Immuneering Corporation (IMRX) Earnings Call Transcript & Summary

Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Immuneering with CEO, Ben Zeskind. Welcome.

Thank you, Jeff.

So for those who may not be as familiar with Immuneering, can you just provide a brief introduction?

Sure, happy to. First, I want to thank you and the entire Morgan Stanley team for having us here today. I want to thank everybody listening both here in the room and online. And just to remind everyone we'll be making forward-looking statements, so please see our disclosures for more information. But since you asked about the background of the company, I'll start with some backward-looking statements going all the way back to 16 years ago, which is when we started the company. And really, we started it with the belief that every cancer patient deserves a durable complete response. And that's not the -- it wasn't the case 16 years ago, and it's still not the case today, right? That still sounds like a very ambitious goal. And the question is why, right? Why is it that most cancer medicines eventually stop working. And we spent a decade doing informatics work, trying to understand questions like that. And I think it's fair to say that cancer is very well understood at this point, right? There's not a lot of mysteries to cancer. It's not some paranormal force. But the reason it's been hard, I think, generally to make cancer drugs that keep working is really to -- cancer is not -- it's not that smart, but it has 2 kind of tricks, right? Number one is it's very good at hiding among healthy cells, right? It's a very subtle change to a healthy cell. And that means that most drugs when you try to target cancer cells, you end up harming a lot of healthy cells as well. And it's that -- that's made it tough. And then the second thing is it's just very adaptable, right? If cancer is driving down the highway and you block all the lanes of the highway, it's going to pull over, get out of the car, go to a train station and take the train, right? It will find another pathway. It has a high mutation rate. That's one of the hallmarks of cancer. So cancer has this adaptability that's made it hard, particularly when drugs try to narrowly target it. So really what we did when we started developing our pipeline was we set out to try to address those 2 things in a new way and a unique way, right? How do you selectively target the malignant cells relative to the healthy ones in a unique way? And then how do you go broad? How do you sort of make it so it's harder for cancer to get around even with its high mutation rate? And so those were some of the goals as we started to develop our pipeline of which IMM-1-104 is the lead program.

Great. Let's start with that. You announced top line Phase I results early this year. Can you just remind us what you saw?

Sure. Yes. And that was in March of this year. And the first thing we saw is that 104 was well tolerated. Look, this is the endpoint, right. Phase I, this is the goal, the endpoint of the study. And it wasn't just well tolerated. We believe it was uniquely well tolerated. I think if you compare it certainly to prior MEK inhibitors, but even really to anything that's out there for the MAP kinase pathway, the tolerability profile was quite attractive. So the table that we shared in March, right, it's the typical table of treatment-related adverse events that occur in more than 10% of the patients. There was one single grade 3 on the table, which is a rash that resolved with topical cream. You can count on one hand the number of grade 2s in the table and a modest number of grade 1s as well. So if you look at, say, any grade rash, it was around 15%, which compares, I think, very favorably against anything that's out there. And look, tolerability isn't just about patients feeling better, I mean that's obviously an attractive feature of it. But the key thing that makes tolerability so important is it's linked to combinability, right? And I think we all appreciate most cancer drugs are ultimately used in combination and the thing that limits the ability of most drugs to be used in combination is tolerability. So the tolerability that we showed, we believe, unlocks a huge number of opportunities for combination. So that's the first thing we showed. The second thing we showed was in the ctDNA data, particularly in the acquired alterations, right? So what this data shows you is how a cancer is getting around the drug, right? And this gets back to that ability I talked about earlier of cancer to adapt if the highway is blocked to take a train, right? So you look at that through acquired alteration data, which is sort of in the circulating tumor DNA, it's new mutations or CNVs that arise during the course of treatment. And several companies have published very informative studies of this -- these acquired alterations, particularly in response to G12C inhibitors. And with G12C inhibition, you're basically blocking one lane of the MAP kinase highway. And so that -- it helps, right? If you block a lane on the highway, you're going to get in a traffic jam. But eventually, the tumor kind of gets to that blockage and it switches lanes, it goes around it and what these companies saw and published was that with the G12C inhibitors, the tumors would acquire alterations and other KRAS mutations, KRAS-G12D or G12V or they'd get an NRAS mutation or BRAF mutation. And these were the ways that tumors were getting around the G12C inhibitors. So the acquired alteration data that we shared in March showed not one single acquired alteration in any RAS gene. So what does that tell? It tells us that we're effectively blocking all the lanes of the highway. There's no mutation in RAS that a tumor was able to use to get around 104. So that certainly was very encouraging from this goal we have of sort of going broad, right, being able to block a wide range of mutations, certainly the MAP kinase pathway. Now what we did see in that -- in those data were quite alterations in other pathways unrelated to the MAP kinase pathway. And so what that told us is the tumors are being -- they couldn't change lanes on the highway. They had to do when I said -- they had to pull off the highway and get out and go to the train station and use an entirely different pathway to try to get around 104. So I think that was encouraging and that we are achieving this goal of sort of having the broad activity across the MAP kinase pathway. We've blocked all the lanes of the highway. And then we saw one other thing, too, which we talked about, which is shrinking lesions, right? Even in this early study, where the primary endpoints were around safety and tolerability, we saw shrinking lesions in about half the patients, even though most of them were pancreatic cancer and most of them were in the later-line setting. So -- and I think everyone appreciates pancreatic cancer lesions don't generally shrink on their own, let alone by 35%, which is what we shared in that March update.

Can you talk a little bit more on that last point? Did the magnitude of the lesion regressions, do they vary by indication?

It's a good question. We didn't -- as we talked about it at the time in March, the majority of the patients on the Phase I or pancreatic cancer patients, more than 60%. So I don't think we have the numbers in other cancers to really draw conclusions around that. But certainly, encouraging to see multiple -- lesions in multiple patients shrinking by 1/3 or more that was encouraging. And look, that was in March, and we look forward to providing additional updates in the future.

And then maybe a follow-up question on your prior analogy and question in terms of the tumors basically getting off the highway and going to the train station. So with those acquired alterations and what you saw, what effect do those compensatory pathways have on the ultimate tumor regressions that you saw? And then how do you think about the fact that yes, 104 is forcing the tumor to change its methods, but then you can maybe just talk a little bit more about how you're thinking about all of that?

Yes. No, that's a great question. And look, it's important, right? Because in these patients who are in the later line setting, that probably limited the kind of the scale of the aggressions that we saw, we believe. And why was that? Well, we believe one of the reasons is in this later line pancreatic cancer setting, the patients have been through multiple rounds of chemotherapy. And chemotherapy itself is mutagenic, particularly FOLFIRINOX, which is one of the standard of care chemotherapies in pancreatic cancer, causes mutations, right? So it's essentially the -- when you have patients who have been through multiple lines of immunogenetic chemotherapy, you're -- they're sort of -- you're buying them train tickets and ferry tickets and a trip to the airport. It's creating additional ways for the tumors to get around. And so what we said in March is the design of the Phase IIa is very different. First of all, response is an endpoint. So it's designed to look at this. But we're moving into earlier line patients. We've been through fewer rounds of immunogenic chemotherapy. And then we're also in 2 of the arms of the Phase IIa combining with sort of standard of care agents. And I think that's a big difference that helps, we believe, to sort of block those -- block the trains, block the ferries, block the train station.

And how does the MAP kinase pathway dependent? How does that vary across indications or lines of therapy? And I guess, where do you see the best opportunity for your approach?

Sure. Yes. Look, I mean, we're excited about all 5 arms of the Phase IIa for various reasons. I think it's the -- certainly, the earlier you are in treatment, we believe the more dependence there is on the MAP kinase pathway. So I think that's important. One thing that I think was important and underappreciated was our AACR data that we shared in April. So here, in an animal model of pancreatic cancer, what we showed is that the standard of care chemotherapies do a reasonable job of slowing tumor growth, 104 does a better job on its own. But when you combine the 2 of them, you see a very strong tumor growth inhibition that's very durable in these animal models. And we had in the AACR poster as well, the kind of the molecular underpinnings for that, right, which is that the pathways that -- every drug has pathways that the tumors used to get around it, right? So the pathways that tumors use to get around chemotherapy were being blocked by 104 and the pathways of the tumors were using to get on 104 were being blocked by the chemotherapy again in this animal study. So particularly, the gemcitabine-paclitaxel data was just really a very nice flat line in that animal data. And we said at the time, and it's the case today -- I mean, that's one of the arms of our Phase IIa that's active. So yes.

Now in the past, you talked about your interest in colorectal cancer for 104 such as in combination. Are you still planning to pursue colorectal in the Phase IIa? And maybe you could talk about your interest in that indication.

Yes, absolutely. So it's not one of the arms of the Phase IIa right now, but we certainly remain very interested in colorectal cancer, particularly -- so what our preclinical data shows in colorectal cancer and we shared this previously is combinations there are really sort of the optimal approach. So we absolutely believe 104 ultimately has great potential in colorectal cancer as a combination therapy. But with the Phase IIa, you sort of only -- you only have so many arms and so many resources to pursue. So we selected the 5 arms that we did as higher priorities.

And you talked a little bit about combinations with 104, but maybe if I can just dig into that a little bit and ask a couple of questions. So you've talked about different types of combinations such as vertical immune-modifying, orthogonal mechanisms of action. So how do you think about different types of combinations? What magnitude of improvement would you expect to see with each? And how are you prioritizing combination development?

Yes. Great question. I mean the -- as you know, our Phase IIa has 2 arms that are in combination, both in first-line pancreatic cancer patients with standard of care chemotherapies, ones with gemcitabine and nab-paclitaxel, the others with FOLFIRINOX. So clearly those -- we have prioritized as the top priority combinations given that we're already testing them clinically. But we have encouraging animal data with quite a few other combinations. You alluded to some of them, between 104 and 415 our other program, we have encouraging data with immuno-oncology agents, with G12C inhibitors, with RAS inhibitors. So there's really quite a few possibilities the animal data is telling us have potential and warrant further exploration. But I think it bears repeating that the reason we believe we'll ultimately have all these options is the tolerability, right? Ultimately, the fact that we showed publicly in March that this is a uniquely well-tolerated MEK inhibitor and uniquely well-tolerated drug for the MAP kinase pathway, in general. I mean I think if you compare it against anything that's out there for the MAP kinase, you have KRAS, Pan-RAS, RAF, I think it's the tolerability 104, we believe, is favorable. So that opened so many doors for assessing possibilities. I believe that's one of the reasons we're able to do the combinations we are in Phase IIa. And we really believe -- we're big fans of the FDA's Project FrontRunner, right? So this is the effort where the agency has really been, I think, very forward-thinking and encouraging companies to not always look at late-line patients, but bring novel medicines that are being tested to earlier lines, even to frontline -- first-line patients, even if that means doing it in combination with standard of care, right? And those 2 arms in the Phase IIa, I think, are very well aligned with the philosophy of Project FrontRunner, which again, we think is very thoughtful. And so that getting those treatment combinations in first line and having the tolerability to do it, we think are all important aspects of 104.

And then we talked about different types of combinations, but one that I wanted to ask about was combinations like PD-1, CTLA-4. What kind of data have you generated in that with that combination? And how does that inform your combination strategy?

Yes. I mean it's certainly one of the combinations of interest. I think the data we shared publicly, it was actually at the SITC meeting a couple of years ago was with 415, our second program, which is now in the clinic. But we saw certainly improvement by adding in our drugs to the IO therapy. So it's certainly one of the areas in combination that we're very interested in exploring further.

That data from your Phase IIa that's expected this year, and what should we expect to see and what do you need to see to consider it good results?

Yes. Great question. It's a key question. Look, we have 5 arms of the study, right? We started in March. We said that enrollment is progressing well. And each of the arms of the study is important for a different reason. I will say we're -- the AACR data we shared, the animal data, we think is underappreciated, right? I mean I think that, that data really was striking in what it showed about the combination of 104 with some of these chemo agents in the animal studies. So I think that warrants emphasis. And look, we look forward to sharing data this year, right? We've guided to data this year, initial data from multiple arms of the Phase IIa. In terms of benchmarks that you asked about, look, the nice thing about these arms is that there are clear benchmarks, right? We know how the chemotherapy performs alone, right? If you look at gemcitabine nab-paclitaxel, for instance, right, there's the Phase III MPAC study, right? It's 23% ORR in that study, mostly PRs, by the way, there's only 1 CR out of 431 patients. There's -- the disease control rate in that study was 48%. So that's what that chemo does alone, right? If you look at FOLFIRINOX, there's similar benchmarks from the Phase III studies, right? About 1/3 of the patients responded based on ORR to FOLFIRINOX. The disease control rate was a little higher than gemcitabine-paclitaxel. But the toxicity was higher, right? And there's also a tolerability component to all of this. So -- and the other arms as well, there's clear benchmarks based on standard of care. So that's the advantage of a Phase IIa study, where the endpoints include ORR, right? There's clear benchmarks for showing how your drug, whether alone or in combination, differs from what's currently available for patients.

Now maybe if I can ask a question on 2 words that you said. You indicated an initial data from multiple arms are expected. So which monotherapy and combination arms are most likely? And how many patients' worth of data might we see?

Yes, we haven't really guided more specifically to that. So I think I would just -- I'd say, stay tuned. In terms of the number of patients, right, I think the -- our attitude has always been, when there's a clear signal, we talk about it, right? And I think that can -- that's a function of both the number of patients and the strength of the signal that you're seeing.

Great. Let's shift to 415. Can you provide an overview of the program?

Sure. Yes. So 415 is also -- it's also an inhibitor of the MAP kinase pathway at MEK. It follows the same kind of deep cyclic inhibition approach that we take with 104. I didn't really talk about it much at the beginning, but this is how we're able to achieve the kind of tolerability that we showed with 104 in that March data update, right? So basically, what we're doing is we're hitting the tumor with a very high concentration, a very high free fraction Cmax of drug, 20x to 60x higher than what prior MEK inhibitors were able to achieve. But then with a short half-life, we're quickly dropping off to a near-0 drug trough. And what we found through our early research is that while healthy cells and malignant cells both need the MAP kinase pathway, right? I mean we have the pathway for a reason other than for cancer to hijack it. So they both need the pathway, but they need it a little bit differently, right? So the malignant cells are always on, right? Sustaining proliferative signaling is one of the hallmarks of cancer. If you go to the classic Hanahan and Weinberg hallmarks to cancer papers, the second one, sustaining proliferative signaling is a hallmark, they have to be on all the time. Whereas, the healthy cells are a little more easy going, right? They can have a shorter and more intermittent level in MAP kinase signaling and be okay. So the way we like to think about it is, the healthy -- the malignant cells, sorry, the cancer cells need MAP kinase signaling the way a person needs air, right? You can't hold your breath under water for more than a couple of minutes. They can't go along without this sustained high level of MAP kinase signaling. Whereas, the healthy cells, they need the signaling more of the way a person needs hydration, right? A couple of hours without a drink of water, you're fine; 5, 6 hours, you get pretty thirsty. It's really not until 24 hours that it's a medical situation. So 104 and 415 are both designed to exploit that difference to take it to -- and what we showed with 104 in the March data update and the PD data was that we're essentially shutting down the MAP kinase pathway, right? We're above the IC90 for kind of 2 to 3 hours each day, depending on the dose. And so that's a lot of time to -- for a tumor to be without it's air supply, if you will, right? But it's -- we give the pathway back by the end of the day, and that's really helpful, we believe, for the healthy cells. So that's the deep signal inhibition design. The difference between 104 and 415 or one of the key differences is the fact that 415 has a shorter half-life actually than 104 for faster cadence. So it's designed to be given twice a day in humans, whereas 104 is once a day in humans. And based on our preclinical data, that difference in cadence has an effect on the particular mutation and types of disease that are sort of most optimal. So for instance, in the Phase I for 415, we're taking all comers with evidence of mutations in either RAS or RAF. Whereas, with 104, it was only RAS. I shouldn't say only RAS, it's pretty -- still pretty broad, right? It was any RAS mutation. So I think that's one of the key differences with 415 is this faster cadence of deep signal inhibition, which makes it twice daily.

Now you highlighted the differences and talked about how the differences in potential tumor types are that you could use between 415 and your other program. But based on your preclinical data, which tumor type specifically seem most promising from the early data that you've generated?

Yes, there's a number of them. So I wouldn't want to list all of them, but I will say that I think some of the data we've shared, which has generated the most excitement, was data we shared at the Triple meeting where we showed 415 in combination with a RAF inhibitor, encorafenib in BRAF-mutant animal model. And so what we showed is if you look at kind of the standard of care combination, which is a RAF inhibitor plus a MEK inhibitor, you saw this nice tumor growth inhibition, but then it flattens off and then eventually in the animal, it starts -- the tumor starts to grow again, it escapes, you get resistance. It goes all the way back to what I was saying at the beginning of our discussion, where you have this resistance developing where the tumor finds the way around. And if you look at the literature for RAFs and MEK inhibitors in combination, often the way the tumor gets around it is by an NRAS mutation, for instance. So what we theorize is that 104, by having this broader activity, could potentially help with that. So when we combine the RAF inhibitor -- I'm sorry, 415 in this case. When we combined the RAF inhibitor with 415, we see not only a deeper initial tumor growth inhibition, but a much more durable effect. We don't see that uptick that comes with the escape. And even during a 7-day drug holiday, when we stop treating all together, the tumor doesn't grow much, and then it kind of resumes its downward trajectory when we continue dosing. So that was the combination, and I think that was really striking to people at the Triple meeting, especially the -- being able to sustain that through a week of drug holiday. The other thing we did in that study was -- that animal study was to -- for the tumors on the standard of care, the RAF inhibitor plus the MEK inhibitor, after they were escaping, we also gave them a 7-day drug holiday and the tumors kind of took off like a rocket. But then we did kind of a crossover where we switched those mice over to 415 plus encorafenib and it knocks them back down. So to us, it supported the hypothesis that 415 was able to have this broader effect where it could address some of those mutations that the tumor was using to get around or adapt to the kind of the standard of care treatment.

Now how far are you on the Phase I dose escalation? Can you just give us an update on enrollment of like where you are in the study?

We haven't shared anything publicly just yet. So stay tuned for that.

Okay. Well, you plan to report data from the Phase I/IIa study by year-end, what should we expect to see?

Safety, tolerability, PK and PD, right? So these are the endpoints of the study, and that's what we're looking at.

And then like what do you need to see to advance it to IIa? Can you just talk about like what you would consider like good results? And I don't know to the extent that you can, how many patients worth of data might you have?

Yes. I mean I think we would need to see good safety. We need to see PK kind of as intended or as designed and PD showing effective pathways suppression. So basically meeting the endpoints that are laid out for the study.

And then for the IIa, how many tumor types would you expect to explore in parallel? Maybe can you just talk a little bit about the IIa or your current thinking on that?

Yes. I mean I think it's early to talk about the IIa given that we're still in Phase I. But in Phase I, it's all comers with evidence of RAS or RAF mutations who meet our other enrollment criteria. So as with the prior study with 104, we're open to a variety of tumor types. That being said, I think everyone -- the sites are familiar with their preclinical data, and they're generally sites that kind of focus on the tumor types that -- where we've shown the most preclinical data, right, which is generally pancreatic cancer, melanoma, lung cancer, colorectal, so for what that's worth.

Great. You have multiple additional programs in discovery. Can you just talk maybe a little bit about your expectations on when we might get updates for those? Or is that potentially going to happen over the next year, for instance?

So we haven't guided to the timing for those updates, but we're certainly excited about those programs. I think there's a lot in the preclinical pipeline that we're excited about.

Okay. Great. Maybe last question. Could you just remind us of your cash position and the runway?

Sure. Yes. So as of June 30th, we had $59.7 million in cash and cash equivalents and that supports our unchanged runway guidance into the second half of '25. I think it is worth noting, we did file our Q in August without a going concern, so that's relevant for anyone who's looking closely at the runway.

Great. Well, let's leave it there. Thanks so much for your time.

All right. Thank you, Jeff, and thanks, everyone, for listening. Appreciate it.