Like analysts at Leerink Partners. Thank you for joining us on day one of our healthcare conference from Miami. Very happy to have with us today, Immuneering, CEO Ben. Thank you. Thanks for having me. Great. Why don't we start with an overview of the company for those that may not be fully familiar with the story? Sure. Thank you. Our goal is to improve overall survival in First-Line pancreatic cancer and beyond. In order to do that, what we had to do is invent a new category really of cancer medicines called Deep Cyclic Inhibitors. They're really designed to be kind of a triple threat to cancer. They're designed to really have 3 distinct mechanisms that all work together to promote overall survival. Atebimetinib is the first drug candidate of ours that's a Deep Cyclic Inhibitor. It's really exciting. You know, we're seeing 64% overall survival at 12 months in First-Line pancreatic cancer. That's data we announced in January. We're getting ready to dose our first patient in the phase III study. We've guided to Mid-Year for first patient dosed. We have alignment with FDA and EMA. The study is fully funded. It is called MAPKeeper 301. We are getting ready to do that. Really the 3 mechanisms that promote survival are shrinking tumors durably with less resistance, preserving body mass by countering cachexia, and really minimizing side effects to maximize combinability and performance status. That is how it is working. It really has broad potential because it is targeting MEK in the MAP kinase pathway. Pancreatic cancer is just the beginning. We have a combination study in lung cancer with Regeneron, with their Anti-PD-1 Libtayo. We are looking at quite a few other combinations. We have a preclinical pipeline. Really a broad set of applicability and the ultimate goal is to make cancer kinda how HIV has been transformed in our lifetimes from something that was fatal to something that's, chronic and people can live with it. Okay. why don't we go into the Deep Cyclic Inhibition before we talk about the individual program? I think that's, you know, that is a very unique approach. It's a departure from current mantra in targeted oncology and that, there's generally a belief that you have to continuously suppress the pathway, above a certain level, or otherwise the tumor is able to circumvent it. There's obviously some challenges with that, including safety tolerability with therapeutic window. There's potential for resistance mechanisms to emerge. What is it that, you know, led you guys to choose a non-conventional approach? Thanks for the question. Deep Cyclic Inhibitors really are this new category of cancer medicines and we invented it. Atebimetinib's the first one, and let me tell you both what it does and how it does it, right? You're right, it is a departure from the kind of the prior generation. The conventional wisdom was just shut down the pathway 24/7. Try to shrink the tumor as quickly as possible with really not as much regard for side effects and other sort of consequences of that approach. What, you know, what atebimetinib is doing is shrinking tumors durably. You can see that in our disease control rate of 81%. You know, it's well established. Disease control, shrinking tumors, of course, associated with overall survival. Actually, in the literature, the correlation coefficient is 0.74. Disease control rate shows that you're shrinking tumors and that durably, and that ultimately contributes to survival. That's the first mechanism. The second thing we're doing is preserving body mass. Preserving body mass by counteracting cachexia. That's less well appreciated, but it's a mechanism that affects survival. In fact, if you know, if you look in the literature, in pancreatic cancer, patients who lose body mass in pancreatic cancer, their hazard ratio is 1.55. Patients who lose weight compared to those who don't, that's a 55% increase in the risk of death. In fact, a 1/3 of all pancreatic cancer deaths are linked to this muscle wasting, this cachexia. While it's not as widely appreciated and it's not really focused on by traditional kind of prior generation targeted therapies, it's really an important and distinct mechanism for promoting survival and keeping patients alive. The 1/3 one is really around minimizing side effects. Again, you know, that's. It's not just about quality of life. It's not, it's not just kind of a qualitative soft and fuzzy thing. It has a hard connection to survival. For instance, if you look at patients whose performance status declines from ECOG one to ECOG 2, the hazard ratio associated with that in the literature is 1.48. When a patient, you know, when a patient can't get out of bed, they can't go to work, they can't take care of themselves, it increases their risk of death. Similarly, if a patient is so beat up by side effects in the First-Line setting that they can't go on to the second-line setting, again, the literature, the hazard ratio is 1.51. Minimizing side effects is really about maintaining performance status, enabling patients to go on to subsequent therapies, and all of that contributes to survival, really in a way that's distinct from either preserving body mass or shrinking tumors durably. That's kinda what it does. I mean, in brief, kinda the way it does it, you know, the durability comes from reducing adaptive resistance. Relative to continuous inhibition of pathway, we're basically depriving tumors of the sustained high level of proliferative signaling that they need to rapidly grow and divide. It's actually one of the hallmarks of cancer. If you go to the classic Hanahan and Weinberg hallmarks of cancer papers, sustaining proliferative signaling is one of the hallmarks. The signaling is always on in cancer, and it has to always be on. I think the mistake the field, you know, the advance really we're making over the prior generation is. Just because it's always on in cancer doesn't mean you have to shut it off always. It doesn't have to always be off, right? In fact, that's harmful to healthy cells because we have the MAP kinase pathway for a reason other than for cancer to hijack it, and if you just shut it down 24/7 like most targeted therapies do, like classic continuous chronic inhibitors do, you're really harming the healthy cells that need this pathway. You know, the healthy cells need it too, but they need it a little bit differently. They, they need it differently than malignant cells. They don't need it all the time. They just need it transiently or intermittently. By giving them the pathway, you know, essentially what we're doing is we're hitting the pathway hard with a very high free fraction Cmax, we're above IC90 for several hours a day, it prevents the cancer cells from having the sustained signaling that they need. We, through a fast off rate and a short half-life, 2 hours in humans, we basically release the pathway. We give it back to the healthy cells by the end of the day. We thread this needle, and we take advantage of this difference in the timescale, to in a new way, basically enable better tolerability 'cause the healthy cells get their MAP kinase signaling, deprive the malignant cells of the sustained signaling they need. In doing so, we don't drive resistance as quickly because you're not giving the tumors a sustained, predictable signal to adapt against. You're much more kind of keeping them off balance by giving them the pathway and taking it away. That's really how Deep Cyclic Inhibitors work. Okay. It's, I think it's obvious how you wouldn't have resistance, as much resistance by not continuously creating pressure on the pathway, create, you know, less impetus for the tumors to adapt. It's also, you know, pretty obvious why you would have less safety tolerability. What about the cachexia part of the equation? What is it, other than, you know, you not having as much maybe nausea, safety, you know, tolerability issues? Is there more to it? Good question. There's specifically MEK inhibitors, as a class, have been shown to counteract cachexia. There's actually literature on that going back several years from some of the first generation MEK inhibitors, and it has to do with how muscle satellite cells use the MAP kinase pathway. Actually, this is something that's true of MEK inhibitors in general. You don't see it with RAS inhibitors or others, but it's true of MEK inhibitors. It really interferes with the mechanism by which the tumor causes the loss of the muscle mass. It is unique to MEK inhibitors. What about using Deep Cyclic Inhibition for another class of drugs other than a MEK inhibitor? Would you expect to see similar benefits other than maybe, I guess, cachexia, probably not. Yeah, harder to say with the cachexia, but certainly the improved tolerability and the not driving resistance to the same extent. Both of those we would certainly expect by applying Deep Cyclic Inhibition to other targets and other pathways in cancer. In fact, we're doing that quite actively in our preclinical pipeline that we're working on in-house at our labs in San Diego. We're really excited. I mean, it's not applicable to every single target and pathway in oncology, but it's applicable to quite a few beyond the MAP kinase pathway. We're actually quite excited about bringing forward a really a new generation of cancer therapies for a number of targets that, you know, just patients don't have to, you know, shouldn't have to deal with grueling side effects to get benefit. We shouldn't just sort of play to cancer's strengths by giving it a predictable signal to adapt against. Deep Cyclic Inhibitors don't do either of those things. Why don't we start talking about atebimetinib and the. Sure ... the MEK program. Yeah. Can you give us an overview of the program, what you've shown to date, and then, where the program's headed? I think the first thing to appreciate is, you know, atebimetinib's target is MEK, right? This is important because MEK's a validated target, right? It's been validated clinically in the COMBI-D study. You know, adding a MEK inhibitor on top of a RAF inhibitor extends survival by six months. It's really been validated commercially as well. If you look at Novartis in 2025, their number 5 product by sales, you know, in the top 5, is a combination that includes a MEK inhibitor, over $2.2 billion in sales, and there's several others. MEK's really validated both clinically and commercially as a target. We decided to go after it in a new way because what's really held back the MEK inhibitors from achieving their full potential has been 2 things. That they haven't really been applicable to RAS mutant disease. They've been limited mainly to RAF mutant disease and then the toxicity, right. They've really been limited by side effects. So we, you know, we decided to change that. We developed atebimetinib. It's novel composition of matter. You know, it's a MEK inhibitor. It sits in the pocket differently in a way that blocks RAF-mediated phosphorylation of MEK, which expands the applicability to RAS mutant disease. That's important for pancreatic cancer. Then it also because of the Deep Cyclic Inhibition mechanism, it's much better tolerated, and it doesn't drive resistance in the same way. That's really how we sort of took this new approach to MEK, and I think you can see the results of that in the survival data that we presented in January, which I'm happy to summarize if you... Sure. Yeah. Let's go through the data, yeah. In January, we shared 64% overall survival at 12 months in a group of 34 First-Line pancreatic cancer patients treated with a combination of atebimetinib and modified gemcitabine Nab-Paclitaxel chemotherapy. Just to put that in perspective, if you compare that to the pivotal study of standard of care, gemcitabine Nab-Paclitaxel, the MPACT trial, and you got to take it with a grain of salt as you would any cross trial comparison, but that's nearly double. You really double the overall survival at 12 months in the benchmark from standard of care, which is 35%. We're at 64%. It's really encouraging to see that kind of survival. Again, that's been our goal from the start. We believe that survival is driven by 3 distinct mechanisms, right. Shrinking the tumors durably, counteracting the cachexia, and minimizing the side effects, all of which we think are contributing to that. We see really good separation, not only from Gem-Nab, but from other standard of care treatments, FOLFIRINOX and NALIRIFOX. It's just really encouraging. All the secondary endpoints also show good separation as well. That's on top of the chemo. What would you expect with chemo alone? Chemo alone, the overall survival at 12 months would be 35%. Okay. We're at 64. In terms of Progression-Free survival, you know, it's less important. It's a surrogate endpoint, but still, we have median Progression-Free survival of eight and a half months we announced in January. You'd expect 5 and a half months for the chemo alone. Okay ... from the pivotal study. We just had Richard Pazdur, here, and he was, you know, talking about, how, you know, response rates are very important, in oncology. What type of response, did you see? Yeah, I mean, we saw both ORR and DCR that were substantially higher than the pivotal studies as well. You know, I think what's, you know, what's most important in oncology is overall survival, right? If you look at the secondary endpoints and how well they're correlated with survival, right? Survival is the gold standard. You know, PFS is pretty well correlated with a disease control rate somewhat, and then ORR, overall response rate, is really the least correlated with survival. While we're thrilled that we show good separation from standard care on all 3, you know, really the best surrogate for OS is OS, right? I mean, overall survival is most important, particularly when your mechanisms for supporting it include multiple mechanisms not just shrinking the tumors. Okay. What about some of the other metrics that you mentioned or the Deep Cyclic Inhibition benefits like quality of life and toxicity and cachexia weight, you know, weight gain? Absolutely. Of the patients where we have data at 3 months, 84% of the patients in our study were either stable or gained weight. We have some really dramatic cases of patients who gained a substantial amount of weight, which again, is really important in pancreatic cancer when patients lose weight. The hazard ratio is 1.55, so it really increases the risk of death to lose weight by giving patients stable or increased weight. We believe atebimetinib is helping contribute to their survival through a really, really distinct mechanism. In terms of tolerability, was excellent. If you look at adverse events occurring at the grade 3 or higher level in more than 10% of patients, we saw only 2 categories: anemia and neutropenia, both of which are associated with the chemo that we're combining with, and neither of which did we really see in the monotherapy study. It's really not clear that atebimetinib is adding much of anything in the way of harsh side effects on top of what you would expect for the chemo alone, and that was really exciting to see. Again, not just because it gives patients great quality of life, but also because that helps them maintain performance status, which is directly linked to survival. What percentage of patients after atezo got additional treatment? Cause obviously, pancreatic cancer can be tough. A lot of patients may not go on to get anything else, and they may die. In your trial, what percentage got subsequent therapies? Yeah. Yeah. It's an important question. Of the patients where we have the information, about half of them go on to subsequent therapy. The other half don't. That's pretty consistent with what's out there in the literature. Again, as you pointed out, sadly, pancreatic cancer, a lot of patients don't make it on. Of that half that did go on to subsequent therapy that we're aware of, the vast majority went on to chemotherapy. We're really only aware of one that went on to any kind of experimental agent after that. The vast majority got chemo. It appears to be driven by the experimental drug. Oh, absolutely. ... in this. Absolutely. Our experimental drug, atebimetinib. Right. Yeah. Yep. Okay. Let's talk a little bit about, you know, the developmental path from here. I guess, you know, I know you're talking about combination. Obviously, PDAC has become very, very interesting to a number of companies, pursuing a very high met need. You know, what do you foresee as the development path? Yeah. We have our phase 3 study, our pivotal study in First-Line pancreatic cancer, we've guided to enrolling the first patient midyear. It's called MAPKeeper 301. It's comparing atebimetinib plus the modified GemNab against a standard of care GemNab control with overall survival as the primary endpoint. Really, a plain vanilla design, we're just really excited about it and the kind of the opportunity that it presents for First-Line pancreatic cancer patients. It's actually a really exciting. Well, you know, I'd say there's kind of a hope on the horizon, glimmers of hope on the horizon for pancreatic cancer patients, you know, to have these kinda new agents in development. You'll enroll all comers, not enrich for any biomarker? Correct. Yeah, that's right, all comers with respect to mutational status. I think that's an advantage over, say, RAS inhibitors where, you know, there's more of a testing requirement to get into the study. We don't have that, so patients can enroll faster, and it's a little easier. Okay. How large is the trial? 510 patients. Okay. What is the control arm? What are the assumptions on statistics? We, you know, we haven't shared that publicly. But in terms of how we did our math, but if you look at the, you know, the MPACT trial, it was 8.5 months median overall survival. You know, I think that's one relevant reference. NAPOLI-3, which was a little more recent, the control arm was GemNab, and there it was around 9 months overall survival for the median. Okay. Those are just some helpful. you've yet to hit-. helpful ... median? Correct. In our January announcement, median overall survival not yet reached with 13.4 months of median follow-up time and 64% overall survival at 12 months. Okay. Yeah. When will we get an update on that? We've shared in the first half, we plan to give an update not just on those 34 patients, but on an expanded cohort that includes those 34 plus another 20 or so. You know, our goal was 30 patients. We took 34. There was so much demand from the sites. They were seeing what was happening in those patients. They wanted to get more patients on. After a period of time, we took another 20 or so patients on the study. We're calling that combination of 20 plus 34 the expanded cohort. You know, it pulls the median follow-up time earlier, of course, because they started later. We think that that group's approaching kind of sufficient median follow-up time to be able to talk about, and we've guided to sharing an update from the expanded cohort of over 50 patients in the first half. You know, I think one of the most important things we said in January that maybe didn't get a lot of attention was, the overall survival in the expanded cohort is trending consistently with the overall survival in the 34. Okay. When we get this update, are they gonna be lumped together to the 50, 54 patients, or it'll be broken out by the initial cohorts? We haven't guided to the kind of the details of the, of the update yet. Okay. Certainly we know there's a lot of interest in seeing how these patients are doing. Right. Okay. Then it'll give us some idea about the MAPKeeper, you know, how they... Is there anything different about the 20 that you enrolled demographically from the 34? Are they pretty much the same? Pretty similar. Yeah. It's a similar cohort. Okay. What, what about the inclusion criteria for MAPKeeper? How, how does that compare to...? Similar. It's all quite similar. You know, I think the only thing I would point out is if you look at the 34 patients that we reported on in January, the median age was 69. The patients were a little bit older than the pivotal studies where the median age was more in the low to mid 60s. I think the fact that we're able to show 64% overall survival at 12 months, even in a meaningfully older patient population where the benchmark is 35% overall survival at 12 months, I think it just adds a little more robustness to the survival that we're seeing and it bodes well for a phase 3 where it would be randomized. You'd likely have a more balanced distribution of ages, which again, we think could favor atebimetinib. Right. I think it does also, you know, provide some validation for the hypothesis of a gentler approach to, you know, MEK inhibition. For sure. For sure. Yeah. Okay. Let's talk a little bit about the combo strategies. You mentioned, combining with Regeneron, I mean, obviously there's a lot of interest in RAS inhibition, with Revolution Medicines and a number of other classes of drugs combining with RAS inhibitors. What do you think about combining with a RAS inhibitor? Then maybe you could talk to us about the strategy with the Regeneron program. Yeah. So we believe in combining with mutation-specific RAS inhibitors. We think that's the best path forward for combinations just because you have a much better tolerability profile and again, we think that's a mechanism that contributes to survival. We've shown preclinical data combining with a mutation-specific RAS inhibitor increases the depth and durability of response. We're excited about that. You know, we're excited about the Regeneron the study with Libtayo in lung cancer. We've guided to dosing the first patient in the second half. That... You know, there's great preclinical data both from us and that's published more generally on pulsatile MEK inhibition enhancing immune activity. Really, you know, really excited to start that study. I'm also happy to talk more about the competitive landscape if that's helpful. You mentioned, Yeah, no, it'd be very helpful because it's gotten more competitive. I mean, it's been a tough area to treat, and all of a sudden we've had some what look like victories. So... Yeah, absolutely. I mean, look, I think it's Like I said, there's sort of finally a glimmer of hope on the horizon for these patients, right? I mean, there's 2 First-Line pancreatic cancer phase 3 studies that are gonna be enrolling this year, right? There's our MAPKeeper 301, and then there's the RMC-6236-003 study. You know, I think for patients, it's really important to be able to kind of understand the pros and cons, right? These are 2 very different treatments, with very different targets. We welcome everyone working in this area, right? I mean, there's so much unmet need. There's so much room for different treatments. Right now it's kinda challenging for patients and oncologists to really compare the pros and cons between those 2 studies and make a decision. I mean, we've asked our friends at RevMed privately, we encourage them publicly, let's put out all the data in an educational format, in a, you know, in an event or a, you know, in an article so patients can really weigh the pros and cons. Right now there's just a lot of unanswered questions about their data in the first line setting and that's where the majority of patients are. If you really sorta strip away all the hype and the noise and you try to compare apples to apples, atebimetinib has a lot of advantages right now in the first line setting. I mean, I can walk you through what some of those are. Sure It's pretty interesting. Look at overall survival, for instance, right? We shared 64% overall survival at 12 months in First-Line pancreatic cancer. Their overall survival data in first line in combination with GemNab for divarasib is undisclosed and we call on them to share the data. Share the data so patients can make an informed decision. Let's see the data. For the sake of patients, we hope it's great. That'd be great for patients. You know, 64% at 12 months is great. We hope theirs is great as well. Progression-free survival, I said we're at 8.5 months PFS. 5.5 for the benchmark. Theirs is undisclosed. It'd be great if they could share that data so patients can make an informed decision on PFS. You know, weight gain, 84% stable or gaining weight for us, undisclosed for them. It'd be great to see that data. Let's put it out there so patients can make an informed decision. I mean, you look at grade 3 or higher side effects in 10% or more of patients. I mentioned we have neutropenia, which is likely from the chemo. They do too. We have anemia, which is likely from the chemo. They do too. They also have on that list rash, fatigue, and diarrhea, which we do not. I think that's important for patients to know when they're weighing the pros and cons, right? You know, again, we're talking about atebimetinib plus Gemnab compared to divarasib plus Gemnab, right? If you go beyond grade 3, you look at, any grade treatment-related adverse events occurring in at least, you know, at least 30% of patients, we have fatigue in 53. They have it in 68, right? We have anemia in 41. They have it in 43. We have rash in 38. They have it in 85. I mean, these are big differences. These matter to patients. They matter to survival. Ours is nausea in 35. They have nausea in 63. That's the end of our list for occurring at least 30% of patients. Their list goes on. Diarrhea, vomiting, stomatitis, edema, platelet count decrease, alopecia. There's really a dramatic difference there as well. You know, you look at overall response rate, right? You know, they report 55%, but if you look at their most recent slide deck, 42 and 43 are the slides. You know, overall response rate is a, it's a ratio, right? It's a numerator and a denominator. To really compare apples to apples, you gotta go with confirmed responses, right? Unconfirmed, it's harder to know. If you compare confirmed responses, we're at 12, they're at 15. If you look at the denominator, you know, they have 40 patients in their ITT safety population, but it goes down to 31 for their denominator through the fine print around response evaluable. To really compare apples to apples, you know, compare the confirmed responses over ITT safety population. When we do that for them, it's 15 over 40 or 38%. For us, it's 12 over 34 or 35%. When you really compare apples to apples, you know, the overall response rate is pretty similar. You know, it's the same for disease control rate as well. Pretty similar when you sorta do the math in a way that's really comparing apples to apples. You know, when you look at treatment beyond progression, right? We didn't do that very much in our study, only 9% of the patients. There's emerging research that shows that this can really help promote survival when you have heterogeneous responses. You know, certain patients, if they're treated beyond progression, it can really help. They haven't disclosed their percentage. We call on them to share the data. How many patients in their First-Line study in combination with GemNab were treated beyond progression? That would be really helpful. On their most recent earnings call, they said it was encouraged in the First-Line setting. There's just a lot of unanswered questions right now and we really think for the sake of patients, it would be educational to really put all the data out there. Look, there's gonna be pros and cons to each, but ultimately if you look at it right now, again, in First-Line in combination with chemo, atebimetinib has a lot of advantages and they have a lot of question marks. Okay. Let me see if there's any questions from the audience. Any other tumor types you guys can update us to share? We haven't guided to updates on other tumor types. The main update that we've guided to is the in First-Line pancreatic cancer in the first half, that expanded cohort. That's what we've guided to. Certainly we're, you know, we've guided to dosing the first patient in the lung study in the second half. That's the combination with, you know, with Libtayo with Regeneron. We're excited for that. You know, I think behind your question there's, you know, MAP kinase pathway drives about half of all cancers. There's really a broad set of opportunities across a variety of cancers. We hear that all the time from our sites. You know, generally word gets around at the sites that there, you know, there's finally a MEK inhibitor that's really well-tolerated and really durable. People come to us with ideas for a lot of different combinations and different cancer types. There's really a broad applicability there that we're excited about. Rene? A mechanism question. When you talked earlier about the impact that a tumor will have on muscle, you know, the sort of, I'm gonna call it the sort of promotion of muscle catabolism. Yes. Would it be fair to think that the tumor is sort of promoting sort of muscle breakdown in order to create nutrients to feed itself? Is that kind of what the tumor is doing? Just trying to understand like biologically why that happens. I think that's a fair way to think about it. You know, it's really well established that tumors have this mechanism that they're, you know, they're essentially causing the breakdown of muscle cells. This is why sadly you see in a lot of late stage cancer patients this emaciated appearance, which again affects survival. When pancreatic cancer patients lose weight, hazard ratio is 1.55. By interfering with that molecular mechanism, the... You know, what we believe atebimetinib is doing is basically blocking, you know, blocking the tumor from breaking down the muscle. We believe that's a distinct mechanism that contributes to survival along with the minimal side effects and the reducing the tumors durably. We're really excited about that as well. All right. Thank you, Ben. Congrats on all the progress and for willing to take a non-conventional approach. Thank you, Andy. Thanks for having us. Yep. Thanks, everyone. Thank you.