Hello, everyone. I'm Jay Olson, one of the Biotech Analysts at Oppenheimer, and it's a pleasure to welcome you to Oppenheimer's 35th annual healthcare conference and our discussion with Immuneering. It's a pleasure to introduce Ben Zeskind, CEO and Co-Founder. Thank you so much for joining us here today, Ben. Hey, Jay, thanks to you and the entire Oppenheimer team for having me, and thanks to our audience for listening, and happy to be here. All right. All right, happy to dive right in. I'm from Immuneering Corporation, and you know our goal is really to help cancer patients live longer and feel better, and the "and" is important. Too often, those goals kind of come at the expense of each other, and our goal is really to make both happen simultaneously. I will be making forward-looking statements today, so please see our disclosures for more information. We wanted to make medicines that would help patients live longer and feel better, and MEK inhibitors were a natural place to start because MEK inhibitors already help patients live longer. In the phase III COMBI-d study that Novartis ran, adding MEK inhibitor to Tafinlar, their BRAF inhibitor, in BRAF mutant melanoma patients actually added six months of overall survival just with the addition of a MEK inhibitor. MEK inhibitors have already shown that they can do great things for patients, and they're also good business. Alone and in combination, the four registered MEK inhibitors drove about $2.4 billion in sales in 2023. Yet, you know, with all that benefit and both for patients and commercially, those MEK inhibitors, we believe, are really just getting started, and we believe there's an opportunity to improve them. We set out to make a new kind of MEK inhibitor really with two goals. The first was to expand the indication beyond BRAF. The existing MEK inhibitors have been really limited mainly to BRAF mutant disease, and what we wanted to do was, you know, because MEK's downstream not only of BRAF, but also of RAS, we wanted to expand the applicability also to RAS mutant disease. The second thing that we wanted to do was improve the tolerability. Those existing approved MEK inhibitors, you know, have faced challenges with tolerability, and we saw there was an opportunity to really substantially change that. Those were two of the goals around which we designed our novel MEK inhibitor, IMM-1-104, and we believe that the clinical data we've announced already, which I'll walk you through today, really shows the potential of IMM-1-104 to do much better. Let me just summarize the data, and then we'll get more into it. First, in terms of that goal of expanding indications beyond BRAF to RAS-driven cancers, you know, pancreatic cancer is really kind of the beachhead for that. Pancreatic cancer, over 90% of it is driven by RAS mutation, and we've shown a 43% overall response rate for 104 plus modified gemcitabine nab-paclitaxel in first-line pancreatic cancer. That's nearly double the benchmark for the standard of care chemotherapy alone, and that includes a complete response, which is exceedingly rare in this setting. Consistent with that, we've also seen a 50% overall response rate for 104 plus modified FOLFIRINOX, again in the first-line pancreatic cancer setting, and that included a patient who had a 100% reduction in their target lesions for a very deep partial response. We've also seen very encouraging signs of activity in later-line patients. You know, 104 treated later-line pancreatic cancer patients included a patient with a deep 67% partial response in second line and a patient with over 12 months of progression-free survival in third line, which we'll talk more about that patient, just an extraordinary outcome. Based on the strength of these data, we're already planning for the 104 plus modified gemcitabine nab-paclitaxel pivotal trial, and we're adding additional phase 2A combination arms that we have planned for this year. All that's really under the banner of expanding the indications for a MEK inhibitor beyond BRAF to RAS mutant disease. In terms of that second goal of improving the tolerability, we've observed highly differentiated tolerability. We've now released nearly 100 patients' worth of data with IMM-1-104 both alone and in combination with modified gemcitabine nab-paclitaxel, and that really highly differentiated tolerability demonstrates the broad potential of 104 both to enable new combinations and really to, we believe, to replace existing MEK inhibitors in established combinations for patients with tumors driven by BRAF, RAS, and beyond. The way we do that is really to inhibit MEK a little bit differently. While the approved MEK inhibitors generally follow an approach of chronic inhibition with low Cmax, lower Cmaxs, and higher drug drops and longer half-lives, what we do with 104 is to come in with a PK profile that cycles daily between a higher Cmax and a near-zero drug drop with a shorter half-life, and at the same time, we prevent MEK activation by RAF. Having that cyclic approach and hitting the pathway in two places with the higher Cmax, all of that enables us to achieve these goals. That is kind of an overview. Let's take a closer look at our trial now. This is our trial design in the phase 2A. The first five arms of this ongoing study really are focused on that first goal, expanding beyond approved MEK inhibitor indications. We have three arms in the pancreatic cancer setting, two combination arms in the first-line setting, and a monotherapy arm in the second-line setting, as well as monotherapy arms in RAS mutant melanoma and RAS mutant lung cancer. For pancreatic cancer, we have achieved FDA designations, including orphan drug designation, fast track in the first-line setting, and fast track in the second-line setting. We have also received a fast track designation for NRAS mutant melanoma. Let's talk first about that first arm, the combination arm in the first-line setting with 104 plus modified gemcitabine nab-paclitaxel. Let's first think about the situation today for first-line pancreatic cancer patients because it's really tough. First-line pancreatic cancer patients really have faced a difficult choice, essentially live longer or feel better. About half the patients today get FOLFIRINOX or a kind of related regimen, and the other half get a gemcitabine-containing regimen, typically with nab-paclitaxel. When you look at efficacy, FOLFIRINOX is a little bit better on overall response rate, on survival, but the trade-off is it's less tolerable. There are more adverse events and they're more severe. The gem-nab is the opposite, a little bit worse on efficacy, a little better on tolerability. Look, it's bad enough getting a pancreatic cancer diagnosis, but then for the patient to have to make just a terrible choice like this, really we think we can do better. Our goal for 104 plus modified gemcitabine nab-paclitaxel is to give those first-line pancreatic cancer patients a better option, an option with good efficacy and good tolerability. They deserve that. They shouldn't have to choose. Let's just get into the numbers a little bit more. For FOLFIRINOX, the objective response rate is 32%. For gem-nab, it's 23%. All these numbers are established in their phase 3 trials. Disease control for gem-nab is about half the patients, about 70% for FOLFIRINOX. Complete responses are exceedingly rare in both cases, and the progression-free survival is really tough at five and a half months for the gem-nab and 6.4 months for FOLFIRINOX. We aim to do better, and I think the data we're going to show you today shows that we're on that track. In terms of tolerability, nearly half the patients on FOLFIRINOX have grade three or four neutropenia. Gemcitabine nab-paclitaxel is better, but it's not great. I mean, 38% is still a lot of grade three, grade four neutropenia. Fatigue is common. Serious diarrhea occurs as well. These are just selected examples. There are other adverse events as well. This is really the bar that we're comparing against, starting with the 23% ORR. When we combine 104 with modified gemcitabine nab-paclitaxel, we see a 43% overall response rate, nearly double that 23% benchmark for the gemcitabine nab-paclitaxel alone. This includes a complete response. Let me just emphasize, in the MPACT study, the phase III study for gemcitabine nab-paclitaxel alone, there was one complete response in 431 patients, exceedingly rare, and yet we have one in our first seven patients in this arm. Certainly very encouraging to see that, very rare in pancreatic cancer. Great to see additional PRs, partial responses driving that 43% overall response rate. You know, I think the other thing that's important to appreciate is with a 48% disease control rate for the chemotherapy alone, you'd kind of expect a whole left half of this waterfall plot, if you will. You'd expect a lot of patients with tumors growing, and we just don't see that. You can see that it's kind of missing the left half. It's the right half of the waterfall plot, and I think that we believe that speaks to really the unique ability of 104 plus the modified gemcitabine nab-paclitaxel to really move these target lesions in the right direction and get the tumors shrinking. All that we find really very encouraging. You know, in terms of response, both overall response rate, disease control rate, complete response rate, so far all compares very favorably to the benchmarks from the chemotherapy alone. And so does the safety. What we're showing you here, these are treatment emergent adverse events, so not just the related ones, but everything because it's the combination. It's harder to tease apart that are observed in at least 10% of the patients. What you can see is there are no grade four events, and you can count on one hand the number of grade threes in any given category. Even the number of grade twos and ones is relatively modest, as are the any grade numbers for these various treatment emergent adverse events. Just to kind of highlight again the three that were highlighted on the previous slides, we actually see no grade three, four fatigue in this combination, 5% diarrhea, and only 10% grade three neutropenia. Again, it was 38% grade three, four for the chemo benchmark. Just really encouraging on the tolerability as well. Just to kind of put that in the same format we talked about before, you know, to date, and look, you always have to take cross-trial comparisons with a grain of salt, but to date, what we're seeing is a 43% overall response rate, 86% disease control, 14% complete response rate. We don't yet have the survival data, but also safety, which is all favorable relative to those benchmarks that we've seen previously. You know, as of today, the data we have so far, we believe shows, you know, if these trends continue, this could be a better option for those first-line pancreatic cancer patients, an option that yields both better efficacy and better safety, and that would really be great for those patients and really give them a clear choice as opposed to this difficult decision between efficacy and safety. Look, you don't have to take our word for it. You know, I think the KOLs in the field have also really noticed the potential of really a unique profile here. Dr. Bekaii-Saab at the Mayo Clinic, great pancreatic cancer KOL there, member of our scientific advisory board. You know, he said these phase 2A data and first-line pancreatic cancer are very promising. You know, if these trends continue, the combination may provide improved efficacy and tolerability versus gemcitabine nab-paclitaxel in the first-line pancreatic cancer setting where patients continue to urgently need better options. In addition, having a MEK inhibitor that appears to be as well tolerated as IMM-1-104 may provide new opportunities for patients with different types of cancer. Just taking a step back and appreciating that this pathway and this target are applicable to quite a few different types of cancer, with pancreatic cancer kind of just the beginning. Dr. Bekaii-Saab is great. We have three other great SAB members, Dr. Chung at City of Hope, Dr. Pant at MD Anderson, and Dr. Berlin at Vanderbilt, all very excited about the data that we're seeing so far. Let's now talk about the second arm of this study, the first-line patients receiving 104 plus modified FOLFIRINOX. You know, what's particularly encouraging is that the data we're seeing so far here are so consistent with what we're seeing in the prior arm, with what we're seeing in the gem nab-paclitaxel arm. You can see that right away just in the shape of the curve, right? Again, you know, missing any significant left half of the waterfall plot, you know, we're seeing really tumors shrinking in a lot of cases. We have a patient with a 100% reduction in target lesions. Target lesions are gone. The only reason this is a PR and not a CR is there's one lymph node that's hanging on so far, but you know, this patient remains on treatment as of the data cutoff. It will be interesting to see what happens there. Other responses as well driving a 50% overall response rate and a 100% disease control rate. You know, and in this patient in particular, we have CA 19-9, which is a blood-based biomarker of pancreatic cancer tumor burden and survival, and we've seen that plummet by more than an order of magnitude. Again, just a very encouraging sign there. You know, these data are so consistent with what we're seeing in the other arm, in the modified gemcitabine nab-paclitaxel arm, both on ORR, on the shape of the waterfall, and really on having patients with 100% regressions of their target lesion, all of which we find very encouraging. Let's talk a little now about the third arm, the monotherapy arm in the second-line setting. Here, the benchmark for gemcitabine nab-paclitaxel alone, it's really tough. It's just a dismal 3%. In that context, you know, we in our SAB, we're all really pleased by what we're seeing so far. You know, we have a patient with a deep confirmed partial response, -67%, a number of other patients with lesions that are shrinking and on treatment as of the data cutoff date. All very encouraging in terms of the activity there in the first-line setting. What's also encouraging is the tolerability. Here, we can really, you know, because it's a monotherapy arm, we can really isolate the effect of the drug alone, the tolerability of 104, and it is, I believe, exquisite. What we're seeing here, this is treatment-related adverse events observed in at least 10% of the patients in this monotherapy arm, second-line pancreatic cancer, 21 patients' worth of data. There are no grade fours on the table and no grade threes on the table. You can count on one hand the number of grade twos, modest numbers of grade ones as well. If you look at even the any grade numbers, and you know, there aren't even that many adverse events that make the table at all. We believe this compares favorably, certainly with any MEK inhibitor we've seen, but anything else that we've seen for the MEK kinase pathway, this is a highly differentiated tolerability profile. This was one of our goals. This is consistent with how we designed 104 with the deep cyclic inhibition, the pulsatile approach. This matters for a lot of reasons. It matters to patients because they feel better, right? You know, it affects their experience on the drug, but it also matters because it enables combinations, right? You know, most oncology drugs are ultimately used in combinations, and the key factor that limits combinations, that prevents them from being used, is tolerability. To have such strong tolerability here really creates an enormous array of opportunities for 104 to be combined with many different drugs across a variety of different types of cancer. We'll talk more about that in a minute. Before we do, you know, I want to share a case study from phase I, which is very striking, and I alluded to it earlier. This is a patient with third-line pancreatic cancer who's been on the phase 1 monotherapy for over 12 months, over a year. This is a patient who had progressive disease in the first-line setting with FOLFIRINOX, progressive disease in the second-line setting with a gemcitabine-containing regimen. You know, the typical overall survival expectation for a patient in this setting would be around five months. Instead, in this case, we have a patient who's been on treatment for over a year. Their target lesions have shrank by about 24%, including just a terrible, monstrous 11 cm tumor, and we shrank that, we shrank the other lesions. Just very encouraged to see that kind of reduction in the target lesions. Importantly, you know, it's not just that. We've seen reductions in the KRAS mutant circulating tumor DNA. The CA 19-9 levels, again, that's that blood-based biomarker of pancreatic cancer tumor burden, that's dropped from peak by an order of magnitude. We have a quality of life instrument, quantitative instrument that we use, and we've seen improvements there that have been sustained. Also weight gain. This patient has gained nearly 20 lbs, which is really unheard of. Pancreatic cancer patients typically lose weight. They don't generally gain weight. You know, as important as all the numbers is the patient experience, and what we hear is that this patient has been essentially living a normal life for the past year with third-line pancreatic cancer. That's extraordinary. We believe that's a profound impact. Let me just say, this is a patient who technically has stable disease, right? Because their target lesions did not shrink by 30%, only 24%, you know, this is a patient with stable disease. You know, I think it makes the point that when you have great activity and tolerability, as we believe 104 does, and you can keep patients on treatment for long periods of time, you know, the relationship between overall response rate and PFS, you know, may be different than what you typically see, right? You know, even those patients that have stable disease have the potential to really do quite well. We are very encouraged by this patient and what it says for the durability of 104. What are we doing next? We are continuing to execute on these phase 2A combination arms. I'm excited to see how they play out those five arms. We're also adding additional arms. We're adding an arm in BRAF mutant melanoma for 104 in combination with a RAF inhibitor. We have that planned. That, you know, that's starting to turn our attention to kind of the areas where MEK inhibitors have shined in the past, right? The idea is, you know, we've now shown this really extraordinary tolerability profile. We've shown activity even in settings that have been proven challenging for MEK inhibitors in the past, like pancreatic cancer. Now we're sort of going back and saying, you know, how do we, you know, let's try 104 in this setting where MEK inhibitors have already done well. We're also running combination arms with 104 in combination with an anti-PD-1 checkpoint inhibitor in melanoma and lung. We just announced an agreement with Regeneron to collaborate on a study of 104 in combination with their anti-PD-1 Libtayo in lung cancer. We're really honored to be partnering with them on this. They're a great company, great, widely respected R&D. And you know, the scientific rationale for this arm is really clear. I mean, no less of a luminary in the immuno-oncology field than Jedd Wolchok himself has recently published a paper showing not just MEK inhibition, but specifically pulsatile MEK inhibition. Pulsatile MEK inhibition enhances anti-tumor immunity. So you know, really strong preclinical rationale. And of course, we believe 104 is the only true pulsatile MEK inhibitor that's out there. So really excited about the scientific rationale for that study with Regeneron and what that could potentially mean for lung cancer patients. Of course, as I mentioned, we're, you know, we've started planning the pivotal study in phase 3. This would be a prospective global randomized phase 3 based on our trending phase 2 data. Proposed population would be first-line, locally advanced, unresectable, or metastatic pancreatic cancer patients. Of course, all this is subject to change based on the ongoing data from our trials and regulatory authority feedback. What we have planned is 104 in combination with the modified gemcitabine nab-paclitaxel compared to gemcitabine nab-paclitaxel standard of care chemotherapy with typical endpoints around survival and secondary endpoints around response, disease control, and quality of life. Again, quality of life is so important, not just for the patient experience, but also, you know, really to be able to keep patients on study longer, which really directly impacts survival. In terms of what else is coming up, you know, we've guided to further phase 2A data from IMM-1-104 in the second quarter of this year, as well as initiating those new phase 2A arms in BRAF mutant melanoma and in combination with checkpoint inhibition in 2025 as well. We have cash runway into 2026. You know, I think a good way to kind of sum it up is a question one of our investigators asked, is this the MEK inhibitor we've been waiting for, right? I think everyone already appreciates, you know, MEK inhibition has the potential to, you know, to help patients live longer. You know, with our goals of expanding the indications beyond BRAF to RAS-driven cancers and improving the tolerability. I think the data we shared today really shows that we're on track for that, you know, 43%-50% overall response rates, well above the benchmarks for standard of care in first-line pancreatic cancer with two patients that have seen their target lesions completely go away. You know, nice activity in later-line settings, including that deep PR, the patient with 12 months progression-free survival. We're planning the pivotal study. Again, the tolerability, highly differentiated, nearly 100 patients, great potential for combinations. I just say we believe, you know, we're well on track towards our goal of helping cancer patients live longer and feel better, and that's what they deserve. I want to thank everyone for your attention, and Jay, happy to answer any questions. Yeah, thank you so much, Ben, and congrats on all the progress. Really appreciate your providing this exciting update in the wake of your recent news last week. Super timely. Maybe just to focus in on that for a minute, congrats on this collaboration with Regeneron. It sounds like the biology here is really compelling, especially with the feedback from Jedd Wolchok, such an illuminary in this space. Can you just talk about what kind of synergies you expect to see, not just on the efficacy front, but the tolerability as well, especially since we've seen some challenges, for example, combining KRAS inhibitors with PD-1 antibodies? How do you expect the synergies between 104 and Libtayo to play out in terms of efficacy and tolerability? Yeah, thanks, Jay. That's a great question. You know, the literature on, there's extensive literature really on the, you know, the ability of MEK inhibition to really modulate anti-tumor immunity and specifically to overcome resistance to checkpoint inhibitors in preclinical models. There, you know, there's quite a bit of data there. The paper I mentioned out of Jedd Wolchok's lab, you know, was specifically focused on pulsatile MEK inhibition and showed that to be particularly impactful. You know, I think all of that bodes well for the, you know, the synergy of this combination. You know, we've also shared our own data at SITC, Society for Immunotherapy of Cancer in 2022. We had a poster there. You know, it was with our other program, 415, but you know, a similar kind of deep cyclic inhibitor of MEK. Again, you know, we showed, you know, really nice ability of a MEK inhibitor to enhance those responses to checkpoint inhibition. Just really encouraging preclinical rationale there. Again, you know, the tolerability of 104, we believe, is highly differentiating, right? That matters here as well, right? It matters for a whole host of combinations, but being able to, you know, combine a checkpoint inhibitor, which is, you know, pretty, in general, checkpoint inhibitors are pretty well tolerated in many cases, to be able to combine that with something that has the differentiated tolerability profile 104, you know, again, we think this has the potential to just provide a really, you know, a really attractive option for patients. We are, you know, looking forward to evaluating that. We think, you know, we are honored to be partnered with Regeneron. We think Libtayo is a great program. We, you know, look forward to, you know, running that study for lung cancer patients. Likewise, we're super excited about it and it provides great external validation to your science. Thank you. Just as a quick follow-on, are there other tumor types besides non-small cell lung and melanoma where you're thinking of studying the combination of 104 with Libtayo? And then since you're making a lot of progress with 415 as well, do you plan to study combinations of 415 with Libtayo? Yeah, great questions, Jay. You know, I think, you know, stepping back a little bit from just Libtayo specifically, but more broadly, I mean, there's a whole host of different cancers where we believe 104 has applicability, right? I mean, you know, we treated colorectal cancer patients in our phase 1. So I think that's another sort of immediately obvious area. You know, there's certainly blood cancers as well that are driven by the MAPK kinase pathway. Look, I mean, we picked this pathway for a reason and this target for a reason. It's broadly applicable. You know, I think each of those tumor types, though, there's going to be a different optimal entry point, right? There's going to be different standards of care that are already established, different drugs that are approved. You know, for us, just as we did in pancreatic cancer, where we really took the two first-line standard of care options, gemcitabine nab-paclitaxel and FOLFIRINOX, and found a way to combine with them, you know, I think, you know, we'll really have to follow a similar thought process for each of the types of cancer that we go into. Certainly, there's a broad range of different opportunities there and different combinations. Again, the tolerability is what makes it all possible, right? To have this, you know, this combination of great activity that we've seen already in the pancreatic combinations with just this really differentiated tolerability, that's what enables us to really contemplate so many different combinations and so many different types of cancer. Ultimately, that really gives 104 the potential to have a, you know, a very broad impact for a lot of patients and, you know, a large market as well. Excellent. This has been super informative. We'll wrap things up there. Thank you so much, Ben. It's always a pleasure chatting with you, and we really appreciate the opportunity to learn more about the impressive work you're doing on behalf of cancer patients. Thank you so much. Thanks, Jay. Great to see you. Thanks to the Oppenheimer team, and thanks to everyone for listening. Appreciate it. Our pleasure. Thanks to everybody for joining us today.