We're really excited about sharing with you some new data that we just shared earlier today on one of our assets, mRNA-4359, that's quickly becoming one of our newest late-stage assets, similar to INT, which you've heard a lot about. I'm going to walk you through some of the INT data. We're just pleased to have some experts in the field that have joined us tonight to talk to you about melanoma and to talk to you about the data that was presented, the mRNA-4359 data. That's Dr. Sullivan and Dr. Pinato. We'll bring them up shortly. Before we do, let me just talk to you about our pipeline. At Moderna, we use mRNA in many different creative ways. We use it for personalized therapies, which is our intismeran autogene program. I'll talk to you a little bit about that. We also have some off-the-shelf therapies.
Those are our cancer antigen therapies, which we affectionately call our CATs. We have a T-cell engager program. I'll share some preliminary information about where we are with our T-cell engagers. We also have some cell therapy enhancing and in- vivo cell therapy programs, which are also really exciting for us to advance into the clinic. All of these programs have, we believe, the promise of potential efficacy across a broad range of indications, as well as a broad range of different settings, from early-stage disease all the way to metastatic settings. What I'll share with you this evening is that if you had looked at a pipeline slide like this a couple of years ago, it would have been about half the size.
This is a testament to the hard work that our clinical development colleagues have done, as well as our research colleagues, to bring all of these new programs into clinic and to expand those programs in clinic to so many different indications. As an example, our INT program now is evaluating efficacy across melanoma, lung cancer, renal cell, bladder. We have a metastatic melanoma study, so many different indications that we believe INT could have the potential for efficacy. Across our cancer antigen therapies, we have both our mRNA-4359 program, as well as our mRNA-4106 program. Our T-cell engager, as I mentioned, mRNA-2808, which we have our sites open and active. Lastly, we have our sites open for mRNA-4203, which is our cell therapy enhancing program. I'll walk you through intismeran . Many of you may be familiar with intismeran.
In case you're not familiar with it, very quickly, it's a program that is extraordinarily unique in the field, and not just unique in terms of the oncology field, but unique overall. There's never been a medicine that is quite so individualized as the i ndividualized as antismeran. So, antismeran is a program where we start with understanding the patient and the patient's tumor. We take that biopsy from the patient's tumor, as well as a blood sample. We look at and sequence the tumor DNA, as well as normal tissue DNA. We HLA type, and then we do an assessment of the mutation status and compare that to normal tissue and tumor tissue. We look at the different mutations. We decide what the unique mutations are in the tumor. We use that information to put into the algorithm, along with their HLA typing.
This algorithm then predicts which ones of these mutations may be more immunogenic. We also, as I didn't mention, do RNA-seq to understand how many of these mutations may lead to RNA and eventual proteins. The algorithm predicts the antigens that are most likely to cause an immune response. Then we encode these into one concatemer. We encapsulate this into an LNP. We ship this back to the patient, who can then receive the intismeran . We do all of this in less than six weeks. This is our three-year follow-up data that we presented at ASCO. This data comes from our randomized phase II trial. This is P201. P201 was a randomized trial looking at high-risk patients with melanoma, who had their tumors resected. These patients were then randomized to receive the intismeran plus pembrolizumab, the standard of care, or pembrolizumab monotherapy.
We followed them for recurrence-free survival, distant metastasis-free survival, and we are also following them for overall survival. Our five-year follow-up is expected to mature later this year. We hope to have data to share either at the end of the year or early in 2026. These are the data that we presented on RFS. We reduced the risk of recurrence or death by 49%, which was super exciting. This is the data that led us at an earlier snapshot to proceed with our randomized phase III study. RFS was not the only endpoint, however, where we saw some benefit. We saw a 62% risk reduction in distant metastasis or death. We also saw a trend towards an improvement in overall survival. These are the safety data from our randomized phase II trial. Importantly, we did not see any increase in immune-related adverse events. Overall, it was very well tolerated.
There was some pain in the arm, some fevers, and fatigue. Those were self-limited and went away over a couple of days. This has been very consistent across our platform. These types of safety data are data that we've observed now with mRNA-4359. We've also observed this with intismeran. Frankly, it's similar to our other products in our platform, including our ID vaccines. As I mentioned, it was these data that led us to mount the randomized phase III trial. This is called INTRAPATH-001. This study has already finished accrual. We're following up for events, and we hope to be able to assess these patients next year. The study is very similar to our randomized phase II, with the one exception that we're allowing some patients with earlier-stage disease to enroll. Those are Stage II patients.
As I mentioned, we're now in the midst of a whole series of different trials, some phase III trials, some randomized phase II trials. We even have an ongoing P101 study that's assessing pancreatic cancer and gastric cancer in single-arm studies. We hope to have data from some of these studies over the next year or so. With that overview of intismeran, I'm going to turn things over to Dr. Sullivan, who will talk to you about the melanoma landscape, in particular, the metastatic melanoma landscape. That will lead us into the results that we observed with 4359. Ryan .
Thank you so much. I'd like to talk about the advanced melanoma treatment landscape, which will make more sense when Dr. Pinato talks about the update that he presented earlier today. This is a busy slide that we've been making busier over the last 15 years, which is a wonderful story in and of itself. I'm not going to go into the details, but just to say that in the advanced space, we have a lot of things at work. We have the first immune checkpoint inhibitor approved in advanced cancers in ipilimumab. Normally, I try and do that. You can read. We had the first anti-PD-1 antibody approved for any indication in 2014, followed soon after by pembro, then nivo. We had the first BRAF-targeted therapies. We had the first combination checkpoint inhibitor, the first oncolytic virus. We've done well. We've had a lot of success.
Remarkably, despite all of the success, we still have more work to do. I'm not going to take you through all of the data supporting this slide and the statements I'm going to make on the slide. Needless to say, if a patient arrives in our clinic remarkably armless, even if they have arms, we have three options. We can give single-agent anti-PD-1. We can give the combination of an anti-PD-1 antibody and anti-LAG-3, which would be Opdualag for single agent. The approved agents are Keytruda and Opdualeg. We can combine anti-PD-1 and anti-CTLA-4, whether it be Nivo. Even if you have a BRAF mutation, this is better, and that's been shown in a number of studies. Here's a summary of that work.
Basically, if you look across the agents, you see varying response rates, but combination therapy is typically more effective than single-agent therapy, both from a response rate, progression-free survival, overall survival, melanoma-specific survival. While the CheckMate 067 study was not powered for overall survival, which is the IPI-NIVO trial versus Nivo versus IPI, the 10-year OS and the 10-year melanoma-specific-free survival are higher than for Nivo alone. The Nivo data and the bembro data are actually fairly comparable. It likely is true that a patient who has one of two options, if it were IPI-NIVO or single-agent PD-1, has a similar chance of being alive 10 years if you get either the single agents, but a little better chance if you got IPI-NIVO. We don't have 10-year data with Nivo/Rela. We have three-year data. The first three years look pretty good and comparable to IPI-Nivo.
There's a long way to go there. All of that said, the majority of our patients don't respond, or if they do respond, they recur. Despite that we have, with IPI-NIVO, slightly more than 50% melanoma-specific survival, the majority of our patients die from melanoma, from metastatic melanoma. The patients that are not candidates for trial, who almost always die from metastatic melanoma, were not enrolled onto these studies. In the scenario where we have PD-1 resistance, we have also a few options if we're just not very clever and just say, we gave this, let's try that. There's actually now data from all of these scenarios where there's error. If you were to have received anti-PD-1 single agent and received combination anti-PD-1 and anti-CTLA-4, there's an approximate 25% - 30% response rate for that population of patients.
If you got anti-PD-1 single agent or, sorry, anti-PD-1, anti-LAG-3, and then received a combination IPI-NIVO, response rate's less. It's about 11%. Although there's now data that's just being published about anti-PD-1 or anti-PD-1, anti-CTLA-4 pretreated patients receiving anti-PD-1, anti-LAG-3, which looks better than this, ultimately, the current data that is published and available is about 11% response rate. The updated data that was, since this is from a prospective study of Nivo and Rela following anti-PD-1, either single agent or combination treatment, there's a real-world publication that got published last week. I didn't put it in, but it's actually about a 25% - 30% response rate with anti-LAG-3, anti-PD-1 following a frontline PD-1 single agent or combo. That's what exists.
That's the actual standard of care, but for one additional thing, which is in a scenario where a patient has received checkpoint inhibition, we have one additional option, certainly in the States anyways, which is tumor-infiltrating lymphocyte therapy with lifalusil or w e have clinical trials, or we can recycle checkpoint inhibitors. If that patient has a BRAF mutation, that patient can go onto a BRAF-MEK inhibitor combination, and almost always, that treatment will fail that patient within 6 months- 12 months. There's still an awful unmet need here because TIL looks promising, and obviously, you've received approval. It's not perfect. This is just a summary. I decided not to show you all the clinical trial data with lifalusil. Needless to say, response rates in the early days of TIL, which was developed at the National Cancer Institute in Bethesda, were 25%- 50% response rates.
That was included pre-PD-1, post-PD-1, with lifalusil response rates of 30%- 35%. For the first time, seeing durable responders, not just incomplete responders, but in patients who had partial responses, which was never seen at the NCI. It was either CR or BUS. There is randomized data from a Netherlands Cancer Institute, a randomized trial of their TIL approach, which is very similar to lifalusil in the NCI, compared to ipilimumab and mostly previously anti-PD-1 previously treated patients, which showed an almost 50% response rate and a clear improvement in progression-free survival. Lifalusil was approved in February 2024. There is a randomized ongoing study in the front line. What I'll say about lifalusil, it's not for everybody. It requires lymphodepleting chemotherapy. It requires then receiving your TIL, which usually isn't a big deal, and then receiving IL-2 following that. It's a big ask for a patient.
It's about a three-week hospitalization. It can be amazing. It's associated with durable responses. We totally believe that this is the right option for some patients. It's not the right option for all patients who are in the setting of PD-1 resistance with melanoma. Clearly, it suggests that more approaches are necessary, both in cell therapy and beyond. There are some additional data that's emerging with other TIL products. There is a very interesting study that was updated at ASCO this year with OBX-115. It actually avoids the IL-2 because there's conditional expression of membrane-bound IL-15 that actually gets activated when you give a carbonic anhydrase inhibitor. The early data suggests that there's a better toxicity profile if you figure out when you should give the carbonic anhydrase inhibitor, which was sorted out, and may have equally good efficacy. It's a big statement. There is a randomized trial that's happening.
There is also a randomized trial with a PRAME-specific T-cell receptor, T-cell, that is looking at, again, targeting PRAME. That data has been presented and is now a definitive study in patients with anti-PD-1 resistant melanoma. That's where we are with the state of the field. I don't know, Corey, should I take questions now or just get all the data and then take questions? How would we like to do it?
After.
All right. You're up.
Oh, sorry, Kyle, not Corey.
Thank you.
OK. Thank you, Ryan. Great overview of the melanoma space. We're going to move on to the next mechanism. After intismeran , we also now have some cancer antigen therapies, including our most recent presentation, which was mRNA-4359. mRNA- 4359, I've got a mechanism slide here. It targets both PD-L1 and IDO. This is important because it can help with immune evasion and help get rid of some of the tumor suppressor T-regs. It also may target the cancer cell itself by activating T-cells against the target when the tumor may be expressing PD-L1. It may work in multiple different mechanisms. We presented our safety data last year at ESMO in 2024. Today, we had our first presentation of our efficacy data. We presented that it was safe and well tolerated last year with toxicities that Dr. Pinato will describe in detail. We're excited about seeing some preliminary evidence of anti-tumor activity and where this may lead for further development options for mRNA-4359. With that, I'll hand things over to Dr. Pinato. You can walk through the data with us. Thank you.
Thank you, Kyle. Good evening, everyone. The first advantage of me being able to give this presentation tonight is that I can do it in a little bit more relaxed way without having just five minutes to concentrate on all the data. For a non-native English speaker, you can imagine that every time you're stressed, you lapse back into your original language, for me, is Italian. My accent might not have sounded exactly British earlier on. Thank you very much for the opportunity to represent this data to you, which basically goes and shows how mRNA-4359, which is a lipid nanoparticle mRNA molecule that is characterized by its ability to enhance T-cell responses against two key fundamental actionable drivers of anti-cancer immunity. PD-L1 does not need an introduction.
I think IDO specifically is one of those targets that was actually one of the first that created the bubble of anti-cancer immunotherapy to burst, especially when the enzymatic inhibition of this enzyme, which basically catalyzes the transition between tryptophan and kynurenine, so deprives the T-cells from a nutrient, tryptophan, and catabolizes to kynurenine, which is a toxin for the lymphocytes themselves, was actually attempted to be targeted. Unfortunately, the data in lung and in melanoma were a failure by targeted inhibition of this enzyme. mRNA-4359 elicits a different mechanism of action, uses these two flags, as I describe them to my patients whenever they come to clinic and get these types of treatments, little flags outside of the tumor cell or the microenvironment, as a specific target.
The way I tell my patients about how this drug works is that it gives the immune system a sort of an instruction booklet to try and identify a better and more tailored, the more precise way to treat cancer as a result of a specific and targeted approach. The data that we presented today stem from an ongoing phase I-II clinical trial, where the objective initially was to describe the safety, as we always do in drug development. One of the features of phase I trials in oncology is that we give these molecules to patients with active disease. The most legitimate question that we have is, are the drugs working? What is the efficacy? Although the data that we presented today are essentially preliminary in nature without control arms, I think it's very important to go through the data with you, particularly in the CPI-resistant refractory melanoma cohorts.
This is the patient distribution with 29 patients. Specifically, there were two different subcohorts to the group of patients that we're talking about tonight: 14 that received the dose of mRNA-4359 of 400 μg and 15 that received the dose of the mRNA-4359 at 1,000 μg. Together with this, the backbone PD-1 therapy of pembrolizumab was continued. We have seen what the expected response rate is for these patients who are basically challenged with the PD-1 inhibitor. The median follow-up was in the region of about 20 weeks. You can see on the right-hand side that there is a bit of a difference in terms of the duration of follow-up between the 1,000 μg cohort and the 400 μg cohort, the reason being that, as you can imagine, the study was done in a dose escalation manner. Patients treated with 400 μg are the ones that were treated first. Patients treated in 1,000 μg have got necessarily a shorter follow-up.
Another important aspect to say, these patients are the classic early-phase clinical trial population, so good organ function, good performance status, heavily pretreated. The unifying factor, though, for this population is a definition of CPI-resistant refractory, which stems from clearly defined criteria by the Society of Immunotherapy of Cancer. These include patients that might have either had an initial response to anti-cancer immunotherapy and then have developed resistance as a secondary mechanism, or those that had primarily refractory disease, so those where there has never been a response and basically patients progressed later on. These are the safety data, which, as we said, one of the primary objectives of this study is the treatment potentially going to be deliverable in these patients. Whenever I look at safety data, I do this little scanning in my head.
I always go to the type of adverse events that would concern me as an oncologist. There is a formal way of grading adverse events. Grade III events are the events that cause patients to turn up to hospital. Those events that, especially in the setting of anti-cancer immunotherapy, alarm us for the concept of synergistic toxicity. If you combine more immunotherapy agents together, and it's certainly been the case of IPI-NIVO, you have a certain likelihood of increasing the chances that the patient will have an adverse event. What we can see here is that we had to divide events on the basis of relatedness to either mRNA-4359 or the background therapy, pembrolizumab. As you can see, the mRNA-4359-associated adverse events, which are listed here, first of all, they are not particularly different across the cohorts.
Those that are characterized by an incidence above 20% are essentially fairly well manageable. We're talking about tiredness, injection site pain, which is expected from any of these therapies, a tiny bit of fever, erythema, chills, flu-like symptoms. There is nothing that really speaks for the high-grade immune-related adverse events that can be either systemic or organ-specific. We do have a few of those, but those are classically related to pembrolizumab. The ones that I would like to basically point out are the ones that were specifically labeled as immune-related, so the ones that require steroid therapy, et c. Those are in the region of 13.8%. It is what is normally expected as a result of exposure to PD-1 monotherapy only.
This study, because it's an early-phase study, looked at DLT, so dose-limiting toxicities, if there are any events that in the follow-up of the patients through subsequent dosing lead to the treating clinicians to say, we must stop the treatment, or this is a serious event that does not warrant us continuing in that individual patient. For this particular group, there were absolutely no events that were labeled as DLT, which is also quite important, as well as very strong and debilitating or potentially lethal adverse events were not registered in this cohort. Moving on to the efficacy, we have stratified efficacy data on the basis of each individual subcohort per single level of dosing. In looking at the differences between 38% and 8%, you have to consider that the maturity of the data across the two cohorts is unbalanced, and so are the characteristics of the patient population.
If you were to read a phase III randomized clinical trial, you can infer differences across the two columns here. We have to read the data descriptively. We have an overall response rate of 24%, which in the setting of a refractory patient is notable. You can see the description of each individual response. Mostly, we're talking about partial response. There is a complete response and some stability of the disease. The disease control rate is a measure that encapsulates also the proportion of people that have got disease stability, not just shrinkage of the tumor. That is actually quite good, considering that we have a lot of patients that were very heavily pretreated, including the responders over 50%. The idea of having stability of the disease in the majority of patients across the different arms, as well as in the totality of patients, is fairly encouraging at this stage.
One of the things that is perhaps differentiating this specific molecule compared to others and was also picked up by the discussant is the fact that we do need biomarkers. We need to know whether or not there is scope for this specific treatment to identify a subset of patients, which is the holy grail of oncology, precision, trying to pre-identify who are the patients that would benefit. I think it's fair to say the overall response rates are early surrogates of what the natural course of the disease would be. In a study of this kind, seeing a difference based on the PD-L1 TPS, so the number of tumor cells that are picking up one of those flags, the PD-L1 flag, is actually quite encouraging.
You can definitely see an enrichment in all the patients that score more than 1% of 67%, which is compared to data in the PD-L1 negative, extremely encouraging. Here, you can see the waterfall plot. This is the unidimensional view of how the response looks like in the individual patient, expressed as a percentage change compared to baseline. You can see that one patient obtained a complete response. A lot of patients had partial responses. There is definitely a differentiating factor, which you can see in the color red versus blue, which is the PD-L1 status. If you're not convinced by this, you can also look at the other aspect of the data, which is this spaghetti plot, which looks at essentially the characteristics of the reduction in size over time.
This is important because it enables us to understand what is the durability of the response throughout the course of treatment. Some of those responses are highly durable, especially in the red patients, the PD-L1 positive. These data are, to me, particularly important because when we try to develop new drugs, especially in early-phase clinical trials, we have to ask ourselves whether there is enough support for the predicted mechanism of action of the drug that we are developing. This is important because it enables sponsors to make go/no-go decisions, enables clinicians to understand how we are using these drugs, what is it that we are targeting. On the left-hand side, there has been a meticulous collection of peripheral blood mononuclear cells. We've been asking our patients to donate extra samples for research to try and understand how these drugs work. Some of these patients donated a sample at baseline.
The sample of treatment is at the point of maximal response to the treatment. In these two assays, basically, the T-cells, as well as the peripheral mononuclear cells, are incubated against the very antigens that actually compose the treatment itself, so IDO-1 and PD-L1. There is an imperfect, which was pointed out by the team earlier, relationship between the responses as measured as an immunological readout compared to the responses measured radiologically. There is not a perfect correlation. You can see that some of the patients have a trend towards an upward trend, both in the IDO-1 and PD-L1 responses, irrespective of whether they have a response. The trends are actually quite important, more to see whether or not there is any form of immunogenicity, not as a predictor of response in these patients, which I think is very, very important here.
On the right-hand side, you have something that, to me, was even more appealing. One of the key characteristics of anti-cancer immunotherapy is to expand T-cell clones. In this particular graph, you can see that across the two dosing cohorts, in patients particularly that achieve a CR or a PR, you can definitely see that there is an emergence of new clones, so T-cell clones that were not present before. This goes to support the fact that these patients might not have had an intrinsically present immunogenicity to the antigens. They acquired such immunogenicity, and the clones expanded thereafter. I actually personally like these images very much, perhaps even more than the response data, because they go and support the mechanism of response, which is ever so important in early development. With that, I thank you very much for the attention. I'm happy to answer questions.
Thank you. Thank you for that overview. The data are exciting enough for us to expand our current protocol, where we have now amended the study to include different treatment arms. We have arm IIA, which was the arm with the pembrolizumab frontline with mRNA-4359. We have arm IIC, which is a frontline melanoma arm that includes mRNA-4359 in combination with ipilimumab and nivolumab. Arm IID is an arm where we're looking at melanoma patients. This is an expansion of the previous data, where we're expanding upon the CPI refractory patient population. Because of the data that we've observed, we're restricting that arm to patients who have some evidence of PD-L1 expression. We're also looking at mRNA-4359 in non-small cell lung cancer patients. This is in combination with pembrolizumab in the patients that have a TPS score of greater than 50%.
Moving on to our next product in this class of cancer antigen therapies, which is mRNA-4106. This is a program that we're rapidly advancing through our phase I trial. This is a cancer antigen therapy that has antigens that are across a broad range of different targets in multiple different tumor types. It's, again, an off-the-shelf program so that we can manufacture large batches of drug and administer this to patients. So far, we've escalated through dose level I, dose level II. We're now enrolling in dose level III. I'll share with you that we're seeing so far similar types of safety and toxicity events that we've seen with our other programs. In terms of our T-cell engagers, I'll move on to our mRNA-2808 program. This is a program that we're evaluating in patients with multiple myeloma. The T-cell engager program has sites active.
We haven't enrolled our first patient yet. We hope to have that happen very soon. This is a multi-targeted program that targets different targets on myeloma cells, including GPRC5D, FCRH5, and BCMA. The study design is similar to other study designs that you might expect from a phase I trial, where we have multiple dose levels that we're escalating and then an expansion cohort to evaluate efficacy. We also have plans to expand on our T-cell engager program in other tumor types with other targets, as well as looking at targets not only that are displayed by the cancer cell, but also targets that are displayed by MHC. Those allow us to target then the internal antigens that may not be expressed on the surface of the cell. It opens up a whole new range of different targets that perhaps haven't been used in the past.
Lastly, I'll walk you through our cell therapy enhancing and in vivo cell therapy programs. mRNA-4203, this is a collaboration with a partner called Immatics. They've been an outstanding partner. Ryan talked a little bit about this program earlier, where they're seeing exciting results with their IMA-203 program, which is a cell therapy program. One of the challenges, however, with cell therapy in solid tumors is that the cells are unfortunately not something that don't have a long lifespan. By administering an antigen through the use of a vaccine-type approach, we can expose the antigen to these modified and engineered cells and therefore make it more potent and durable and hopefully improve the clinical efficacy of IMA-203. This study is open at a few different sites. We have patients that are consented and enrolled.
We hope to be able to present data, hopefully, in the next year or two on this program. It's an exciting new way to evaluate our platform. Lastly, another exciting new way to evaluate our platform is looking at in vivo cell therapy programs. As Ryan mentioned with TILs, but also with other cell therapies, it can be very difficult to administer cell therapies to patients because it involves myoablation. It involves then engineering these cells with shipment, which is very difficult to manufacture, and then reinfusion protocols. By delivering an in vivo cell therapy, we can achieve similar results, but without the manufacturing challenges and without the toxicities of myoablation. That's a review of our oncology pipeline. I think with that, we probably can go ahead and begin with questions for both me and Dr. Sullivan and Dr. Pinato. Thank you for your attention.
Oh, take this down? OK.
Yeah, Q&A.
Great. Thank you so much. Special thanks to Dr. Ryan Sullivan and Dr. Marco Pinato for sharing their expertise with us. We'll start with any questions from the room. If you do have a question, please raise your hand and let us know your affiliation as well.
Hi. Thanks for taking my question. This is Greg from TD Cowen, representing Tyler Van Buren. Can you please elaborate on the mRNA-4359 PD-1 and IDO mechanism in particular and the flags outside the cancer cells and how it is differentiated from the IDO inhibitors that did not succeed?
You want to go ahead?
Of course.
Dr. Pinato?
The small molecule IDO inhibitors targeted the mechanism inside the cell for, as you mentioned, reducing that cell therapy, the T-cells from being active. Unfortunately, it wasn't very effective. We target IDO in a very different way. We target it using a direct effect on the cell, either through reducing the T-regs, which helps with the immune evasion techniques, or we use it also for T-cells to attack the cancer cell itself by using that as, you mentioned, a flag to directly affect the cancer cell. We're having a direct effect on the cell as opposed to an effect internally at reducing the metabolism from IDO. Anything you'd want to add to that, Dr. Pinato?
Yeah, IDO is a fascinating target. I think if you think about blocking it from the perspective of its function rather than using it as a flag to identify cells that have it or don't have it, there is still a lot that we don't know about how IDO really works enzymatically. There are a lot of other enzymes that, like IDO, support that process of depleting the T-cells from the nutrients. As part of the failure of the old programs, we've been left with a lot of questions as to why, for instance, other enzymes could have overcome the blockage of IDO specifically. With mRNA-4359, the mechanism is completely different. We're not using IDO inhibition. We're using IDO as a flag that pertains to the characteristics of the tumor microenvironment.
Our next q uestion.
Salveen Richter, Goldman Sachs. I have a couple of questions. For mRNA-4359, the discussant today mentioned that you need to see T-cell response at the tumor site to validate efficacy. Have you seen any data there or any early indications?
My answer was relating to the fact that in a phase I trial of this kind in an expansion cohort with limited patients, imagine having paired biopsies of pre and post-treatment. Technically speaking, it's what we would all want to have. Practically, on an individual patient level, it's actually very difficult to prove those changes in the tumor microenvironment prior to and after treatment. It's challenging to rebiopsy the same lesion. It's challenging to also standardize the evaluation of the changes in the tumor microenvironment. Although I believe that these data are in support of the mechanism of action, ultimately, whether or not a drug makes it, and I put my own academic drug developer hat on, is whether or not they actually change the natural history of the disease from a response perspective. I believe that those data are important.
Together with Moderna, we're working on a lot of additional translational endpoints in the biopsy materials. Some of these will be presented at other meetings later on this year. I do believe that the key differentiating factor is whether or not a drug of this kind is capable of shrinking the disease. That's an early indication. We did mention the IDO-1 program, the old one. I mean, drugs of the likes of epicardostat, for instance, which was one of the IDO inhibitors which unfortunately didn't make it, had a 0% response rate. They didn't have any form of single-agent activity. You can imagine that in absence of any surrogate evidence of the drug changing the natural history of the disease, it becomes very difficult to support the ongoing development. Whereas, on the other hand, the biomarkers are absolutely interesting. They're very, very important. In this case, we have one that is perhaps placed at the early beginning of the patient's journey, which is PD-L1 status, as opposed to the dynamic changes across different biopsies, which would also be very difficult to propose from a clinical perspective. I'm not sure.
Yeah, I will share, though, that we have been asking patients to have biopsies because it is important. We have captured some tissue, and that analysis is ongoing. Hopefully, we'll have some data. As you mentioned, it's difficult for patients who don't have accessible tumors, and even patients who might have really great responses, we no longer have tissue to be able to biopsy. It's not easy. We're going to try our best to capture that tissue and then analyze it.
The only thing I'd add is, with all due respect to the question, not yours, but the question that was asked, the most important, I guess, to the discussant, the most important thing is, do you actually have clinical benefit? We've been able to show that if you, I mean, there's a 35-year history of tumor vaccination data that shows that you can immunize but not actually therapeutically advance the care of that patient. If you're actually able to immunize, that's great. If you're able to prove that the T-cells are in there, that's even better. If you're actually able to show that the tumors shrink in the setting of the therapy, that's actually more important. They're all important. The end point is, are what we're seeing clinically better than what we'd expect if we were giving pembrolizumab alone? That's the question that's out there. In the absence of a randomized trial, all we can say is it looks like a higher response rate than we would expect if we were just giving pembrolizumab to those patients.
Just a question on the INT program here. Can you speak to the mechanistic rationale for going after metastatic melanoma versus adjuvant melanoma? Also, just given the number of programs you have ongoing, if you could give us a sense of the timelines beyond the phase II five-year data.
Sure. For INT, we've always wanted to explore the metastatic setting. In fact, the mRNA-4359 data gives us more confidence in this approach for intismeran. Most people in the field have stated that this approach with antigen therapy is likely only to be effective in adjuvant settings because you have a very small amount of disease. The mRNA-4359 taught us that it can be effective even outside of the adjuvant setting, and that gave us confidence that maybe intismeran could be effective in that setting as well. I will also share with you that in our P201 study, we had patients who had Stage IV disease who did well on therapy with preventing their recurrence. We had patients who had ctDNA positive disease, and I would argue that they were close to metastatic, as close as could be, and still had benefit with clearance of their ctDNA. That also gave us confidence that maybe we'd have activity in the metastatic setting and why we wanted to explore it further. We're excited to see the results of that 01/02 study. I'm sorry, you had another question, I think, right?
The phase III readout in 2026, I think.
Oh, yeah, 2026. Yep, we'll get it next year.
Gotcha.
I wish I could give you an exact date on that. Unfortunately, it's an event-driven study, and we have to wait for the events to mature before we can run our first analysis. I can't predict when patients will have their recurrence, and I hope no one does. Maybe we won't have a result until 2027. That'd be great news for patients, right? We're thinking the way events are tracking, it'll be sometime in 2026.
OK. Next question.
The duration of the response was not reached either. Could you give us maybe a first feeling on the trend compared to the standard of care? Is it possible to come back on the nature and the persistence of the new T-cell clones receptor? What could we learn for the future on these aspects? Thank you.
I'm not sure I followed the first part of the question. If I understood correctly, how does the duration of response for mRNA-4359 compare with the duration of pembrolizumab on its own? Yeah, if there is an advantage from adding not just on the response rates, but on the durability of the responses. I mean, to be honest, in the setting of rechallenge, when we rechallenge patients, and I don't treat melanoma patients.
Yeah, I can get that one. In melanoma patients, mostly when you get a response, it generally lasts, not always, but the majority of patients, if you see a curve like this in the frontline setting or in the, sorry, frontline setting or even second-line setting with a checkpoint inhibitor single agent or combo, if you see a response, it tends to look like this, that there tends to be durability. Not everybody's response tends to be durable. This is going out certainly a year, year and a half for many of those patients. It's hard to know what to expect in years three through five or two through five. I think it looks like a melanoma response curve in patients who are benefiting from immunotherapy, which is a good thing. I don't think that cheapens the impact of mRNA-4359. I think it sort of suggests that if you can trigger this response in a patient with melanoma, even if they're PD-1 resistant, you might be able to have that durable control in disease.
What have we learned about the T-cell responses? Maybe we could move to the following slide.
Yeah, yeah, yeah.
Back to the graph. What do I think when I see these graphs? Two things. First is whether or not there is a difference in people that have or don't have a clinical response, looking at these curves versus these curves, and being mindful of the small numbers. We have to allow for the fact that these are exploratory analyses. They're not definitive on hundreds of patients. I think it's very important to look at the trends and to look at what happens to these patients. The T-cell clonality is a readout of whether or not there are existing clones or new clones. A new clone is expected if we think that there has been a new immunization in the patient.
If the patient's immune system has been exposed to something new that wasn't seen before because, let's say, the cancer had their own ability to hide the information from the immune system itself, seeing an increase over time, we are thinking here is cycle one, two, seven, so over a protracted duration of time, enables me to be more confident that what we are seeing is due to mRNA-4359 as opposed to pembrolizumab. It goes back to your original question around the durability of responses. The vast majority of immunotherapy agents that we have work against what we call anonymous antigens. We know that something happens in the patient. We know that we enhance the capacity of the immune system to see something. What that something is remains a mystery. It can be different from one patient to another.
When, however, you see a clonality, a clonal response of zero at baseline, it means that that patient did not have that capacity to recognize that specific stimulus, but then becomes educated later on. That education can only really and truly come, especially in a patient that has been refractory to immunotherapy, stopped responding beforehand, can only really come if you give that instruction booklet to the immune system. Am I making sense? What is this making me learn about? This is, to me, some of the most exciting data, to be honest, because it could be that these immunotherapy agents might not work the way we think they are. Actually, presenting this data so early and also having done the experiments gives you a little bit more credence as to what is it that you're seeing because the responses are a blind readout. You know that the cancer has shrunk. You need to understand why. I think this is actually particularly important.
Maybe I'll also share my comments on this slide from the T-cell specific responses. If you look just at the patients who had partial responses, those are the purple patients, those patients all had T-cell specific responses either to IDO or PD-L1. You can see the increase in the purple lines. There were some patients who had stable disease or progression and still had the responses. I think that T-cell specific response may be necessary for a response, but not sufficient. You can have T-cell responses, but still have progression of disease. What we're seeing here is that the patients who had partial responses had T-cell specific responses to the targets.
Great. I'll take some questions from online. Dr. Sullivan, you just spoke to potentially potentiating IO therapy in these highly refractory patients. Can you also speak to the safety profile of the combination of mRNA-4359 and pembrolizumab and if there is anything remarkable there?
It's a good question. I think the most important thing that we can, there's a few different things you can look at with TOX. Are you seeing additive toxicity that are independent of the two agents together? Are you seeing synergistic toxicity? We're certainly seeing toxicity from mRNA-4359. It's injected intramuscularly. People's arms hurt. There's fevers. People feel a little ill for a day or two, but generally get over it pretty quickly. There's the toxicity from anti-PD-1. The rate, as Dr. Pinato mentioned, was about at least significant immune-related adverse events was about 14%, which is about the rate we'd expect with single-agent anti-PD-1. It certainly doesn't look like there's an additive immune-related adverse event or synergistic immune-related adverse event rate with the combination. Ultimately, those are the toxicities that we worry the most about.
We don't love that patients have a sore arm and are not feeling great for a day or two after receiving treatment. That's very different than a combination therapy that dramatically increases the rate of colitis or pneumonitis or myocarditis or any of the other entities that we see and call immune-related adverse events. I would say that each agent causes toxicity. They don't potentiate the toxicity, but may potentiate the efficacy. If that's actually what's happening, that's an ideal combination for this because as much as immune checkpoint inhibitors have transformed the way we treat this disease, one of the major issues that we struggle with is the development and the management of immune-related adverse events.
Another one from online. Dr. Pinato, you mentioned differences in follow-up between mRNA-4359 dose cohorts. What was the median follow-up for mRNA-4359 at the 400 μg dose versus the 1,000 μg cohort?
I think it was close to 20 weeks, if I'm not mistaken, the 400 μg. I think it's one slide earlier. We can one earlier again. There we go. It is probably one slide earlier. There we go. Yes. The follow-up is here at the top of the table. It's 22.5 weeks for the 400 μg and 10.4 weeks for the 1,000 μg. That's the difference. The overall median follow-up time is 20 weeks for the whole cohort. When we're looking at the overall response rates, we should take into account the 20-week. When you look at the different cohorts, there is that difference.
OK. Is there monotherapy overall response data for mRNA-4359? Can you recap that, please?
Monotherapy.
We have not published that data, I believe. Have we published the monotherapy data? Oh, that was part of the ESMO presentation? Yeah. The monotherapy data, which we don't have in the slide, is hard to interpret because we had multiple different dose levels in that program. We did not see any partial responses or complete responses in that cohort in those escalations. It enrolled a whole variety of different tumor types, including colorectal cancers and other cancers that maybe you wouldn't expect an immune therapy to have an effect on.
There are definitely some stable diseases that lasted longer than we would have anticipated, particularly in MSS colorectal cancer.
For the key opinion leaders, can you remind us what you think pembro retreatment gives you for ORR in PD-L1 positive patients specifically?
As a single agent?
As a single agent.
In PD-L1 positive, there's zero data that's been presented or published or probably even been looked at in that population. We can say with good confidence that the anticipated response rate of single-agent anti-PD-1 after patients have had progression on an anti-PD-1-based therapy is less than 10%. I don't anticipate that it would be substantially higher than that in PD-L1 positive patients. There's actually no data on that.
One other question from online. This may be our last question. Can you speak to competitor data with a similar mechanism of action with a peptide approach and why they are seeing higher PD-L1 negative response.
Yeah, happy to do so. I think they're probably referring to the IO Biotech data, if I would take a guess, which will be presented on Monday. There's a couple of critical distinguishing factors between the IO Biotech data and what we've presented here with mRNA-4359. One is they're very different populations. We're studying a refractory CPI refractory population, which is very different than the population that they're studying, which is the frontline patient population. The other important factor here to consider is that they're looking at different endpoints. Their assessment was on a PFS endpoint. Our assessment is on a response rate endpoint. In fact, if you compare response rate to response rate, IO Biotech showed a higher response rate in frontline melanoma in the PD-L1 positive patients. They actually had a similar type of efficacy that we've observed in mRNA-4359.
I don't honestly think that they might be that different. We'll see the response rate data on Monday. Hopefully, they'll present that. The last thing I'll just mention when you're comparing the two is that there's a different scoring method that was used between how we're scoring patients for PD-L1 positivity and how they're scoring. They used a MEL score for their phase III study. We're using a TPS for our scoring method, which has some nuance in how you declare PD-L1 positive. That could amount to some differences between the two.
Are there any differences between an mRNA approach versus a peptide approach?
Yeah, for sure, there are differences. We believe an mRNA approach is very effective at mounting an immune response for a couple of reasons. One, there's a natural processing of the protein that is created intracellularly that then is displayed on the surface of the cell. I think that can mount a particular heightened immune response. We also are seeing both a CD4 and CD8 response in our platform. This is true for intismeran that we published. We've also seen both a CD4 and CD8 response across our ID vaccine portfolio. We would expect the same to be true for mRNA-4359. I think that may lead to increased efficacy for mRNA-4359. Early days, and we haven't assessed the difference, the CD4 and CD3 population in our T-cell assessments. We will be doing so. I think I would expect we would see the same for mRNA-4359.
OK, great. That exhausts all the questions, both online and in the room. I want to just thank our speakers again. Thank you so much, Dr. Marco Pinato and Dr. Ryan Sullivan and Dr. Kyle Hogan.
Thank you, Lavina. Thank you all for coming.
Thank you.
We'll be around for a bit.