Good afternoon, everyone. Thanks again for joining, next session here with Immuneering. I'm Ami Fadia, biotech analyst here at Needham. As a quick reminder to our listeners, you have the ability to send me questions that you want me to ask the management team through the dashboard. And with that, I wanted to introduce the team here. We have Ben Zeskind, who's the founder and CEO of the company, along with Brett Hall, who's Chief Scientific Officer. Thank you both for being with us today. What I'd like to do is to have Ben start by giving us a quick overview of the company, and we can dive straight into Q&A. Great. Well, thank you, Ami. I want to thank you and the entire Needham team for having us today. I want to thank everyone for listening, and just remind the audience we'll be making forward-looking statements, so please see our disclosures for more information. So yeah, our company is 16 years old, and we were founded really with the goal of making medicines for large populations of cancer patients. We spent the first decade working with pharma on existing medicines, really to understand why they were working better in some patients than others. Over time, we built a proprietary computational platform for analyzing transcriptomic data in that context. About 6 years ago, we began developing our own pipeline, which is when Brett joined us as Chief Scientific Officer, and we focused on the MAP kinase pathway because, I mean, it drives half of all solid tumors. So if you want to go after large populations, that's the place to start. And we kind of zeroed in on MEK because, you know, it's downstream of RAS, and it's downstream of RAF. So in, you know, in theory, a good MEK inhibitor should have this ability to block any mutation in either of those genes. But of course, first-generation MEK inhibitors had been pretty disappointing, you know, very toxic, very poorly tolerated, and really limited mainly to RAF mutant disease and mainly in combination with RAF inhibitors. We wanted to know why. So we ran our transcriptomic platform, and we found that early time points, like 3 and 6 hours, these first-generation MEK inhibitors were doing really well. But later time points, like 24 hours, were actually counterproductive. They were making things worse. And this really ran against the conventional wisdom, right? Conventional wisdom in targeted oncology has been chronic ablation, shut down the pathway 24/7, make drugs with long half-lives. But our data was really telling us to go in a different direction, and that's really what led to the concept of deep cyclic inhibition and ultimately to IMM-1-104. Okay. And what are some of the features of IMM-1-104 that make it very different from the other MEK inhibitors? Yeah, Brett, you want to take that one? Yeah, absolutely. So one of the things that we set out to do was to evaluate, you know, target engagement, right? So kind of classically in small molecule oncology, the classic wisdom has been if you have an oncogene that's turned on, you must turn it off 24/7. Our approach was different. What we wanted to do was impose basically a homeostatic use of the pathway, where basically the pathologic addiction would be thwarted, but we would allow normal healthy cells a chance to basically use a very critical homeostatic pathway. And by basically, you know, looking at the ways to do this and the bioinformatic data that we had in hand, we came up with the idea of deep cyclic inhibition where we make molecules that engage, you know, with very high Cmaxes to really ablate the pathway for a period of time in a given day. So for our 104 program that we'll talk most about today, it has a two -hour half-life, and it’s scheduled as once a day. So we're achieving—we've already mentioned, in our phase I data—we're achieving 1-3 micromolar Cmax free fractions, which is really just orders of magnitude higher than any MEK inhibitor has ever achieved. And to do that, and to split that out, you can get that depth of inhibition, but you need to allow a pathway reset so that normal healthy cells have an opportunity to recover. And in doing this, you can basically create MEK inhibitors that are active and well-tolerated. And that's really been a challenge in the field. Okay. Now you presented data from your phase I dose expansion study last month. Can you recap some of the key takeaways from that data? You know, I think maybe as you talk through that, one of the feedback that we received from investors was that we did not see complete responses or even partial responses. Can you talk to whether or not that study was designed to be able to demonstrate that? Yeah, absolutely. It's a great question, Ami. So, this was a phase I study of a fundamentally new mechanism in deep cyclic inhibition with these incredibly high Cmax peaks, against a target that has been poorly tolerated. So not surprisingly, the primary endpoints were safety, tolerability, and candidate RP2D, right? You know, these were open questions at the time we, you know, we started the phase I. And so that, you know, as a result of that, the secondary endpoint was PK. You know, of course, we had some exploratory objectives around activity, but really the goal of the study was safety. In keeping with that goal, we really took a broad and inclusive population of patients, you know, 12 different RAS mutations at baseline, more than 60% pancreatic cancer patients, more than 80% had never responded to any prior therapy, and about 2/3 were in the third-line setting or later. So, you know, this was a population of sadly very sick patients, you know, really in a study where the objective was to assess tolerability. And, you know, on that primary endpoint, you know, we believe it went quite well, actually. I mean, the drug was well-tolerated. We believe it has the potential for a differentiated safety profile. I mean, you can see in the table of tumor-related adverse events occurring in more than 10% of the patients, there's one single grade 3, which is, you know, a rash that was reversible with topical cream. You know, on the activity front, certainly we showed greater than 90% suppression of the pathway on the PD. You know, at 320, we're spending 2.7 hours above the IC90, meaning we're suppressing the pathway as measured by p-ERK more than 90%. Just to put that in context, prior MEK inhibitors really only got up to around the IC50. So we're really shutting down the pathway. And we also saw 100% suppression of acquired RAS alterations, meaning, you know, there's no mutation that the tumor can turn to in RAS to get around 104. And then, of course, we saw individual target lesion regressions up to -35.7%, and, you know, best RECIST SLD of -18.9% in an advanced, heavily treated population where it wasn't an objective of the study. So, you know, we're very pleased with these results. I mean, 104 is showing clear clear signs of activity in phase I in the tumors that it was designed to target, right, in lesions that are dependent on the MAP kinase pathway, even though this wasn't an endpoint of the study. You know, we think the, what was an endpoint was tolerability. And here we believe the, you know, the data we reported for 104 is highly differentiated, certainly relative to any prior MEK inhibitor and really anything that's out there for the MAP kinase pathway. That's, you know, that's a profile that could potentially make it a combination partner of choice for a wide range of combinations. So it, you know, I think you mentioned sort of RECIST PRs. You know, we believe the reason we didn't see RECIST PRs other than the fact that our study wasn't designed to observe them is because many of these late-line patients had lesions that were no longer dependent on the MAP kinase pathway. I mean, you can see it clearly in our ctDNA data, as the tumors are acquiring alterations in genes that are unrelated to the MAP kinase pathway. You know, and this is the case in late-line patients after mutagenic chemotherapy. We believe it'll be much less of a factor in the phase II-A population. Mm-hmm. That's very helpful. Now, we know that—and you just sort of ended your response here with that—that, you know, patients in late-line, patients that are in late-line treatment tend to have a much greater heterogeneity in terms of the mutational profile. Can you talk about how homogeneous mutational profile could be in early lines of therapy? What can we look at from the literature to kind of be able to understand that? And does it vary a lot depending upon the type of tumor you're looking at? And maybe a different question, and maybe that's a second-part question, is, you showed us sort of the PK profile where for about 2.7 hours you achieved greater than IC90. Could you talk about some of the data points that give you confidence that that much of exposure is adequate to drive tumor regression? Sure. Brett, you want to speak to those? Yeah, absolutely. So, I mean, I think just to reiterate something that Ben said, you know, and is actually demonstrated on our slide on activity, we have observed one or more RECIST target lesions regressions in over half of our phase I patients who are treated at 240 or 320. Of course, as everyone knows, RECIST require at least some of the longest diameters of all RECIST target lesions to be -30% or more, right, for a PR, along with stable non-target lesions and no new mets. You know, on our ctDNA slide, you can see the clear challenge in the advanced, heavily pretreated metastatic setting, which is these new mets that arise are driven by these new ctDNA features that are not MAP kinase pathway dependent. and that's really, you know, speaking, you know, more broadly to, you know, heterogeneity of late-stage disease, when you're working with a single agent to evaluate safety, PK, PD, and, you know, identify your candidate RP2D. So we believe that patients in earlier lines, which is the focus of phase II-A, keep in mind, this has always been a phase I 2a study, approximately 200 patients between the phase I and II-A component, where the phase I was really focused on safety, tolerability, PK, PD, and identifying your candidate RP2D. And now we're shifting to the phase II-A signal finding activity aspect of the phase I/ II-A study. In these earlier line patients, they'll have lesions that are more broadly dependent on the MAP kinase pathway. We observed this, actually, in the AACR gene database, which we actually presented a couple of days ago at AACR. We believe this translational data that we've generated will better approximate what you'll see in earlier line patients, which is, of course, the goal of the phase II-A. We're also excited, in the phase II-A, the two arms in the first line patients that will be treated with 104 in combination with chemotherapy. Our recent poster, again, a couple of days ago at AACR, showed that chemotherapy can also help address emergent non-MAP kinase pathway resistant mechanisms of 104. When we evaluated chemotherapy plus 104 in these animal models, we observed deep, durable anti-tumor responses out for 60 days, which is really a long time for a xenograft study. I'd add one more thing too, just on, you know, our belief, you know, and confidence in, you know, 104 and deep cyclic inhibition and our emergent programs like 6415. You know, based on evidence by recent Form 4 disclosures, eight members of our board and senior leadership team have expanded Immuneering stock positions in the open market after release of our data. So I think I believe this illustrates our level of confidence in deep cyclic inhibition and the initial activity and safety profiles that we're seeing. Okay, great. I also want to talk about, you know, although we did not see any acquired mutations, in the MAPK pathway, how do sort of the adaptive mutations that we see in other pathways impact the efficacy of IMM-1-104? You know, is the time taken to develop that adaptive resistance different depending upon the tumor type and treatment setting, whether it's sort of first line, second line? Yeah, no, it's a great question. I think, you know, fundamentally, any tumor that is able to use a pathway that bypasses addiction or minimizes addiction to the MAP kinase pathway, would be able to get around a single drug that selectively blocks that specific node in that pathway. In metastatic pancreatic cancer, first-line treatments are mutagenic chemotherapy. So it really stands to reason that the tumors become more and more mutagenized as they progress into second, third, or later line settings. And as Ben mentioned earlier, we were basically treating patients in the median third line setting all the way up to the seventh line setting. So consistent with diverse molecular biology across patient metastases into the advanced disease, we observed early onset timing of those adaptive or acquired mutations in our phase I population. Often, those were in under three months. These data, combined with the individual RECIST target lesions that we observed in over half the patients treated at 240 and 320, suggest that 104 is active in tumors addicted to the pathway, but is not going to be able to control in the advanced, heavily pretreated patient population the metastases and individual tumors that have clear pathways that minimize the addiction to the MAP kinase pathway. And this is really the goal of phase II-A study, is to move into earlier lines to enrich for patients that have less metastatic molecular diversity when it comes to, you know, their ability to bypass addiction to the MAP kinase pathway. And you'll see that in the overall, you know, kind of goal of the phase II-A cohorts. I would just emphasize, though, that melanoma and lung really were not evaluated at scale in the phase I, right? You know, not only were more than 60% of our patients pancreatic, but, you know, the specific numbers—I mean, you can do the math, right? 5% of 40, that's two patients, right? One of whom was at a, you know, at a half dose, 100, 160 mg. And lung, you know, four patients. So, you know, from a data perspective, I think it's too early for us to say if, you know, if those tumors would sort of have, you know, have the same set of challenges in the late line setting. So, you know, I think that this is why we're so excited about the phase II-A. As Brett pointed out, you know, eight of us on the leadership team and the board, buying shares in the open market, as you can see from our Form 4, is because, you know, in panc, we're moving to earlier lines, which are more, you know, better, you know, more uniformly depend on the MAP kinase pathway. We're combining with chemotherapy, which, as we've seen in the animal data from AACR, you know, has the potential to really be synergistic and sort of address. Really, they both address each other's resistance mechanisms, is what we showed at AACR, right? The resistance mechanisms to chemo, 104 addresses and vice versa. And then in melanoma and lung, you know, it's really our first opportunity to evaluate 104 in these tumor types at scale. So, you know, people sometimes ask us, well, which arm are you most excited about? And, we're equally excited about all five arms. Okay. You mentioned the data that you presented at AACR. Could you actually take us through it? I believe you used 3D assay, you know, MIA PaCa-2 model. Can you sort of take us through what that showed us in pancreatic? Sure. Yeah, Brett, do you want to walk through this slide? Yeah, I think there are five key top line, take-home points from these data. The first two are really shown on the top left panel, where the triple combination of 104 plus gemcitabine and nab-paclitaxel gives you the maroon line, that basically is right along the axis, just sustained near complete response the entire time. This is really the triple combination that is one of the cohorts of our phase II-A study, just demonstrating the synergy of 104 plus that chemo combination. The just to kind of walk you through it, the pink line on the top left is gemcitabine alone, nab-paclitaxel is the red line alone, and then gemcitabine plus nab-paclitaxel is the gold. So you see the additivity between gemcitabine and nab-paclitaxel. But, you know, it really, you know, needs more help. You know, so that's the gold line. Now, the first part is the triple combo with gem-containing chemo. The bottom left panel, the second part, shows 5-FU-containing combinations. And you see the green line, which is the double combo with 5-FU and IMM-1-104, also showing the synergistic response between the orange monotherapy 5-FU and the purple monotherapy of IMM-1-104. So that is the other that modifies or models the FOLFIRINOX combination advantage in that combination. So that's one and two. Three is the dotted line in each. So we'll stay in the bottom left. The dotted purple line demonstrates post 5-FU-containing treatment. So this would be a second line monotherapy play. Can you regress an escaping 5-FU-containing chemotherapy tumor population? We can. You see that in the dotted line. That really is symbolic of the second line setting post 5-FU-containing chemo. On the top left, you see the purple line, dotted purple line dropping down from the gold line. That's where we basically randomized those 12 mice, six and six, and dropped, again, that post gemcitabine, nab-paclitaxel doublet in that second line setting, which would be a post Gemzar Abraxane type of second line monotherapy setting. So the combination of the two dotted lines gives you kind of the third, which is that third component of our three fifths of our cohorts for phase II-II-A. The last two, we'll go to the right, in the inset panel. And one of the things that we also did is, on the top right panel here, the maroon line coming into day 42, we randomized the mice into two groups, six and six, and treated half the mice continuing with the triple combo, right? 104 plus gemcitabine and nab-paclitaxel, and then split the other mice into only receiving 104 as maintenance. And even 104 as maintenance, after you, you know, stop pulling the triple combo and pull chemo off, you can sustain the inhibition of those tumors right along the axis, the entire time. Now, if you go down a little bit more, the 5-FU component of this is the same. And you can see there's the dotted purple line underneath in the maintenance setting after randomizing the 5-FU plus 104. And maintenance basically keeps the tumors down just as well. So basically, this is the 4th and 5th observation from the study. So a big overall in vivo study, really, pleased with the synergies that we were seeing with chemo plus 104 in the first, second line and maintenance setting. Well, what your sort of the two graphs on the right seem to demonstrate that you don't need to continue with chemotherapy for, you know, at least some period of time, right? Definitely. Yeah. Our in conversations with our investigators, they're actually quite excited about this because, as you know, the, you know, one of the challenges in the front line chemo combination setting is neuropathy, which is often irreversible, particularly with FOLFIRINOX. And so what'll happen is you'll either pull back, the oxaliplatin and then continue to treat with FOLFIRI, after basically that sets in. But once it sets in, it's often permanent, you know, damage, nerve damage, which is really challenging and tough to manage clinically. So if you can start to rectify that and move into more of a maintenance with 104 setting, that would be a really interesting treatment option for physicians. Okay. I just want to add that on the poster, we also sort of demonstrated some of the potential molecular mechanisms behind that. So, you know, in this analysis on the poster, we showed that the, you know, the mutations that are acquired during treatment with each of the chemotherapies alone, you know, anything above the dotted line is significant, are sort of one set of pathways. You know, the mutations that arise with 104 treatment alone are a different set of pathways. But when you combine 104 with the chemo, you see there's nothing significant, nothing above the dashed line. So that's just kind of the molecular view or, you know, kind of mechanism by which we're seeing that real synergy in the that you saw on the prior slide with the animals. So it, you know, it's nice that the molecular data sort of helps to explain that synergy that we're seeing in the animals. And again, those are arms in the phase II-A that are underway as we speak. This is when you're initiating treatment as a combination, not when you're sequencing, right, with chemo first and then with 104. Correct. Yeah. So these are basically from the treatment groups of that same experiment. When we, at the very end, we harvested those tumors and then ran ExomeSeq, to evaluate what the interactions were on the protein level, that drove so mutations in these pathways that drove through these hubs, the resistance mechanisms. And the PRKACA is a hub associated with increased signaling through the MAP kinase pathway. So interestingly, all three of the chemotherapy treatments enrich for a resistance mechanism utilizing the MAP kinase pathway. You don't see PRKACA hub show up in the 104. What you see is an example of ARRB1, which is basically a hub that facilitates ERK autophosphorylation in the absence of MAPK. And so when you combine the two, you don't see either, right? That's where you actually have sustained suppression, synergistic inhibition of the tumors throughout the 60-day study. Okay. We did not talk a lot about safety, but the, you know, there was just one case of rash that you had seen in your dose expansion study. Maybe just a quick comment on, you know, as you sort of test the drug in a larger patient population, are there any adverse events that one should be watching for? Yeah, look, I mean, I'm glad I'm glad you kind of brought it back around to safety because again, that that was the primary input, right? That this is what the phase I was designed to assess. And you know, we believe 104 is, you know, demonstrated incredible tolerability in these in these data. I mean, I would challenge challenge you to find an, you know, another drug where in the table of treatment-related adverse events occurring in more than 10% of the patients, there's only one single grade three event, not to mention it was just a rash, you know, a rash that was reversible with with topical cream. So look, we we never take safety for granted. You know, we'll be monitoring it closely in in phase II-A. But as of now, we view this as a competitive advantage, in general and particularly for combinations where, of course, tolerability is, you know, generally what limits combinations. So, you know, I think for us, with 104, with what we're seeing, so far in these data we've released, you know, those possibilities are wide open because it's, you know, so well tolerated. Now, your phase II-A is underway. Can you remind us, and you know, you showed us a slide earlier which talked about the different cohorts that you're evaluating patients in. But maybe I think for listeners who don't know the story as well, just remind us the basis for selecting those five cohorts and what data can we expect to see in 2024 from either some or all of these cohorts. Thank you. Sure. Yeah, Brett, maybe you want to talk through the rationale for the cohorts and then I can speak to the guidance. Yeah, sounds good. Yeah, I just—I'll reiterate. I mean, we talked a little bit about it earlier, but we're definitely looking forward to the phase II-A portion of our phase I/II-A study. And I just want to reiterate, this has always been a phase I/II-A study with approximately 200 patients where about 40-50 were in phase I to really make sure that we get the dose schedule, safety, tolerability ironed out, and then really go for the signal finding aspect in the phase II-A portion. So this slide really shows kind of some of our thinking around this. We mentioned already 3/5 of these arms. So I'll start on the right, the combination and first line setting, where the goal is to move, you know, consistent with Project Frontrunner of the FDA, with a safe active drug, move quickly into, you know, first line, you know, setting treatment options. And in here, you know, we're setting up two combinations, IMM-1- 104 plus modified FOLFIRINOX, approximately 30 patients. And then IMM1-1 104 plus modified Gemzar, nab-paclitaxel, approximately 30 patients. And we talked a little bit about the rationale here is really, you know, we know that pancreatic cancer, 90% of it has, you know, basically presents with a RAS mutation. Most of the remaining 10% have some other forms or variants of activation of the MAP kinase pathway. So you'll notice that we don't have a prerequisite to be RAS mutant in the in this combination setting in the first line. Nor do we in monotherapy. So on the left, monotherapy, in the monotherapy setting, we're looking at mainly at second line. We did hear back from our investigators, make sure you don't close the door for first line because sometimes patients want a non-chemo option, you know, right out of the gate. And so we don't expect many, if any, for the first line, but you know, it's not excluded. So we mainly expect this to be a second line monotherapy, which we also discussed kind of in the rationale previously. But basically, the two gold standard trials right now were both combination chemos, and they showed 15%-17% ORR. So really, it's you have to beat that response rate in the second line setting and have some durability. For the combinations, you're looking at at least, you know, 20%-30% ORR for the existing, you know, gemcitabine, nab-paclitaxel in the in the low 20s% and FOLFIRINOX in the low 30s%. Of course, there's NALIRIFOX now in the low 40%. So you really have to weigh all of that in in the competitive landscape. But really, the name of the game is going to be ORR and how that translates into durable response, you know, in PFS and OS. And these are very aggressive disease states. So, I mean, you can run OS studies in a short order. The next two on the left, melanoma monotherapy, all of our preclinical models have constantly pointed to NRAS melanoma as being, you know, one of our, you know, most sensitive populations, tumor types. There's just really high intrinsic addiction to the MAP kinase pathway. So we've set up this melanoma study and has been mentioned already, you know, really just to get, you know, a bigger body of work in melanoma. We're looking at second or third line, mainly post-immune oncology. This is the dream sequence that was established with, you know, the checkpoint inhibitors, PD1, CTLA4. First sequence before trametinib and dabrafenib, right? The MEK and RAF inhibitors and BRAF mutant melanoma. That way had the best advantage because the front line IO and second line IO narrows the molecular diversity of the tumors so that you have less, you know, kind of or more singular core addiction. And in this case, you know, any responses or non-responses in the NRAS melanoma would basically enrich for melanoma addiction to RAS. And then 104 would be that dream sequence at a molecular level. So that sets up for, you know, different possibilities, either a monotherapy play and or a combination with IO play, you know, you know, beyond this initial signal finding phase II-A portion. And then last but not least, second line, third line, RAS mutant non-small cell lung cancer. Here really it is it's really a diverse population and of course, as you know, quite a segmented, you know, tumor type with respect to the competitive landscape and standard of care options. And so it really depends on how the second and third line signals look, but you can really start to set up, you know, the initial signal finding for either monotherapy, vertical combinations with G12C inhibitors, or IO combinations. All of these start to basically set the playbook based on the clinical data that we see in, you know, the phase II-A, which is really founded, is set up to look for ORR as well. And just to cover the back half of your question, Ami, on the timing and the guidance. So we, you know, we've got initial data from multiple arms of the phase II-A in 2024. So that, you know, this year, not too long to wait. You know, and as we've always done, you know, we'll share data as it kind of matures and there, you know, there's sort of a clear story to tell. But really based on the enthusiasm of our investigators, both existing sites from carrying over from the phase I and then a whole host of new sites that we've added, including sites with expertise in each of these, you know, each of these tumor types. You know, we're very optimistic about the pace of enrollment. You know, we've you know, we've already said there's multiple arms. There are already patients being treated, including multiple patients in the chemo combos. So we're, you know, we're pleased with the progress. Okay. In the last few minutes, I want to cover 415, which is sort of your molecule and development, which has a BID dosing. Perhaps you could share with us the concept around that. Why one should be thinking about sort of maybe twice a day deep cyclic inhibition and maybe talk us through some of the data that you've generated with that product as well. Yeah, absolutely. I can start off. So, you know, with 6415, an even shorter-lived molecule that is amenable for twice a day. So the idea here is higher Deep Cyclic Inhibition frequency of target engagement, right, in the BID setting versus 104's QD schedule. As most people who followed our story know, most of our preclinical data has really been centered around BID dosing. That's because 104 itself has a 1.3-hour half-life in mice and a 2-hour half-life in humans. That difference in half-life shifts basically the ideal cadence for 104 to once a day. And in preclinical models with 415, it only has a 20-minute half-life in mice and we're projecting about a 1-hour half-life in humans. And so basically what that does is sets up nicely for a twice-a-day cadence. So you get the bookends of once-a-day cadence, deep cyclic inhibition, and twice-a-day cadence. And the advantages and differences really are broad. So for example, if you look at immuno-oncology data that we've generated with 415, 415 combinations with CTLA are favored with a once-a-day format. Whereas if you look at PD1, PDL1, then that's a twice-a-day format that favors. And it really has to do with how you're impacting T cell biology. So not the tumor compartment, but the actual immune compartment. Because as these inhibitors are giving, you know, orally, they systemically distribute, they're also shutting down, you know, T cells. So interestingly, Roche Genentech had demonstrated challenges with cobimetinib, a chronic MEK inhibitor that interferes with T cell priming. So you can imagine why a once-a-day cadence might be preferred with CTLA4 with 415 because you're allowing more time for T cell homeostasis to use this pathway and it's basically mounting immune response. So that's one example. Another example is RAF biology. So we actually now are moving into BRAF, ARAF, BRAF, CRAF mutant disease as well with 415 that we have so far not ventured into with 104. 104 is active in RAF mutant preclinical models as well as RAS mutant, as is 415. But the cadence of 415, we believe, will better, you know, basically set itself up to manage BRAF V600E's disease because BRAF mutant proteins can directly activate MEK and there's a higher intensity of activation. And so that twice-a-day cadence gives you the higher target engagement frequency with the BID format. And we've demonstrated it preclinically using these models. So on the model on the right side, you can see kind of a blowup from the left. This is an A375 BRAF mutant melanoma model. Where we treated with human dose equivalent of binimetinib and encorafenib and very much like, you know, they've shown in their NDA and have published by Ray and others. You actually see nice regressions in the brown line for the first three weeks or so. And then after three weeks, you notice that even on treatment, that basically the tumors start to regrow, right? This is a strong signature of either acquired resistance or probably because it happened so quickly, adaptive resistance. So this is just an upregulation of transcriptomic addiction to other pathways. And so, you know, like you would in the clinic, the patient is now, the tumors are growing positive after a good response, a partial response. And now they're growing out, you would stop and look for another treatment option. In this case, you see for the gray vertical bar, the brown line, that the tumors explode, right? They regrow because the pathways have been compressed and now you release the MAP kinase pathway and you get this explosion of growth. We then changed over to the treatment, got rid of the chronic inhibitor binimetinib, swapped in IMM-6-415, we label it I for Immuneering. And then plus encorafenib at the same dose of encorafenib was given before. And we can recapture those tumors and re-regress them, right? Using a DCI MEK inhibitor with encorafenib. Now you might ask, well, why do all of this? Why not just go back to the beginning and treat with a DCI, a deep cyclic MEK inhibitor like 415? And then combine that with encorafenib. So we did. That's the purple line. We get deeper, more durable responses. We've seen the same type of thing when we did combination studies, vertical combinations with G12C inhibitors in the G12C, you know, space as well. So this vertical combination really does favor the deep cyclic inhibition approach because you're allowing maximal activity of both drugs to work in concert with each other. And so you can see that stays right along the axis the entire time. So deeper, more durable responses. And so, you know, we're excited about the BID format giving us optionality in certain situations. Now, there will be areas where it may not matter if it's QD once a day or BID twice a day. I can tell you in talking to clinicians, what's going to happen then if there's no difference in the certain, you know, areas, then clinicians and patients are likely going to favor 104 because once a day is easier than twice a day. You can do probably more combination options as well. Sure. Yep, that makes sense. We are almost out of time, so I'll ask you one last quick question, which is just on, you know, cash and cash runway. As you obviously generate this important data in the phase II-A ongoing study, what is sort of the cash runway through those readouts? Yeah, so our current balance sheet supports cash runway into the second half of 2025. So that includes recruiting and enrolling all five arms of the phase II-A for 104. It includes the phase I dose escalation and dose evaluation for IMM- 6-415. And we've gotten to, as I said earlier, initial data from multiple arms of the phase II-A in 2024, as well as for 415, initial phase I PKPD and safety data. So really we believe a, you know, a data-rich 2024 as we as we move forward here. Okay. When can we see some clinical data in 6-415? So what we, you know, what we've guided to is in 2024, we'll have that initial PKPD and safety data. We haven't yet guided to anything beyond that. But, you know, clearly we're, you know, we don't wait around, right? We're seeking to move that trial forward as quickly as possible. Okay. All right. We are out of time, so I wanted to close the session here. Thank you so much, Ben and Brett, for taking the time to do this with us. Thanks to all our listeners for joining. Yeah, thank you, Ami. We really appreciate it. And thanks. Thanks to everyone for listening. Okay.