it could be perhaps late 2027 maybe into 2028 is where we think that this might be resolved. But again, that's a moving target.

And for the question on the FDA and the -- particularly the flu 1010 program, we continue to progress well in that review in the normal back and forth with the review team and the folks in the office of vaccines towards our PDUFA date, obviously, at this point through a mid-cycle. And we would describe that as a pretty normal course, the kinds of exchanges we're having. And so we're encouraged by that and look forward to that August 5 PDUFA date. Obviously, we'll work hard to answer any questions, any remaining questions that the FDA has as they complete that review.

As to the senior leadership, whether it's [indiscernible] or otherwise, we don't usually interact with them in these reviews at all. Really, this is the review staff, the folks in the office of vaccines, and that is the only place that we've been going back and forth. And we don't expect any impact, certainly didn't before, today or after as a result of the new Acting Director. We do look forward to working with the leadership of [indiscernible] broadly across our portfolio. So the 1010 flu vaccine review continues somewhat independently, but we have a large portfolio of other products from in Intismeran, INT to norovirus to our first rare disease program, the propionic acidemia program, all of which we hope have pivotal readouts this year, and we look forward to bringing those forward. So it's an exciting time for us, hopefully, for the field, and we are very grateful for the partnership across FDA and CBER as we try to bring these medicines forward to patients.

Our next question comes from Tyler Van Buren with TD Securities.

Congrats on the quarter. For the Phase III Intismeran adjuvant melanoma top line data, can you remind us what it is powered for? And perhaps more importantly, can you give us your latest thoughts on what constitutes success from a clinical standpoint? And what you need to show in RFS on an absolute basis or as we think about relative benefit there?

Thank you, Tom, for the question. So we haven't disclosed the powering assumptions for the IA. Suffice it to say, we -- the Phase II data had a really strong hazard ratio, very narrowly missed and a substantially smaller powering 150, 160 participants as opposed to 1,100. And so we're -- we think we are well powered -- very well powered if we see a similar hazard ratio. That would obviously be a huge success. But to your second part of your question on sort of the range of things that we would be pleased with, obviously, anything looks like the Phase II would be spectacular. But candidly, we think the opportunity for benefit could be anywhere between that 1.5% that we saw in a number like 0.8, where there's a significant benefit still in terms of survival and treatment of melanoma -- adjuvant melanoma, Stage II melanoma. Now across that range is a wide range of outcomes that we want to understand the raw data in what's happening. If you see really strong RFS and really strong eventually overall survival, as we've seen so far in the Phase II study, that's encouraging. If you saw maybe the overall survival or just a [indiscernible] data was better even if the RFS was not, that would probably equally be encouraging. And so there's a range of outcomes for how we would declare success that will depend upon the different clinical benefits that we see in the study.

But for now, we feel like we are well powered going into that interim analysis. If not, we look forward to the subsequent analysis. And we think there are a range of outcomes here ranging from the Phase II results to a whole bunch of events that are much more modest, that could still be really meaningful patients and move forward successfully commercially as a treatment for Stage 3 mono.

Our next question comes from Ellie Merle from Barclays.

Curious what your expectations are for timing for data from RCC and muscle invasive bladder cancer. And can you elaborate on what good data would look like in these indications? And then what the next steps would be in those indications if the data are positive?

Yes. Thank you for the question. As we've previously said, both of those randomized Phase II studies are fully enrolled, about 300 participants in each. And so we're really excited to to fill in the picture on the strength of performance for INT across a range of different tumors. I would point particularly to the RCC as 1 that we're we're interested to see whether or not we can provide a really meaningful clinical benefit because we still think there is an opportunity, headroom for improvement there that's quite significant.

Now those are event-driven trials, and we did want to protect the registrational possibility for those trials. So we're blinded, and we're accruing events towards that first interim analysis in both. For obvious reasons, we -- if possible, we would want those studies to be registrational. And so we want to make sure we accrue a good number of events and that we treat those analyses the right way. And because that it's hard to guide right now.

We don't exactly know when potentially this year or even early next year that those results could come in because they are event-driven analysis. But when we have accrued sufficient cases to conduct that blind analysis, we will definitely be doing so. And all of us are eager to see the results because it will help not only guide whether or not those products or those indications are reasonable to move forward more quickly, again, potentially to a registrational study or towards a Phase III pivotal study, which we would look to start quickly. But also, they feel in that picture of how broadly INT is going to play. And in some ways, if you think of RCC as an example of a place where it's relatively far from melanoma in terms of mutational burden, and therefore, an opportunity for us to demonstrate a potential benefit that would then widen the aperture of where we think INT might have a role.

So we're keen to see that data, but we are blinded at this point. We're following those events, and we are eager to provide updates once we have more. But for now, we can't guide on when that timing would be.

Our next question comes from Michael Yee with UBS.

We have 2 questions on INT. The first was on the melanoma study. Would we expect that, that's a similarly designed protocol as it relates to the interim? I recall that the Phase II strongly hit at the interim. And so just trying to understand if a similar type of standard interim was built in here such that if it doesn't stop at the interim, it would imply some sort of different hazard ratio for the first term versus the second room?

Similarly, on the renal study, we understand that this is a much slower progressing tumor if you look at the KEYTRUDA adjuvant studies, just trying to understand how it would be possible that a potential interim would come this year, or that's a much differently designed study in terms of an interim?

Yes. Thank you, Michael, for both questions. So first, we obviously haven't given any statistical guidance on the Phase III interim analysis. But suffice it to say, I just did a moment ago. We wouldn't be conducting the interim unless we thought there was a chance of success. And in that sense, we are not defining that as the hazard ratio that existed in the Phase II. There were some differences in the population, but certainly, that would be a situation we would want to have a relatively early look at. And so it's somewhere between there and obviously, not significant that we're looking for.

We are -- we have -- we are really excited, but we also just need to wait and let the data mature and see those results. And so we're optimistic about that first interim. But it's fair to say that if it isn't successful, there's still opportunity in the second and the final. And we definitely have reserved alpha for both of those for what we think would still be commercially important products. So that's Point 1.

Now on the renal, the renal is -- RCC is, as you said, the events can happen more slowly. There is a benefit, obviously, from KEYTRUDA, but there's a substantial headroom still. Even if you look to the combination products, KEYTRUDA plus Bezu, Merck has just had a great success there, with a hazard ratio of 0.72, there's still headroom even above that for improvement in terms of disease free survival. And so we're keen to look at that result. There are about 300 participants enrolled in that study. And I'll remind you as a reference, that's about twice as large as the Phase IIb adjuvant melanoma study that we've all been speaking so much about.

We're not intending to power that as a registrational study, but it has registrational potential. And what that means is we could have a lower statistical threshold for declaring that there's a strong result there, a strong signal, I think, again, like what we saw in the Phase IIb with melanoma. The key there though, would be we would not want to unblind that study if at a lower threshold, call it 0.1 -- alpha 0.1, we wouldn't want to unblind the study if it was trending towards statistical significance and registration potential. And so that's the key unknown in that RCC study in terms of timing is we will hit a trigger for conducting human analysis based on events. The DSMB will look at that result and then advise us whether it's appropriate to declare early success or whether to remain blinded or alternative outcomes that are more like futility, but that would cause us to want to look at that data and quickly determine whether or not we want to run a Phase II.

And so it's a high degree of uncertainty of what that looks like, but it's all about trying to make sure that if we have a drug here, a strong signal in RCC with registrational potential, we did not disrupt that. Or if it's strong, it needs a Phase III more powered analysis that we get that going quickly. And I think that's the decision that lies ahead of us in partnership with the DSMB.

Our next question comes from Courtney Breen with Bernstein.

Just a couple more on INT. What I wanted to understand as we're getting closer and closer to the kind of it's becoming a meaningful lot of model [indiscernible], but there's obviously still a big [indiscernible], but also on revenue recognition between you and your partner. Number one, can you help us kind of understand the parameter here, and I think through what this might look like to moda kind of realized contribution in the P&L recognizing that it is [indiscernible]?

And then second, in the Stage 1 monotherapy and combination study, can you just again help us understand a little bit about that Stage 1 prevalence of diagnosis relative to later stages? Cancer lung cancer is obviously relatively, compared to other cancers, age quite late. So it would be helpful to understand how you think about this market and potential building if we can see kind of some opportunities for those patients? And speaking of that opportunity, any comments on kind of what the bar looks like particularly compared to a watching and waiting scenario?

Yes. Thanks, Courtney. I think we're breaking up a little bit, but I think the first question was around rev rec as it pertains to INT. So let me take that one. And I'll put a caveat out there that we don't even have the product approved. We're working with our auditors. It's not a traditional joint venture. So -- but this is -- I'll give you to the best of our knowledge, how we think it will work. So it will end up being that we deliver the product to Merck because they're obviously the market authorization holder, and they were sell it on to the customer. So that will be the first part of our transaction. And so you can imagine some amount of our COGS plus some markup. Thereafter, whatever the profit split is, then we will take that share -- Our share of that of 50%. So it ends up being naturally somewhat greater than 50% of the profit share because it's predicated upon first shipping the product and having some markup on that and then taking the margin on top of that. So that will change over time because we -- as we've laid out before, we're working on our cost of goods sold and with that will continue to come down over time as we continue to drive automation. So it will start a little higher as our cost of goods sold. Well, obviously, like any product starts higher and then get more productive over time. But that's the general framework, and I hope that helps. But again, we hope to be in that position next year to be able to start recognizing that revenue.

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[indiscernible] cancer Stage 1. So lung cancer really represents a pretty unique opportunity because screening through X-rays has actually been an important intervention for identifying early-stage disease, Stage 1 disease. Now the majority of diagnoses still show up later at Stage 3, Stage 4, in particular, but you're seeing an increase almost 1/3, north of 30% of diagnoses are now earlier stage, Stage 1, Stage 2. And that has grown over the last decade and hopefully continues to grow through better screening, including a relatively easy intervention, a chest x-ray that your primary care doctor can provide.

So we do hope and expect that there's a big push on earlier -- catching lung cancer earlier. And that is a natural place, therefore, to try and intercept and intervene if you have a great benefit risk profile, again, to be proven, but we know we have the safety profile. And if we can do that, then we'll be able to dramatically impact the number of Stage 4 or Stage 3 and 4 diagnoses that start to show up.

You've already seen evidence of that, right? I mean if you look in the United States, over the last decade or 2, there has been an increase in the number of diagnoses that have -- the percentage of diagnoses that are happening in earlier stage and a commensurate decrease that are happening in the later stages. And so we do think it's a unique tumor opportunity for us to go demonstrate Stage 1 intervention because of that screening regime around chest x-rays and the overall trajectory in the field.

Our next question comes from Jeff Meacham with Citigroup.

I have 2 quick ones. The first 1 on Intismeran, as you grow the experience and data here, I know most of the trials are in combo with KEYTRUDA are there other I-O combo mechanisms that could also bear fruit, or is that better addressed with the rest of your oncology pipeline? And the second 1 on norovirus. As we get closer to data, do you have any updated view of what success looks like here, just given the standard of care? My sense is a significant benefit is all you need, but want to get you guys' perspective?

Yes. Thanks for both questions. So first, on the alternative IO-IO combinations, we are looking in the adjuvant setting and earlier in many of these Phase III studies. We do have a metastatic melanoma study, as you know. But we -- in that context, generally IO-IO combinations and the toxicity associate has not been seen as advantageous. And so for now, most of our focus is on the combination with the PD-1 and KEYTRUDA because of our partner, Merck.

We would be interested in subsequent studies in exploring alternative I/O combinations. But as you kind of alluded to, that's already something we're starting to do in the rest of our pipeline. And in particular, I'd point to 4359, where we are looking in metastatic melanoma and alternative regimens, CTLA-4 plus PD-1 combinations, EPI, Nivo as an example, have been important intervention showing benefits in those populations. And that's a place where, if we want to add a third I-O agent for hopefully some benefit, we are doing some early Phase I/II exploratory work right now.

So you might see, just as a function of the huge amount of work we're already doing in INT, you might see us first explore those other combinations for our cancer vaccines platform in the other off-the-shelf context first. But that doesn't rule out that in the future, we might explore the use of INT on top of other regimens. Certainly, both ourselves and our partner, Merck are interested in that.

Now on the norovirus side, I think you hit the nail on the head. We we think given that there is not currently an approved vaccine for norovirus, and given that particularly for those at highest risk, those over the age of 75, those that have other medical comorbidities, there really is a high societal and medical costs associated with the profound dehydration that can happen with even just what might feel like a 2-day norovirus infection, not just hospitalization, but the significant exacerbations of underlying medical diseases as well and some death.

And so that population, anything that can be done to reduce that burden would be ultimately value creating for the health care system, put aside the benefits for the individual patient. And so we're -- we think statistical significance is the bar. Obviously, we want to see a vaccine efficacy that's also meaningful and so north of 50%. But on -- but given that there currently is no standard of care or treatment, we would take anything above there as a success.

Our next question comes from Cory Kasimov with Evercore ISI.

I also have 1 on Intismeran. So wondering how critical is it to demonstrate an overall survival benefit in Interpath-001. Given the challenges of showing OS and adjuvant melanoma, do you believe physicians would interpret the data set any differently absent a clear OS signal?

Yes. So I'd make a couple of observations. So first, RFS is a pretty good predictor. I mean this is a relapse-free survival. So again, it's not progression-free survival, it is survival, and tends to correlate. And if you look at our Phase II study, we have released previously the RFS, DMFS and even OS trend data. We look forward to the ASCO presentation to provide the 5-year update and the view on RFS, DMFS and OS. And I would point to that presentation and the data, and we hope that, that will provide confidence for physicians, for health care systems, for patients on that relationship in this case and in the case of Intismeran in combination with KEYTRUDA in the adjuvant melanoma setting, and that, that would provide sufficient confidence to move forward if the Phase III is positive.

Now the Phase III data, we will follow OS. And we're through 5 years in the Phase II. So it will take us some time to get to that same level of data in the Phase III, but it will be a part of the trials going forward and can provide a significant degree of confidence going forward, but again, RFS really is survival in this case.

Our next question comes from Simon Bick with Rothschild & Co Redburn.

Just looking at the Q2 revenues, a couple of quick questions. Firstly, should we -- or could you give us any color on the split? Or should we assume that the entirety is SPIKE vax? And also, Jamie, I wonder if you could give us any comments on phasing. It was a very strong number against our expectations, but I just wanted to know if there was any pull-through of expected revenues from Q2, particularly with some of those governmental orders outside the U.S.?

Yes. Thanks, Simon. So let me address the first question. as it pertains to product split. This was largely, the majority is COVID still. So we have not been -- as we've always said, we don't anticipate RSV being a significant growth driver in the year 2026. We believe that will take a little bit of time for us. So this is still primarily COVID-related.

As for the timing, we laid out the second quarter. So -- and then I think maybe your question is more on the second half. But for the second quarter, we laid out $50 million to $100 million in the second quarter. So that should bring our first half to almost $0.5 billion of revenue. And that, if you look at that as probably $400 million outside the United States and $100 million in the United States.

So let me talk to the timing of the year and give big picture and kind of compare it to last year. Last year, we had $700 million of sales outside the United States, and it was $100 million in the first half and $600 million in the second half. So with $400 million is in the first half of this year, if we repeat last year, that's $1 billion. And we've been talking about saying that our mix between the U.S. and international is going to be about a 50-50 split. So if we just repeat last year, that should get us $1 billion. And then in the U.S. last year was $1.2 billion. I said in my prepared remarks that we're expecting some amount of decline and we've modeled for that.

So hopefully, that gives you a little bit of the phasing and timing here. And the last point I'll say is back to the question that was asked earlier, is in the second half of last year, we didn't have any U.K. revenue. So to Stephane's point that if there is a fall season, in last year, $600 million outside of the United States. We did not have in the U.K. There are other puts and takes that's why we've guided up to 10%. I'm not giving explicit guidance here, but I'm trying to give you the picture and contextualize what the year might look like from a U.S. versus OUS split.

Next question comes from Andrew Tsai with Jefferies.

It's a bigger picture question. I'm just curious what your guys' latest thoughts are on BD and even considering technology or assets beyond mRNA. Does it make sense to add more assets to your pipeline? Or do you think you're right sized for now?

Thanks for the question. So if you think about the company, as you know, we've always focused on building the most impactful mRNA platform to enable modalities, families of medicines to enable them a lot of medicines happening using the same technology components. We've done it with infectious vaccines. We don't it with Intismeran. I look at a number of studies now. We are doing it in rare disease. And as we share more at our Science Day on June 25, we have been investing heavily to keep increasing in new modalities. You see it with a T cell engager that Stephen talked about [indiscernible]. You see it with 1439. And there's many more assets, we're going to walk you through what the science has enabled. So we're very focused on expanding to new modalities to enable new families of medicine.

As you've seen in the past, we acquired a company in Japan a couple of years ago because it was expanding the mRNA operating growth of Moderna. We are continuing to look at science across the board, whether it's from academic labs or from companies, public or private. If we find the right opportunity to increase what we can do, we will, of course, execute on those priorities. But we don't have a pipeline problem like most companies in the industry. We have an abundance of products. As you know, we have been very disciplined on cost right now to get back to breakeven. But we have a lot of exciting science that is waiting to go into the clinic soon, and we'll share more of that on June 25.

Our last question comes from Alex Alexandria Hammond with Wolf Research.

So with the recent approval of the COVID flu vaccine in the EU, can you just walk us through your commercialization strategy? And I guess what is the successful launch of like a year from now and 5 years from now?

Yes. Thank you for the question. So first, I want to start by saying, as is our pattern, our path, we do not expect revenues in the year of approval for these vaccines. And so 1083 [indiscernible] or flu in the United States, none of those are in our guidance that Jamie was speaking about. Now your question is more kind of looking forward in '27 and '28, what does success look like? The first step, the one we're engaging in right now across the major markets in Europe is securing market access and so that is pricing and reimbursement. That is a national process, and one that is underway, even publicly underway, for instance, in France, where they have initiated that, frankly, quite quickly after approval, which we think is an encouraging sign.

It's important to note that across Europe, there's about a $2 billion respiratory vaccine market. We previously sort of summarized that. Flu is a big part of that, and COVID is the second large part of that and it's much more portion reserve for RSV. So we see it as a very large opportunity for our combination COVID vaccine.

Lots of benefits to payers, to health care systems, to patients. Patients appreciate the -- it's only 1 shot and there's a strong preference on that. But payers and health care systems really appreciate the lower burden of work. It's a single product. It's only 1 injection. You don't have to procure both. And the amount of time you get back from a health care provider, be that a physician, a nurse, a pharmacist that they can get back to do other things that are value creating for the health care system is actually a huge part of the value proposition of the product.

And so what we've been doing with those governments, and we will do throughout the back half of this year, is help build that economic value story. We've got real-world effectiveness coming -- data coming out from our products, and we hope to be able to show their benefit for the individual, but we also want to help the health care systems understand and value the savings that they will get from a respiratory combination vaccine. And so that's the big push really over the next 12 months. We do hope for a successful launch in '27 in the first markets where we can get pricing and access. And in some cases, in Europe, that takes a couple of years as a process, and it would really be 2028 when you'd start to see that more significant uplift.

Our hope is that we end up with a very large share of that $1.8 billion to $2 billion respiratory vaccines market because we really do think we have a unique product that can save the health care system money and deliver better value for patients and providers. And so we're -- we'll have more guidance as we move forward. But rest assured that we are spending the next year securing that market access pricing and reimbursement and helping people understand the value of that combination. Patients get it quickly, health care systems are also getting it quickly, and we've got the work ahead of connecting those dots so that we can have a successful launch in '27 and really drive growth of the business in '28.

Thank you, ladies and gentlemen, this concludes the question-and-answer portion of today's program. I'd like to turn the call back to Stephane for any further remarks.

Well, thank you very much for joining us today. As you can see, we're excited about 2026, returning to sales growth and critical Phase III readouts norovirus, Intismeran and propylene acidemia. We look forward to talking to many of you over the next few days and a few weeks. We're excited to host you more from them Monday, June 1 at ASCO. And on June 25, Han Cambridge for a Science Day. Have a nice day, and have a great weekend.

Thank you. Ladies and gentlemen, this does conclude today's presentation. We thank you for your participation. You may now disconnect, and have a wonderful day.

Hi, guys. Good morning. Welcome to sunny Miami. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very happy to have Lavina Talukdar here with us today, Head of Investor Relations at Moderna. It's been a very eventful year for you. So maybe if you could start with an overview of some of the key highlights from Moderna over '25 and into the first quarter of '26.

Sure. Thank you so much for having me, Ellie. This is great to be here. So for 2025, I'd characterize 2025 as a year of execution, and we really executed on all fronts. On the revenue side, we came in at $1.9 billion, which is towards the high end of the revenue range we gave on the third quarter call. And that was really driven by execution from the commercial teams. We were very happy to get mNEXSPIKE, our second COVID vaccine approved in June, and they really executed and made sure that, that was available on the market for the fall season.

We also brought down costs. We set out in 2025 to take $1 billion of cost out, and we ended up achieving in excess of $1 billion. So in total, $2 billion of cost that came out in 2025. And that's really a testament to the finance team setting targets and the broader Moderna teams taking cost out of the system. So it really positions us nicely for 2026. It led to a cash balance of $8.1 billion, which also includes $600 million that we took down from a credit facility with Ares that we executed in 2025 as well.

And that brings me to the pipeline, which was also a lot of progress that we saw. We had mNEXSPIKE approved. We had 2 other programs approved. RSV 18- to 59-year-old high-risk individuals saw a broadening of the indication there. And we also were able to get our COVID vaccine approved in the pediatric setting. We're the only ones that has an approval in 6 months old to 5 years of age.

Aside from the approvals, we had positive data from our Phase III study in flu, which then led to the filing of the flu application in the U.S. and other territories around the world. So we're looking forward to that approval. And we also advanced our cancer pipeline, intismeran, which is already in a Phase III for adjuvant melanoma continues to accrue events there. But we -- in that program, we also fully enrolled the renal cell carcinoma study in 2025. PA in rare diseases was also fully enrolled. So it really sets us up nicely for 2026 as we look forward to pipeline readouts.

Yes. Certainly, a lot of exciting pipeline readouts, which I'm sure we'll get into. But maybe first, just starting with the respiratory vaccine franchise. So you're guiding for up to 10% revenue growth in 2026. I think that number may be surprised some investors given some of the trends that have been seen in the COVID landscape. I guess, what's underpinning your confidence in the potential for a return to growth this year?

Yes. So we have 2 contributors to growth that we see in 2026 that gets us to get up to 10% revenue growth that we've guided to. And the 2 major growth drivers is continuation of mNEXSPIKE penetration in the U.S. We have 24% market share as of the end of the fall season in 2025. So we expect that to continue to penetrate into the U.S. and also some approvals outside of the U.S. as well. And then the other major driver for that up to 10% growth is going to be from our strategic partnerships with the U.K., Canada and Australia. And in those partnerships, we've built facilities to make vaccines and other products. And so those facilities all came online in 2025 throughout the year, towards the end of the year. And they will go into full effect this year, those agreements. They are multiyear agreements that provide us visibility. We expect to see a major step-up in revenue from those 3 countries because of these strategic partnerships.

Interesting. And yes, I mean, the ex-U.S. revenue, I think that's particularly interesting considering a lot of that is essentially locked in through contracts.

That's right. And we'll have visibility for multiple years. The step-up in revenue from our guidance last year, we did $700 million in ex-U.S. revenue. The bulk of that $700 million was made up of Canada, Australia and the U.K., both the 3 strategic partnerships. This year, we're expecting international revenue to be $1 billion. So the key step-up in our up to 10% growth is predominantly coming from ex-U.S. revenues. In fact, in the U.S., last year, we ended the year with $1.2 billion in sales. And this year, we are planning for another decline in U.S. sales down to about $1 billion, which is a 20% decline to be prudent. Obviously, we're not aiming for a decline. But to be prudent, we don't actually need the U.S. to grow in order for us to meet the up to 10% growth.

That's interesting. And congratulations on the positive CHMP opinion with the flu, COVID combination. I think that's a very interesting program. It certainly differentiated from Pfizer-BioNTech, where you have the combination. I guess maybe starting first with in Europe, how we should think about the opportunity for this combo vaccine and when we could potentially start seeing revenues from these programs?

So we are very excited about the combination flu plus COVID product. In Europe, you're right, we just received the CHMP positive opinion. So we do expect an approval later this year. However, it will be contributing to revenue in the 2027 time frame. I'll remind you that, Europe, is right now a territory that we're not selling in because it has been locked up by a competitor contract in COVID. And that contract will lapse later this year, opening the territory up to us in 2027. So we'll be ready with the approval in flu plus COVID with that product, but it won't contribute to revenue until 2027.

Okay. Makes sense. And the U.S., a little bit more of a complicated situation. Sort of -- and I'll leave it to you in terms of what you can or can't say here. But how should we think about the latest in terms of the 1010 filing for flu, got the RTF, now the filing is accepted. How are you thinking about the outlook for this in the U.S.?

So you're right. We did have the RTF reversed and it's now accepted to have a PDUFA date of August 5 later this year. So we look forward to continuing the engagement we have with the FDA review staff. They've been phenomenal with all of our applications in the past. And so we look forward to continuing that collaborative work on the flu application. For the combination flu plus COVID, we still are seeking guidance from the FDA in terms of when we will refile that program. So as we have more information, we will update you.

How should we think about the uptake of the COVID flu vaccine? I mean I think just there's more investor skepticism on sort of the vaccine landscape. But then again, you'd be the only ones with this combination. How can we think about how this could impact, say, market share from a pricing dynamic, how this might play out?

So I'll answer that question ex-U.S. and in U.S. as well. So ex-U.S., we've received a lot of feedback from health ministers about the combination of flu plus COVID. They're pretty excited about that program. It's mainly because in countries outside of the U.S., you have single-payer systems, and it's those single-payer systems that are very incented to make sure that their populations are protected against pathogens that could lead to bad outcomes or hospitalizations, because it ends up costing the system more -- it's more expensive for the system, for the medical system. Preventing those hospitalizations is something that health ministers are very keen on. And when you can do it through one vaccine and you're protecting the individual against 2 different pathogens, it actually is -- leads to better compliance, lower administration costs. It's something that health ministers are looking forward to. So internationally, we think it's going to be a great product.

In the U.S., we also think there's a place for a combination flu plus COVID vaccine that could be competitively advantaged. And that's because, again, you have compliance, you have lower health care costs and potentially a better economic backdrop for the customers as well. In terms of the pricing, we're still strategically thinking through what that might look like. It's a little bit premature. But obviously, there's lots of ways to think about that. We can just price it some of the parts or we can price it at a premium to some of the parts and possibly even at a discount. It's still yet to be determined.

I think an interesting contributor potentially to keep an eye on in the coming years. So in terms of the pipeline, an incredible amount of focus on the upcoming melanoma data. Maybe can you frame for us first sort of just how we should think about from a timing perspective? You said 2026. I think a lot of investors are curious as to the confidence that it will come in 2026 or if you have any granularity on when in 2026, we might see this data?

So it's really difficult to pinpoint when we think the data is going to read out because it is an event-driven trial. The confidence around 2026 really just comes from using the Phase II data set as a proxy. And the Phase II data read out 18 months, you started to see the separation in the curves around the 18-month time frame after the last patient was enrolled. And so since the Phase III study was enrolled in September of 2024, we hit the target enrollment. If you add 18 months to that time frame, you get to about the first quarter of -- early second quarter of this year. However, there are differences in the study. First and foremost, it's a Phase III study, so much larger, you'll need more events to actually get to the point where you can look at the data. It also has patients that are Stage II patients, which may lead to longer time frame before we start seeing recurrences. And so when you put all of that together, you're still solidly in that 2026 time frame, but it is event-driven. So it's impossible for us to know exactly when in '26 or possibly even in early '27, it may read out.

Makes sense. I had to try. Can you frame for us maybe what the relevant benchmarks are here from a data perspective and what you would consider, I guess, good data from this Phase III?

So I'll remind everyone about the Phase II data set. We had a hazard ratio at the 3-year follow-up of 0.51, which is remarkable and on the recurrence-free survival endpoint. That continued and sustained itself at the 5-year mark, which we just reported earlier this year. And that data is really remarkable. In terms of benchmarks, we would be thrilled to see data like that, but I don't think it's necessary.

If you were to look through the oncology landscape, you would quickly realize that there are products on the market that have had hazard ratios in the 0.75, 0.8, that are now successful products on the market. So that hopefully gives you a sense of what may be necessary to have a meaningful benefit. And the other thing I'd say is this is intismeran plus KEYTRUDA, which is above and beyond a very active drug in KEYTRUDA monotherapy. And so even seeing a 0.8 hazard ratio, I think, would be a clinically meaningful result.

And how should we think about the market opportunity in adjuvant melanoma?

So in adjuvant melanoma, the way we characterize the market opportunity there is worldwide, it's a multibillion-dollar opportunity. We are 50-50 with our partners, Merck. And in that scenario, we would still consider our share as a multibillion-dollar opportunity at peak worldwide.

And I guess if this data are positive, how should we think about the read-through to other indications?

It's a great question. We believe that there is a synergism between intismeran and KEYTRUDA. And we've seen that in a number of tumor types during our Phase I study, the basket study, where we saw data in adjuvant melanoma, in non-small cell lung cancer. But again, it's a Phase I study. So the synergism we think, is there. However, we do have to run these studies to see what the magnitude of benefit there may be in all the different tumor types and the different histologies. So we're running a pretty extensive development program with our partners, Merck.

We have 8 late-stage studies and the different cancer types, obviously, are adjuvant melanoma as we just talked about, renal cell carcinoma in a Phase II study. Muscle invasive bladder cancer also in a randomized Phase II study. All 3 of those studies are fully enrolled. We continue to enroll 2 studies in Phase III for non-small cell lung cancer. And we just initiated Phase II studies in first-line melanoma and first-line non-small cell squamous lung cancer. So we're active in the program for sure and really eagerly looking for additional histologies that may read out in the future.

And I know you mentioned some of these studies are fully enrolled like RCC. How should we think about the cadence of readouts after we get the melanoma data?

So the Phase II studies, RCC as well as muscle invasive bladder cancer, our Phase II studies. So the number of events you need there are lower than a Phase III study. They also have different rates of when recurrences happen. So I would say that after the adjuvant melanoma data, you should think a cadence of several months for each of these potential programs to read out. And then when we update you on full enrollment for non-small cell lung cancer, then that's when the clock starts ticking for when that particular histology reads out as well.

And how long from when non-small cell finishes enrolling, should we think about when we would get data?

It's really hard to speculate on that. But I think the key thing to hear -- to listen for is when that study -- when those 2 studies are fully enrolled.

Great. Well, certainly an exciting program. I know a lot of eyes are on it this year. Turning to some of your other pipeline programs. So, norovirus, we could potentially see Phase III data this year. I guess, can you help frame what you're looking for in the data and what benchmarks would be for good data here?

Sure. So norovirus, we just announced that it was fully enrolled in that second Northern Hemisphere season. And we're accruing cases. So this is another event-driven or case accrual dependent readout. We do anticipate that, that will happen in 2026. In terms of what we expect on the vaccine efficacy side there, because there aren't any products or any vaccines approved for norovirus, we do think that a minimum of a 50% vaccine efficacy rate would be needed to get this product through and on to the market. And that's because you've had other vaccines come to market with a 50% vaccine efficacy rate. Obviously, we're shooting for better than that, but a minimum of 50% is what we think you would need to come to market.

And obviously, a huge opportunity, but it's been challenging from a vaccine development perspective. What are some of the reasons why Moderna could be successful, whereas our focus in the past have faced challenges?

Great question. So we are targeting the adult population with a predominance in our clinical study of the older adult population. I think other programs that have failed in the past we were looking at children or infants. And in that population, I do think you need to vaccinate people multiple times in order to get them primed against the pathogen. And so having the benefit of going into seropositives in that adult population, I think, gives us a benefit. The other thing is that it is an mRNA therapy that we're using versus some of the others that have failed, our recombinant protein. So there is something to be said about that as well.

Great. Turning to operating expenses and your assumptions for breakeven. This is another area where we get a lot of investor questions given sort of the degree of investment in R&D. Maybe can you walk us through what your current assumptions are in terms of time to breakeven and what some of the levers are in terms of the ability to ramp down spend if, say, some of these Phase III trials are not successful?

Yes, great question. So obviously, we're planning for many of the Phase IIIs to be successful. But there are Phase IIIs that will be rolling off, particularly in the seasonal vaccine space. So norovirus is the last of the Phase IIIs in the seasonal vaccine portfolio that we're still running and that will run through 2026, and it will start winding down after that. So we do anticipate the anniversarying of the data sets in Phase III to be a big contributor of why our R&D spend comes down. We're going to continue to spend in oncology and invest in the clinical programs there, both with our partner, Merck, on the intismeran programs, but also our emerging oncology programs.

The cost of oncology Phase III development or Phase II development is much, much lower than the cost of developing vaccines because of the sheer number of participants in vaccine studies versus the patients that we treat in the studies for oncology. And so all of that being said, we do anticipate that costs overall, cash cost for the company will be coming down to the tune of $3.5 billion to $3.7 billion in 2027, which would mean that we would need to be in that range for revenue in 2028 to breakeven. And we've got multiple growth drivers, 2 of which we talked about for 2026. Next year, we have Europe opening up, and that's a $1.8 billion respiratory vaccine market where currently, our sales are less than $100 million. So that's a big opportunity for us in 2027.

Flu is a big opportunity as well in 2027 around the world, should we get the approvals as they come through later this year as well as partnerships now internationally in Lat Am, Latin America as well as Asia Pacific. So we just announced a deal with Mexico and Taiwan. Brazil was one that we announced last year. Those are also multiyear contracts that start to go into effect in 2027. And in 2028, on top of all of that growth, we anticipate the combination flu plus COVID coming to market as well as norovirus, both of which could be multibillion-dollar products at peak.

How should we think about the time frame for when the strain selection might vary for your flu products, I guess, thinking ex U.S. now because we'll have to wait to see what happens in the U.S. But I mean, there's so much data that shows that better strain selection and strain selection closer to the season leads to better efficacy. So I mean, now that you have the approval in Europe, how should we think about when we could potentially see you targeting different strains?

Yes, I think that's an excellent question. So one of the advantages of mRNA vaccines is that we can make a vaccine very close to the flu season. In fact, we've already demonstrated that in COVID, where we typically just need 2 months of heads up on the strain selection for COVID before having enough product to supply to the market. And indeed, for COVID, selections for the strain are happening in the May, June time frame, and we're able to have product on the market by late August.

Similarly, with flu, we'll be able to do that as well. The difference between mRNA technology and traditional flu vaccine technology is that traditional vaccine makers require 6, maybe 9 months of lead time to make the product for the fall season, at which point you may have the flu virus mutate away from what's in those traditional vaccines, which leads to this mismatch that you're talking about. If you can minimize that mismatch because you're closer to the flu vaccine season, then that should, in theory, lead to better vaccine efficacy. And mRNA vaccines are the only ones that can actually achieve that at the current time. And so we look forward to that opportunity. There are many years. Last year was a big year where there was a mismatch in terms of what was in the flu vaccines versus what was circulating that, another opportunity like that could really help mRNA technology shine in that respect.

Yes, it's really interesting. On the rare disease side, you mentioned the PA study being fully enrolled. Can you talk about sort of how we should think about the opportunity here and the landscape for treatment?

Sure. So yes, we fully enrolled that study in 2025. We're expecting the readout later in 2026. It will be our first rare disease program, knock on wood, that comes to market. And we recently had some news, in a partnership with Recordati, who is already a major player in the PA landscape, which is our first rare disease that we're bringing to market. So we're thrilled at this partnership with Recordati, because they have a commercial presence, have the infrastructure already set and in place, identify the patients already. So it could be a very quick launch. And from that deal, we expect $160 million in milestone payments and then a royalty rate based on tiered sales. So we're looking forward to the data set first, and then this partnership with Recordati on that program.

Great. Well, an exciting year ahead. So Lavina, thank you so much for joining us, and thanks for everyone in the room for attending.

Thank you so much.

Thank you.

All right. Okay. Good afternoon, everyone. Tyler Van Buren here, senior biotech analyst at TD Cowen. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference.

For this next session, it's a privilege to be hosting a fireside chat with Moderna management. And from Moderna, it's my pleasure to introduce Jamey Mock, Chief Financial Officer of Moderna. Jamey, so great to have you. Thank you for joining me.

Thanks for having us, Tyler.

So we'll start at a high level before we get into some of the more detailed programs or specific programs. But for the full year 2025 product revenue came in at the high end of the guidance, which I think surprised some given the COVID normalization concerns and macro factors throughout the year and volatility on that front. But maybe you could just talk about what drove the resilience of the COVID franchise and the great result you guys ended the year with?

Sure. Well, thanks, everybody, for your interest in Moderna. So yes, I would say, obviously, a lot of things going on from a macro perspective. That said, I think the team executed extremely well, number one. And I also think it tells you that there's still plenty of people that want to get vaccinated. So in the U.S., for example, there are over 30 million Americans that got vaccinated against COVID last year.

But if I break down and kind of go through the numbers, we had guided $1.6 billion to $2 billion of revenue, and we came in at $1.9 billion. And if you double-click on that, we had said the U.S. would be about $1 billion to $1.3 billion. And 2 things happened there. Vaccination rates were on the better end of what we thought they would be. And then mNEXSPIKE, which is our latest COVID vaccine, performed very well. So we did well from a share perspective, particularly in retail.

And then outside the United States, there wasn't a lot of volatility left. We just had to execute. There was a little bit around vaccinations, but we hit the high end of that guide. So we had guided $600 million to $700 million. So we had $700 million outside the United States and $1.2 billion inside the United States. And we're really pleased with the execution. So that's a little bit about how we hit the high end.

Great. And mNEXSPIKE, which you mentioned, 24% of the U.S. retail channel, impressive early uptake for that product. Is that the penetration that we should expect moving forward? Or ultimately, what share of your franchise -- COVID franchise do you expect mNEXSPIKE to take?

Yes. We were -- thank you for saying that. We were really encouraged by what we saw. So I think the product was approved in mid-June. So for 6 months of the year, having a product that was just approved going into the season, we thought have performed extremely well.

And I think it really just comes down to the product profile. It has superior efficacy versus Spikevax, particularly in older adults, which is really who we're targeting. It's high risk and older adults. I think that's where the large majority of vaccinations are targeting. It's 13.5% better from an efficacy perspective versus Spikevax. And so that got in the marketplace and performed extremely well. So looking forward, that is one of the growth drivers we're hoping for, in 2026 as well and beyond, and that we do hope that it takes up a larger share of our -- of the market overall and of our proportion of the market as well.

So for '26, another recent surprise was the up to 10% growth guidance. I guess that means anywhere from 1% to 10% over the course of the year. So how should we think about the potential outcomes within that range, swing factors? What gives you confidence that you can potentially hit that up 10%?

Yes. I guess it's 0.1% up to 10%...

Decimals.

But I think the other important thing that we've said about that, and I'll come back to that, but I think it's telling when we break down and as I talk about what is going to drive growth is we also said that the geographic distribution was roughly 50-50 inside the United States and outside the United States. So I'll speak to each geography and talk about the upside to your point or the range of outcomes.

In the United States, I just mentioned in 2025, we had $1.2 billion in sales. So if you take a 50% midpoint of our guidance, that's about $2 billion. So that would imply $1 billion in the United States and $1 billion outside the United States at the midpoint of up to 10%.

So that means that we are expecting or planning for -- not expecting, we're planning for the United States that could potentially drop from $1.2 billion to roughly $1 billion. That's based on vaccination rates or -- and/or market share or competitive forces, whatever it might be, but that is our planning assumption in this guidance.

Now what could be the upside to that? mNEXSPIKE could continue to perform well and take a larger share or vaccination rates might not be done as much. So if it's another $1.2 billion overall, that would be on the higher end. If it's down to the $1 billion, that would be towards the midpoint or lower end.

And then outside the United States, I said we had $700 million of revenue in 2025. And again, that's going to go to $1 billion. And that's really based upon we've been talking about these large partnerships we have, primarily in 3 geographies in the United Kingdom, in Canada and in Australia. And those we started to execute against in 2025, particularly in Canada, but many of them, particularly, in the U.K. and Australia, we had very nominal revenue.

So as those annualize and they can continue to grow over time and we can get into that, we're getting a big uptick. So that is why international revenue mix growing. And you'll see it in the first half. We mentioned back in 2025 that some revenue that we thought might land in 2025 slipped out to the first half of 2026 for about $200 million. So we expect that you'll start seeing the fruits of that in the first half of this year.

Great. And Moderna has stated that its path to cash flow breakeven in 2028 is dependent on flu outcomes where we've seen some volatility lately and cost discipline. And you have levers to adjust across '27, '28. So can you outline what sits under your control bucket versus what's external?

Yes. Well, maybe I'll start with cost because that is in our control. And we had guided, if I just look at 2027, we haven't guided 2028. We guided 2027 to a midpoint of $3.7 billion. So that means by 2020, we either have to be at $3.7 billion from a revenue perspective, which I'll talk about in a second, or we're going to have to take down cost a little bit or have a mixture of both growth and cost. And this breakeven story is both a growth and a cost reduction story.

So just to kind of talk a little bit more about cost because I think the bigger story is really the revenue side. Costs, we have great line of sight to this $3.7 billion. There are some trials ongoing in the year 2026, specifically in our infectious disease with norovirus as that completes and some other things going on with COVID. Those will roll off, and we have terrific visibility to the $3.7 billion.

After that, it's really a bunch of capital investment choices that we've made and have made over the last 3 years. So we've always had the high-level strategy of investing behind the business, but monitoring the revenue line and '26, '27 and '28 are no different than that. So costs very much in our control.

I think the bigger story is, and we try to lay this out at Analyst Day, is we have 10 shots on goal of what we call growth drivers that we -- that are all several hundred million dollars. And there's no revenue item that is perfectly under our control. Even the solidified contracts with the 3 geographies I just talked about, it's not -- I mean, we have obviously greater control, and it's more on our execution. But at the end of the day, it's still 2 parties for any kind of revenue. So we've got that.

We've got -- and it's really a mix of international expansion as well as new products. So international expansion, we've got the contracts I've mentioned. We've announced additional partnerships in Mexico and Taiwan recently. Europe will open up in 2027, and that's a rather sizable market, not just for COVID, but for all infectious disease. So we plan to grow there.

And then on the new product side, we'll talk about flu, I'm sure. We've got flu and plus COVID from a combination perspective, both inside the United States and outside the United States. We've got norovirus. And so that's kind of the, I'll call it, infectious disease or vaccines portfolio. And on top of that, I'm sure we'll get into it, but hopefully, our INT product reads out well and is approved, PA reads out well, 4359. So we have a lot of shots on goal. But getting back to answer your question, cost is in our control. We have a good line of sight to it to bring it down to at least $3.7 billion. And revenue, we've got a lot of shots on goal to get that up to some level like that.

Great. And maybe related to the cash flow breakeven plan and thematically, you all have been clear about reallocating capital towards area with better risk-adjusted returns. So before we get into respiratory franchise and vaccines, just talking about potentially oncology, autoimmune, rare disease and, of course, partnered vaccine. So can you elaborate on these recent comments? And also if that means that you might explore other modalities outside of mRNA as well?

Yes. I don't read into those comments as much. Let me just step back for a second. Over the last 5 or 6 years, we've probably invested 80% of our research and development into infectious disease. And we've been very conscious about doing that, and we knew we wanted the full portfolio. When we have the full portfolio, we think that brings a lot of value to our customers and what is the full portfolio? That is 2 COVID vaccine, that is RSV, that is flu, hopefully, that is flu plus COVID and that is norovirus, which can also sell through the retail channel.

So those investments will largely be done. And that's not to say that there can't be more, and we will continue to invest in more. But after investing all that capital, we've got to make that business a profitable, growing, sustainable business. And that's really been the strategy. And I think you'll see that over the next coming years as each of those products grow and as I talk through the international expansion as well.

But that said, we've always been trying to diversify into oncology. We've always said mRNA is not going to be a one therapeutic area company. It's going to be many different modalities and therapeutic areas. So we're excited about what we have in oncology, INT, which we'll talk about, I'm sure, which we think can break through on cancer vaccines broadly should INT do well. It's kind of the bellwether for cancer vaccines, and we have numerous ones behind them.

And then we've got other mobilities in vivo CAR T therapy, T cell engagers. And then there's rare disease as well and an entire pipeline in our research and preclinical behind that as well. So I think it's just the time that we are kind of completing some very heavy investments. We have to make that business grow and be profitable. And it's the time to diversify the company as well.

And my final general questions is actually going to be on AI. I think this is the first time I ever asked about AI at our conference. But I can't include a line item in my model in AI yet. But can you just talk a little bit about that, what we might be underappreciating and when might the fruits of that labor become more obvious?

Yes. It's a great question. It is a total game changer. And we are obviously in inning 1, and we believe that we are very far ahead at Moderna, across all areas, which I'll get into. But there is so much productivity, not just from a cost perspective, but from a speed-to-market perspective, from a working capital perspective in terms of materials management, from a scheduling perspective for patients, which really affects our INT business.

There is an enormous amount of returns, and we've been very broad across all functions, very methodical about it. I had -- I just walked out of a 2-hour review with our entire digital team walking through exactly what we've got going on. And AI is one thing that it has to be backed by a terrific set of software and data, and we have that. So there's back office productivity. There's front office productivity. There's -- we've got -- and I think we've actually started to realize some of those benefits in 2025.

So if you remember, we entered 2025 believing we would be $5.5 billion of cash cost and ended at $4.3 billion. Not all of that is AI and probably a small portion of it, but it's still yielding benefits. It is difficult to model. I can totally understand that. But I think you can see -- you will see the productivity through what is our operating cost and what are those metrics? What does it look like from a margin perspective? What is our working capital? Our working capital last year ended at $150 million. So it's very capital efficient. And you'll see that over time as we grow that the cost of the infrastructure of our company does not have to grow nearly as much and which is why we're still confident in our overall breakeven and our ability to impact costs in the coming years.

That's great. So we'll get to the specific programs, starting with mRNA-1010 and flu, an unusual regulatory sequence with the RTF and then the BLA acceptance a few days later to say the least. So maybe you could walk us through that briefly and also touch on the post-marketing confirmatory study in adults 65 plus and how you plan to fund that?

Yes, it was -- what happened was certainly unexpected to be specific about it, the refusal to review our application was related to the control arm and whether it was at the right standard. And so that was surprising to us because we had years of dialogue with the FDA.

So when we reflected on that, we said we've got to dig in and understand a little bit more, and we requested a Type A meeting. And through that Type A meeting, worked through it with and we came to a good spot. So what is that spot? That spot allows us to be fully approved from ages 50 to 64. And then 65-plus requires a -- will be accelerated approval, should this all be approved. And then we will -- what is required is a post-marketing commitment, which I'll talk about, which was one of your questions.

But I mean, the PDUFA date we got is August 5 or 2, which is now 5 months away, which is terrific. That is probably faster than we originally anticipated, frankly. So we're excited about the opportunity. It is in the near future. We're working well the FDA on it. So that's what I'll say about that overall then.

In terms of the post-marketing commitment, this is a pragmatic real-world evidence study that will take place over several years. So it is much more cost efficient than what one might think is a typical Phase II or even Phase III trial. So it doesn't affect our breakeven or our cost estimate at all. We always had some ability -- we always knew that we would need some real-world evidence over time and had already positioned and planned for this. So we're excited about what's coming.

And remind us briefly in the 50-plus age group, what percent of the flu market that is in terms of vaccines roughly? Is it similar to COVID?

I think COVID makes up a larger majority of 50-plus. So I think 150 million patients or people vaccinated in the United States. I think it's probably not the same split. I think it's more [indiscernible]. I think it's a little bit less than that. So COVID has, I think, 55% ,65% plus, 65%, 70%, 50% plus. It's not at that level. It's more split 50-50.

Got it.

But it's 5x the market.

Yes. And then for ex U.S. regulatory reviews, can you elaborate on that? Has it been -- has your experience been a little different there than the U.S.?

I'll just say that they've all been approved for a review in Europe and Canada and Australia.

Great. And the flu/COVID combo, just remind us the time lines there for ex U.S. how meaningful that is for the opportunity ex U.S. over the next few years? And then maybe you could touch on your U.S. plans for the flu/COVID combo.

Yes. So on Friday, actually, we announced that we received a positive CHMP opinion on our flu plus COVID combo, which is exciting. And so therefore, we believe that it could be approved in Europe in the coming months. So that's terrific and would be the first combination vaccine in that market as it pertains to infectious disease.

And we've also filed -- if you think about the U.S., the U.S., we are still waiting now that we have a discussion on flu. We need to understand what is required on flu first. So I think that will take a few months and be further along into what the FDA is seeing. But I'll remind investors that none of this is planned as revenue in 2026, not any stand-alone flu revenue and not any combination revenue. So we really are not expecting this to be a 2026 revenue driver whatsoever. We think it's a substantial growth for both of them or a substantial growth driver, come 2027.

And the combination, particularly in Europe, as Europe opens up, it happens to coincide with Europe opening up. And what do I mean by opening up? We've been basically locked out of Europe for the last few years because a competitor has a contract there, which ends by the start of 2027. So we'll be able to compete ideally with both a combination product, with a flu product and with a COVID product, RSV, obviously.

So we're excited about what that means to 2027, particularly in Europe. We're excited for flu in the U.S. in 2027. It remains to be seen what it means for the combination vaccine, which we had planned really to be a 2028 revenue driver. So none of our plans have COVID in the U.S. or the combination in the U.S. in 2027 or 2026.

Understood. RSV quickly, any -- should we start to get a little bit more excited about that with a potential flu approval? Or do you think you need further maturation of your portfolio to -- in terms of contracting for RSV? should we keep expectations low?

Yes. We intentionally tried to keep expectations. There will be growth, but it is nominal growth. It's coming off a low base and any growth is helpful, but it is not to the tune of 10 growth drivers that I've been speaking about. And I think what's really required there is clarity around what is the revaccination schedule. So in the first year, I think there were 12 million Americans that got vaccinated. This is back 2023 and that's down to, I think, $2 million or less last year.

And we were third to market. So therefore, you kind of need another revaccination period for it to warrant us kind of breaking in. And that comes at a time, ideally, in the next years here, where we will have a fulsome portfolio and think we will be able to compete very well. So -- but in 2026, we're not counting it as -- actually in the next few years, we're not counting it as a growth driver. But should there be a revaccination year that is in this time period, that would be upside to what we are planning for.

Great. And norovirus, you're now guiding the 2-season interim data in '26, which was earlier than prior expectations. Have you provided any granularity on that timing? And what would a successful interim readout look like with that program?

Yes. We're -- basically, we -- what we've said is that we are enrolling a second Northern Hemisphere cohort, and there will be a readout in 2026, and we haven't really adjusted the timing of all that much. So we're excited about it. I mean, just stepping back from norovirus, I think it's getting more and more press nowadays, actually. But it is a significant unmet need out there and does impact many lives, again, particularly older adults.

And so what we're -- I think what most people -- most FDA or most agencies look for is at least a 50% vaccine efficacy. And based upon the data that we saw from our immunogenicity studies, both in Phase I and Phase II, we're encouraged, and we're a whole optimistic that it will be a terrific vaccine and read out well. And so then it actually enters a pretty large market. So the market for occupational health and health care workers and lifestyle travelers, we think it could be rather substantial. I think we put this one also as of 2028 revenue driver, just to be clear.

So we're hopeful that it is a terrific interim readout this year. But right now we're planning on a 2028 launch. And that really does pair well. We believe it will go into the retail channel where many are sold and going back to this whole portfolio approach. That's why 2028 is such a difficult year to call from a revenue perspective. That's why we've only guided through 2027, but we know that we can get to 2028 with a lot of these growth drivers and the ability to take down cost. So we're excited about it.

Great. Transitioning to oncology with Intismeran, INT and several other programs now. Possible pivotal readout for adjuvant melanoma in '26. If this hits, could transform the entire company. You made a recent hire in terms of -- on the R&D front, Head of R&D, David, who has a tremendous background who I'm a big fan of. Can you -- so I guess the timing of this readout is it's very -- it's impossible -- it's event-based, right? So you can't give perfect granularity. But what do you think is the probability that it comes in '26 versus '27 and slips into '27? Can you give us anything on that front?

Yes. I mean, all I'll say is everything -- I'll just echo everything you said. I can't give a probability, but it's obviously enough that we said it could come in 2026. So therefore, we don't control that, obviously, because it is event driven. But obviously, the last thing -- maybe the other thing I'd say is just to remind investors, the adjuvant melanoma trial was fully enrolled in September of 2024.

And what we're looking at the shape of the curves on the Phase II versus this Phase III, which was fully enrolled in September 2024. And if you look at that, if it performs similarly, then you should see some kind of readout in 2026. So I can't assign a probability to that. I would just say that we've obviously said that it could read out in 2026, which must mean that there is some additional confidence in that.

Yes. If it similarly to Phase II, it's going to be a huge success, clearly. The data were really impressive. But maybe you could just talk -- have you guys said anything on powering? Or kind of what's the minimum bar in RFS or DMFS that you guys need to meet in the Phase III to be successful? And can you give us your latest thoughts on the size of that market?

Yes. Let me back up and talk Phase II and then I'll answer your question on Phase III and then the market as well. So the Phase II, just to replay the results at year 3, RFS, so no recurrence or death was 49%. And so really, obviously, a remarkable impact on patients. DMFS was at 62%, I believe, at year 3. And then, I guess, it was January. January, we just came out with -- it's a lot going on.

So in January, we came out with our 5-year data on Phase II, and that basically replicated. We only came out with RFS data, but it was exactly 49% again. So remarkable durability through 5 years Phase II, which we're encouraged by. If we saw close to that on the Phase III, we'd be thrilled.

And I think more importantly, patients would be thrilled. And as a reminder, it was one of the fastest Phase III trials ever enrolled. So we are -- I think there's a lot of -- we know there's a lot of excitement about it. We're excited about it. And if we see something even remotely similar to what we saw in the Phase II, I think many stakeholders will be quite pleased.

As for the market size, the market size, there's, I think, 100,000 patients that have melanoma and I'm just talking United States here -- in the United States. But when you whittle it down to what phase are they in, have they been resected, it's down to -- I don't know if we've given out specifics, but it's in the lower thousands, let's call it, 10,000 to 20,000. That is the market opportunity. And so -- and then you have to apply a price to it. We think it brings substantial value to patients. So it's a pretty significant opportunity for us. Even 1,000 patient, which we just enrolled in 14 months or whatever it was, in the first year would be phenomenal.

5-year OS data from Phase II expected later this year, I believe. Is there anything you could say about that? What level of benefit would be meaningful or what we should expect?

Yes. What we saw in the Phase III was early. It was promising, but early from an overall survival perspective. So we're excited to release what the Phase II data will be through 5 years at an upcoming conference, both -- for both DMFS and for overall survival. But we were encouraged by what we saw 3 years in.

Great. And beyond melanoma, let's see lung, RCC, bladder, others. When -- can you lay out the time lines for readouts in those potential indications? Which ones could come sooner than later? Could we get some of those this year?

Yes, great question. So I think first, it speaks to just how excited both Merck and Moderna are to invest behind this. We now have 3 Phase III trials and I think 5 Phase IIs or 2 Phase Is. So we've got a lot going on. To speak to what you just asked. So I would follow when these trials fully enrolled. So we had previously announced that renal cell carcinoma was fully enrolled sometime in the second half of last year. I forget the exact date.

And then in our recent earnings call, we said muscle invasive bladder cancer was fully enrolled. So that starts ticking to when are the events and when can we have a readout similar to what I just spoke about from a melanoma perspective. And so that's what I would track.

And then same thing with non-small cell lung cancer. We are still enrolling. But once it enrolls, then the events start ticking. But there's clearly a lot of investment behind this. They are enrolling rather rapidly. We now have 3 fully enrolled, and I would track enrollment is the best thing I would tell investors.

Great. In the last couple of minutes, maybe we'll touch on rare disease. You made the decision to out-license the PA program to Recordati. So maybe you could touch on that decision as well as also the decision to keep MMA in-house and the status of that program and the future of the rare disease portfolio.

Yes. I mean it really -- it's -- so we're thrilled to have Recordati as a partner. They already sell into PA with a different type of therapeutic. So they already have that commercial infrastructure to really rapidly identify patients that have proprionic acidemia. So this was a capital allocation decision. We think that's the most efficient way to have an impact for PA patients and obviously, impact as many as we can as pet quickly as we can. Not -- but it's also we don't have to invest in advance. So we can wait to see the data. We already have a commercial partner. And there are many numerous rare diseases behind that.

So before going and investing ahead of hopefully, a positive outcome, then we can do this with somebody that already can do it, accelerate that program and then hopefully, MMA and many numerous ones behind them, we can make that choice whether we're going to create our own infrastructure. But then you'll have a data point.

So they have a data point on is this performing well? First of all, did a read out well? Is it commercially performing well? So we really -- we're excited for patients, but it was also a capital allocation and I think a prudent one to not advance our investment before you actually have a readout on this.

Great. And maybe related to rare disease, but you mentioned a continued focus on nucleic acid technologies. So outside of mRNA that would include RNAi potentially or DNA. Could we see something like a new program on that front anytime soon? Or is that a very long-term statement? What's the latest there?

Yes, nucleic acids includes that. And we've -- I think that's a long-term statement. I think we -- I know we have a lot on our plate to execute and a lot of opportunity, which we are enormously excited about, including in the very near term, next 3 years. And so we have enough with mRNA technology to keep us busy for the coming years, and we're excited about it.

Fair enough. In closing, maybe I'll ask you, Jamey, what aspect of the Moderna story do you believe is most underappreciated by investors right now?

It's a good question. Well, the first one, I'll just put in the plug, and I'll answer it in 2 ways. One is the people. I think the people at Moderna are incredible. I think they are extraordinarily accomplished and have an enormous expertise.

I think they are passionate, and I think they are resilient, particularly in a time over the last 2 years that have been challenging for many different reasons. So I'll put that plug in for people. Then I think in terms of the business we're building, I think it is both durable and diversified. So I don't think investors and part of this is us trying to guide investors as well that we have a pretty durable COVID franchise, perhaps more so than others might think.

And I think we look at some of the contracts that we have, particularly outside the United States, that should provide a solid buffer for us for years to come. And then from a diversified perspective, I won't reiterate everything I just said, which is all the shots on goals and the fact that we can grow internationally.

And then you combine that with a pretty strong balance sheet that we just ended the year with, both the cash on hand plus the liquidity we have through the loan that we have at our disposal. I think it's a really exciting story that we can invest behind and be excited about. And we are -- I'm not sure that's always appreciated.

Wonderful. Jamey, thank you so much for your time.

Thank you.

Thanks, everyone, for joining.

Good day, and thank you for standing by. Welcome to Moderna Fourth Quarter 2025 Conference Call. [Operator Instructions] Please be advised today's conference is being recorded. I would now like to hand the conference over to your speaker today, Lavina Talukdar, Head of IR. Please go ahead.

Thank you, Kevin. Good morning, everyone, and thank you for joining us on today's call to discuss Moderna's Fourth Quarter 2025 financial results and business updates. You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the Investors section of our website.

On today's call are Stephane Bancel, our Chief Executive Officer; Stephen Hoge, our President; and Jamie Mock, our Chief Financial Officer.

Before we begin, please note that this conference call will include forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please see Slide 2 of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements.

With that, I will turn the call over to Stephane.

Thank you, Lavina. Good morning or good afternoon, everyone. Thank you for joining us. I will start with a quick review of 2025, Jamie will present our financial results and 2016 outlook, Stephen will review our commercial outlook and clinical programs, and then I will come back and share our key value drivers as we look ahead before we take your questions.

Let me start with a review of 25%. Our revenues were $1.9 billion, driven by sales of our COVID vaccines, Spikevax and mNEXSPIKE. We continue to make tremendous progress on costs in 2025. Operating expenses were down $2.2 billion or 30% for the year. I would like to thank the entire Moderna team for this great accomplishment in 2025. I'm very proud of this.

Net loss for the year was EUR 2.8 billion, and we ended the year with $8.1 billion in cash and investments.

Before I start a review of 2025, I want to express all this appointment to the FDA, who will be able to file later on our full program, mRNA-1010. The current uncertainty in the U.S. FDA regulatory environment creates real challenges for businesses, patients and the broader innovation ecosystem. When expectations and review time lines are unpredictable, companies face greater risk and can hesitate to invest, slowing the development of breakthrough medicines. This delays patient access and increases overall health care costs.

Sustained regulatory uncertainty frightens U.S. leadership in innovative medicines. This can also result in transformative medicine developed by U.S. companies becoming available to patients outside the U.S. before reaching American patients.

Turning now to the execution on commercial and pipeline. On the commercial side, in 2025, we have 3 products on the market, Spikevax, mNEXSPIKE mRESVIA. Spikevax was approved in the U.S. in 2025. It has an excellent launch, quickly became our leading product in the U.S. In the past 2 weeks, we announced 2 commercial agreements. First, an agreement with record at for the global commercialization of our propionic acidemia rare disease candidate, currently in the pivotal study. We call that he brings deep rare disease commercial expertise and an established global infrastructure with a prophetic acidemia community. We also announced earlier this week a 5-year strategic agreement with the government of Mexico for respiratory vaccine supply. We currently have 2 products under regulatory review in multiple countries. Our seasonal flu vaccine is filed another review in Europe, Canada and Australia. Our flu plus COVID combination vaccine is filed and under review in Europe and Canada.

Additionally, we made strong programs across the pipeline. For [indiscernible], our individuals cancer therapy developed in partnership with Merck, we recently reported positive 5-year Phase II data in adjuvant melanoma, demonstrating the durability of clinical benefit, and we are foreseeing our confidence in the program's long-term potential.

I am very happy to announce that we have completed enrollment in our Phase II study in muscle-invasive bladder cancer. This marks fully stage studies in 3 different cancer tacks that are now fully enrolled: adjuvant melanoma, adjuvant renal cell carcinoma and now muscle-invasive bladder cancer. We look forward to the data with us from these studies. For cancer antigen therapy, mRNA-4399, we announced positive Phase Ib data and the promise now in Phase II. Our Phase III novirus program is now fully enrolled, so we could see Phase III data in 2026. In our peer program is still fully enrolled in this retraction study and with UTC data in 2026.

I am free to welcome to Modena, our new Chief Development Officer and Executive Committee member, Dr. David Berman. He has contributed to the development of more than 1,000 clinical stage immunotherapies at BMS and AstraZeneca. His expertise will serve Moderna well as we continue to expand our oncology pipeline. David served most recently as Head of R&D of Immunocore. We very much look forward to David joining Moderna's team on March 2. I work, of course, to take this opportunity to thank [indiscernible] for her many contributions in over the last 5 years of the company, especially a tremendous leadership during the pandemic.

With this, I would like to take over to Jimmy.

Thanks, Stephane, and hello, everyone. Today, I'll cover our fourth quarter and full year 2025 results and then wrap up with our 2026 financial framework. I'll begin with our 2025 revenue performance on Slide 8. For the fourth quarter, total revenue was $700 million, coming in at the higher end of our recent guidance. Our revenue split in the quarter was $300 million in the U.S. and $400 million from international markets. For the full year, total revenue was $1.9 billion, with the majority generated from COVID vaccine sales, along with approximately $100 million of other revenue.

From a geographic perspective, U.S. revenue totaled $1.2 billion, while international revenue was $700 million. In the U.S., while overall COVID market demand declined year-over-year, we had strong market share in the retail channel, supported by the successful launch of mNEXSPIKE. In international markets, we landed at the higher end of our range, driven by operational performance and vaccination rates, which were above or in line with our expectations.

Turning to Slide 9, I'll review our fourth quarter results. As we discussed on the prior slide, revenue was $700 million. Compared to the fourth quarter of last year, operating expenses were down 31%, reflecting continued cost discipline and execution across the organization. I'll discuss these expense trends from a full year perspective on the next slide.

Our net loss for the quarter was $800 million compared to a net loss of $1.1 billion in the fourth quarter of 2024. Loss per share was $2.11 compared to a loss per share of $2.91 last year.

Now turning to Slide 10. I'll walk through our full year 2025 financial results. As I mentioned earlier, total revenue was $1.9 billion. Cost of sales was $868 million, representing a 41% decrease compared to 2024, primarily driven by productivity and lower inventory write-downs, contract manufacturing wind down costs and sales volumes.

R&D expenses were $3.1 billion, representing a 31% decrease compared to 2024, driven by continued investment prioritization and efficiency gains in the execution of our clinical trials. These reductions were partially offset by increased investment in our neuro virus vaccine and oncology programs.

SG&A expenses were $1 billion, representing a 13% decrease compared to 2024. The decline was driven across all functions, and reflect our continued focus on operating efficiently while supporting the business in a disciplined manner.

Our income tax provision for 2025 was immaterial. We continue to maintain a global valuation allowance against the majority of our deferred tax assets which limits our ability to recognize tax benefits from losses.

Net loss for the full year was $2.8 billion compared to a net loss of $3.6 billion in 2024. Loss per share was $7.26 compared to a loss per share of $9.28 last year.

We ended 2025 with cash and investments of $8.1 billion, compared to $9.5 billion at the end of 2024. The year-over-year decrease was primarily driven by operating losses as we continue to invest in R&D and advance our pipeline, partially offset by the $600 million initial draw of our $1.5 billion credit facility. Excluding the credit facility draw, we would have ended the year with $7.6 billion of cash and investments, which was above our 3Q guidance of $6.5 billion to $7 billion due to lower operating expenses, lower capital expenditures and working capital improvements.

Now let's turn to our financial framework for 2026. We expect total revenue growth of up to 10% in 2026. This growth is expected to come primarily from international markets, and we estimate our geographic mix will be well balanced between the U.S. and markets outside the U.S. in 2026. This is a shift from our 2025 revenue split of approximately 62% U.S. and 38% international. We will begin selling locally manufactured products in both the U.K. and Australia in 2026, which is the largest driver of our international growth. Our 2026 revenue guidance factors in future potential declines in COVID vaccination rates and also assumes no revenue from our flu vaccine or our flu/COVID combination vaccine.

Similar to 2025, we expect 2026 revenue to be weighted to the second half of the year, with approximately 15% of our revenue in the first half and approximately 85% in the second half. Cost of sales is projected to be approximately $900 million. While this is flat year-over-year in absolute terms, we are expecting gross margin rate improvement from manufacturing efficiency gains and volume leverage. R&D expenses are anticipated to be approximately $3 billion as we continue to invest in our late-stage pipeline while maintaining financial discipline. It's a relatively small decline from the $3.1 billion we had in 2025 due to the continued execution of our late-stage trials in infectious disease.

For modeling purposes, we expect our R&D spend to be relatively balanced in the first half versus the second half of 2026, similar to what we experienced in 2025.

SG&A expenses are expected to be approximately $1 billion, flat versus the prior year. We remain focused on driving efficiency and cost savings across the organization, which we will use to fund new commercial investments to support both geographic expansion and future product launches. Similar to 2025, our commercial spend will be more heavily weighted to the second half of the year due to the seasonality of our commercial business.

In aggregate, we are expecting total GAAP operating expenses of $4.9 billion and $4.2 billion of cash costs, which excludes stock-based compensation, depreciation and amortization. We expect taxes to be negligible in 2026.

Capital expenditures are projected to be between $200 million and $300 million. This guidance includes our previously announced investment in building our own fill/finish capacity in the United States at our existing site in Norwood, Massachusetts.

We expect to end 2026 with $5.5 billion to $6 billion of cash and investments. Our cash guidance does not assume any additional drawdown from our credit facility.

In summary, 2025 was a key turning point in our financial story. We improved our commercial execution, exceeded our cost reduction plan by over $1 billion and ended the year with over $2 billion more cash than our original 2025 guidance, all while still advancing our pipeline. I want to thank the entire Moderna team for their efforts over this past year, and we have strong momentum heading into 2026, with multiple levers for revenue growth and a strong commitment to drive additional cost reductions across the company.

With that, I will now turn the call over to Stephen.

Thank you, Jamie, and good morning or good afternoon, everyone. Today, I will review our commercial outlook as well as progress across our pipeline. As Jamie mentioned earlier, we expect 2026 to mark a return to revenue growth for Moderna. This year, we expect growth to be driven primarily by our strategic partnerships and the second year of launch for mNEXSPIKE, which I will discuss in more detail in a moment. But first, looking forward to 2027, we see 3 additional growth drivers. We look forward to significant expansion of our addressable market with the opening of the $1.8 billion European respiratory vaccines market. As a reminder, we have been excluded from this region for several years due to a competitor pandemic contract, which expires in 2026.

We expect to launch mNEXSPIKE, our stand-alone flu vaccine mRNA-1010 and our combination flu/COVID vaccine in the European region by 2027 winter season. adding to mRESVIA and mNEXSPIKE, which are already approved. This broad portfolio represents the opportunity to grow our share in the large European market, which will contribute to meaningful revenue growth from 2027 forward.

Second, we expect growth from our new multiyear strategic agreements in Latin America and Asia Pacific. And third, with the acceptance of our flu filings in Europe, Canada and Australia, we anticipate that our flu vaccine will begin to contribute to revenue internationally.

In 2028, we expect continued new product-driven growth opportunities with both our combination flu/COVID and norovirus vaccines potentially being launched across many of our markets. Recent execution supports this growth strategy with approvals for mNEXSPIKE in Canada and Australia, and the approval of our strain updated Spikevax co-vaccine in the U.K.

We have already shown strong momentum against the 2027 growth drivers. We announced a multiyear strategic agreement with Mexico earlier this week and Taiwan last month and we continue to make progress under our previously announced strategic agreement in Brazil.

Finally, although not a major driver, we also signed a global commercialization collaboration in PA with [indiscernible] as we prepare that potential launch in 2028. The U.K. is both -- let's take a closer look at the key contributors to that growth in 2026, beginning with our strategic partnerships with the U.K., Canada and Australia. As a reminder, these are long-term agreements, under which Moderna has built local manufacturing sites and committed to ongoing domestic research and development. These partnerships are core to each country's national security and public health strategy, strengthening preparedness against current viruses and future pandemic threats.

The U.K. is the largest of these markets, and we expect a $200 million U.K. COVID order to be fulfilled in the first half of 2026 for their spring booster campaign. We also expect to supply vaccines for the U.K.'s fall vaccination campaign, initially this year for COVID, with the potential to expand to other respiratory vaccines such as flu, RSV and our combination vaccine in the years ahead.

In Canada, we are thrilled to deliver a -- we were thrilled to deliver made in Canada COVID vaccines in 2025 and expect to see the full annualized impact of the agreement in 2026. And in Australia, we expect to deliver the full annualized benefit of our agreement in 2026 as well.

Moving to Slide 15. Our second major expected growth driver in 2026 is our new COVID vaccine, mNEXSPIKE. mNEXSPIKE had a very successful launch in 2025. This is especially notable because mNEXSPIKE was approved midyear in '25 and was only available commercially in the United States. We are extremely pleased with the market share achieved in that first season with them mNEXSPIKE capturing 24% of the total U.S. retail market and 34% of the retail market among adults aged 65 and older. As a reminder, the retail market is the largest customer segment, representing approximately 3/4 of the U.S. COVID market, and the majority of that volume is in seniors.

Looking ahead to 2026, we expect to continue to drive the uptake of mNEXSPIKE in the United States. And internationally, we look forward to approvals and launches in multiple countries this year and the years to come.

Moving to Slide 16, which -- this outlines the latest developments in our infectious disease portfolio. Starting with our approved products. The updated formulation of Spikevax is approved in countries around the world. And importantly, in 2025, we received the supplemental BLA approval in the United States for high-risk children as young as 6 months. As mentioned earlier, mNEXSPIKE was approved and launched in the U.S. It was approved in Canada in 2025 and recently approved in Australia as well. We are targeting further approvals in -- of mNEXSPIKE in Europe, Japan and Taiwan this year. mRESVIA, our RSV vaccine has been approved for adult age 60 and older in 40 countries and approved for high-risk adults, age 18 to 59 in 31 of those 40 countries. In addition to those 3 approved vaccines, we filed for 2 additional approvals. MRNA-1010, our flu vaccine has been accepted for review in Europe, Canada and Australia with the first potential approvals coming late in '26 or early 27.

We were disappointed with the FDA's refusal to file letter for mRNA-1010 and have requested a Type A meeting to understand the path forward for the program in the United States. mRNA-1083, our flu plus COVID combination vaccine is under review in Europe and Canada, with first potential approvals in 2026. And finally, our norovirus vaccine is in an ongoing Phase III trial, which is fully enrolled in its second Northern Hemisphere season and is accruing cases towards its interim analysis.

Now turning to our therapeutics pipeline. [indiscernible], our individualized cancer therapy developed in collaboration with Merck has a total of 8 Phase II or Phase III studies ongoing. The most advanced of these is our Phase III adjuvant melanoma study as well as our Phase II randomized adjuvant renal cell carcinoma study, both of which have been previously announced as fully enrolled. As Stephane mentioned previously, we are very excited to announce that we have now fully enrolled our Phase II randomized muscle invasive bladder cancer study. Bladder cancer is the third cancer type now in a fully enrolled late-stage study.

In addition to these 3 trials, we are looking forward to completing enrollment in our ongoing Phase III studies in adjuvant non-small cell lung cancer. We also look forward to completing enrollment in our ongoing Phase II trials in non-muscle invasive bladder cancer, first-line metastatic melanoma and first-line metastatic squamous non-small cell lung cancer.

Beyond these Phase II and Phase III studies, we are fully enrolled in our Phase I studies for adjuvant pancreatic cancer and perioperative gastric cancer. And we look forward to data from these studies in the year ahead.

Aside from -- aside from our collaboration and Intisarin with Merck, we continue to make progress in additional oncology programs. In the Phase II study of our cancer antigen therapy, MRNA-4359, cohorts are enrolling in first-line metastatic melanoma, second-line metastatic melanoma and first-line metastatic non-small cell lung cancer. In mRNA-2808, our T-cell engager in multiple myeloma, we are dosing in our Phase I/II study. We're also dosing in the Phase I study of our cancer antigen therapy mRNA-4106. And rounding out our early-stage oncology programs, our Phase I study is also dosing in our cell therapy enhancing program, mRNA-4203, in collaboration with [indiscernible].

In rare diseases, our proprionic academia or PA program is fully enrolled in its registrational study. And in methylmalonic acidemia, or MMA, we expect our registrational study to start in 2026.

With that, I'll hand the call back over to Stephane.

Thank you, Stephen and Jamie. Looking ahead, we see multiple commercial, pipeline and financial value drivers that will move Moderna forward in 2026. Commercially, we believe the market share gains from mNEXSPIKE will continue in 2026 and beyond. We will also benefit from a full year contribution from our strategic partnership in the U.K., Canada and Australia. That will be an important growth driver for Moderna in 2026. And we expect up to 10% revenue growth in 2016.

From a pipeline standpoint, we look forward to potential regulatory approval of mNEXSPIKE in Europe, in Japan and in Taiwan. We also expect potential approval of our combination flu plus COVID vaccine in Europe and Canada, where regulatory filings are under review. In the U.S., we plan to refile planning further guidance from the FDA.

For seasonal flu vaccine, we look forward to an approval in Canada this year. This is going to be an important year for oncology patients and for Moderna. We also expect continued clinical momentum from our Intismal program, as Stephen just described. Last month, we reported positive 5-year Phase II data in adjuvant melanoma. Potential clinical milestones from [indiscernible] program include Phase III adverse melanoma data, Phase II adjuvant renal cell carcinoma data and Phase I data in adjuvant pancreatic and perioperative gastric cancers, all of which have been fully enrolled for quite some time.

We also look forward to a Phase II result for our cancer antigen therapy mRNA-4459, the Phase II results for norovirus and the pivotal data readout from our PA program. That will be a busy year.

From a financial standpoint, teams across the company continue to make progress on cost discipline, and we expect cash costs to decline approximately to $4.2 billion in the year. As part of our cost efficiency program, the adoption of AI tools as such every part of our business, and we expect further productivity improvement in 2026.

Moderna has a strong momentum as we head into 2026. We are poised to deliver up to 10% revenue growth as we continue to reduce costs. We expect to see approvals of infectious vaccine that will expand our commercial portfolio. And we foresee multiple potential clinical data catalyst, driven by our [indiscernible] oncology programs in rare disease and infectious disease.

In closing, I want to recognize the entire Moderna team for their [indiscernible] drive. Our progress, clinical, commercial, operational, is dedicated to one mission, delivering the greatest possible impact to people for [indiscernible].

With this, operator, we'll be happy to take questions.

[Operator Instructions] Our first question comes from Terence Flynn with Morgan Stanley.

I had 2 parts. I guess the first 1 is just on the flu RTF implications for the 2028 cash flow breakeven guidance? And then timing of the Type A meeting like when you might get some visibility on next steps? And then the INT program in adjuvant melanoma. I know that's a very important program and catalyst for the company. And so can you refine at all the timing of that data, whether it's going to be first half or second half?

Sure. Maybe I'll take the questions on regulatory first, and then, Jamie, hand it over to you on any breakeven implications. So we're actually very pleased that the flu file is under review now in Europe, Canada, Australia. We'll be filing in additional countries this year. And all of that is with an eye towards having that start to contribute, as I said a moment ago, in 2027, in the fall of 2027 to our growth. We also are pleased that the flu/COVID combination product remains under review and making progress in Europe for this year.

As it relates to the U.S. timing, it really -- we need to engage with the FDA in the Type A meeting, that's usually 30 days as a process, and understand from them what is going to be required to get that product moving forward in the U.S. We absolutely feel that American seniors should have access to the same innovations. We do think this year, in particular, where there's a potential for a mismatch in one of the strains, it's particularly important that technologies like Moderna's mRNA platform are used to advance new and potentially improved products. But at this point, until we have that Type A meeting, we won't really know how quickly we can get moving forward with the 1010 file in the U.S. as we've been doing outside the U.S. Jamie?

Yes. Terry, thanks for the question. I appreciate it, and I recognize that it's on investors' minds. As Stephen just said, though, this is a bit of a fresh and fluid situation. And without understanding the resolution of what is next for our flu product, it's a little bit difficult to comment at this time. But here's what I would say. If you go back to the growth drivers we laid out at Analyst Day as well as Stephen had in his prepared remarks, we have 10 large shots on goal to increase revenue over the coming years, all with a wide range of potential outcomes. And Stephen mentioned some of the progress. We announced our long-term partnerships with Mexico and Taiwan. We're excited about -- as I said, we're excited to deliver for the U.K. and Australia this year, which will be substantial revenue growth. mNEXSPIKE had a great first year. We're excited about the second year, both in the U.S. and outside the United States. We're looking forward to Europe opening up. So it's really -- there's still so many scenarios that could happen here, Terence, that it's a little bit too early to tell. On top of that, we have a ton of momentum on productivity and what we're doing from a cost perspective. So we're really excited about our financial profile. We ended the year with over $8 billion in cash. We have a ton of momentum from a cost perspective, and we have a lot of opportunities for growth. So at this point, without knowing resolution to what's going to happen on flu, I think it's a little too early to tell.

And on INT, the second question. We we don't have, obviously, more specific guidance than we previously put out there. I'd highlight, as I said a moment ago, that there are 5 histologies now under review or under different stages of clinical development. So INT for melanoma, the adjuvant melanoma study is 1 that we are confident will read out this year. It is an event-driven trial, and so it will depend upon the accrual of those events. We have RCC, renal cell and bladder are now fully enrolled. And again, those are going to be event-driven and milestone-driven readouts. And so it's possible.

And then the Phase I data that we referenced before for our periadjuvant gastric and adjuvant pancreatic monotherapy cohort. And so it's going to be a busy year for us over the next number of months. But we don't have more specific guidance because some of the most important readouts are ultimately event-driven.

Our next question comes from Salveen Richter with Goldman Sachs.

This is Elizabeth on for Salveen. We wanted to ask about the flu and COVID combination vaccine and just given the RTF for 1010, how should we think about this refiling? And is there any read through from a regulatory standpoint in the U.S.? And then maybe just remind us of the study data that went into the submission initially and with the latest thinking is on what might be needed to be added for refiling? And then a second question on an wanted your thoughts on which of those 5 histologies you just mentioned have the highest probability of success kind of based on the read through from data generated to date?

Thanks for both questions. So first, on the 1083 file, again, I'll underscore that we're hoping for approval of the flu/COVID combination product in Europe first in the this year. And so we'll move forward there. As it relates to the U.S., we were holding back on refiling the combo vaccine until we completed some portion of the review of the flu vaccine. With the refusal to start the review of the flu vaccine, I think that is now gated on, again, the feedback from the Type A meeting, which we haven't had about what more would be necessary for us to refile for the mRNA-1010 program. And then we would be able to provide more clarity on the flu/COVID program and refiling there, again, all of this in the U.S. because all of those files are moving forward internationally.

You asked about the data that was in the file. We had a Phase III study for the mRNA-1010 file, which we have previously presented the results on. And actually, it's out for a peer-reviewed publication right now. But really excited by that Phase III study, which is a randomized 41,000-person study that we had agreed with the FDA and agencies around the world with prior to initiation. In that study, as a reminder, we saw 27% superior relative vaccine efficacy compared to the standard dose control. And just to give you a sense of where that stands relative to comparators, the 2 of the licensed preferentially recommended vaccines for those over the age of 65, had run essentially the same study design, one of them even with exactly the same comparator. And those, if you look at the USPI for Fluzone, they had seen 24% relative vaccine efficacy for flu block. If you look in their USP IOC, 30% relative vaccine efficacy. So at 27%, we felt very good that we were in line in demonstrating superiority in exactly the same way that those standard of cares have in the same population as over the age of 65.

We also ran a Phase III study, an immunogenicity and safety study, comparing our vaccine candidate for flu against [indiscernible] high dose. And in that case, we showed statistical superiority to [indiscernible] high dose on immunogenicity. That study has been published in the journal of Vaccine, and is available, I think, on our website for those who are interested in. So that package was in the initial file. We think it's a very comprehensive data set. We do think if we can get the review initiated, it will support the use of the product. But we do need to understand first from FDA in that Type A meeting what they would need to initiate the review of the file that they previously had agreed to review.

Moving to entismarin. I think it's obvious that you ask where we see the highest probably success. It's hard to argue with the Phase IIb results that we have for adjuvant melanoma. As we announced last month, the 5-year survival data continues to look really strong, approximately a 50% reduction in the rates of relapse or death from melanoma, real stability in those curves through now 5 years. And if you ask me, where do I think the read-through of that is, I think it's clearly, we hope, into the Phase III adjuvant melanoma study that is testing in largely the same population and exactly the same standard of care.

I think if it works, if we see that there, one of the reasons we and our partner, Merck, went in with renal cell and and bladder was we thought muscle-invasive urothelial cell carcinoma is -- we thought those would be places where we might also see relatively quick read-through. And so I hope that those also have positive readouts. But I think if you're asking where we think the probably success is highest, it's clearly in the -- it's in the Phase III adjuvant melanoma.

Our next question comes from Eliana Merle with Barclays.

Just can you elaborate a little bit on how you're thinking about the European COVID vaccination market, and how you see the vaccination rate and pricing evolving there? And also how, outside of the U.S., you're thinking about the pathway for potential flu/COVID combination vaccine approval?

And then also on that topic around flu, just in your filings for flu in Europe and Canada, has there been any discussion around potential strain selection in the future and potentially selecting the strains closer to the season start?

Yes. Thank you for all 3. So first, I'll take the combination question. So -- actually, the COVID question. So mNEXSPIKE is moving forward with approvals internationally, and we're really pleased with the profile of that product. As I'll remind you, we had demonstrated in that Phase III study higher relative vaccine efficacy. In fact, in a post hoc analysis, very high, approximately 25% higher relative vaccine efficacy compared to mNEXSPIKE in older adults with comorbidities. And so I really do think it's got a strong profile as the European COVID market reopens.

Now as to pricing, we haven't issued that yet, but we do believe that the current market is, as we've shared, approximately $700 million today. And that doesn't account for wastage that exists in the market. There are many doses that are being -- more doses that are being purchased under that dynamic contracts that are not getting used. That estimate of approximately $700 million is just what we see as shots in arms. So we do believe that market will be larger than that -- larger than even if we see nothing more than the approximately 20 million shots in arms that currently are happening, and we do hope to get a sizable share. We think mNEXSPIKE will be a very competitive product profile in that market, and we're scaling up for that launch.

As you know, Europe is not 1 market, it is a series of different markets and some places we'll compete traditionally with sales and market activities. Other markets are more tender-driven, and we're preparing for all of that activities really starting this year, but as we said, as a meaningful driver of growth in '27 and beyond.

On the combination product, we actually think that's the next step in that strategy. We're very pleased by the combo products progress in its international reviews. As we've said, based on timing, we do expect a European review to move forward, and we are hoping for approval this year, which gives us a chance to launch as early as this year, more likely in '27, again, it just depends on timing of these events because proximity to the season will make a launch very difficult. But it is clearly a great opportunity for us to move beyond just COVID into a combination product and an opportunity to both expand our share in the COVID space, but also grab share in the flu space. And we are proceeding with the filings elsewhere. I think we referenced in the PR Canada for that combination product as well and hope to similarly bring forward that innovation because we believe there's strong demand from health systems as well as patients for 1 shot or 1 vaccine that does multiple things.

Now as it relates to the flu, we have been having those conversations. So mRNA-1010, as we've proceeded outside of the U.S., there has been strong appetite for the question of better strain matching. And in fact, in some public comments, you've seen some European regulators, but also some from other markets. Vocally advocate for later strain selection and more diverse strain selections happening in flu vaccines, because of the precedent we've shown with COVID vaccines. I'll remind you that in -- we sometimes forget in the U.S., but in this country, we've actually -- the FDA has chosen different strains of COVID vaccine than the rest of the world in 2 out of the 4 past seasons. And the data has shown that, that better matching for the market has led to slightly better efficacy. In fact, we ran a clinical trial once head-to-head back in the bivalent days and showed higher point estimates for efficacy, which makes sense, better match vaccines, you would expect to be better at protecting people.

And what we're hearing from the international flu community, including, as I said, in Europe, is quite strong support for that. It's a real question today. I mean, just to make the point, there is a -- there are a couple of different strains of influenza B circulating around the world right now. In the United States, it is a different strain than is circulating in the rest of the Northern Hemisphere. And there doesn't look like there would be great cross protection. And so it just highlights that the right answer for this fall could be very different from a composition perspective for Europe or North America or other regions. And that's where the technology that we have that has allowed us to tailor and meet regional needs with COVID, we think, can have an impact. There are many other things we need to do to improve flu vaccines, but this is 1 we can -- we know we can do right now.

Our next question comes from Tyler Van Buren with TD Cowen.

This is Greg on for Tyler from TD Cowen. So some investors have been surprised by the higher-than-expected cash balance at year-end. So can you explain why that occurred and what the additional levers to lower cash costs are moving forward?

Yes. Sure, Greg. Maybe I'll just go back to our original guidance. So when we laid out our original guidance, we said $1.5 billion to $2.5 billion of revenue. So $2 billion at the midpoint. And we said $5.5 billion of cash costs. So if you take those 2 together, it's a $3.5 billion usage from a starting point of $9.5 billion, which is why we guided $6 billion. Since then, revenue essentially came in online. We had [ 1.944 ] let's call that pretty close, cash cost came in at $4.3 million. So we beat by $1.2 billion. On top of that, we took $600 million of the initial drop from the loan, so that's now $1.8 billion better. Our capital expenditures were $100 million less than we forecasted at the outset of the year, so that's $1.9 billion better. And then if you look at the working capital, I am really pleased. It doesn't get a lot of attention with how the team has performed. Our receivables are at $180 million. Inventory was flat year-over-year at $270 million, payables at $300 million. We have a net working capital balance of $150 million to which we run this company on. And that is really incredible performance from the team, and that drove the last $200 million.

So I don't think it should be too much of a surprise that it's mostly cash cost for $1.2 billion above our original guidance, the loan, little bit less capital expenditures and then terrific performance on working capital from the team.

Our next question comes from Michael Yee with UBS.

We had 2 questions as well. First, on the adjuvant Phase III melanoma study. Can you remind us that, that study has interims built in and then, of course, a final, and so like other design studies you've done, there's a certain number of cases you crew, you take a look at it and then if it doesn't stop, you move to the next case next interim, can you just describe a little bit of how that works and remind us the Phase 2, I think, did stop at an interim, if I was correct there.

And then on norovirus, I don't think anyone's asked on that, but can you just remind us there you are enrolling or expect to complete enrollment and then there's actually a readout, I think, planned this year. What is your confidence level there? I know there's been a lot of disappointments previously, but I think you are targeting a different approach and using 3 different strains, which I think I assume you believe will capture the majority of coverage. Can you just remind us there and how you think about that result?

Yes. Thanks, Mike, for both questions. So first on the INT Phase III for adjuvant melanoma, you're correct. It's the first analysis that we'll see this year will be an interim analysis, looking at our primary endpoint of relapse-free survival. We have a number of additional analysis. If that -- if you get there and we don't have the statistical power to declare early success then, then we would move forward to subsequent analyses and ultimately, additional endpoints, including things like just a metastases-free survival. What I'd remind you is the Phase II hit essentially a statistical hypothesis at the interim. And then what we've been following since are the others. And we believe we've conservatively designed this study so that if those results are repeated, we would be well powered to see that in this first interim. But if for whatever reason, we're told to continue forward, there would be a subsequent analysis. And that, again, will be event-driven, but presumably would come the year after.

As to the norovirus study, we are very excited to see those results potentially this year, again, a case-driven trial. As you highlighted, there had been some previous efforts in norovirus. Ours are quite different. So first, the composition of our vaccine, as you highlighted, is a trivalent here, and we are looking at strain-matched efficacy, which is important because it does allow us to make sure that we're looking at the performance of the vaccine, which is matched at strains that are in approximately in most years, 2/3 to 70% of the circulating norovirus disease. And so that trivalent composition and the VLPs that our technology make, we think, is a differentiator.

But perhaps the more important one relative to the trial, I think you were referencing is we're looking in seropositive populations, not children. And so earlier studies that have struggled in norovirus have looked at in children in primary vaccination often a couple of doses as opposed to really where the burden of disease is as you become an adult is in older adults, those particularly over the age of 65, where the threat of really profound dehydration can lead to hospitalization and complications of a whole number of medical comorbidities. And so there's a actually even bigger need in that population.

And in that case, it's more of a booster trial. It's much more like -- it's a bit like primary vaccination for whatever it is, RSV or flu or COVID, being very, very different than boosting seropositive people so that they can protect, which is a lot more like what you see with our senior flu, COVID and RSV vaccines, which have obviously been successful. Norovirus is a different one, but we do believe that, that difference in population will make a difference in terms of the ability of a vaccine to help protect them against this disease.

And as a follow-up, do you think that the guidance with FDA or the discussion or regulatory path for this would be very different for an put another way, much more obvious than perhaps what's going on with.

So look, Michael, I'd remind that we have -- we got 3 products approved last year in the U.S. or some label expansions, RSV and a new COVID product and a pediatric COVID. And in those cases, the guidance was different. What we're experiencing with flu is, I think we hope flu specific. Our norovirus study, to your point, is a very large placebo-controlled study. And so the Type A -- the refusal file letter that we have received from the FDA on flu really speaks to a change in their perspective on the comparator used. But in the case of norovirus, there is no comparator to use. And so the comparator in that clinical trial is placebo. If we're able to demonstrate efficacy over placebo, it's hard to argue that there's a problem with the comparator.

Our next question comes from Luca Issi with RBC Capital Markets.

This is Shelby on for Luka. Maybe on IMT. congrats on the recent 5-year data for melanoma, and it's great to see the hazard ratio for RSS is remaining consistent with prior cuts. However, what about OS? I remember at ASCO in 2024, you said some pretty compelling data with the initial separation of the curves, but the press release this time was silent on OS. SP715608970 How should we read that? Does that mean the OS curves are no longer separated? Or are you just keeping the details or maybe an upcoming medical meeting? Any color there? Much appreciate it.

Yes. Let me say it this way. We look forward to sharing the OS curves at an upcoming medical meeting. We -- where you see relapse-free survival holding obviously, included in relapse-free survival is survival. And so we obviously didn't put that out because we want to make sure that we're able to bring that forward to the community in a place where they can see all of that data, but all data from the 5-year interim analysis will be presented at an upcoming medical meeting. Until then, I really shouldn't say more.

Our next question comes from Courtney Breen with Bernstein.

just a couple in building off the conversation around the ITS that you got for the flu 1010. With bench defined kind of an immunogenicity substudy. I think of that Phase III efficacy study, which suggested -- and it was a very small population of that study suggested there was a 50-50 ratio between those under and over 65. Can you just remind us or share with us what percentage of patients in that efficacy study were 65 or older?

And then additionally, as we think about kind of INT and the path to approval and kind of -- have you had any feedback in the design of that clinical trial that perhaps provided some recommendations that weren't followed. Additionally, kind of will it be you or Merck taking that file forward? And kind of can we assume that CIBA will be the FDA group that will assess that particular file?

Yes. Thank you for the questions. So first on the Phase III trial design for our flu vaccine. You're correct, and your memory is right. More than 50% of the population of the study was stratified that at least 50% would be over the age of 65. We also had a very large population, north of 10%, that was above the age of 75. And as we have presented at medical meetings and will be available in the upcoming publication, we've seen really strong superior efficacy across all of those populations. In fact, it's remarkably consistent. And as you add frailty or other risk factors to age, or as you look to severe outcomes such as hospitalization, you'll see those point estimates for superiority go even higher, and in many cases, become even more statistically significant.

So we feel very good about that 41,000-person study which, as you just described, or as I just said, has more than 20,000 people over the age of 65 in it. I did describe a separate Phase III study just to avoid confusion, the P303 study Part C. That has 3,000 people in it, and that was the study that was head-to-head against Fluzone high dose that showed superior immunogenicity. But the efficacy study, I think, was the 1 that you were asking about.

Now as it relates to INT, INT is -- we're moving forward in a very novel field. And so we've had robust and I would say, highly productive engagement with the FDA and truly global regulators around the -- what will be a first of its kind individualized neoantigen treatment. Those dialogues are detailed. And I think broadly, we are very aligned, both ourselves and Merck with those regulators. It is with CIBA FDA, but obviously, other offices are involved because it is an oncology therapy of high import, it gets a lot of attention. And I would just say, generally, we're working closely with regulators to make sure that we're doing everything they want so that they can conduct rapid reviews of the file.

Merck is our partner in this. Merck is the sponsor for the Phase III study. So they -- we and they participate in those discussions and back and forth, and we each have different responsibilities in our 50-50 joint venture partnership. But the BLA submission, if it goes forward, will be from Merck.

Our next question comes from Alec Stranahan with Bank of America.

SP35268589 This is Matthew on for Alex. Maybe for RCC, can you walk us through what makes you confident that Phase 2 could be registrational? And what hazard ratio or benefit you think would be compelling? And then if you do need to run a Phase III, curious whether you think KEYTRUDA be the appropriate comparator arm or whether KEYTRUDA elutipan combo would be preferred pending the LightSpark22 data.

Yes. That's a great question. One of the exciting things in oncology is it's a fast-moving space. And then individual histology is sometimes the standard of care will evolve and you're highlighting [indiscernible] for RCC. Look, first, I'd say the Phase II study is blinded, it's powered. And if we see a really significant or profound benefit. We haven't guided on what that hazard ratio will be, but let's assume it's something that would look really dramatic and highly statistically significant. Then it is structured so that it could be a registrational study. But it wasn't initially intended empowered as that. It's not a Phase III study because our primary goal here was we wanted to confirm the hypothesis that INT works well across a range of tumors and in particular, places that we thought there was an opportunity to improve apron pembro as a standard of care.

And since we started and enrolled that study, there's obviously been the good news of the [indiscernible] result. Again, that's with our partner, Merck. And so if we see equally great response here for INT, we'll have a conversation with Merck about what we do with INT. It may mean going forward, it may mean adding it to those because there's always a desire to improve outcomes in cancer. It will entirely depend upon what the data actually says. And so at this point, we're just excited to look forward to it. But once we have it, the thing that I think we will be most focused on is, does this confirm the opportunity for INT to work across a range of different cancers and other histologies?

Our next question comes from Cory Kasimov with Evercore.

This is Eddy on for Cory. We had a question on the adjuvant melanoma as well, could you share how do you anticipate use across the broader PD-1, PD-L1 class or primarily only with pembrolizumab? Separately as subcu pembro and other options become more prevalent, do you see any impact on regimen selection, logistics or ultimately uptake for [indiscernible]?

Thank you for both questions. So first, I think we will be pursuing a label. Obviously, it's on top of a standard of care in the trial, which is pembro, but we believe that, that label could broadly apply to other PD-1, PD-L1s that are approved in the same indication for adjuvant melanoma. Obviously, that will depend upon discussions with regulators, but I think that would follow the precedent of other approaches. And it's in our mutual interest with Merck. We want to see INT be used for as many patients as possible. regardless of the choice of the PD-1 or PD-L1 backbone.

The -- as it relates to subcu, I think that's really within the PD-1 class question. And so how do those antibodies get subbed out for each other going forward. It really wouldn't really, in our mind, to INT, which would be a category of 1 and the benefit that INT provides, we believe, would apply equally well, although we'll have to see what regulators want to see this, but I think the community would agree that would likely apply equally well whether you're doing a subcutaneous or IV use of PD-1 antibody. But that's really a question about what they're doing in terms of class share there because INT will be in a category unto itself.

Ladies and gentlemen, this does conclude the Q&A portion of today's presentation. I'd like to turn the call back to Stephane for any further remarks.

Well, thank you very much, everybody, for joining. We look forward to speaking to many of you in the coming hours, days and weeks. Have a great day.

Thank you.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.

Great. Welcome, everyone. My name is Jessica Fye, large-cap biotech analyst at JPMorgan, and we're continuing the 44th Annual JPMorgan Healthcare Conference today with Moderna. First, you're going to hear a presentation about the company, and then we're going to go into some Q&A. So if you're in the room and you raise your hand, someone will bring you a microphone or alternatively, if you're listening on the webcast, you can submit questions on the portal and I can read them off the iPad up here. So with that, let me pass it over to Moderna's CEO, Stéphane Bancel.

Thank you, Jessica. Good afternoon, and welcome to Moderna's presentation at this year's JPMorgan conference. Let me start by reminding you that we're going to be making forward-looking statements. You can find those on our website or on the SEC website. What we're working with the team to do in the next few years is basically to build a respiratory vaccine franchise to generate cash to be able to invest in our oncology and our rare disease assets. And if you look at it, we are quite underway. We have now 3 products approved by the FDA and around the world. We have 2 products that we've submitted to regulatory approval, flu and flu plus COVID. And then norovirus is in Phase III. And in oncology, and we're going to come back to it in a minute, we have a very exciting pipeline full of catalysts in 2026. So we are very excited to see what we can do to help patients.

But let me start by 2025. In 2025, our sales guidance was $1.6 billion to $2 billion, and we're very pleased to report this morning that we think this is pre-audited numbers that we should land around $1.9 billion of sales for the year, which is $100 million better than the midpoint of the range. We got 3 products approved in the year. We filed products for flu and flu plus COVID for approval, and we have quite a number of catalysts in the pipeline. So the R&D team was very busy to build the future of the company and to diversify away from COVID to grow the company.

As you know, we have been marching towards a multiyear process to resizing the company because, of course, of the very high demand we had during COVID is not necessary in the endemic setting, and so we had to do a lot of restructuring. And I'm very, very proud of the work that the team has done over the last few years. In 2024, we had around EUR 6.3 billion of cash cost for the company. At JPMorgan last year, we set the ambitious goal to deliver EUR 5.5 billion of cash cost for a year. Quite a number of people were not so sure we could achieve it. Well, the great news is for an amazing work by the team across the entire company, across the entire P&L and the balance sheet and the working capital. We, in August on the Q2 call, said that we should land around $5.1 billion cash cost. At the Q3 call, we said $4.6 billion. And this morning, we announced, and again, those numbers are unaudited. We are going to go through the audit process. We think we should finish the year at $4.3 billion to $4.5 billion of cash cost. So if you look at it just compared to last year, the team has worked across the board to take almost $2 billion of cost for the company. That is a massive achievement, and I'm extremely grateful for all the team and for Fila CFO, Jamie, to driving the charge across the company. And really, it has been everything, working with suppliers, we making business processes, renegotiating prices, taking down manufacturing, working on the working capital. I mean, everything we left no stone unturned, and we're still turning stones as we speak.

So with the sales in a good place and costs in a much better place, we are very pleased where we're finishing the year in cash. So last year at our Q1 earning call -- Q4 earnings call, sorry, in February, we said we think we should end 2025 with $6 billion of cash. In November, we raised that to a range of $6.5 billion to $7 billion. And if you look at the cash we had at the end of the year before the drawdown from the credit facility, we achieved $7.6 billion. This is all within our control on a like-for-like basis. So it's a tremendous achievement by the team. You add on to that, the line of credit, the drawdown we did from Ares in November, that takes us to an actual cash balance, cash and cash equivalent at the end of '25 of $8.1 billion. And because we still have $900 million we can draw down from the facility, we have actually a credit facility giving us liquidity of $9 billion. So we think we are really in a great place to be able to navigate the growth over the next few years.

So if I now run to 2026, '27 and '28, we are very focused on driving profitability back to the company by 2028. And for that, we see 2 big drivers of growth in '26, '27 and '28 in terms of sales. One is geographic diversification, which I think is really important. And the other one is, of course, new product launches. So if you look at '26, we think we can grow the sales and we can grow the sales potentially up to 10% -- so the first vector of growth is going to be the partnerships we have in the U.K., in Canada and Australia, where we agreed with the government a few years ago to build dedicated factories in their countries in exchange for basically a multiyear partnership in terms of volume commitment. And those are really long-term partnerships. They have also R&D investment across the country, including in the academic labs of those countries. There's also a national defense and the pandemic readiness clause in those contracts, meaning we can any day flip those factories into pandemic factories. If God forbid, there was an H5 outbreak tomorrow, we could in any of those countries at the government's decision, flip any percent of our capacity towards pandemic readiness onshore.

The other thing, of course, is new product growth. So last year, we're very pleased to get mNEXSPIKE a vaccine with a higher efficacy for COVID versus Spikevax approved by the FDA. We're starting to get approval around the world, and that will drive organic growth. And in the U.S., because we didn't have a full year of launch with a full year of launch because we have higher efficacy, we're seeing a very good response from customers. We saw 24% market share in the retail segment. And if you look at the elderly segment, we actually achieved a 32% market share in the first year. We believe that for a full year of contracting, we should be able to achieve potentially better than that. And with the launches in the countries listed on the slide, this should really drive growth.

So if you think about the geographic growth we're going to get from a basis standpoint in U.K., Canada, Australia and the mNEXSPIKE, continued growth in the U.S. and new growth outside the U.S., that will help Moderna grow for the first time in a few years in 2026. Then if you look into 2027, which we're already preparing right now, -- we are quite excited about the opportunities ahead of us. And the first one is in Europe. As some of you know or might remember, we have been excluded from the European market for now several years because of a partnership between Pfizer and the EU, which expires at the end of '26. So we're going to get access again to the COVID market, which is a very big market in Europe. In Europe, you have 90 million people compared to 60 million people in the U.S. above 65 years of age. And the price differential on vaccine is not very, very high. So the volume and the number of people you can treat is actually really important.

The other piece that could be very, very helpful to us in terms of sales growth in '27 is the flu plus COVID combo. If we're able to get an approval of flu plus COVID combo in Europe in 2026 that will allow us to get NittA recommendations, so CDC equivalent recommendations and pricing negotiation to be able for the winter of '27, '28 to be able to be in the market. And most probably given where other products are right now, we will be the only product in the market with flu plus COVID combo. So we think that's really important for '27. The other piece we are doing to continue to drive geographic expansion is to do more partnership with governments like we've done in the U.K. around the world. We are very pleased to announce a partnership with Brazil that is ongoing, and we are discussing several other partnerships to be able to extend those multiyear agreements. And of course, in '27, with a flu already being filed, we should have an approval starting in flu in '26, the balance in '27, allowing us for sales impact in '27.

E in '28, we should have flu plus COVID, including in the U.S., Norovirus if the Phase III is positive. So as you can see, you have this accumulation of new product up to 6 products in the vaccine portfolio of Moderna by 2028, driving growth not only in the U.S., but very importantly, outside the U.S. So that's how we see the growth over the next few years. So with that growth, we're going to see an expansion in gross margin because we have bigger volume, and we're going to continue to work on yield and improvement in productivity and manufacturing. R&D costs, as we said at R&D Day in November, are going to come down because we're not going to commit to new Phase III. So we basically have the sunsetting of the existing Phase III. Even a product like mNEXSPIKE, even though it's launched, we still have Phase III cost commitment for safety follow-up. But as those things sunset, we're going to have a reduction of R&D for vaccines. The SG&A investment should be pretty flat because we don't need to add sales force capacity to sell seasonal vaccine in the U.S. to the retail or to the hospital. And so there's going to be a pretty interesting story in terms of EBIT and cash generation to invest in oncology and in rare disease.

So in oncology, we are very excited about 2026. If you look at Intismeran that is combined with KEYTRUDA, we have now 10 clinical studies ongoing. We have 3 Phase III study. We have 5 Phase II across multiple tumor type, and you have 2 Phase I. And then there are the next wave of oncology products coming, and those are fully owned by Moderna. mRNA-4359, we spoke a lot about this year. We saw interesting signals in the Phase I/II early in the year. And what we did with the team, we very quickly reprioritized the portfolio to not increase R&D costs because we want to be very disciplined about cost. And we basically funded the Phase II in lung and melanoma for 4359. 459 is used in metastatic setting. And what we have seen is patients that were refractory, meaning they did not respond to checkpoints like KEYTRUDA and Durva and the others. And then you give them KEYTRUDA plus 4359, and we saw a pretty high response rate. Of course, it was a Phase II, so the end is small, which is why we are chasing this signal. The patient stories are quite moving when you hear those patients that went through one checkpoint, stage 4 cancer, do not respond. Go to a second checkpoint, do not respond, get our drugs. There's actually a patient who did a testimony in the Guardian, I think, last week. explaining that now she's tumor-free she Stage IV cancer patient. So again, it's early studies. We're doing the right thing, which is chasing the signal. This is an asset we own, but because it's Stage IV cancer, this could go very fast and there's potential readout in 2026.

And then there's some earlier drugs that we are very excited about like mRNA-2808. It's a T-cell engager making free antibody at the same time in multiple myeloma. So we think this should improve care to patients. And again, we are going into the clinic, doing dose escalation. And if we get signal in patients, we'll expand this very quickly to see if we can improve patient care. Then you have a couple of more programs that are early, but they're going to progress pretty quickly. And then on rare disease, PA should read its Phase III in 2026. The FDA endpoint is a 12-month endpoint. We announced at our November earnings call that we were fully enrolled. So you can do the math yourself by the end of the year in 2026, we should have a Phase III data. And MMA is ready to move into pivotal study. Again, we want to be disciplined about investments. So we'll not move this until we have signal on Per, but it's ready to go into Phase III study. And so if you think about it, with Intismeran potentially reading its Phase III in '26, that could be a '27 launch. And then with Pierre reading its Phase III and with 4359 having a potential Phase II in a setup metastatic disease where patients do not respond to checkpoint. That is really game-changing for patients. So that also could be an accelerated approval in '28.

And then there's other products that a lot of people don't pay too much attention to right now, but are quite important. If PA works, the read across to MMA is pretty strong. It's a same lipid. It's also a rare disease in the liver exactly like PA is. And we've had some very interesting data out of the Phase I/II. We have the other oncology asset I started to talk about. And then in vaccine, we still have a few interesting assets. We have currently a Phase II study, multiple sclerosis treatment that is an EBV product. As you know, there's been a lot of progress in the field on the hypothesis that MS is mostly induced by EBV activation. And so what if you could use a technology to control the viral load of EBV-positive patients like you do with HIV, to control the viral load so that you don't have flares of MS. That's what we are trying right now in the clinic in MS patients. We're also working in the clinic on a Phase II study for an EBV vaccine that is prophylactic to be used in teenagers a bit like you have for HPV, a vaccine that could be used with teenagers to prevent mononucleosis. And if positive and approved, you could potentially do a very large study with the government to look at scale. Could you prevent multiple sclerosis? It's a bit like what Merck did very successfully with HPV. This is a very interesting product because we think the unmet medical need is very large, not only for MS, but EBV has been shown to also drive some cancer, which is not surprising, having a virus in your body all your life as you age and the immune system becomes weaker might not be a great thing for our health. We have a Lyme vaccine in the clinic, which is our first antibacterial vaccine before it was only antiviral and CMV ongoing in transplant. So quite a number of products that could also complement the sales in the coming years. And then we have a lot of products waiting to go into the clinic because the team is very active with the platform. And the more they learn about the platform and the mRNA technology, the more they have ideas in infectious disease, in cancer and also we are playing with autoimmune disease.

We've committed to continue to be very disciplined about cost. Our goal is very clear. We want to drive breakeven -- cash breakeven in 2028. So we continue to work on cost to reduce the cost as we increase the top line with those product launches and those geographic expansion. So to close, maybe if you look at 2026, we are quite excited about 2026. The last few years have been difficult, as you can imagine. resizing the company coming from the scale up that the team did an amazing job during COVID was difficult. And of course, last year was difficult with all the changes in the vaccine field. But if you look at '26 commercially between the geographic expansion that is happening because those plants have been approved by their local regulators. So you're going to have a base effect in terms of full year impact of sales in Canada, U.K. and Australia. and mNEXSPIKE growth in the U.S., both market share for the full year and expansion on geographic, we are very excited to go back into sales growth. Then the pipeline, there's going to be a lot of catalysts in 2026. mNEXSPIKE approvals, flu plus COVID combo in Europe and Canada for potential approval and flu in U.S. and Canada and a few other countries, we provided a list last Monday. And then, of course, Intismeran. If you look at the list, there's a world when there is a lot with that on itisiran. What we should get very soon is the 5-year data of a Phase II in melanoma. That should come very soon. That will be really important because 5 years is a very important point in cancer treatment. We've shown the 2 years, we showed the 3 years, the 3 years were better than the 2 years. So we're really eager to see the 5 years and to share it with you. Then, of course, the Phase III in melanoma, but also because RCC, renal cell carcinoma is fully enrolled and has been for a while. We could have data in Phase II in RCC Also, we have several Phase I ongoing in pancreas cancer and also gastric cancer. So those things could read out, and we will share, of course, the data. So I think we could move from a world where a lot of people are quite hesitant about INT or Intismeran to a world where you have a different tumor from melanoma and you have a Phase III and you have duration. So it's going to be a very exciting year. And we are really working hard with our colleagues at Merck to be ready to potentially file very quickly. The factory is ready in Marlborough, Massachusetts. So the product is fully made in America. And we should be able to move pretty quickly as the teams are preparing for BLA filings of the CMC package. We could have because it's in metastatic setting, some readouts in the Phase II of 4359. Norovirus should read this year, as it should, knocking on wood, is last year, we got unlucky with the epidemiology, the strain of the virus. This year, so far in the season is tracking positively. So again, I want to be cautious because we don't control the strain of virus circulating, but we think we have a good chance to read out this year. And of course, the PA is going to have a mechanical readout this year. We're going to continue to work on cost and continue to drive productivity for throughout the whole company. So sales growth for '26, expansion of potentially up to 2 new product approvals, so we could go from 3 products approved today to potentially 5 by the same time next year and a lot of clinical readout in oncology, in infectious disease and also in rare disease. So we're quite excited about '26.

Great. And just as a reminder, if you have a question in the room, just raise your hand, someone will bring over a microphone. But I will start. So for Intismeran, with the potential for that interim readout from the Phase III trial in adjuvant melanoma coming up, what effect size do you need to see to claim success at the first interim?

Sure. It's nice to start by the question on Intismeran. You get the question on COVID right the way. So Intismeran, if you look at what we've done in the Phase II, so just to reground everybody, the Phase II was a randomized study with a 2:1 ratio between Intismeran plus KEYTRUDA to Intismeran. And because it was randomized and it was 157 people -- sorry, patients, it's quite a good-sized study. And if you remember what we saw, we saw -- the 3-year data being better than the 2-year data, which is always encouraging in oncology compared to KEYTRUDA monotherapy. We saw a DFS of around 49%. So 1 in 2 people benefited from a DFS standpoint compared to KEYTRUDA mono. And in DMFS, distance metastasis-free survival, which oncologists think is a very interesting metric for long-term survival because, of course, people die of metastasis, not the primary tumors, was actually 62% -- and the p-values were very strong. And so we're going to get the 5-year data soon. So I think that gives us a better sense of how well does the signal hold. And so as you know, when you go to Phase III, it's really hard to know if you get the same type of numbers or not. But because of the mechanism of action of a drug, which is really -- and we showed that at ASCO in 2018 is really to reprogram the T cell of the patient. We think we should have nice duration and nice effect size. So we have not disclosed with Merck kind of where the goalpost is, but I think if we see a material improvement versus KEYTRUDA alone, if you just look at the number of lives impacted, we think there's a product there. So...

What about a scenario where we don't hear about an interim readout from the Phase III this year? What would the most likely reason be?

Sure. So as I mentioned, this is an event-based study like most Phase IIIs in cancer. So if we don't have data this year, given that now we have reconfirmed '26 several times, if you look at the last few quarters, our statistician look regularly at the data set, what we know number of events and so on. This might be actually a good news because it means that we don't have events, meaning people don't have their cancer coming back, which might be very good news for the drug and for patients. So I will not panic if we don't get the data in '26. We think it should come in '26. But again, it's event-based. And I think every month, it's delayed, it might be a good sign.

Okay. So what about the kind of read across to other settings, right? So to what extent if we do get positive Phase III data in adjuvant melanoma, does that read across to other settings? So how would it?

So with oncology, one always has to be cautious. We will have to do the clinical studies, which is why Merck and ourselves are invested in those 9 additional studies to melanoma. But if you go back to what we showed at ASCO over the last few years, including pre-COVID, we had signal. So again, it was a small sample in the Phase I/II, which was an all-comer study in lung, we had signaled in head and neck -- and so Merck and us believe that because of the mechanism of action and because KEYTRUDA has worked in so many tumors that we should have an incremental patient benefit compared to KEYTRUDA alone. I think, again, given all the things we collectively don't know about cancer and about the drug yet, it will be arrogant or unscientific to actually make any claim about the effect size we could see in other tumor, which is also why we are very eager to see what signal do we get or not in those Phase I. They're going to be, of course, small numbers. But if in gastric and/or in pancreas, you see signal, that's interesting. And then the Phase II like RCC and others and bladder. So we should be -- because a lot of data should come this year, which should potentially be sitting here this year if we invite us with actually quite a number of readouts where we'll be much better informed by the true potential of Intismeran because, of course, -- if it's a drug only in adjuvant setting, melanoma is going to be great, but it's going to be in the many billions of dollars. But if you have multi-tumor responding, if you have metastatic, you might have seen this 2 study in metastatic setting in lung and in melanoma, then you can start to see, okay, this is really like a very impactful drug that's going to save a lot of lives, just if you look at the effect size, and that's going to be a big commercial product.

So I guess related to that, can you just take us through -- so like the 5-year follow-up on the Phase II, we're certainly getting that this year. And then what's the cadence of the updates after that?

So you're going to get it this year because the 2-year and the 3-year data came in December. So because it's a 5-year study, we have to do a lot of cleanup and scans and so on to make sure everything is right before we lock down everything. It's the end of the study. So because he was December of the 2 and the 3 year, we're talking weeks or months, I'm not talking quarters. Then for the other readouts, it's really hard to predict because those are all event-driven. All the studies are event-driven. So could I see a world where we see melanoma sometime this year and before there's maybe another study that has read out? Yes. Could there be studies on both sides of the Phase III melanoma? Yes. It's really hard to predict. We just share the data as we have them. We always do that. When good data like flu, I think shared it 48 hours after we got the data or bad like CMV, we shared also, I think, 2 days after we got the data. We'll get the data out. We want the scientific community to know about the data. We want to be transparent with investors. So as soon as we know, you know probably quickly right after.

Okay. So you mentioned a couple of metastatic studies. What is your latest thinking on the potential for this approach in metastatic disease...

Sure. So I think it comes from what we are learning with our colleagues at Merck, not only about Intismeran, but also the other products of Moderna and also the field. If you look at it, what we have seen with 4359 in metastatic setting is really interesting that mRNA technology can have an impact in metastatic setting. If you look at what we have learned about T cells and all the biomarker we've looked at across all the studies listed, we've learned a lot. We keep learning a lot. We keep digging at data. We keep looking at the new antigen and so on. And so we believe it's a quite interesting possibility that INT because of disability to really reprogram T cell, which again, for those that have not seen the data, I go back to ASCO 2018 or AS Lavina, she'll get you the data. Once you've seen that data that you can see in patients that if you take their blood before starting Intismeran and you look at the antigen coded in the Intismeran drug, the T cell response. And then you look at 4 dose after and you take the blood of those same patients and you see T cells popping up, that's quite profound. And so with a lot of things we have learned, Merck and us because we have to go through GSE process and to mutually agree to do the investment because we have 50-50 cost-wise on those studies. And there's already always more ideas by our oncology colleagues than we have resources that we didn't go lightly into metastatic setting. We think there's a chance for having a signal there. But again, with oncology, you have to be cautious.

And I guess beyond Intismeran, what other assets are you most excited about in the oncology pipeline? And how are you prioritizing them? And just what are the next readouts we should be watching for that aren't Intismeran?

Sure. So one I mentioned briefly is mRNA-4359. We expected signal based on the mechanism of action, but we didn't expect what we saw. And the patient stories we reviewed with the team were very profound. You have people 70-year-old, Stage IV skin cancer, you have metastasis everywhere, get on the checkpoint, go through the whole cycle, no response. Get another checkpoint, go a full cycle, no response, get on to sometimes a third checkpoint, no response and then get on to 4359 plus KEYTRUDA. When if you think about it, the disease is much more progressed. And the immune system, which is a key component of how our technology works, is also weaker, and we've seen responses. So again, it's Phase I/II, it was early data. So the end is small, but it was in melanoma and in lung, which is always a little pin for the Intismeran question across tumor types. And so what we decided with the team is like we need -- look, we need to chase that signal. And so because we're so disciplined on cost, we just look at the whole portfolio, we delayed other things to be able to fund, which was not in our initial 2025 plan to fund the Phase II in lung and in melanoma. And because those are metastatic patients and the control arm, of course, are not getting 459, you have a case where you could have data in '26. And so that's something also that could be quite a surprise because then you could go very quickly to regulators. There is no manufacturing critical path because this is done in Norwood. And because it's metastatic setting for patients who do not respond to checkpoints, what do you have left when you have a patient and you've gone for 2 or 3 or 4 checkpoints and you don't respond. So that's quite exciting. The other one I'm quite excited about is 2808 in multiple myeloma. As you know, the standard of care is you go antibody after antibody when the cancer escape. What if you could have one product with 3 antibodies in a single dose to try to really stop the cancer from evading. It's in the clinic right now. in patients, obviously. And so we get data of this. So this is one that I see as a low biology risk because those are targets that have been used in the field. Some of them are products approved. But it's a good use of the mRNA technology where you can combine all those things, you can go quickly in the clinic. There's incredible manufacturing leverage. We can make that between 2 COVID batches. And so that's another one that I'm quite excited about in oncology. But there is more coming.

Any pipeline questions from the audience? Maybe shifting to kind of the financial outlook. Can you talk about what supports your ambition to deliver up to 10% revenue growth in 2026?

Sure. So I think we need to look at the U.S. and outside the U.S., in the U.S., if you look at this year, there's been a decrease of the COVID volume. A lot of it is due to the start of the season. As you know, the start of the season with the products approved, but with a new AC panel recommendation. In a lot of states, pharmacies could not deliver the vaccine if you walked in a pharmacy and ask for a COVID vaccine. So it took several weeks. Some states move very quickly. But even in a state like Massachusetts, where we live, you could not walk into a pharmacy, I want a COVID shot, I couldn't give it to you if you don't have a script. Of course, you had a script because the product was approved by the FDA with an SBLA, you could get the product. But if you were without a script, you wouldn't get the product. So some states move very quickly to allow pharmacies for local public health decrease for the state to allow this to happen. Some states took like a month. And so that was, of course, not helpful. What is interesting is if you look at the last month or so, the decrease compared to last year is quite modest. Another thing to appreciate is that the guideline for the spring booster is still for COVID shot for the spring for people at high risk, the elderly and people at high risk cancer people, patients and so on. And so even if the U.S. were to go down a little bit in volume, like we've seen in the last month, -- if you think about mNEXSPIKE, which because of high efficacy has a premium price and the share we are potentially going to be able to gain into 2026 because with a product approved, it's a much less risky proposition for the retailers. That should help to potentially even have a flat sales in dollars if we had a small decrease of the volume of COVID. But with what's happening in flu and with COVID right now in the country, people might be more motivated to get a flu shot because I think too many people still do not understand that when you get a viral infection, if you have it for several days and you start coughing and you damage your mucus, you're going to start to have bacteria going down from upper track to lower track and that's how you get pneumonia. And if you get pneumonia for too long, that's how you get sepsis. So if you think about the cascade that we see a lot in people at high risk, that's the cascade, which is why if you're at high risk, you absolutely need to get a vaccine for all those viruses because any one of those can be done. And if you're unlucky, you can come from a through infection and be recovering from it, still not be in great shape. And then you get COVID or vice versa. And that's the second one that really put you down and you get pneumonia and then you're done in downward spiral. And so that's for the U.S. Outside the U.S., as we said, there's 2 things, the incremental from 0 of mNEXSPIKE sales in many countries. And 2 is the deals we have in Canada, U.K., Australia. In '25, you only had part of the years where you had revenues because the factories were not approved until late. But next year, you're going to have a full year effect. So if you just from a basis standpoint, you just want to get mechanical growth from there.

So underlying the up to 10%, which direction is the U.S. going if we think U.S. volume is maybe drifting, but mNEXSPIKE.

Look, it's a bit too early to tell, which is why we're not guiding precisely. The contracting season is ahead of us. We're going to try, of course, to do the best we can to get as much share as we can. I'm sure competitors will be fighting back. The uptake we saw in the first half season is pretty good. And so we're quite optimistic. But until we get the contracts, we want to have more precision. So I just want to stay cautious because there's a lot of contracts to happen in the next 6 months. But as I said, even if the U.S. were to be flat in dollar, we'll grow -- the company will grow outside the U.S. mNEXSPIKE and those 3 countries where we're going to have a very material FX size.

Walking through kind of the flu and then flu COVID time lines. I guess, just first, what season do you expect the monotherapy flu vaccine to launch? And how do you plan to drive adoption of that product?

Sure. So for flu mono, mRNA-1010, we have filed in all the key geographies. There's more coming. The regulatory team like in most companies prioritize and just get going. So there's more coming. But because of the time lines, if some countries approve the product in 2026, which we expect, you should see minimum, if no sales. because by the time you get the product approved, contracting is behind you. The retailers want the product for the season to guarantee their EBIT margin and serving the customers. So there will be some potential tactical sales right and left. But the true impact of mRNA-1010, if it's approved by regulators is really in '27, which is why I talked about it in my '27 growth. Same with COVID plus flu, if it's approved in Europe, given the time line should lead to a '26 approval based on when we filed it. It will have most probably no sales in 2026 because by the time you get it approved in Europe, you need to go country by country to get the CDC equivalent, the NTA recommendations. And then you need to negotiate pricing by country. Pricing is not at the European level, it by country. But what we're really trying to aim there and the timing works really well because remember, in '26, anyway, there's a COVID Pfizer contract, block on COVID and government, given their budget situation, do not want to spewice buying a COVID mono and then buying a COVID flu combo. But what is key for us is to play the time lines, we should be able to do all that to get into '27, early '27 to be able to be in countries where you have tenders like Spain and Italy, be able to participate in all the tenders and in countries where it's negoti with government to be able to do that. So we really expect flu COVID sales if again, the product is approved to really have a big impact in '27.

And what about flu COVID in the U.S.? What's the status of that?

Yes. So as you know, Jessica, it's more for the audience. We had filed COVID flu in the U.S. When we got the Phase III flu data, the FDA so a bit earlier in the press release, they asked us to basically withdraw the file of a combo and refile after we filed flu. So we just filed flu just before Christmas. We just announced it last week. And so we are in active discussion with the FDA of what timing will be appropriate to refile the flu post-COVID combo.

Okay. So that launch season for the U.S.

So that's why we did it for '28 to be conservative. Okay. If you look at the slide I presented, it's not for '27, it's for '28. '27 is really flu U.S. and Europe reopening and flu plus COVID in Europe.

And how long do you expect to be the only flu-COVID combo?

So it's interesting. It's a good question. As you know, Pfizer BioNTech had a vaccine that they shared the data recently that didn't look so great. And by the way, they never showed the data of 65 and above, I don't know why. They're going back to the drawing board into Phase I/II. So we'll see how this one work out. There's another one by Novavax that we're also waiting data. So it's -- for '27 in Europe, it seems like nobody can catch up. Then the question will be, as those other programs progress or not, what happens, what's the timing. So we're going to really use being the first in the market, of course, to really build a lot of brand equity. And remember, the piece that is also interesting is that the COVID component is mNEXSPIKE. So it has a higher efficacy than Spikevax. And as you remember, during COVID, there were a lot of real-world evidence studies showing that Spikevax has a higher efficacy than COMIRNATY. So you're going to basically have a COVID component way better than COMIRNATY. And then the flu component 1010, we've showed has a much higher efficacy than standard flu product. It's in the same ZIP code. There's no head-to-head study, but in the same ZIP code compared to standard flu vaccine to Fluzone High-Dose. And so we're going to be basically coming to market with a best-in-class product in terms of the flu component for people at high risk like Fluzone High-Dose and of mNEXSPIKE better than Spikevax, better than COMIRNATY. So being the first to be able to share that data and to just keep talking about that data all the time should help us a lot in terms of how we set up the marketplace.

Okay. You also talked about kind of once Europe is kind of back on the table, having more volume and that helping you drive better gross margins. How much does gross margin improvement from here hang on top line growth?

So it's interesting. We have not given the split, but if you think about gross margin in the next 3 to 4 years, let's say, you're going to have a few things. You're going to have pure volume, all those product launches in vaccines. Then when we have non-vaccine product to launch like PA, mRNA-4359 in cancer, mRNA-2808, -- those products will be made off-season of respiratory vaccine. Because today, if you think about it, we are really penalized in terms of gross margin because in Q1, the factory is not very busy because we supply the Southern Hemisphere, it's not big volumes. And so you could make PA product or any of those other products that are not individualized in your off-season time line, absorbing your fixed cost. So that will be helping. The other piece is that the team is continuing to work on productivity internally in terms of yield, in terms of reducing deviation, be able to -- and then the third piece is productivity through AI. We're doing a lot of investment in AI across the company. We're still negotiating with suppliers better deals. And the last piece, which we announced at R&D Day is we are bringing for the U.S. market prefilled syringe manufacturing in Norwood. And so this also should improve margin because today, we pay a third party and we pay the margin and we pay the taxes. When we bring this, we're actually going to amortize the fixed cost of Norwood, including the assets, the building which we own and the personnel. So I think that's going to -- so you see there's 4, 5 levers of gross margin improvement. But again, in the next 1, 2, 3, 4 years. It's not a magic one that next year, it's going to be a continuous improvement. I really think year-on-year, it's going to be better and better.

Okay. Great. is it for our time. So we'll stop there.

Thank you.

Thank you.

Next presenting company, Moderna. My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler. And before I begin, I am required to point out certain disclosures regarding the relationship between Piper and Moderna that are listed at the back of the room and also at the registration desk.

So as you know, Moderna is a leading developer of messenger RNA vaccines and medicines. Moderna shares have been under pressure over the last couple of years after really helping us through the COVID pandemic, in part as a result of decreasing immunization rates. I got my mNEXSPIKE vaccine. I think anyone who gets a flu shot should get a COVID vaccine as well as long as they're recommended by their doctor. And now under the FDA and RFK Jr., it really feels like they've declared war on mRNA vaccines. And then we recently had the setback with the same victory. So it's been a tough slog here. But you guys just recently had an R&D Day and really pointed to all of the new vaccines and medicines that are coming. And I think it's a really exciting time. And Jamie, you always do such a great job going through sort of the financial underpinnings of what Stephane and Stephen and everyone are working on and how you're going to get there.

So I'm pleased to introduce Jamie Mock, CFO.

Jamie, I'm sorry to put you in the hot seat, but I have just gotten overwhelming number of questions, as I'm sure you guys have as well. What's really behind the FDA's claim that COVID vaccine caused these 10 children's deaths there's offsetting news too from experts that are refuting these claims. And I guess, firstly, what's really behind the sort of onslaught on mRNA? And then we can kind of get into what you guys know about sort of the findings.

Yes. Well, first off, thanks for having me, Ted. It's good to see you, and thank you for getting your COVID vaccine. That's always helpful and I think important. So look, I don't know what's behind it, to be honest. We haven't seen any data. We haven't seen the analysis. So here's what I can say. We take safety very seriously at Moderna, as you would expect. We have rigorous monitoring across ourselves, across the FDA, across over 90 countries across the globe that have been looking at it. And there are multiple overlapping safety systems that look for any new data point, any evolving safety consideration. And remember, we've delivered over 1 billion doses over the last few years. And so all those safety monitoring systems haven't really given us anything new or anything undisclosed at this point. And that's really all we can say. We haven't seen the data. We haven't seen the analysis. So it's inappropriate for me to comment on something that we haven't really got with it.

And I think I've seen someone said that 10 out of 96 were related to the vaccine. But then at the same time, I think over 800 children in their teens or below died from COVID in that time frame. So I think it's really -- we're going to have to weigh both sides of this for the 2. So I'll just pause. Are there any questions about that from anyone. Again, I think the answer pretty much is we're going to see what becomes of this and what additional data comes. So Jamie, I mentioned this in the beginning, you always do such a great job setting the framework for the company's commercial and financial performance. Let's start with COVID. Vaccine rates are down kind of high 20%, maybe 30% from last year. You're really now selling both Spikevax and mNEXSPIKE, which I think is a great product, like 1/5 the dose, lower side effects, higher potency. What's the current outlook for COVID vaccine revenues for the remainder of this year and beyond?

Yes. Thanks for the question. So yes, we really think this is a turning point financially for our company. And COVID will be the lion's share of our revenue until flu comes online and hopefully norovirus and our combination vaccine, which we'll get into. But let me just start with 2025 where we guided $1.6 billion to $2 billion. That was $1 billion to $1.3 billion in the United States and $600 million to $700 million outside the United States.

And so let me start with the United States. The only thing -- all the contracting is done, I mean, we're 80% through the season at this point. So the only remaining variable is vaccination rates, as you mentioned. And at the time of our guidance, we provided for vaccination rates that could be down 20%, so that would be on the low end of $1 billion -- or on the high end of $1.3 billion or down 40%, which will be on the low end of $1 billion within the United States. And I think through last week, we're down 27% or 28%, as we said. So we feel very confident in our guide for the United States as well as outside the United States. The only remaining items are delivery timing. So a little bit that could push into the first quarter or maybe it happens this year. And there's only a few markets that are actually vaccination rate driven. Many are just contracted demand, but there are a few. So there's a little bit of variables there.

So we -- for 2025, it's predominantly 99% COVID related. I'm sure we'll talk about RSV in a moment as well. Then when we look out to the next 3 years, I'd really encourage everybody to look at our Analyst Day webcast, which we really laid out, as you mentioned, what are the growth drivers for the next 3 years, which we see 10 of them. I won't get into all of them. But I think the punchline there is it's still largely COVID until flu and norovirus come along. And it's largely outside the United States. And it starts with a few contracts we have with 3 countries across the globe in the U.K., in Australia and in Canada, where these are long-term contracts that we believe we're fulfilling on right now in the case of all 3 of them. But the majority of the revenue, the full year revenue will be in 2026 versus 2025. So that's significant growth for us, particularly in those 3 areas.

And then you mentioned mNEXSPIKE, which we're quite encouraged by. I think it's got 55% of our overall market share out of our Spikevax being the 45%. And we didn't even know coming into this year whether it would be approved. So it got approved in early June. So we had to double produce this year for both mNEXSPIKE and in Spikevax. And we're really encouraged that because of the product profile and the higher efficacy on mNEXSPIKE, it's doing extremely well, particularly in older adults. So we're really excited to go into 2026, knowing that we have this product approved, knowing that it's had terrific uptake already in the year that it was only approved in June, which I think provides another growth driver for 2026.

And then -- and we said we'd grow up to 10%. So that's part of this whole story is that I think moving forward, starting in 2026, we believe we will start growing. And then in 2027, Europe opens up for us. We believe that we'll win in other regions around the world in 2028. We have norovirus coming on. We have the combination vaccine, which could come in '27 as well. And so we're quite excited for the growth rate of the company, and that's really just in the seasonal vaccine business. If we are able to have terrific data in INT, if we're able to have terrific data in our 4359 product, which I'm sure we'll talk about more in PA, that is upside to our overall revenue here. So we're really excited about the future here.

Yes, I agree. I think at the R&D Day, I kept feeling that you guys are turning the corner. So it's what really came through. So we'll go into a couple of these vaccines individually. So for seasonal flu, I believe you guys are preparing to complete regulatory filings by January. Could they be approved this year? And how do you really envision kind of penetrating into the traditional seasonal flu market?

No, we're excited about it. So yes, we will complete our filings for the U.S., Europe, Australia, Canada by January, as you mentioned. And if the filing is done in January, it's really not a 2026 product. This is really the 2027 market that we are shooting for. And we love the product profile, and it really starts with the efficacy of the product and how it compares to standard dose. And so we believe that will play well in older adults, which often have enhanced dose or high-dose flu, and that's where they compete. And if you look at the relative vaccine efficacy of our product versus -- that we showed in the Phase III trial versus standard dose, it's 26.6% better than standard dose.

So we really do think we'll compete in that market well. And that, I think, speaks to our entire strategy here, which is we really need the breadth of products. I'm sure we'll get into the other ones. But in the seasonal vaccine business, you have more power -- purchasing power if you have COVID, if you have 2 products in COVID, mNEXSPIKE and Spikevax, you have RSV and you have flu, perhaps a combination vaccine and norovirus. We think that, that bundling effect is really helpful when we go to market with all of our customers.

I really think the combo product is a game changer, and it combines 110 with mNEXSPIKE right?

That's right...