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Welcome to the Immuneering Fourth Quarter and Full Year 2022 Financial Results and Corporate Update Conference Call. At this time, all participants are in a listen-only mode. Following management’s prepared remarks, we will hold a Q&A session. [Operator Instructions] As a reminder, this call is being recorded today, Monday, March 6, 2023. I would now like to turn the conference over to Laurence Watts of Gilmartin Group. Please go ahead.

Thank you, operator. Joining us on the call today from Immuneering are Chief Executive Officer, Ben

Thank you, Laurence. Good afternoon, everyone, and thank you for joining our fourth quarter and full year 2022 financial results conference call. The first such call we are hosting in our company’s 15-year history. Let me start by assuring you that we do not plan to host an earnings call every single quarter, we will probably do them more than once every 15 years, though, maybe somewhere in between. Today, we have a lot to say, though, about our plan for the upcoming year, and about the timing of our ongoing clinical trials. Our goal is to create medicines for large populations of cancer patients. And we took one giant leap in that direction in 2022, as the first patient was dosed in our Phase 1/2a trial of IMM-1-104 for the treatment of RAS mutated solid tumors. We are proud to be a clinical stage oncology company thanks to years of hard work by so many Immuneers, and we are looking forward to sharing updates as the trial proceeds. Before I cover our achievements in 2022 and recent events, let me first take a step back and give everyone context on our counterintuitive approach to drug development. It is our belief that the name of the game in cancer therapy is not how do you kill cancer cells? It’s how do you kill cancer cells with less risk to the healthy cells. It’s all about therapeutic index. And historically, that has been really hard, and that’s why cancer drugs are so commonly associated with such bad side effects, such poor tolerability. At Immuneering, we are developing what we believe is a fundamentally new way to achieve therapeutic index, a novel way to hit the tumor hard, while going easy on the healthy cells. And we think it’ll enable us to develop treatments with the potential to benefit large numbers of patients globally with RAS-driven cancer. Most companies either go narrow by developing medicines that target specific individual RAS mutations such as KRAS-G12C, or they go abroad and hit wild type RAS in healthy cells, and they hope to find a dose that harms the tumor more than the patient. In other words, unfortunately, this approach frequently leads to high toxicity. They say no pain, no gain. We believe cancer patients deserve better. They deserve less pain, and more gain. We are working to rewrite the rules to develop therapies that are designed to help patients with any mutation in KRAS, NRAS or HRAS, and that aim to provide more durable effects with better tolerability. Our approach utilizes a novel mechanism called deep cyclic inhibition, which is designed to maximize therapeutic activity, while providing improved tolerability and durability. We aim to do this by taking advantage of the fact that the cancer cells are always on. They need the MAP kinase pathway all the time, whereas healthy cells use the pathway more intermittently. And I’ll have more to say on that shortly. But first, we needed to figure out how to describe our approach and there really wasn’t an existing prefix or a suffix that works. The closest ones were multi and pan, and it’s not wrong to say we see pan-RAS activity preclinically. But pan is a prefix from the ancient Greek and it sounds like cookware, and it just doesn’t capture the excitement and the newness of what we’re trying to accomplish. Importantly, both pan and multi tend to be associated with therapies that do not distinguish between the wild-type RAS in healthy cells, and the mutant RAS in cancer cells, which raises concerns about therapeutic index and long-term tolerability for those therapies. So we adopted a phrase that aptly describes this uniquely broad approach, and are fundamentally new way of achieving therapeutic index, and it’s universal-RAS. And I’m being a bit light hearted about the name, but let me assure you that we believe the potential for universal-RAS activity is incredibly serious and incredibly important to cancer patients and to their oncologist. The potential of our approach is supported by our preclinical data, and we are sharing some of our modeling data this week as the AACR targeting RAS conference. As described in our poster presentation, we tested 132 different cancer cell line models in our proprietary humanized 3D tumor growth assays in our labs in San Diego, including 75 models with RAS mutations. We’re not saying that every single RAS-mutant model response, but 64 of the 75 models tested, or approximately 85% did respond. And at least one model displayed response to IMM-1-104 for each observed RAS mutation, regardless of the mutation position, or amino acid substitution. So this preclinical data suggests there’s no RAS mutation we know of that’s off limits to IMM-1-104. And for our clinical trial enrollment criteria, any solid tumor patients with any mutation in KRAS, NRAS or HRAS is eligible to be screened for our Phase 1 trial. As a result of these broad inclusion criteria, and the robust preclinical data we have generated to date, we’re seeing great enthusiasm from our clinical investigators, and one indicator that is the fact that we dosed the first patient less than 2 months after receiving IND clearance. With enrollment ongoing, we are today providing guidance on when we could expect to report initial data readouts from the trial. Currently, we expect to share initial PK and safety data in mid-2023, initial pharmacodynamics and updated PK and safety data in the second half of 2023, the announcement of a recommended Phase 2 dose and additional safety data in mid-2024 with additional trial updates on a periodic basis. We believe human PK data is a particularly important milestone for IMM-1-104, because PK is such an important part of how IMM-1-104 achieved universal-RAS activity in preclinical studies. I mentioned earlier that malignant cells depend on continuous signaling of the pathway, while the healthy cells can tolerate more interruptions. But one of the rules of targeted cancer therapy has been chronic pathway inhibition, which means if a pathway is locked on by a driver mutation, you must lock it off, or chronically ablated 24/7. And the problem with this approach is that healthy cells use the MAP kinase pathway too. We have this pathway for reasons other than for cancer to hijack it. But the conventional wisdom is you make drugs with long-half lives, and they’re dosed in such a way as to always maintain target occupancy to maintain a drug trial. And it’s intuitive right to shut down the pathway 24/7. But if we keep doing the intuitive thing, we’ll keep getting the same result. The old no pain, no gain philosophy. So we decided to rewrite the rules in the design of IMM-1-104. IMM-1-104 began with a counterintuitive observation from our disease canceling technology platform, that earlier time point did a better job of reversing disease at the transcriptomic level than later one. And that helps us to realize that you may not actually have to shut down the pathway 24/7, you just have to prevent it from being on 24/7. So we designed IMM-1-104 to pulse the tumor with a manyfold higher free fraction CMAX, or in plain English, a very high peak drug exposure. Yet we also have a short half life in order to enable sufficient inhibition of the pathway, while still achieving a near-zero drug trough to allow the drug to clear the system and reset the pathway each day, a process we call deep cyclic inhibition. So our approach aims for every day to be a drug holiday for the healthy cells, and every day to be judgment day for the tumor. IMM-1-104 has demonstrated preclinical activity with strong tumor growth inhibition in each animal model we have tested, including KRAS-G12C, KRAS-G12F, KRAS-G12D, KRAS-G12V, as well as NRAS mutant animal models. And as I said earlier, we can now also say approximately 85% of the 75 RAS-mutant models we tested in our humanized 3D tumor growth assays responded to IMM-1-104. This positions IMM-1-104 to be the first and only MAP kinase pathway inhibitor with the potential for universal-RAS activity. Achieving that in humans depends on good tolerability with a short half life and a high CMAX. And that’s why the PK and safety data we expect to share in mid-2023 is so important. If IMM-1-104 achieves in humans, and things like what we have observed preclinically, I believe, it has the potential to be truly game changing for large numbers of cancer patients in the near-term. This is also a serious responsibility, and it requires our full focus and our undivided attention. So we have made a decision to suspend our early stage neuroscience program and focus ongoing development activities solely in oncology. Suspension of our neuroscience program, as well as other non-core adjustments, extends our projected cash runway by one quarter into the fourth quarter of 2024, which is reflected in the updated runway guidance we have provided today. The oncology pipeline, which is now our sole focus, started less than 5 years ago as a research project by an extraordinary consultant named Brett Hall, who subsequently became our Chief Scientific Officer. Let me now turn the call over to Brett to say a few words about our unique approach and our latest data.

Thank you, Ben. I’d like to start off by highlighting a key factor that we believe truly differentiates Immuneering from other biotech companies in the oncology space. Our aim is to develop drugs for larger patient population using translational bioinformatics and humanized 3D tumor growth assays. We believe this approach enables us to design drug candidates with distinguishing features that select for a favorable activity and toxicity profile. One example of this application is the pharmacokinetics and target gate engagement of our lead asset IMM-1-104. IMM-1-104 was designed to have a short half life that can lead to many full higher drug free fraction, while still achieving near-zero drug trial. We believe this profile enables deep cyclic pathway inhibition. We also designed IMM-1-104 to overcome resistance from CRAF-bypass. We said that we project approximately a 2-hour half-life in humans, which is much shorter when compared to other MEK inhibitors in the space that have up to multi-day half-lives. Our preclinical data suggests potential for robust activity in pancreatic cancer, melanoma, non-small cell lung cancer, colorectal cancer, and other solid tumors with RAS-mutant disease. Using humanized 3D tumor growth assays followed by select in vivo studies, we have identified NRAS-driven melanoma in KRAS-driven pancreatic cancer has two potential high priority indications that we believe are both largely unaddressed and may be broadly sensitive to IMM-1-104. But as Ben mentioned earlier, we have reported on 132 tumor models that span over a dozen tumor types with various mutational profiles. And we observed brought activity in 64 out of the 75 models, or approximately 85% that display mutant RAS. And there was no specific RAS mutation where we didn’t see potential activity. Additionally, our translational research team is further evaluating KRAS mutant lung cancer and KRAS mutant colorectal cancer to identify biomarkers that enrich for highest potential for monotherapy response. In 2022, Immuneering presented 3 abstracts on 2 programs: 2 at the American Society of Clinical Oncology, or ASCO, in May of 2022; and 1 at the SITC Annual Meeting in November of 2022. The first abstract, a head-to-head comparison of IMM-1-104 versus sotorasib or adagrasib in KRAS mutant pancreatic cancer demonstrated lack of tumor growth inhibition by both sotorasib and adagrasib in the KRAS-G12V mutant Capan-2 pancreatic ductal adenocarcinoma tumor model. In contrast, IMM-1-104 observed tumor growth inhibitions of 49% to 84% across all doses and schedules tested consistent with other IMM-1-104 in vivo studies, median body weight was no more than 3% to 6% at the top doses. The second abstract we presented at ASCO found KRAS mutant pancreatic cancer and NRAS mutant melanoma were the most broadly sensitive to IMM-1-104 in patient aligned 3D human tumor growth assays, and thus are included among the expected target indications for Immuneering Phase 1/2a clinical trial. Finally, the third abstract presented at SITC highlighted the preclinical activity of our second pipeline asset, IMM-6-415 as a single agent, as well as a combination therapy with checkpoint inhibitors in RAS-mutant colorectal cancer and non-small cell lung cancer models driven by diverse MAP kinase pathway mutation. IMM-6-415, in combination with immuno-oncology agents may have the potential to overcome resistance in the MAP kinase pathway, and to provide deeper and more durable responses. We expect to file the IND with the FDA for IMM-6-415 in the fourth quarter of 2023. As Ben mentioned, for IMM-1-104, we expect to share initial Phase 1 pharmacokinetic and safety data in mid-2023. With that, I’ll turn the call over to Scott to share an update on our Phase 1 clinical trial program.

Thank you, Brett. Just before you do that, if I could just say that Scott joined our team in 2019, and at the time, everyone said, why do you need a Chief Medical Officer, when you’re a few years from the clinic? And we said 2 reasons. We want a clinicians’ perspective in our preclinical development, and so we can lay all the groundwork to really hit the ground running in Phase 1. And I’m really proud of what a great team Scott has built and the great job they’ve done getting our trial up and running. So with that, over to you, Scott.

Thank you, Brett and Ben. I’m delighted about the progress that we’re making in our first in human clinical trial, evaluating IMM-1-104 in a Phase 1/2a open-label study, designed to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy. IMM-1-104 is administered as a once-daily oral monotherapy for adult cancer patients with RAS-mutated solid tumors in an advanced setting and/or trial requires that they’ve already failed at least one line of systemic standard-of-care treatment. This Phase 1 open-label study utilizes a Bayesian mTPI-2 escalation design for IMM-1-104. This includes a dose escalation phase and a dose evaluation phase in order to evaluate safety and establish an optimized Recommended Phase 2 Dose or RP2D candidate in mid-2024. This is expected to segue into a Phase 2a dose expansion and approximately 160 total patients in 4 parallel cohorts, which independently evaluate monotherapy treatment effects in RAS-mutated melanoma, pancreatic cancer, non-small cell lung cancer and colorectal cancer. The primary endpoint of the Phase 2 trial will be response rate that’s defined by objective radiographic response assessment, measured by radiographic imaging changes from pre-treatment baseline. This is first observed for each patient at 2 months, and continues every 8 weeks thereafter for patients receiving benefit from study drug for up to 48 weeks of treatment. Overall, we’ve received great enthusiasm from our investigators across 5 clinical sites in the United States, who are all eager to enroll patients as soon as possible. In fact, we have a robust waitlist for patients. Our Phase 1 program is now open to all comers with evidence of any RAS mutation, including KRAS, NRAS and HRAS as IMM-1-104 has been designed to be broadly active in tumors addicted to MAP kinase pathway signaling. In November 2022, we successfully dosed our first patients in the trial. For the time being, that’s all we’ve disclosed, but I expect that much more to say in the coming months as we begin to share data from the trial has been as laid out in today’s guidance. So with that, I’ll turn the call over to Mallory to cover our fourth quarter and full year financial.

Thank you, Scott. In addition to the financial results summarized in our press release we issued earlier today, I will share some key financial highlights on this call. You can also find additional information in our Form 10-K that was also issued earlier today. As of December 31, 2022, our cash, cash equivalents and marketable securities were $105.5 million, compared with $150.2 million as of December 31, 2021. Operating expenses for the fourth quarter of 2022 were $14 million compared with $11.1 million for the fourth quarter of 2021. Full year 2022 operating expenses were $51.9 million, compared to $34.8 million for full year 2021. The increase in total operating expenses in 2022 was primarily due to the advancement of IMM-1-104 through IND and into our Phase 1/2a clinical trial, as well as employee-related costs due to increase headcount. Net loss attributable to common stockholders was $13.2 million for the quarter ended December 31, 2022 compared to $10.8 million for the quarter ended December 31, 2021. Net loss attributable to common stockholders for full year 2022 was $50.5 million, compared to $33.5 million for the full year 2021. As of February 27, 2023, we have 26,436,109 shares outstanding. In terms of our cash runway, management expects our cash, cash equivalents and marketable securities to be sufficient to fund operations into the fourth quarter of 2024. That concludes the financial update. And I’ll now turn the call back over to Ben.

Thank you, Mallory. Mallory and her team are doing a phenomenal job, and we’re very lucky to have them. Let me wrap things up by saying that nobody should be dying of cancer in 2023. I’ll say that again, nobody should be dying of cancer in 2023. Cancer doesn’t work by magic, not some paranormal force. It operates by a set of biological mechanisms that are actually well understood. It’s just really good at hiding among the healthy cells, and it essentially hijacked the person’s body and take them hostage. The challenge is, how do you kill the hijackers with less risk to the hostages? How do you achieve a therapeutic index? And today, companies have either gone narrow by targeting a single mutation such as KRAS-G12C, or they’ve gone broad, but in a way that hits wild-type RAS in healthy cells. At Immuneering, we believe it’s time to go broad. We believe that deep cyclic inhibition represents a fundamentally new way of focusing the activity against the malignant cells of taking out the hijackers with less risk to the hostages. It’s time to make medicine with the potential for universal-RAS activity. In the past 24 hours, we’ve released new preclinical data we’ll be showing an AACR targeting RAS this week, which is a curative force in demonstrating the universal RAS activity of IMM-1-104 in preclinical models, and our clinical trials moving forward rapidly, because our enrollment criteria are truly universal-RAS, and soon it will be time to share data showing how that deep cyclic inhibition is playing out in humans. We believe 2023 is shaping up to be Immuneering breakout year, and we aspire to make 2023 a year that marks an important turning point in the battle against cancer. With that, I’d like to thank all of our patients, clinical investigators, and stakeholders for their continued support of Immuneering. And I look forward to updating you all in the coming months on our progress towards our goal of a universal-RAS therapy for cancer patients. I will now open the call up for questions. Operator?

[Operator Instructions] Our first question comes from the line of Swapnil Malekar from Piper Sandler.

Thank you for taking my questions. I have a couple of them. First one is can you comment on how many patients have been dosed in the 104 trials so far? And what is the extent of the data that will be presented in the mid-2023 update?

Hey, Swapnil, thanks for the question. We’re really pleased with the progress of the trial. And, I think we provided very detailed guidance today, probably more granular than many companies often do. And, we’re really excited to share the initial PK and safety data in mid-2023 and the rest of the data as we’ve outlined.

Got it. Okay. And then I have one follow-up. So regarding the AACR poster tomorrow, what additional data does the poster include that has not been previously presented? And from this new preclinical study, are you seeing any specific trends related to tumor types or mutation status that could inform your ongoing clinical trial in terms of patient selection? Thank you for taking my questions.

Sure. Thanks, Swapnil. I’ll hand it over to Brett in a second to see if there’s anything he wants to add. But, the poster is available already on our website. And, I think, one of the key takeaways from the poster is really the universal-RAS activity that we’re seeing the fact that about 85% of the cell lines that we tested with RAS mutations in the humanized 3D tumor growth assay are really responsive to IMM-1-104. And there’s really no mutation that’s not responsive, right? Every mutation has at least one model within, that’s responsive. But let me see if there’s anything Brett would like to add there.

Thanks, Ben. And, hey, Swapnil. Yeah, I would add that the poster is really a deep-dive into a broad panel of tumor models that we’ve evaluated that have RAS and other MAP kinase pathway and non-MAP kinase pathway driven mutations. And it really is a deep-look or a deep-dive into our core platform are humanized 3D tumor growth assay platform that we’ve used and have vetted additionally with in vivo studies on the back end. So including those that we’ve discussed before like MIA PaCa, A549, SK-MEL-2, and others, have all basically been vetted both in the 3D-TGA as well as in vivo.

So it just really – thank you, Brett. Yeah. So Swapnil, it’s just really broaden the scope of models that we’ve released publicly. And I think all of this contributes to the really the universal-RAS activity that we’ve seen preclinically and, frankly, supports the enrollment criteria for our clinical trial, which is truly open to patients with any mutation in KRAS, NRAS or HRAS. So, with that, thanks for your question, Swapnil.

Thank you. One moment for our next question. Our next question comes from the line of Michael Yee from Jefferies.

Hi, guys, this is Tina [ph] on from Mike, I just had a couple of quick questions, and congrats again on the progress. What doses are you using right now to dose escalate? And are the low doses that you’re starting at therapeutic at all, where we could potentially see responses in that mid-2023, or second half update? I know, you just only said that you would be seeing or sharing PK/PD and safety data, but just wondering if there is a potential for efficacy data or those response that I would see there. And, I guess, another thing, if you could just share some more color on the PD modeling that you are planning to share in the second half? What does that entail? And what type of biomarkers that you’re really looking to share there? Thank you.

Sure. Yeah. Thanks for the question. I can take the first part, and I’ll maybe hand it over to Brett to speak a bit to the second part. But, again, we’re really pleased with the progress of the trial. And, I think, we’ve provided some really granular guidance today that should hopefully be helpful in really knowing when we’re going to share data. So, I think, that’s really what I’d say about the trial. And then, Brett, maybe you want to speak to some color on the PD model?

Yeah, absolutely, happy to. So we’re looking at 2 orthogonal pharmacodynamic assays. One is an induction-based assay, PBMCs, and the other is oncogene driven PD assay, where we’re looking at reduction from baseline of a KRAS-driven model. And so the key thing that we’re looking for there, of course, is attenuation of the MAP kinase pathway at the level of MEK inhibitor [ph]. I believe that was my question. I’ll turn it back to you, Ben.

Yeah. Thank you. I guess, just a quick follow-up on safety. I know you guys are going to be sharing a lot of that data this year. Given that it’s like a cyclical MEK inhibition. What kind of tox profile are you guys looking to see that kind of gives you confidence around the hypothesis of cyclical inhibition, if you don’t mind?

Yeah. Thank you. So, yeah, I mean, look, the tolerability that we’ve seen in preclinical models has been really quite good. So, we’ve described that across the multiple animal studies that we’ve run each of which have shown very strong tumor growth inhibition in different models with different mutations in the RAS pathway in each of those we’ve seen very little body weight loss and no more than 3% to 6% body weight loss, so really good tolerability. And I think that during my comments is really kind of the key thing and, I think, seeing a single short half life is really important to that as well, right. I mean, I think that’s fundamental to the deep cyclic inhibition mechanism is seeing the short half life, seeing the high CMAX, manyfold higher CMAX, and so these are some of the things. But let me just – let me see if Brett wants to add anything there.

No, I think you covered a lot, Ben.

Okay. Thanks again for that question. Let’s take the next one.

Thank you. One moment for our next question. Our next question comes from the line of Yaron Werber from Cowen.

Hi, this is Joyce [ph] on for Yaron. Thanks for taking our question. Maybe just a couple on IMM-6-415. What additional preclinical data are you collecting right now? How are you thinking about your clinical development program and the potential design of a Phase 1 trial? And how are you thinking about selection of focused tumor types versus what are you doing for IMM-1-104? Thanks.

Yeah. Thanks, Joyce. And we look forward to seeing you at your conference tomorrow. So, yeah, I mean, we’re really excited about IMM-6-415 is on track to file the IND by the end of this year. And, just as we’re calling IMM-1-104, the universal-RAS program, we’re actually calling 415, a universal MAPK program. And that’s because we – really, one of the key differences is that 6415 has a shorter halfway. So we project that it’ll end up being the idea [ph] or twice a day in humans versus 104, which is, of course, once a day. And so, we think that just kind of like tuning the dial on old-fashioned radio tunes in a different station with a different frequency, we think that different cadence will be optimized for unique biology. And we showed in our in our SITC poster late last year, responses as a monotherapy, in RAS and RAS-mutant disease. So they’re the universal-MAPK as well as in combination with immune-oncology agents. But, I think, you can expect the clinical trials to really be focused initially on monotherapy that’s really our initial focus, given the really nice data that we’re seeing as a monotherapy. It’s obviously a much clearer path to start as monotherapy. And I think therapies that can do that, too. So we’re certainly excited to pursue it as a monotherapy. And the rest of the trial design, we’ll talk about in due course. So let me see, Scott, did I miss anything on the 415 design?

Well, it’s a work in progress. We’re evolving it. But, obviously, the objective is to integrate multiple aspects of the MAP kinase pathway, and that will include RAS and RAS-driven disease.

Thank you, Scott.

Okay. Thanks.

Okay. Thanks, Joyce. Next question, please.

Thank you. One moment for our next question. Our next question comes from the line of Jeff Hung from Morgan Stanley.

Thanks for taking my questions. I have two on this week’s AACR data. You indicated that no particular mutation physician or amino acid substitution was exclusively found to convert resistance to drug exposure. So based on what you’ve seen, which mutations do you expect to be particularly challenging or relatively easier to treat? And then I have a follow-up?

Sure. Hey, Jeff, thanks for the question. They’re all universal-RAS means universal-RAS, we’ve not seen any difference really among the different mutations at different positions in P-KRAS, NRAS or HRAS in terms of sensitivity or resistance to 104. And, I think that makes sense in that we target MEK, so we’re targeting downstream of RAS. So it’s logical that we sort of be agnostic to the specific mutations, where we do start to see differences in responses, it really has to do with the mutations and other parallel pathways unrelated to MAP kinase. So, for instance, we’ve disclosed that in our Phase 2a in the colorectal cancer arm we plan to look specifically at APC wild-type patients, who are KRAS mutated. And that gives you a sense, for instance that APC mutation on a colorectal cancer model might be a little more challenging. But let me see if Brett wants to add anything to that. And then, we’ll take your second question.

Yeah, absolutely. Hi, Jeff. I would add – we’ve also discussed that really the drivers for resistance to 104 are not really the mutation profile upstream, whether that’s a BRAF or K RAS, HRAS, NRAS. It really has to do with the profile of mutations in a given model. And we’ve outlined this extensively, for example, in NRAS models, where NRAS mutation is something that sets up for utilization or addiction, but addiction is really defined by how many compensatory mutations in parallel pathways exist. And so the more of those events that you see, the lower likely of single-agent response to IMM-1-104, and that’s part of what’s the mapping exercise for the AACR targeting RAS poster really starts to get at.

Great. Thanks. And then the data were generated in 3D tumor growth assays, would you expect some more broad activity in rodent models in humans? Thanks.

Brett, do you want to speak to that?

Yeah, absolutely. Yeah, so we’ve actually also disclosed that. So, for example, when you look at the depth of sensitivity or response in the 3D-TGA, we’ve generally observed in the models that we’ve already published and disclosed on that the deeper responding models such as MIA PaCa-2, which is a KRAS-G12C pancreatic cancer model, as well as SK-MEL-2, which is a NRAS mutant melanoma model, which are highly sensitive in the 3D-TGA and actually show regressions or mid-cycle regressions in vivo. For those that have an intermediate response profile such as A549, which is a non-small cell lung cancer model that KRAS-G12S, as well as Capan-2, which is a pancreatic cancer G12V model, those have an intermediate response profile, and we see stable disease or flat lining the tumor, if you will, in vivo. And so, basically, when you start to look at the profiles and start to map out what those different response profiles are, and then compare them to also we disclosed on what we call upset plots, which are basically projections of the molecular characteristics that align with those models and patients, that you see the broadest single monotherapy response potential in KRAS pancreatic cancer, and then RAS melanoma. We also see very promising single agent monotherapy potential in KRAS mutant lung cancer as well as KRAS mutant colorectal cancer.

Thanks, Brett. And I would just emphasize, Jeff, this is a really unique and proprietary capability that we have. So the 3D tumor growth assays, this is a proprietary assay that we have up and running at our labs in San Diego. And we highly encourage everyone to schedule time to come visit those labs. We give a great tour. Second only to Disney Land in popularity in Southern California, but it really enabled us to very broadly assess the response profiles of different mutational profiles. And that proprietary view, I mean, 132, right, how many companies that have run 132 models on their lead program. And then that really ties in elegantly with all the deep informatics capabilities that we’ve developed over the last 15 years to create these plots that Brett described, where we’re actually projecting onto patient populations using real patient data to really identify and prioritize, which indications we think to kind of go after first. So, it’s really a – it’s a platform that I think is very unique to Immuneering that we’re quite proud of.

Great. Thanks so much.

Thank you, Jeff. Next question, please.

Thank you. One moment to our next question. Our next question comes from the line of Mark Breidenbach from Oppenheimer.

Hey, good afternoon. Thanks for taking our questions. This first one kind of goes back to something Ben mentioned, this is a drug that acts on MEK, which is of course downstream from RAS. I guess, I’m finding myself wondering why we should be at all surprised that activity you’re observing is independent of specific RAS mutations, shouldn’t that be the case for any MEK inhibitor? Or is there something different with this one? And the second question is just with regard to the timing of initiation of expansion cohorts. We’re talking about identifying a recommended Phase 2 dose by middle of next year, can we assume that’s a prerequisite before initiation of expansion cohorts? Thank you.

Hey, Mark. Thanks for the question. So, you’re right. In theory, MEK has always been a great target, right. But it really hasn’t lived up to its potential yet. And I think, really, that’s because the first generation MEK inhibitors really had 2 main challenges. Number one, they’ve been limited mainly to RAS-mutant disease. And, secondly, they’ve really been quite toxic, very, very poorly tolerated. And I think that’s really in part, because they’ve all been developed in this same old chronic inhibition paradigm, where you shutdown the pathway 24/7, you maintain chronic occupancy, you maintain a drug trial, you’d never let the drug – the level of drug get close to zero. And, again, the problem is healthy cells need the MAP kinase pathway to. And so, these first generation MEK inhibitors really just kind of harm or create challenges for the MAP kinase pathway and healthy cells. And so, I think that combined with the fact that they’re also all susceptible to a feedback loop, called CRAF-bypass that makes it really challenging to go after RAS-mutant disease. And so those were some of the design choices we made in creating 104. We gave it the ability to block CRAF-bypass. We gave it the ability to call them manyfold higher CMAX to really hit the tumor hard. And then we gave it a very short half life. So we’ve consistently said we projected 2-hour half life in humans. And the combination of those things gives us essentially the ability to hit the tumor hard, but then allow the pathway to reset, it really the idea that as I said earlier, every day is a drug holiday for the healthy cells, and yet every day is a judgment day for the tumor. And so, I think that’s really why we’ve been able to go after MEK in a unique way that we think certainly preclinically is really kind of living up to the full potential of MEK as a target. And you’re right, conceptually, MEK is a great target to really target any mutation in RAS and really achieve that kind of universal-RAS activity. Let me see if Brett wants to add anything on your first question, and then we can talk about the second question.

Yeah, just really quickly – Hi, Mark. So I would add the strength, our core thesis is that deep cyclic inhibition within novel engagement mechanism that prevents or resist the CRAF-bypass and other bypass mechanisms is critical. And, I think, here is where a good example of the existing MEK inhibitors their strength becomes their weakness, right. There’s 24/7 chronic inhibition sustainably induces these adaptive resistance mechanisms that basically is kind of like having a snowplow where the snow builds up in front of the plow and eventually just slows down the ability for that truck to be effective and remove snow, very similar with MEK inhibitors. And we can avoid that or reduce that significantly by the deep cyclic inhibition approach, where we reset the pathway every day, as well as the novel mechanistic engagement that actually resisted the build up in the first place. And, I think, those 2, the 1, 2 punch of deep cyclic inhibition with IMM-1-104 really stands apart from the other MEK inhibitors.

Okay. I guess, I’m also just wondering if you included any of the more conventional MEK inhibitors in your screen against humanized 3D tumor models, if you saw any sort of difference there.

Yeah, this is a good question. Yeah, so we haven’t guided on that at this point. But what we have actually run and we’ve already mentioned that we do see a nice read through of the 3D-TGA into in vivo. And we did publish, for example, in the head-to-head comparison of IMM-1-104 versus binimetinib in the NRAS Q61R SK-MEL-2 model, where we saw a mid-cycle regressions with 104, but really very minimal to no effect with full dose binimetinib.

Okay. Great. And then with respect to the timing on expansion cohorts?

Yeah, thanks for that second question, Mark. So, given that that RP2D stands for Recommended Phase 2 Dose, I’ll ask Scott to confirm this with his decades of clinical experience. But I think it’d be hard to start the Phase 2 until we have the recommended Phase 2 dose.

I think Mark is asking in the spirit – can you hear me?

Yes. We can.

Right. In the spirit of dose optimization, we’re proactively volunteering to have a dose evaluation phase, where we’re calling internally Phase 1b. And so, we’ll come up with candidate dose or dose, RP2 dose candidates, and then evaluate them further to make sure that we’ve selected the definitive one before we start Phase 2a. So, yes, in answer to your question, Mark, we plan to complete dose escalation before we formally evaluate 2 or more dose candidates.

Got it. Thank you.

Thanks. That’s a great point. And I first heard about the project optimists from Scott and his team, years before it sort of got the popular and gained a lot of prominence and attention. So we’ve been very, very focused on that from the early days. But thanks, again, Mark, for your questions. And let’s go on to the next question, please.

Thank you. One moment for next question. Our last question comes from the line of Michael Schmidt from Guggenheim Partners.

Hey, guys, thanks for taking my question. Just maybe a quick follow-up on the Phase 1 study. Based on the enrollment criteria, what tumor histologies would you expect to enroll predominantly? And based on that, as we think ahead towards you reaching more efficacious or higher doses in the study, where would you expect to see early clinical activity? Thanks so much.

Hey, Michael, thanks for thanks for the questions. And last, but certainly not least, so appreciate the question. And yeah, look, I mean, our phase 1 enrollment criteria is quite broad, right? It’s truly universal-RAS, any solid tumor patient with any mutation in KRAS, NRAS or HRAS is eligible to be screened. So we’re not requiring or specifying particular tumor type as part of the Phase 1. However, as you know, we’ve identified, what we believe are the most likely Phase 2a areas for dose expansion. And that’s based on the use of these humanized 3D tumor growth assays and the informatics that we described earlier. And so all our clinical investigators are familiar with those data and, in fact, we’ve chosen our clinical sites, in part based on their expertise with those types of cancer. So, I think, you can expect – you might expect to see a bit a bit more of those in the trial. But again, we have – and I’ll hand over to Scott to comment. But again, we have very broad enrollment criteria to really kept a wide net. Scott, I don’t know if there’s anything you want to add there.

No. I think you covered it well. They’re all – the Phase 1 investigators are clinician scientists that we’re involved in our protocol developments and are very excited about the clinical proof-of-concept. And so, they’re basically actively looking to enrich for the tumor types that we built [our monotherapy put forward] [ph].

Okay. Thank you.

Great. Thanks, Michael.

Thank you. At this time, I would now like to turn the conference back over to Ben

Great. Thank you, operator, and thanks everyone for the great questions, and to everyone who is listening on the call. In the coming weeks, we plan to attend the Cowen and Oppenheimer Healthcare Investor Conferences, and we welcome your requests for meetings at these events or directly through us. Feel free to reach out to Gilmartin, if you’d like to schedule some time. With that, I would like to thank all of you for participating in today’s call, and wish you a good evening.