My name is Gina Nguyen. I'm a Smith-side Biotech Analyst at Barclays. Thank you for joining our call today. We are very pleased to continue our 8th annual Speaking the Science Conference call series. Our call series is intended to focus on key scientific concepts, progress of preclinical and clinical programs, and, of course, commercial launches and company strategy. Please email me at gina.nguyen@barclays.com for any questions you have during the call. Today on the call with me is Rose Loughlin, EVP of Research. We certainly have Lavina Talukdar, which everyone knows as VP IR from Moderna. Thank you very much for joining our call today. I know today will be slightly different because Rose will have a comprehensive slide deck regarding the oncology pipeline. I think this is also the key focus, actually, is the most inbound questions beyond the current macro environment.
I think that's the key focus from investors regarding going forward. Oncology will be very important for Moderna. I think that will be a great opportunity to let us hear the landscape and the thought process with the current pipeline and the future development path for the key assets. With that, I hand over to Rose.
Fantastic. Thank you so much, Gina. Let me just pull up the slides so we can share these with folks. I really appreciate the opportunity to share our science and specifically how we're thinking about the oncology space. When we think about the portfolio that we're developing in oncology, we are thinking about supporting patients across that journey from early stages all the way to the later end. Our lead program there is Intisurin Autogene, which I'll share more about, also known as INT, our Individualized Neoantigen Therapy. In addition, building off of the data that we've developed with INT, we have been moving forward a pipeline of cancer antigen therapies that are designed to treat multiple patients. We also have diverse therapeutic applications, which happen to use different parts of our platform technology as a part of the oncology portfolio.
These include T-cell engagers and in vivo cell therapy approaches. We'll talk through each of these today. We'll start off in the INT space, where, as you can see, we're initially developing in an adjuvant setting and starting to explore different opportunities both in some of those frontline metastatic patients as well as in earlier stage settings. For those who aren't familiar with INT, it is truly individualized. We take samples from every patient, comparing their tumor to healthy cells from their body to identify specific mutations or neoantigens that are present in their tumor. We then use our algorithms to design this therapy specifically for that patient. We manufacture it for that patient and administer it.
Now, as you may be aware, in our phase II study in adjuvant melanoma, we were very excited to be able to demonstrate a 49% reduction in the risk of recurrence or death. Building on these data, we have continued to move INT into multiple settings. The most advanced there is adjuvant melanoma. We have fully enrolled our pivotal study there. We are cautiously optimistic that we will be able to share data in 2026 from that study. You can also see here we have started to expand into different settings, looking at different types of cancers and also considering different combinations beyond just INT with pembrolizumab. For example, considering INT as a monotherapy.
Now, what's really exciting, because we've spent a lot of time sharing with the public and the data around INT, is that from INT, we are building an additional pipeline of cancer antigen therapies. Now, these are not individualized. These we refer to as off-the-shelf. We manufacture them once, and then they can be used in a variety of different patients. Like many cancer therapies, we're starting development in some of these later-line patients, but we do see the opportunity and the profile with these cancer antigen therapies to move up into adjuvant settings. We refer to these as off-the-shelf, and they encode for antigens that are shared across many different cancer patients. We have two approaches here, and I'll actually start by describing the bottom first, which is designing these therapies to target antigens present on tumors specifically.
Some of these may be very tumor-specific antigens, meaning only tumor cells are expressing and presenting these proteins, and some may be tumor-associated antigens, meaning that they are expressed more highly on your tumor cells than on any other cells in the body. Our lead program in this space is mRNA-4106, which is currently dosing in a phase I. Our other approach, which is more advanced, is mRNA-4359. This targets not just cancer cells, but it also trains your immune system to recognize some of your immunosuppressive cells that are actually making it harder for your body to recognize and kill those cancer cells. To go into a little bit more detail on 4359, this therapy actually encodes portions of the PD-L1 and IDO proteins. It actually, again, trains your immune system to recognize cells that are overexpressing those.
Now, this definitely occurs within cancer cells. It also occurs in different cells of your immune system. You can think T regulatory cells, or if you're thinking myeloid cells, you could be thinking MDSCs, the type of cells that, again, make it harder for your immune system to recognize and kill cancer cells. Because this is such a central mechanism, we believe that this vaccine will be applicable to many different types of cancers. We have previously shared data from our dose escalation. I believe that was ESMO last year, where we saw 8 of 16 of our response evaluable patients demonstrating stable disease. We then moved into a dose confirmation, where we were combining with pembrolizumab and focused on checkpoint inhibitor refractory patients, patients who have already been on a checkpoint inhibitor and stopped responding.
You can imagine there's quite a bit of pretreatment in this setting. We were looking at melanoma and NSCLC patients. We haven't shared these data yet. We are excited to share them later this year, but they have encouraged us to go ahead and expand into phase II in two different settings: first line NSCLC with high PD-L1 and first line melanoma. We are excited. We haven't yet shared the data from the dose confirmation. It did give us the confidence to go ahead and expand. We also really liked the profile that we saw on the safety and tolerability side, where we were seeing mostly low-grade adverse events and no dose-limiting toxicities. mRNA-4359 in our recent quarterly call was shared as a part of our prioritized pipeline.
This is the part of the pipeline where we see this potentially being available to patients within the timeline of 2028. Again, always subject to data and discussions with regulatory authorities. Sort of moving beyond those cancer antigen therapies, we're taking a very complementary but different approach to some of these later-line cancers through our T-cell engagers. This also happens to use a different form of our own platform technology. You may be familiar with T-cell engagers. Rather than training your immune system, we like to say that they guide your immune system. They bind to a T-cell, binding to CD3, and then they bind to an antigen or protein on a cancer cell, holding those in proximity, really helping your T-cell recognize and go ahead and kill that cancer cell.
Now, what's really interesting about the approach that we're able to take is that our platform allows us to multiplex T-cell engagers. I say multiplex and not combine because what we're able to do is in a single medicine, we can encode for multiple T-cell engagers that, yes, bind CD3, but also bind different proteins on a cancer cell. You can imagine there's a lot of heterogeneity in cancer. This is a significant advantage if you can target multiple proteins on the cancer cell. We also know that cancer cells can escape certain treatments by just stopping some of the expression of these proteins. By being able to target multiple, you can sort of get ahead of that escape mechanism. Using our platform, we can also encode for additional proteins that can really enhance the T-cell response and its specificity.
For example, providing co-stimulatory signals. As you're holding those cells together, that T-cell is even more encouraged to go ahead and recognize and kill that cancer cell. Now, when we think about the proteins that are on the surface of a cancer cell, there's pretty much a defined pool of those that are specific to tumors. We take a complementary approach in this part of our portfolio so that we can expand that target landscape. That is to pursue intracellular antigens. Of course, these proteins, as we encode them, they can't get inside the cancer cells. What we do is we actually wait for the cancer cells to digest those proteins and go ahead and present them on their surface so that we can then design a T-cell engager to identify that, really expanding that landscape of antigens that we can pursue.
Similarly, in this part of the portfolio, we have the ability to multiplex so we could go after multiple intracellular proteins. In addition to the T-cell engagers in our pipeline, we are pursuing in vivo cell therapies, again, with the idea that we can develop one treatment that would be relevant for many patients. We are taking two distinct approaches in this space. The first actually builds on ex vivo cell therapy. You may be very familiar with ex vivo cell therapy in the form of CAR-T or TCR-T cells. These are engineered cells. They are actually taken out of a patient's body, engineered to recognize an antigen from your cancer. The patients often go through conditioning treatment so that they make a home for those immune cells to really last when they are infused back into the patient.
Now, this has been truly transformational in the hematological spaces. In solid tumors, what we've seen is there is still room to improve that efficacy. What the field has been demonstrating is that if you have increased proliferation or persistence of those engineered T-cells, once they get in the body, if they continue to multiply and continue to exist and circulate, then you're seeing better clinical outcomes. What we have actually designed is a therapy to enhance ex vivo cell therapy. The patient still goes through the process of having their cells taken out, engineered, and infused back in. After those cells have been infused back into the patient, we come in with our therapy, which was specifically designed to present the same epitope that those infused engineered cells recognize.
We can effectively boost those engineered cells after they are in a patient's body, again, helping those cells proliferate and also persist and be healthier for longer in the body. Now, our lead program there has an open IND. It is in partnership with Immatics and their ex vivo TCR-T, IMA-203, and ours is mRNA-4203, which is combined, again, with Immatics cell therapy. We have a distinct approach, which leverages a different portion of our platform technology and looks to do that cell engineering in the body. With mRNA LNPs, we can directly transfect immune cells, whether those are myeloid cells or T-cells, and actually encode for those receptors, the chimeric antigen receptors, in those cells in your body, creating either CAR-M for monocyte or CAR-T for T-cell therapies, where, again, that engineering is happening inside the patient's body.
As you can see, we are thinking about our oncology portfolio quite broadly across the multiple stages of disease, across the different types of therapeutic applications that you can do, and through different parts of our platform technology and applying this for different approaches to oncology. With that, Gina, I'm happy to hand it back to you.
Okay, great. I think if we can keep the slides also on, since we'll ask a few questions, maybe if we can go back to slide four. I know this is, you know, the most important early data update and generating lots of excitement among, you know, physicians and the companies as well as investors. I think, you know, now, like we continue to see like a, now I've kind of lost track, like three, four years update now from phase II. Is that right?
Or did I miss by one year or five years close, right?
We've presented the three-year data thus far, and the final analysis is at five years.
Five years, yeah. I think it's three, right? Phase II, like three-year update, I continue to see, you know, the benefit and the maintain. That was very impressive. I do have some investor pushback. I wanted to double-check, you know, regarding the control arm on that phase II, you know, how patients are allocated. There was some question on, you know, if, is that true, you know, the patient who failed the drug manufacturer, they would be put on the control arm. Just want to get a clarity regarding how you allocate a patient.
I'm not sure in that specific instance, based on whether they fail to manufacture.
Lavina, you're shaking your head if you want to unmute.
Unmute your line, Lavina. Lavina, if you can't unmute.
She can't unmute. Lavina, you're also welcome to join me in here if we want to share the screen. Gina, maybe while Lavina's coming over, and we've received questions like this in the past for imbalances. Really what we have looked at is, as we look across the different translational factors you could consider, like tumor mutational burden, CT DNA positivity or negativity, HLA heterozygosity, what we see is that the combination of INT and pembro consistently outperforms pembro alone. Where we did see any imbalances in those in the phase II, they actually were not in our favor in INT, potentially giving us the more challenging, more of the more challenging patients.
The last piece that we have shared publicly as well is just looking at our pembro control arm and confirming that its performance is in line with what has been seen in previous keynotes in that setting, as well as checkmates.
Okay, okay, good. Regarding the phase III data, oh, by the way, I think at some point everyone was excited about potential accelerator approval pass. Is that completely off the table now, or do you think there still could be a chance there?
I am not sure what we have shared exactly on that one, but Lavina is stepping in in just a second. We are looking to file off of the phase III data that we are anticipating in 2026. Welcome, Lavina.
Gina had j ust asked if accelerator approval from the phase II is completely off the table, and I had shared that we're planning to file off of the phase III.
Yes, we are planning to file off of the phase III. You know, the proximity of that data potentially reading out in 2026, I think, gives us a better opportunity to use the phase III data for approval.
Okay. The phase III, I assume it's also event-driven. I think one, maybe, you know, any pushback on the phase II, you know, other than by itself, it's like outstanding data. Any, you know, we want to nitpicking, and that was, you know, some of the question is, oh, the placebo or the control arm that did not, you know, perform was worse than what historical numbers.
Any thoughts there, you know, regarding the control arm, how we should, you know, when we look at the phase II and then now, you know, fast forward, everyone will be focusing on phase III. You know, are there any big, you know, disconnect there regarding the control arm from phase II to phase III?
Sure. And we, of course, have not looked at, we are still blinded to the phase III, have not looked at the control arm there. Just to reiterate from the phase II, we view the pembro control arm's performance, particularly when you correct for exact stages and try to look at trial comparisons, as in line with what had been seen in Merck's Keynote Study.
That's right.
Okay. Okay. What is the phase III, you know, trial powering assumption? Should we use phase II as a good benchmark?
Any additional color you can share regarding the phase III?
We have not shared the powering assumptions for the phase III study. However, we are very encouraged by what we saw in the phase II study, particularly given the magnitude of response that we have seen, where we have seen, you know, a 49% decrease in the risk of recurrence for a sizable, but yet still, you know, 150-patient study. We think that is a really remarkable outcome. We are looking forward to seeing what the phase III data show.
Yeah, absolutely. We have publicly shared enrollment numbers as of clinicaltrials.gov, which are 1,100 subjects across that study, so well-powered.
Okay. That is the event-driven trial, correct?
Y eah.
Yeah.
H ave you guys shared how many events total you will be looking for?
We have not.
Okay. Okay.
And you did say 2026 data, so which means actually very, very, so I know you complete enrollment end of last year, right? The full Q last year , 2024.
September of 2024 was the target enrollment completion.
Okay. Okay. Good. Good. Okay. That is very good. Now, moving forward, I know your partner, also Merck, seems very excited to move forward with, you know, maybe a little bit more color, you know, on, you know, the so many additional indications, you know, they move forward. Maybe what is the rationale behind that? I think in the past we discussed about, you know, anything, you know, PD-1 or PD-L1 will be active that should be applicable to the same approach here.
Maybe if you can give a little bit more color, you know, regarding the non-small cell lung cancer, you know, additional indication there, and then, you know, giving, like, very quickly, you know, Merck basically started phase III study. What will be the assumption there? Like, what data will make them confident this is the right phase III design? Because one part is that great drug, but if a poor study design, that could be fail. Another, you know, so if you have a, so like, what makes them confident this is the right phase III study design and giving the relatively limited data on the early studies?
Sure, absolutely. I think as we look at the mechanism of action for intismerone as well as the translational data that we have pulled out, it gives quite a bit of confidence in expanding those different indications.
As you can see, you've started in indications that share many features with melanoma, like high tumor mutational burden, quite checkpoint responsive. As we're testing in those, starting to move into earlier studies in settings that are a little bit more distinct from melanoma. Exploring that space, much as Merck did in the past with Keytruda and other therapies, where you start pushing into different spaces with different diversity, similarly testing different combinations. Certainly many in combination with pembro. We mentioned monotherapy as well as a combination with BCG within this. Thinking through how you step by step start to explore INT's efficacy and continue to collect that translational data to guide the different settings.
I'll just add, Gina, that in the tumors that we're in currently, melanoma obviously was the first one to go into phase III because the phase II data was in adjuvant melanoma. We subsequently, with our partner Merck, went into non-small cell lung cancer. As Rose was highlighting, these are IO-sensitive tumors where Keytruda has shown efficacy. That is one part of the rationale for moving into some of these very histologically close tumor types, if you will. In the phase I study, which was a basket study, we also used some of the data from that phase I study to guide, you know, the different types of cance r tumor types to go into.
Non-small cell lung cancer in our phase I study did have, you know, a good two handfuls of, you know, individuals who had non-small cell lung cancer in that phase I study. We did see, although, you know, the numbers are small, but very encouraging data, which was another aspect of why both we and Merck, I think, felt comfortable moving into the phase III for non-small cell lung cancer.
I think, Lavina, to your point, as you look at the phase I we have running now in PDAC and gastric, you can see us in a sort of phase-appropriate way exploring those different tumor settings.
Okay. Is there any certain threshold you will be looking for, like from the phase II?
I know each cancer is different because I also saw you move to the, you know, adjuvant high-risk muscle invasive bladder cancer and a few other renal cell carcinoma as well. What are the, say, threshold you'll be looking for that you think, okay, we feel very comfortable? I mean, for the other two, you went to the phase II. For the non-small cell lung cancer, you did not go directly to phase III. Maybe any additional color, I mean, the top, say, three cancer indications, a little bit more color regarding, you know, what is the threshold, what is the benchmark you are looking for that will give you the confidence to mov e forward?
I'll start. We have not really shared a threshold that we're looking for. It is really, as Rose was pointing out, this MOA method of action, right?
What we are seeing is that there is synergy with INT plus Keytruda, and we are exploring that synergy in other indications where Keytruda has worked. A very good important point that you bring up, which is in adjuvant bladder cancer, in adjuvant kidney cancer, we are in phase II studies. Those phase II studies are going to be looking for, you know, a better signal. Obviously, they are powered well as well. We will have the opportunity to look at that data before having to move into a full phase III, which I think gives you a sense of the strategy behind the, you know, what the question you are asking is. Correct.
They are randomized. We will have a good sense of our performance relative to standard of care and then decide at the time based on the data.
Okay. That is very helpful.
Maybe, you know, beyond the phase III melanoma, if you can, you know, give a little bit of rough outline of the, I know you cannot, it's all event-driven. Like you will not know a precise time, but roughly see in the next, like when should we see rough idea which year we should see which of the data from the remaining studies here listed here?
I do not believe we should timing.
Yeah, it's because it's event-driven, as you just pointed out, Gina, it's very hard to give precise timelines for when those trials will read out, the ones that are on this slide, beyond adjuvant melanoma. I think what you'll see from us is, or hear from us, is just status updates on when they are fully enrolled.
For instance, we've already shared that the renal cell carcinoma study is already fully enrolled as of, you know, our last quarterly call. Once you're fully enrolled, that's when I actually think about the clock starting to, like, collect those events. It'll give you a sense of, like, maybe what the next indication may be that reads out. I think from us, just listen for, like, the updates for when we are fully enrolled in these studies coming forward.
Okay. Very helpful. I think you have a second, you know, basket of the approach. That's the cancer antigen therapy, right? If we move forward to slide seven. Okay, here. Here, maybe, you know, regarding the checkpoint inhibitors, I think we have so many different targets in the past.
Everyone tried, and I still remember, like, the big, you know, the two parts of the, you know, checkpoint inhibitor and the, you know, the two balance there. So many people try different targets. What makes you actually decide to pick PD-L1 and IDO, these two combinations? And then,
I mean, absolutely. Oh, sorry. Did you have?
No, no. Yeah, I think that's my initial question. I will have a follow-up question.
Yeah. Okay, great. PD-L1 and IDO, as you pointed out, have been targets of interest for quite a long time. Now, the approaches to targeting them have been pretty different. If you think about checkpoint inhibitors, inhibiting either by binding to PD-L1 or PD-1, you are really inhibiting that interaction and signaling between those two cells, which does help your immune system recognize a cancer cell.
However, it doesn't actually lead to any toxicity of that cancer cell, right? You can think of it as sort of taking the brakes off of the immune system. Now, in a different approach, IDO is an intracellular protein. There was a significant push to develop small molecules to inhibit that protein. Now, again, the small molecules may have inhibited its activity, but they weren't themselves cytotoxic. They did not, for example, kill either cancer cells or immune cells that might have been overexpressing it. When you think about how you might want to pursue those targets, we've actually taken a different approach where we are actually training your immune system to kill the cells that are overexpressing those, and then leveraging the fact that those tend to be both highly expressed in different cancer cells, as well as some of those immune suppressive cells.
Our translational data is where this gets quite exciting. We shared this publicly, that you do see a decrease in circulating T regulatory cells and those suppressor myeloid cells, so that we can see the effect of eliminating those cells from that immune milieu and really taking their suppressive signals out of there entirely. It is a different approach to two targets that are truly central mechanisms, but is actually pursuing them in a completely different way than some of the both successful PD-1 inhibitors or very successful checkpoint inhibitors and less successful small molecule IDO approaches.
Maybe you want to talk a little bit, Rose, on that point of the safety profile as well. Thus far from this combination.
Absolutely.
We have seen the safety profile that we have seen with a similar to INT, where it's quite well tolerated, and we're not seeing dose-limiting toxicities, and we're seeing pretty low-grade adverse events. You have the ability to sort of select out these cells without a broader systemic safety impact, which has been encouraging.
You have a three-arm study right now, right? Arm one A and arm one B. Maybe, you know, monotherapy or combo, like in the end, your approach will be eventually will be combo therapy. What is the threshold or like you put out, you know, overall response, you know, disease control rate, you know, duration of a response, PFS? What are the, of course, each cancer type is different. You did put in melanoma and the non-small cell lung cancer.
I think everyone understands very well the benchmark there. What will be yours, you know, when you're looking for that will move to the next step?
Sure. Maybe I can take the combination part first and then talk about the response rate. We are again moving with standard of care. We are looking at combining with what that will be in the different settings. Combination with checkpoint inhibitors, of course, in many settings is common, which is why we were encouraged to see that activity in arm one B in combination. We also believe that this mechanism of action could be relevant even without combination with checkpoint inhibitors. As we think through the broader development of 4359 and the different settings we want to take it into, we will take that into account.
Again, for the moment, being focused on combination therapy. Now, the arms that we're describing in the phase II are those types of expansion arms. You are typically looking for your overall response rate there to signal that you're seeing something distinct, activity specific to the combination.
From an investor perspective, Gina, in the frontline non-small cell lung cancer and frontline melanoma setting, obviously, as Rose just said, overall response rate is an important indicator of, you know, activity, but also ultimately PFS would be something that we're looking at as well. Yeah.
You know, we, so like this is the add-on therapy, the combination, right? How much more do you think of like a, say, overall response rate that you would need to have in order to feel confident moving forward regarding the delta there?
Sure.
It is very setting specific as to what that actual delta needs to be. I do think that is where we look at the fact that these are not individualized. These are manufactured and then pulled off the shelf. The safety profile in combination as well is quite tolerable to help us figure out in each specific setting where we would draw that threshold to proceed.
I think our doctor feedback, and of course, depends on the different cancer types, right? Sometimes it will be easily like 10%-20%, you know, overall response rate differences there. The PFS will be slightly different, depends on the cancer type. It could be, you know, even one month or two months in some cancers will be sufficient. Others may be a little bit more. Yep. Yep. Yeah.
Then just coupled with that, I mean, the key point with all of our cancer therapies thus far, because as you know, Gina, physicians will look for a risk-benefit, right? The risk we see here, you know, knock on wood, so far in INT, in 4359, and hopefully in some of the newer technologies that we're working on. Yeah, 4106. We'll continue, we hope to see really this toxicity profile that is very much palatable, particularly in that cancer setting, in that IOIO cancer setting. We're excited to continue to hopefully see that profile because that's really the next frontier we think that we want to change in cancer therapeutics, making it really safer.
Good. I think the last part quickly on the oncology part is, I think, slide nine.
Yeah, slide nine, you know, if we can look at the T- cell engagers, you have two different approaches. Maybe anything you can share regarding the targets there. And then the next step, I know you do have a surface antigen and an intracellular part, you know, any thoughts you can share and then timeline for development there.
I do not know that we have shared specifics on the targets for these, but are looking to move a first program in the surface antigen, T- cell engagers that is multiplexed, and working with our partner Immatics on our lead for the intracellular antigen T- cell engagers. In late preclinical development, we will be excited to share more once we are in the clinic.
Okay. The multiplex, are we talking about like a safety, these three plus two more, minimum two more?
Actually right now, clinically, folks are taking two T-cell engagers that are not multiplexed and combining those. We are looking to outperform that potential in a s ingle medicine through multiplexing. These are extremely potent molecules, and the ability to combine multiple and reach multiple targets is really leveraging the strength of our platform relative to what we are seeing in the clinic with recombinant proteins, where two appears to have been the max for a clinical combination. There was very recent data that was exciting where they did some extensive protein engineering to have one T-cell engager target multiple antigens itself. That has only been able to show two thus far, so binding CD3 and then two different antigens in one molecule. Our approach allows us to do that with separate molecules.
We're truly not limited by the protein engineering aspect of it.
I see. I know you can maybe adjust the ratio in that way because you were separate, right?
That's correct. We can adjust the ratio as well.
Right. Okay. Great. Looking forward to the update. When will be the next major, you know, I'm kind of thinking ASMO will be next natural big conferences, oncology conference. Should we see something there?
We're hopeful, obviously, as you know, the abstracts and things like that for ASMO are not out yet, but we are hopeful that we will update you on 4359, which would be the next data point coming out from this portfolio sometime later this year, and if not this year, early next.
Maybe I think, Lorence, since you're here, throw a question for you.
Any thoughts on a recent, you know, BioNTech partnership on their oncology programs?
Sure. So we saw that and we're very aware of the BioNTech programs that are out there. They're VEGF, PD-L1. And one of the things, you know, as I'm talking to clinical folks here and researchers here, like Rose, who will have a lot of insight in this as well, is again, the ability for us to combine potentially if we do see successes with the VEGF, PD-L1 in that arena. But Rose, if you want to say any more on that. I think we're also quite aware of the recent acquisition of CureVac by BioNTech. And again, we really look to BioNTech as driving that oncology portfolio forward. You know, we keep an eye on it and monitor competition and standard of care. Continue with our portfolio.
Okay, great.
I think we can maybe switch gear talking about now- oncology part. I think we can stop this sharing. Now, Lavina, I will ask a few some tough questions.
I know the, I mean, to be honest, in a way, is a very sad, you know, how the whole microenvironment turning to. I, you know, I still remember clearly 2019, 2020, basically how we see, you know, Moderna and together with other big pharmers and companies, you know, develop, you know, so quickly that the drug basically saved the world. Now the political environment changed significantly. Make it very challenge d in a way. I wanted to maybe, you know, Lavina, I wanted to ask you regarding the policy impact. You know, we, it's truly, I understand nobody really know what will happen next time, right? You see the policy changing left and right.
We know one direction is they are all very, you know, critical and criticism of the, you know, COVID vaccine development become very political in a way. I think we should take one step back looking at the science, but it seems everyone just forgot about that. Giving this challenging, and maybe, and I know Afeyan Jr. is a commentary on the guidance, and we are waiting for the ACIP meeting. I think it was later this month. Maybe just from the high level, I know there are so many individual questions we wanted to ask, but just maybe starting from the high level, how do you, how Moderna, you know, handle the situation? How would you be, you know, navigating? You do have approved drugs and a vaccine, right, for 2025, you know, winter season.
We are hoping, you know, we were able to take a vaccine. So how, and then you have others in the development waiting for approval, and then also the combo, maybe high level. How do you, you know, what's the Moderna's take right now on this whole situation? What is the best strategy approach from Moderna facing such a challenging time?
So thank you for that question, Gina. You're right. I think that entering 2025, it did feel like there was going to be a good amount of change and uncertainty that was lying ahead of us. But as we're moving through the year, we're starting to peel away at a number of those uncertainties. As an example, early in the year, we had the VRPAC meeting for the flu antigen selections was canceled.
Yet the FDA told the flu manufacturers, now we were not part of that, but told the flu manufacturers exactly what antigens to put into the upcoming flu season. We also saw that the ACIP meeting was canceled at first, and then it got back onto the calendar in April. Ultimately, more important for Moderna is that we had two outstanding FDA approvals that were looming. Yet we were successful with both our 1283, now known as mNEXSpike, after the approval approved and on time, as well as just recently our RSV broader indication into 18-49 year olds, high risk individuals. On top of that, we had the New England Journal of Medicine paper that was authored by the FDA commissioner, as well as the head of CBER, put forth what they would like to see in COVID development, right?
I think that if you listen to their words, they want to make it much more predictable so that year in and year out, manufacturers know exactly what to submit to the FDA for those approvals. What did we see with the FDA vaccine framework that they put out? They want people who are high risk, so those who are 65 and older, as well as 12-64 year olds, are encouraged to get the COVID vaccine because they are of high risk. This makes up a population in the U.S. of anywhere between 100 millio-200 million people.
Given that that's an important segment to go after, I think that's why if you look at our label for 1283, which is mNEXSpike now, you'll see on the label it is for people who are 65 and older and those 12 to 64 year olds who have high risk factors. There are many, many risk factors that would fall into what is defined as a high risk individual. I think what Moderna's role is, is to really work with the administration, work with the FDA commissioner and the head of CBER to provide them as much information and evidence that they need so that they can make these decisions, which is what we're seeing. You know, we look forward to continue to work with them.
Okay. Okay. That sounds hopeful. On the other hand, you know, I think Afghan Jr.
Did like say require, say, you know, Moderna agreed on the placebo controlled phase IV study after for the mNEXSpike. Maybe walk us through like how feasible that could be done and how would you do that, you know, while the vaccine rolling out hopefully later this year?
Right. In the approval letter, there were both requirements as well as commitments. One of the commitments is this placebo controlled study in healthy individuals between the ages of 50 and 64 years old. I just want to make a point on this that that indication for the 50 to 64 year olds in healthy people is not currently on the label. We're still assessing in, you know, what it would take for us to do that placebo controlled study. When we do, we'll update you guys on what the assessment is.
Remember that that would be an expansion of the current label, which is again, for those that are 65 and above and 12-64 year olds who are at high risk, which represents again, a very large opportunity in the U.S., 100 million-200 million people who fall into those labeled indication for mNEXSpike, which is much larger than the number of people who took the COVID vaccine in the market in the U.S. just last year in this last season.
Okay. We will know the answer, maybe the final assessment, whether this will be worth further, say, conducting another study. Okay. Regarding, you know, the RSV, you know, just also got approval. I do, I'm very pleased to see that both actually, I think one is actually Saturday when Friday we did not see it.
We thought we're not going to approve it. And then Saturday morning I said, okay, good, they got approval. Now the ACIP meeting later this month, any, you know, thoughts there what could be when we look at it, they did, they will cover pretty broad topics. Any, because one part is the approval and then, you know, that completely in line with what initially study design and everything the purpose. Should we worry about ASAP recommendation now we have new ASAP members there? Should we be worried about could be any drastic differences or certain restriction on even, you know, approval is one part of the recommendation will be different part. Should we be worried about that?
It is always, of course, you know, concerning to see a full scale change in processes that, you know, every manufacturer is very used to with the removal of, you know, these independent experts on the ACIP committee. However, you know, ultimately we think we need to first see the full list of the people who are going to now be on this ACIP committee. I think there are still a number of seats to be filled. You know, it remains really essential that the committee continues to make evidence-based decisions. Again, what the manufacturers, Moderna itself, is going to provide is as much data as they need to make that, you know, decision that is evidence-based.
We're hopeful that they're going to continue to view that data as potentially helping in Americans with those who expect to, you know, have the vaccine available to them and be immunized so that they can be protected.
Okay. Another very specific question regarding, you know, the combo, right? Previously, you know, the flu and the COVID combo. And because of the timing of flu data and then you basically withdraw now waiting for the flu data. After that, assuming, knocking on the wood, if it's positive, you're moving forward with the combo. Now giving current change, you know, any thoughts on, you know, development paths for the combo, flu and the COVID combo from here?
As you rightly pointed out, Gina, we withdrew the combo application for the flu plus COVID vaccine.
It is important to note that the flu component in the combo is the same one as the phase III that is ongoing right now where we expect to see the data in the summer of this year against a standard flu vaccine. The COVID component is actually mNEXSpike, which was just approved. Your question on, you know, what is going on with, you know, the changing environment and what impact we might see on the combination filing as well as the flu filing later is really hard to answer right now.
Given the evidence we've just seen with the approval of mNEXSpike, which is a component of the combo, as well as waiting for the phase III efficacy data later this summer for the flu component, we are hopeful that once we have that data and, knock on wood, hopefully it's positive for the standalone flu vaccine, we will incorporate that data into the full filing and refile that package, the combo package, with the FDA later this year.
Okay. Good. And then, you know, given current situation, do you think that you would need to revise the guidance again later this year, the revenue guidance? Are there any scenario you may need to revise the guidance?
You'll recall that we gave a very broad and wide guidance range at the earlier point of this year.
1.5 billion to 2.5 billion is the range that we gave on revenue. That 1.5 billion on the low end does take into consideration a number of factors. This was given at the beginning of the year. We did not have a ton of visibility at the time, but we thought it was appropriate to include a lot of these factors. I'll just walk you through those. One of the reasons that the 1.5 is where it is on the low end is because we anticipated that potentially there would be another year of vaccination rates going down. That could be for any reason, whether it is rhetoric, you know, in the political scene or just confusion with the population in terms of getting their vaccine.
We also anticipated that we would see additional competition from the likes of Novavax, now partnered with Sanofi in that COVID market, as well as the potential for a delay in our ex-U.S. revenue base from the three countries where we have multiple year contracts. Some or all of those three are expected to come online this year. If there were some delays there, all of these things would have to go wrong for us to get to that $1.5 billion. While we're not updating guidance at all on this call, the range we think does take into consideration a number of these factors into that low end of the range.
Okay. Basically you are very comfortable with the current guidance now. Okay. The other question is regarding the burn.
That's always like brought up by, you know, my conversation with the investors. I think in the past, I think the last update, if I remember correctly, is that in two years you wanted to achieve a profitability. Would that be, and then that also incorporate, you already have the burn, you know, the cost cutting, the R&D cost, the SG&A cost cutting. Any maybe thoughts moving forward regarding, you know, if the scen ario depends on what scenario, do you have a capability to have a further cut in terms of a burn?
Yeah. Good question, Gina. On your point of burn, obviously burn has two components, right? There's the revenue and, you know, sales coming in with cash coming in, as well as what we're spending on a cash cost basis every year.
I'll start with at the end of the second quarter of this year, we ended, sorry, the first quarter of this year, we ended the quarter with $8.4 billion of cash on hand. We guided for year-end cash for this year in 2026, so December of 2025, sorry, to be $6 billion in cash on hand. We've also said that the cash costs for this year would be $5.5 billion. In the first quarter, however, you're already seeing us kind of outperform what we expected to do in the first quarter. We saw a 20% decline on both SG&A and R&D combined year over year in the first quarter. We are finding lots of opportunities to really accelerate that cash out. We are hopeful that we'll continue to do that.
Getting back to your question on burn, the piece that we know we can control is the cost out. It is all hands on deck in terms of finding every way to make sure that each and every business unit is running efficiently. We are hopeful that we will do that $5.5 billion this year. We gave guidance at $4.7 billion in cash costs for 2026. In 2027, at the midpoint of the range, $4.2 billion in cash costs. Now we can talk about the revenue side of things where we do expect to have additional product approvals off of this year's base case, because this year's $1.5 billion-$2.5 billion only really is mainly COVID, as well as a little bit of RSV, depending on, you know, the low end or the high end of that range.
Next year, we should be in a good place to have additional revenue from mNEXSpike, as well as international revenue as both mNEXSpike as well as RSV gets approved in countries around the world. We're hopeful, we'll see what timing looks like for some of the combinations and potentially even flu standalone, you know, still yet to be seen because we need to file, see the data, all of that stuff. Those could also contribute starting in 2026, 2027. When you start layering on new product approvals coming on, by the time you're in 2028, you not only have the respiratory franchise, but as you know, we have norovirus reading out in 2026 as a base case. We'll have INT reading out 2026, we're hopeful as a base case. PA is another one.
By the time 2028 rolls around and you add into the mix CMV, then we should be in a position to really see the base revenue from this year really start to grow as these new product approvals come through.
Okay. The second part is like, you know, giving, you know, what would be like you lay out what could be the revenue contribution, the key focus. You did pause the rare disease development. Maybe thoughts on that, why, you know, pausing this, is that because the market opportunity is not big enough? Maybe any thoughts there like strategic decision wise, you know, what could be the key focus for Moderna from here moving forward and what would be the best way to spend the dollar on?
Yeah, I'm so glad you brought that question up, Gina, because we've been getting this question a couple of times and I just want to correct it for the record. We are actually not pausing anything in rare disease. I think the transcript for the last competitor investor event that we did, when you read the transcript, you do not hear the pause that was taken when Stefan was talking about pausing the latent, the phase I, two studies that we have in the latent portfolio before we move into phase III. Those are kind of on pause because we're looking for partnerships there. It has nothing to do with our rare disease portfolio. That pause word is not actually for rare diseases. In rare diseases, we are moving forward. PA is in its registrational study and MMA will be starting its registrational study later this year.
Thank you for clarifying, letting me clarify that.
Okay. I think that's actually important because rare disease, it's a very straightforward development path. You understand underlying disease and science very well, right? The development path will be very quickly, like phase I and a pivotal study. The FDA seems very open-minded, you know, with the regulatory path there. Okay. Very glad to hear that. The latent virus, maybe, you know, since you already brought up, you did, you know, take a few latent virus, you know, put aside, maybe, you know, share the, you know, rationale behind it.
Sure. Yes, as you know, we are very, very encouraged by, again, the platform and how it's doing in that latent virus portfolio. We've shared data on EBV phase I/II. We've shared data on VZV.
We have an HSV vaccine that's in phase I, II. We are really encouraged with the consistent immunogenicity profile that we're seeing and the safety profile. It breaks our heart to have to not move directly into phase III. However, because we want to get this out into the hands of physicians and patients, given what we've seen so far in the phase I, II, and given the experience we have with the portfolio, we are actively seeking partnerships. You've seen us do this in the past with Blackstone as an example and the flu standalone vaccine study that we took into phase III. There are partnerships the re in the financial realm, but also with strategics as well.
We're hopeful that, you know, we'll find a partner that will be willing to take these into a phase III study so that we can get these into the market, you know, really as soon as possible.
Okay. Great. I know we are on time. Maybe any last words you think, you know, investor major disconnect that you wanted to highlight or emphasizing?
Sure. I'll just start with, you know, first, thank you so much for giving Rose and us the opportunity to walk you through the oncology portfolio. There's a ton of excitement internally, but also as we're talking at KOLs about the potential of mRNA and how it can really augment that whole oncology field. That's one point.
The other, I'd say, is something that you, you know, already brought up in your questions, which is controlling that cost on the cost side, because there are two components to getting to, you know, break even and profitability. One is on the cost side, and obviously the other is on the revenue side. We are really focused on this prioritized portfolio of 10 programs that, you know, two of which have already been approved, and there are many others that are in phase III, and we are hopeful to see those approvals to help on the top line as well so that we can get to our goal of break even and profitability in 2028.
Thank you so much, Rose and Lavina. Thank you everyone for dialing in for today's call. This concludes today's call. Thank you.
Thank you, Gina. Bye-bye. Thank you.