Thank you, everybody. Welcome to the next session here at the Jefferies Healthcare Conference. Up here to give a presentation is the CEO of Immuneering, Ben Zeskind. Ben, thank you for joining us. Before I turn over the podium to you, obviously, you've reported some data in your Phase 1 dose escalation. You've moved to expansion cohorts as well, and so looking forward to all that, and certainly the continued investment in the program, despite the fact that Wall Street seems to be reluctant to believe all the results and to your mechanism of action. So I look forward to a presentation about that and the convincing to us that the drug is gonna be great. So without further ado, Ben Zeskind. Thank you. Great. Thank you for the kind introduction, Michael, and I wanna thank you and the entire Jefferies team for having us here today, and thank everyone for joining us both in person and remotely. Remind everyone I'll be making forward-looking statements, so please see our disclosures for more information. So what are we trying to accomplish with IMM-1-104? Why are we here? Our goal is to make medicines for broad populations of cancer patients. That's been our goal since we started the company 16 years ago. And you know, I think it's very gratifying that our first program in the clinic, IMM-1-104, has the potential for very broad activity, universal RAS activity. And you know, I think our enrollment in the phase I trial really kinda lived up to that. As you can see, we took over a dozen different RAS mutations, both KRAS and NRAS. And you know, the way we're seeking to achieve this kinda, this kind of broad activity is really by targeting the MAP kinase pathway at the level of MEK, right? So you can see the pathway goes RAS, RAF, MEK, ERK. And the idea is by targeting at the level of MEK, in theory, any mutation in RAS, any mutation in RAF, should be blocked by a good MEK inhibitor. But unfortunately, the MEK inhibitors that have come before, the kinda first-generation MEK inhibitors, have all inhibited the pathway chronically. They've shut it down 24/7. And that's unfortunately led to very poor tolerability, and really limited those first-generation MEK inhibitors mainly to RAF mutant disease. So we said, "There's gotta be a different way to help this target live up to its true potential." And what we came up with was a fundamentally new approach called Deep Cyclic Inhibition. And the idea here is rather than the sorta conventional wisdom in targeted oncology, which is to make drugs with long half-lives that stick around and shut down the pathway 24 hours a day, what we said is, "Let's make a drug that has a huge pulse of free fraction Cmax of concentration, followed by a complete release, a short half-life that causes the drug concentration to drop nearly to zero by the end of the day." And the data that led us to this conclusion essentially suggested that. Why have prior MEK inhibitors been so toxic? They've been so toxic because healthy cells need the MAP kinase pathway, too. We have this pathway for a reason other than for cancer cells to hijack it, and if you just shut it down 24/7, it's not surprising that you're gonna get toxicity. So what we found through our research and our platform was that while the malignant cells and the healthy cells both need MAP kinase signaling, they need it a little bit differently. So the malignant cells are addicted to a sustained high level of MAP kinase signaling. They need the signaling the way a person needs air, okay? So you can't hold your breath underwater for more than a few minutes. The tumor cells can't go long without MAP kinase signaling, whereas the healthy cells are a little more easygoing. They can go longer. They need MAP kinase signaling more the way a person needs hydration. So a few hours without a drink of water, you're fine. 5, 6 hours, you're getting pretty thirsty, but it, it's really not till 24 hours that it's a serious situation of dehydration. So the idea of Deep Cyclic Inhibition is really to choke the tumor for several hours of this MAP kinase signaling that it needs, but then give it back by the end of the day for the healthy cells. And, you know, I think it's important to appreciate that this is a fundamentally new concept, and the first thing we really had to do was show that this is safe, right? Can we actually drive concentrations that are 20-60 times higher than what first-generation MEK inhibitors achieved, and do that safely? So that was really the design of our Phase 1, right? If you look at the endpoints, the primary endpoints were safety, tolerability, identifying a dose for Phase 2, and the PK. Now, of course, we also had to make sure the drug is active, so we had exploratory objectives around that. But the fundamental goal of the Phase 1, the endpoints were around tolerability. And as a result, we took an unusually sick patient population, sadly. So the majority of the patients had pancreatic cancer. More than 80% of them had never responded to any prior therapy, and more than two-thirds of them were in the third-line setting or later, up to the seventh line, meaning that many of them had been exposed to multiple rounds of highly mutagenic chemotherapy. But this is the population of patients in Phase 1. So, given all that, we were actually thrilled to be able to report in March, based on a February 20th cutoff date, top-line safety that we believe is highly differentiated. So this is the typical table that you see of treatment-related adverse events occurring in at least 10% of the patients. What's not typical about this table is how empty it is. So you can see only, and I guess the columns are a little bit off, but you can see essentially one grade three in the table, which was a rash that resolved with topical cream. You can count on one hand the number of grade twos in any given category. Even if you look across the any grade rates of these adverse events, we believe these compare quite favorably to really to anything that's out there for the MAP kinase pathway. And that's a, we believe, a competitive differentiator, right? I mean, I think people sort of view safety as a tolerability, as a box to be checked. But when patients feel good on your drug, it changes what you can do, and it also it creates combination opportunities that you wouldn't necessarily have for a drug with a more typical tolerability profile. And we'll talk more about that in a minute. But you know, we are really excited to be able to report this pretty differentiated, we believe, tolerability. Of course, all that only matters if the drug is active, and so we have three types of data that we believe clearly demonstrate that 104 is active. The first is the PK/PD. So what we saw was that the drug actually reaches above the IC90. So we're suppressing levels of phosphorylated ERK greater than 90% for 2.7 hours at 320 milligrams, and for 1.9 hours at 240 milligrams. Just to put that in perspective, first-generation MEK inhibitors really only get up to around their IC50 values. So this is a fairly unprecedented level of suppression of MAP kinase signaling. Okay, so the drug is doing what it's supposed to do at the molecular level. It's shutting down... And keep in mind, this, this is a log scale, so being, being a little, you know, above the IC90, as you see it, is, is really shutting down the pathway effectively for several hours. So the, the drug is doing what it was designed to do at the PK/PD level. So that was encouraging, but obviously just one step. The next type of data we looked at is the, the circulating tumor DNA data, and before I show you our data, just, just to put it in context, this is a publication, great publication, from Genentech and the New England Journal around their KRAS G12C inhibitor, divarasib, and, and what they're showing are acquired alterations. So acquired alteration data is important 'cause this shows you the new mutations that are arising on treatment, and that's important to know how tumors are getting around the drug, right? And, you know, with a KRAS G12C inhibitor... And look, credit where credit is due, before the KRAS G12C inhibitors, KRAS was considered undruggable, so, you know, clearly a huge advance. Essentially, what you're doing is by blocking a single mutation, you're blocking a single lane of the highway, right? And that helps, right? It slows down traffic, but eventually, the tumor can shift lanes, right? It mutates to get around it, and what this kind of acquired alteration data shows you is how a tumor is getting around a drug. So for a KRAS G12C inhibitor, it shifts lanes, it mutates, it develops a KRAS G12D, KRAS G12R, other mutation. So what happened with our drug? If we were truly achieving this, pan-RAS activity that we were aiming for, you know, tumors would not be able to get around our drug, by mutating to other RAS mutations. And in fact, that's what we saw. So the left half of this acquired alteration plot is completely blank, meaning there was not a single tumor that was able to use any mutation in RAS to get around our treatment. So what that tells us is we're blocking all the lanes of the highway. Now, equally important in this graph is what you see on the right side. So how tumors did, in some cases, get around 104, was by acquiring alterations in other pathways unrelated to the MAP kinase pathway. So essentially, we'd blocked all the lanes of the highway. They had to take a train. They had to take a plane. And we believe the reason they were able to do that is, again, because this was a late-line setting of heavily pretreated patients who'd been through multiple rounds of mutagenic chemotherapy. So that's, you know, that's essentially, essentially why. And yet, you know, despite that, despite this being a Phase 1 study where the, you know, the endpoints were around, around tolerability, we still saw, 104 really having this ability to shrink tumors. In fact, it shrank at least one target lesion in about half the patients. We saw individual lesion regressions up to 35.7%. The best RECIST sum of longest diameters we saw, and again, this is... all this data is as of the February twentieth cutoff date, and as we announced in, in mid-March, you know, best RECIST SLD, 18.9%, over 5 months, longest duration on therapy, and again, half the patients having at least one target lesion regress. You know, so I think we can all appreciate that in advanced, late-line pancreatic cancer, lesions don't just shrink on their own. They don't even stay still on their own. They grow fast. So to be able to, to shrink the lesions in this way, in this population, we feel is clear proof of concept that the drug is active. So what's, what's next? That was a Phase 1. Well, I shouldn't even say what's next. What's currently underway is our, is our phase 2a. Phase 2a is currently underway, and, and this is a, a completely different design with a completely different goal and a completely different set of patients, right? So, here, ORR is an endpoint. It was not in Phase 1. What we've done is, you know, each of the five arms of the trial that you see on this slide, in one way or another, you know, has a different set of patients and a different way to overcome this, you know, these alterations in other pathways that we saw in Phase 1. Let's start with the right side. We have two arms of the study in first-line pancreatic cancer. By going to first-line pancreatic cancer, you know, we believe, and what we've seen in the data from the AACR GENIE database also is encouraging, that in first-line pancreatic cancer, the tumors are much more uniformly dependent on MAP kinase pathway signaling. So, you know, we believe in first-line panc, you'll see much more dependence on the MAP kinase pathway. So that, that's the first thing. And then the second thing is, we've combined them with 2 standard of care treatments, modified FOLFIRINOX or modified gemcitabine nab-paclitaxel. And those combinations, we showed in April in our AACR data, have the potential to be synergistic with 104. So we showed in an animal model of KRAS mutant pancreatic cancer. Actually, I'll just jump ahead to it, and then we can jump back. So you can see the plots, the individual lines of the individual therapies, but then if you look at the upper left plot, the bottom line, the sort of dark maroon, that's the combination that we're testing in one of the arms of the Phase 2a, 104 plus gemcitabine plus paclitaxel. So that's... You're seeing sort of stronger tumor growth inhibition than you did with any of the individual therapies alone. And we also showed in this poster at AACR, the reason for that. So you can see here, essentially, the resistance mechanisms for chemo and the resistance mechanisms for 104 are different, and each helps to address the other. So you can see in the bottom two plots, when we're combining 104 with the chemo, there are no resistance mechanisms that make it above that line to essentially be significant. So the MAP kinase pathway signaling is a chemo resistance mechanism, and at the same time, the chemo can help address some of these pathways unrelated to MAP kinase as well. So if 104 is blocking the highway, all the lanes of the highway, the chemo can help block the trains and the planes, and essentially help to address some of those mutations and other pathways. So those are some of the reasons we're excited about the combination arms. The monotherapy pancreatic arm is in mostly second-line patients, also open to first-line patients, but you know, mostly second-line patients. And second-line patients were the minority of our Phase 1. They were less than a third of the patients, but they were also the ones that did the best. You can see our best individual lesion regressions and our best RECIST SLD were all in second line. Again, they've been through fewer rounds of mutagenic chemotherapy, likely more dependent uniformly on the MAP kinase pathway. So we're excited to have a sort of an entire arm of the kind of the second-line patients. And then, the other two arms, we have a RAS mutant melanoma arm and a RAS mutant lung arm. I think the thing to appreciate here is these are cancer types that just weren't well represented in our Phase 1. So if you go back to the chart here, on melanoma, you can do the math, 5% of 41, that's two patients, right? And that's just a function of the fact that we had five sites in the Phase 1. We've more than tripled the number of sites for the Phase 2 a, including sites that are focused on melanoma and lung cancer. You know, again, each of these arms, you know, we consider a kind of a separate shot on goal, if you will, you know, with a very different set of patients and approach that addresses some of those mechanisms that we saw in Phase 1. This is underway, and we've guided to initial data from multiple arms of the Phase 2 a in 2024. You won't have to wait long to hear how this is going. You know, I think the combinations that we're exploring are really just the beginning. Again, because we've shown what we believe is such a differentiated tolerability profile already, it really opens up a lot of combination opportunities for 104, and we've shown animal data for quite a few from a KRAS G12C to RAF inhibitors to IO chemotherapy to RTK inhibitors. So really a lot of opportunities for combination both with 104, which is our Deep Cyclic Inhibition MEK, but also with 415, which is another deep cyclic inhibitor of MEK which recently entered the clinic as well. So just to provide a few words on 415, you know, this has a shorter half-life than 104 for a faster cadence. It's designed for twice daily or BID dosing. And what our preclinical data has shown is that faster cadence of the Deep Cyclic Inhibition may be optimal for certain tumor types and certain combinations. So again, this study is underway. We've guided to initial safety tolerability, PK and PD data in 2024 as well. So you can think of that as a sixth shot on goal this year. You know, a lot of really exciting preclinical data both as monotherapy, we've shown in different KRAS indications, but also in combination. So this is data we shared at the Triple Meeting in October. You can see the brown line on the right is binimetinib plus encorafenib, standard of care for BRAF mutant melanoma, which is what this is an animal model of. You can see nice tumor growth inhibition initially, but, you know, around three and a half weeks, it starts to escape, and if you start treating, it kinda, the tumor kind of takes off like a rocket. If you contrast that with our drug, the Immuneering drug 415 plus encorafenib in the purple, you can see greater tumor growth inhibition to begin with, but, more importantly, nice durability even through that week-long drug holiday. And again, we believe this, you know, the resistance. If you look at the literature on resistance to binimetinib plus encorafenib, it's frequently driven by other MAP kinase pathway mutations, such as NRAS mutations. You know, 415 should have the ability to address that. So you can see we did a sort of a crossover with the animals. After that week-long holiday, when the tumors were escaping from the standard of care, we switched them over to 415 plus encorafenib in the green on the right, and you can see it knocks them right back down. So again, that's that potential for very broad activity. And that's been our goal from the beginning. In fact, you can see that while our Phase 1 study for 104, our first program was universal RAS, all comers with evidence of any RAS mutation that met our other criteria. This trial actually has an even broader set of patients, RAS or RAF. So we'll take patients with any mutation in RAS or RAF who meet our other enrollment criteria. So again, we're very excited to have this study underway, and we look forward to sharing initial data from it this year. So you know, I think that kind of sums up where we are. You know, we have this goal of broad activity. We have two programs in the clinic, one in Phase 2a, one in Phase 1. Really excited about the tolerability profile that we've shown with this fundamentally new mechanism of Deep Cyclic Inhibition. Frankly, excited as well about the activity that we've shown in such a difficult late-stage population, and we think... you know, we believe it's all very encouraging for the Phase 2a. With that, maybe I'll pause here and see if there are any questions. I think I have a couple of minutes, right? Yep. So, uh- Four minutes. Yeah, maybe. So thinking about the data that was disclosed earlier in the year, I'm not sure if there's a summary of the slide. Yeah. I'll go back to it. Yeah. The market reacted, despite the fact that you had good pharmacodynamic data, but then there were not necessarily RECIST responses, and you show that there is some tumor reduction- Yeah ... but no specific RECIST responses or PRs, despite the fact that there was a good number of patients, and they are RAS mutant patients. So given the mechanism that you should be shutting down the pathway with your cyclic inhibition, can you describe why you believe there wasn't, or do you need to go higher? Or explain to folks why you think there should be strong efficacy despite the fact that you did not see RECIST responses. Yeah, absolutely. It's a great question, Michael. Thank you. You know, I think the first thing to appreciate is, again, you know, what the data is telling us is that, you know, the reason we did not see RECIST responses in the Phase 1 data as of the February 20 cutoff date, was really driven by mutations in other pathways unrelated to the MAP kinase pathway, right? That's what we see in the ctDNA data. Just going back to it. Right. Right. And so that, you know, the drug did what it was supposed to do, right? It did what it was designed to do. It blocked the MAP kinase pathway. And it's really the fact that there were these new mutations arising in pathways unrelated to MAP kinase. Again, that's a function of the fact that these are late-line pancreatic patients who have been through a lot of chemo, which is highly mutagenic. The chemo is causing mutations. So, you know, in Phase 2a, where we have first-line patients, where we have chemo combinations, it just gives us a very different ability to both avoid and tackle these other mutations in other pathways to really let 104 shine at what it was designed to do, which is to block all the lanes of the MAP kinase highway. And so what tumor types was that in, and were there melanoma patients and other NRAS mutant melanoma? And how beat up were those patients? Because many people would argue, look, if that it should be the dominant pathway, you're shutting that down, you should see more, particularly in melanoma. Can you just comment to that and how many melanoma patients you have? Because I would agree that pancreatic patients are extremely difficult to treat. So I believe there should be a half pass there, but melanoma, you should see more. Right. So, you can, you can do the math here. 5.5% of 41 is 2 patients, right? You know, one of which was at a, at a, not, not 240 or 320, at a lower dose. So, so really, we just didn't have the, the patients to truly evaluate this in melanoma. You know, I, I think to your, to your point, Michael, melanoma is one of the best indications in our preclinical data. It's one of the strongest. So that- that's why we've, you know, we've added sites in the Phase 2a, including melanoma-specific sites, great sites with great investigators, and we're, we're excited for that. You know, we're excited for each of the arms of the hase II A for, you know, for different reasons, but that, you know, we're excited for the melanoma arm 'cause that, you know, that'll really be the first true test of 104 in melanoma. Yeah, so the key here is that, going forward, this Phase 2 in the green box are the 2. Though there's multiple cohorts. 5, 5 cohorts, yeah. Yeah. And so when would there be data on that? 'Cause I agree that in pancreatic, healthier patients, first line or second line, much better probability of seeing something. Yeah. Melanoma, some fairly beat-up patients there, but should see more patients. And then in non-small cell lung cancer, second and third line, very difficult. Yeah. But you should see stuff there. Do you agree with all that? We certainly believe, we believe we'll see good results in the Phase 2a. You know, I think we've put our money where our mouth is. If you look at the Form 4, eight members of our senior leadership team and board have, you know, bought shares in the open market after the data announcement. So, you know, we're clearly optimistic about this. To your point, too, about melanoma, you know, the prior treatment matters, right? So melanoma patients, a lot of them will have IO as prior treatment, and that actually reduces the mutation load, whereas chemotherapy increases it. So, you know, for a drug like ours, that's, you know, fully blocks the pathway, it really matters a lot what the patients have had previously. I think the other thing to appreciate is those combination arms. I mean, those are really good opportunities for patients, right? I mean, they get the standard of care kind of first-line treatment that they would likely get anyway. But the addition of an experimental agent that, you know, we believe showed really good tolerability in phase I. So it's you know, there's kind of not- When is the data for the monotherapy cohorts? So for all 5 of these cohorts, we've guided to initial data from multiple arms in 2024. So you'll, you know, hear about multiple arms this year. Obviously, not all 30 patients per cohort, but you'll see patients from some of these cohorts in 2024. I think that's fair to assume based on us saying initial, right? Initial data. We're not committing to completing the cohorts. Very good. Thank you, Ben, for the update. Appreciate it. Look forward to more data this year. Thank you, Michael. Appreciate the opportunity to be here. Thank you, everyone.