Welcome to the Immuneering conference call to discuss positive initial data from a Phase II-A arm studying IMM-1-104 in combination with modified gemcitabine and nab-paclitaxel. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ensure that we have ample time to address everyone's questions, we would ask each person to limit themselves to one question and one follow-up. As a reminder, this call is being recorded today, Thursday, September twelve, two thousand and twenty-four. I would now like to turn the conference call over to Lawrence Watts of New Street Investor Relations. Please go ahead. Thank you, operator. Joining us on the call today from Immuneering are Chief Executive Officer, Ben Zeskind, Chief Scientific Officer, Brett Hall, Chief Accounting Officer and Treasurer, Mallory Morales, E.B. Brakewood, our Chief Business Officer, and Dr. Alan Sandler, a consultant for us who recently served as the Chief Medical Officer of Mirati prior to the acquisition by BMS. During this call, management will make forward-looking statements, including statements related to its Phase II-A trial of IMM-1-104, particularly its arm studying IMM-1-104, in combination with modified gemcitabine nab-paclitaxel, as well as timing of additional data from the study and the company's development plans. Our actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. Factors that could cause these results to be different from these statements include factors the company describes in our annual report on Form 10-K, our quarterly reports on Form 10-Q. Immuneering undertakes no duty or obligation to update any forward-looking statements as a result of new information, future events, or changes in its expectations. With that, I will turn the call over to Ben Zeskind, Chief Executive Officer of Immuneering. Ben? Thank you, Lawrence. Good afternoon, everyone, and thank you for joining our conference call to discuss positive initial data from our Phase II-A arm studying IMM-1-104 in combination with modified gemcitabine and nab-paclitaxel. Please turn to slide two. As a reminder, I will be making forward-looking statements today, so please see our disclosures on slide two for more information. Please turn to slide three. Let me start by reminding you that Immuneering's mission is to help cancer patients live longer and feel better. To do that, we're working on therapeutics targeting the MAP kinase pathway. Over two hundred thousand cancer patients in the U.S. alone are estimated to have RAF or RAS-driven tumors, which are two of the genes in this pathway. But historically, inhibitors of RAF/RAS/MEK have faced tolerability issues and eventually stop working when the patients develop resistance. Our uniquely designed MEK inhibitors aim to do better. In Phase I, our lead candidate, IMM-1-104, showed an excellent safety and tolerability profile and clear activity against RAS mutant tumors, including pancreatic cancer, where there remains a high unmet need. Please turn to slide five. Our Phase II-A study is testing IMM-1-104 alone and in combination in a variety of tumor types across five different arms, with plans to share initial data from multiple arms in 2024. That sharing of initial data starts today, and I'm very excited to tell you what we have seen so far. Today, we're going to be sharing data from our combination arm in first-line pancreatic cancer, where patients were treated with IMM-1-104 and modified gemcitabine and nab-paclitaxel. Please turn to slide six. Now, before I share the initial data, I want to start by providing some context on the benchmarks that describe what would be expected for chemotherapy alone. The benchmark is really set by the Phase III MPACT trial, which evaluated unmodified gemcitabine and nab-paclitaxel, and where the overall response rate was 23%. Looking into that response rate, the vast majority were partial responses, with only one complete response out of the 431 patients in the study. Another 27% had stable disease, bringing the disease control rate to around 50%, with progression-free survival at about 5.5 months. On the back of these data, the drug combination became a standard of care treatment for pancreatic cancer for over 15 years, which it remains. It's important to note that in our combination arm, we're using a modified version of gemcitabine and nab-paclitaxel, which is a less intensive and much better-tolerated treatment administered every other week, as opposed to three weeks on and one week off for the unmodified version, and a published retrospective analysis shows that when modified gemcitabine and nab-paclitaxel are used to treat pancreatic cancer, the overall response rate is around 18.6%, with PFS and OS similar to the unmodified regimen. Treatment discontinuation is also significantly lower with this regimen compared to the unmodified version. This is why, although it remains very early in our study, we are so excited to share with you what we have seen so far in this pancreatic cancer combination arm. Please turn to slide seven. These are the initial results from the first five evaluable patients dosed with IMM-1-104 in combination with modified gemcitabine and nab-paclitaxel. What you can immediately see is that the first patient we dosed, the very first patient dosed in our Phase II-A trial, in fact, had a complete response at their first scan, and a response that has so far continued over the course of four scans. That patient has now been on treatment for over six months. As I mentioned earlier, complete responses are very rare in the pancreatic cancer setting, which is one of the reasons we're so excited to share these data with you today. But that's not all. The second patient in the study had shrinking lesions at the time of their first scan. The lesions then shrank a bit more at the second scan, and then by the third scan, the lesions had shrunk considerably more, down to minus 40% and an unconfirmed partial response. The next three patients in this arm are all much earlier in the course of their treatment, but what we saw was a minus 4% reduction for stable disease, a 6% increase for stable disease, and the third patient had a minus 9% reduction, but has been classified as equivocal progressive disease for reasons that we will discuss later. These five patients encompass a variety of different mutations and come from five different clinical trial sites across the country. All five of these patients remain on treatment, and we look forward to future scans for each of them. All five were also part of our safety lead-in and were dosed at two hundred and forty milligrams of IMM-1-104 once daily. We have now finished the lead-in portion with the Data and Safety Monitoring Board recently clearing us to dose patients at either 240 or 320 milligrams moving forward, and the first patients have recently been dosed at three hundred and twenty milligrams IMM-1-104 in combination with modified gemcitabine and nab-paclitaxel. In summary then, and we are aware it is very early days, we have so far seen an initial overall response rate of 40% and an initial disease control rate of 80%, both of which are significantly higher than the historical benchmarks I walked you through earlier. And this, plus the complete response, is why we're so encouraged. If these trends continue, we believe there is a clear path forward for the development of IMM-1-104 in combination with modified gemcitabine and nab-paclitaxel as a very well-tolerated treatment option for first-line pancreatic cancer patients, which could be a material improvement over the existing standard of care. Importantly, these data are consistent with preclinical data we presented at AACR in April, which demonstrated that combining IMM-1-104 with chemotherapies used in the treatment of first-line pancreatic cancer yielded deeper and more durable tumor growth inhibition than either treatment alone. Please turn to slide eight. On this next slide, we show the initial data from the combination arm in graphic form. We have a spider plot on the left, where you can see patient one with the complete response in blue at the bottom of the chart, and patient two with the partial response in purple. You can also see that the black line for patient five actually overlaps almost perfectly with the purple line for patient two, which suggests that both patients have a similar trajectory through the first scan, and then the two other patients in green and gray are relatively stable. And let me underscore, all of these five patients remain on treatment, and we look forward to seeing their future scans. On the right, we present the waterfall plot. Now, for those of you who aren't aware, CA19-9 is a common tumor marker for pancreatic cancer. Changes to the level at which it's detected can help determine if a patient's cancer is responding to treatment. Now, we only have CA19-9 measurements for two patients, but both of them demonstrate a substantial reduction, with the first dropping by more than half and the second seeing a drop of over 90%. So these are very encouraging signs for these patients where we have CA19-9 data, and again, all five patients remain on treatment. The gradually deepening response for patient two over time is noteworthy because it is consistent with our preclinical data, suggests a certain potential durability, and may bode well for the three patients who are earlier in the course of their treatment. Now, let me talk about the patient with equivocal progressive disease. This was a patient who was not dosed for over two of the planned six weeks of treatment due to hospitalization for a preexisting condition. The patient had ascites and a pleural effusion that radiology classified as equivocal progressive disease, but which the investigator believes is due to the recent placement of a hepatic stent and not disease progression. The investigator stated that the patient is improving and continues on therapy, so future scans will better define the patient's response to therapy. Finally, let me comment on the safety profile we are seeing for this combination. To date, IMM-1-104, in combination with modified gemcitabine and nab-paclitaxel, has been observed to be well-tolerated, an observation which is in line with the tolerability profiles for IMM-1-104 and modified gemcitabine and nab-paclitaxel alone. In summary, this is the first of multiple updates we plan to provide on arms in this trial. We believe it is timely in view of our Data and Safety Monitoring Board approving us to go to a higher dose in this arm and this being our most mature data set. Most importantly, given the encouraging results to date, we believe it is important for first-line pancreatic cancer patients and their oncologists to be aware of these emerging results as they consider their treatment options. Please turn to slide nine. In conclusion, we are encouraged by the initial data presented today, which suggests a clear development path forward for the combination of IMM-1-104, plus modified gemcitabine and nab-paclitaxel in first-line pancreatic cancer patients, if the trends we are seeing continue. When we reported our hase I data in March, we noted IMM-1-104's ability to shrink tumors in heavily pretreated pancreatic cancer patients, along with a safety and tolerability profile that lent itself to possible combination. Today's initial data supports that potential. We are actively considering a number of additional combination studies for additional patient populations in the future. We're obviously delighted to see that the first patient we dosed in this arm, and in the Phase II-A trial overall, was a complete response, and we're encouraged by the initial overall response rate of 40% and initial disease control rate of 80% as they currently stand, specifically in the context of benchmark data for the current standard of care for first-line pancreatic cancer. Let me also say that enrollment is progressing across all arms in our Phase II-A study, and we are aiming to provide initial data from at least one additional arm of the trial before year-end. Additionally, we look forward to providing further updates from this arm as it develops. With that, I will now open the call up for questions. Operator? Thank you. We will now begin the question-and-answer session. If you have dialed in and would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star one again. If you are called upon to ask your question and are listening via loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking your question. Again, press star one to join the queue. Your first question comes from the line of Michael Yee with Jefferies. Your line is open. Hey, guys, this is Matt on for Mike. Congrats on the update. Really exciting data. I wanted to ask if you could just speak to the overall enrollment progress across the entire Phase II study, and just help to guide us in terms of patient numbers and maybe cohorts and kind of what to expect in your next update this year. Thanks so much. Sure. Hi, Mike. Thanks for the question. So overall, we're, you know, we're pleased with enrollment across the full trial. As you know, the design of the trial includes 30 patients per arm in each of the five arms, and we've guided to sharing, you know, initial data from at least one additional arm by the end of the year. So, that's what you can expect. Got it. Thanks. Thank you. Next question, please. Your next question comes from the line of Jay Olson with Oppenheimer. Your line is open. Oh, hey, Ben. Congrats on these results, and thank you for providing this early, impressive look at the data. I guess we had a few questions. Maybe just to start with patient one, was there anything about their particular MAPK mutation variant that would have led you to predict they would have such a rapid and deep response to one oh four? Hey, Jay. Thanks for the question. Hope you're doing well. No, I mean, you know, I think the design of IMM-1-104, of course, is such that we're, you know, we're targeting lower down in the pathway at the level of MEK. So, you know, biologically, we really wouldn't necessarily expect that any particular mutation, whether it's that patient's mutation or, you know, other mutations, would really necessarily change how the patient responds, right? It's really just a function, we believe, to a large extent, on their the degree to which the lesions are addicted to the MAP kinase pathway. So nothing specific about that mutation that we necessarily would expect to be different. Okay, great. That's good to know. And then, I guess, is there anything from this promising early data that would impact your clinical development plans for 104, especially in the context of Project FrontRunner? Yeah, it's a great question, Jay. I think it's too early to comment on development plans, you know, given the initial nature of these data. We'll obviously keep everyone posted as our thinking on that evolves. But certainly, it's really encouraging. And as we've said, you know, we believe, if these initial results continue, that we'll have a very clear path forward for the development of one oh four in this combination for first-line pancreatic cancer patients. And certainly that's you know well aligned with the philosophy of Project FrontRunner. ... Okay. All right, excellent. And maybe one last multipart question. Can you just let us know the scope of data that we should expect at the end of the year in terms of the number of Phase II arms and patient numbers? Should we expect to see data from patients on the 320-milligram dose or from the combo arm? I'm sorry, the full FOLFIRINOX combo arm. And also, are you gonna be discussing these data with the FDA? Yeah, thanks, Jay. You know, certainly by the end of the year, we plan to share initial data from at least one additional arm of the study. So that's the, you know, that's really our plan, and we look forward to sharing it. And then certainly as to additional updates from this arm, we'll share them as the data warrants. Okay. And I presume as part of Project FrontRunner, this data will be discussed with the FDA? I'm not gonna comment specifically on our regulatory plans or interactions right now, but appreciate the question. Okay. All right. Well, totally understood. Thank you again for this impressive look at these data, and we'll stay tuned for future updates. Thanks for taking all the questions. Thank you, Jay. Always a pleasure. Next question, please. Next question comes from the line of Allison Bratzel with Piper Sandler. Your line is open. Hi, good afternoon. Congrats on this update, and thank you for taking the question. Maybe just kind of a broad question. You know, what gives you confidence that this, you know, promising response data you've seen in the first five patients can be repeated in a larger cohort? And just any thoughts on read-through from this and your earlier data that would speak to your confidence in monotherapy arms of the trial? Thank you. Yeah, thanks, Allison. Good to hear from you. Look, I mean, these are early but encouraging data, right? And we're certainly describing them as initial. But it's also true that complete responses in pancreatic cancer are rare, right? So I think that's the first thing. And then certainly to see, you know, to see that in our very first patient and then to have the very next patient, you know, follow the trajectory that we've seen and sort of all five patients remain on study, you know, we find very encouraging. It's encouraging relative to what you typically see for gemcitabine and nab-paclitaxel. So certainly early days, but we're very encouraged by what we're seeing. Next, next question. Next question comes from the line of Jeffrey Hung with Morgan Stanley. Your line is open. Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our questions, and congratulations on the initial Phase II-A results. Could you help to elaborate a little bit more on the safety profile you've observed thus far with one oh four in combination? Any evidence of, like, any grade rash, or, like, how would you expect, based on what you've seen at two forty milligrams to, like, what would you expect to see at the three twenty milligram dose on safety? Thank you. Yeah. Hey, Michael, thanks for the question. You know, the safety, as we said, you know, the combination was generally well tolerated and kind of in line with what you would expect from either therapy. So certainly no surprises there. So I think that's kind of the bottom line with regard to the safety here. Okay. And then, I guess maybe just taking a step back, from what you've seen with deep cyclic inhibition and thinking about the trajectory across patient scans, is there a reason to suggest or, like, to have rationale for a sudden uptick in efficacy? Like, why do you think patient number two really started to accelerate on clinical benefit after the twelve-week mark? Yeah, that's a great question. You know, it's, look, it's consistent with what we've seen preclinically, right? We've certainly had preclinical models where you know, where we see kind of mid-cycle regressions or kind of later onset. So it's you know, it's consistent with what we've seen preclinically and frankly, consistent with mechanism, right, in terms of how we would expect this to work. So we you know, we find it encouraging in general and particularly encouraging given also what we've seen so far with those other three patients who are earlier on. Perfect. That's very helpful. Thanks, and congrats again on the initial data. Thank you. Next question, please. Next question comes from the line of Ami Fadia with Needham. Your line is open. Thank you. Good afternoon, Ben and team. Congrats on the really interesting initial data. I had a couple of questions. Firstly- ... if you could talk about, sort of the screening process into this trial. I noticed that one of the five patients did not have a MAP kinase mutation, and so I'm just wondering, are you enrolling all comers into the trial, or are there some patients that are not or that are being excluded from the study during the screening process? Yeah. Hey, hey, Ami. Great, great question. So, in Phase II-A, we opened up pancreatic cancer to patients with any mutation. You know, we no longer restricted it to RAS mutation. And we did that because about 97% of pancreatic cancers are dependent on the MAP kinase pathway. So it, you know, given the broad activity that we see preclinically with one oh four, really regardless of the specific mutation that's driving MAP kinase pathway activation, we felt comfortable doing that. And, you know, I think we're all glad we did, because certainly GNAS is an example of a mutation that activates the MAP kinase pathway, but is not RAS. You know, it's, we think it was the right decision. Mm-hmm. And would it be fair to assume that the mutations that you've cited for these patients are the only mutations that were identified for those patients? And if you could give me a sense of what% of pancreatic cancer patients have the GNAS mutation, or GNAS mutation? Shreya, could you repeat the first part of the question? I'm sorry, I missed the first part of it. The first part was just to clarify if these were the only mutations that were found, or were there any other mutations that these patients were carrying? Oh, yeah, I mean, these are not the, you know, and maybe I can ask Brett to comment on that a little bit further, but you know, we have ctDNA for all these patients, so it's not the mutation we report in the table. The mutation we report in the table is not necessarily the only mutation that that patient had. Brett, I don't know if you want to comment further on that. Yeah. Hi, hi, Ami. Yeah, so it's a great question. With in on slide seven, we show that there are multiple sources, right, for basically determination of the MAP kinase variant that was found. We're not reporting all non-MAP kinase pathway variants, but we're reporting the ones that were found for MAP kinase variant. And there's one other caveat. Since we're evaluating circulating tumor DNA, just because a mutation isn't detected in the systemic circulation doesn't mean the tumor harbors it, it just doesn't shed it. But these are the ones we did identify. Got it. Okay, and I'll ask one last question. Based on your preclinical data, how do you anticipate, or what did you see in terms of response differences between the 240 and the 320 milligram doses? Thank you. Yeah, thanks, Ami. I'll take a first pass at that, and then maybe Brett wants to weigh in. But, you know, we certainly saw even, yes, frequently, but even clinically in the Phase I, we saw lesions shrinking at both two forty and at three twenty. So, you know, certainly these are, we believe these are both active doses. But Brett, I don't know if you want to comment further. Yeah. I'd add is that at three hundred and twenty milligrams, we have a broader population, full DCI Deep Cyclic Inhibition profile. But as has been mentioned, we have really good Deep Cyclic Inhibition profiles in most patients at two forty and three twenty. There's a slight edge to three twenty from a overall greater population basis. Thank you so much. Thanks, Ami. Next question. Next question comes from the line of Graig Suvannavejh with Mizuho. Your line is open. Hi, team. Congratulations on the data. Very exciting. Maybe a couple on my end. I guess on the topic of mutations, any color on when we'll get the additional data just in terms of the ctDNA and data for acquired alterations in RAS to see the consistency between the phase one we're seeing and the Phase I trial? Yeah. Hey, Graig. Thanks. That's an excellent question. We obviously don't have that for you today, but I believe it's generally been consistent with what we saw previously. Yeah. Got it. Thank you. And- And a little- Oh, go ahead. Yeah. So just one other note on that is that we are collecting ctDNA, circulating tumor DNA, and evaluating the baseline one month in to get an initial kind of trajectory, and then end of treatment. And the end of treatment will probably best answer your question, and we haven't gotten to end of treatment on any of the patients yet. Got it. Thank you. Yeah. Maybe I just- That's a great point. Yeah, thanks. Thanks for clarifying, Brett. Yeah, yeah, I don't. For these particular patients, I don't, I think it's just too early to say. I was speaking more generally, that that's a trend that's generally continuing. Thanks for clarifying, Brett. Got it. And maybe- Go ahead, Graig. You had another question? Yeah. There are no further questions at this time, and with that, I hand the call over to Mr. Ben Zeskind. Okay, well, thank you very much. I wanna thank everyone for joining our call today. We're delighted to share response data for IMM-1-104 in combination with modified gemcitabine and nab-paclitaxel for first-line pancreatic cancer patients. We'd like to thank all the patients and investigators involved in our ongoing study, and we look forward to providing additional updates in the near future. Thank you, everyone. This concludes today's conference call. You may now disconnect.