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 wanna thank you and the entire Morgan Stanley team for having us here today. I wanna thank everyone who's listening, both here in the room and online, and just remind everyone we'll be making forward-looking statements, so please, 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. You know, that's not the case. 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 you know, 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 two. Cancer's not that smart, but it has two kinda tricks, right? Number one is it's very good at hiding among healthy cells, right?
It's just, 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 gonna pull over, get out of the car, go to a train station, and take the train, right? It'll 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 be narrowly targeted.
So, you know, really what we did when we started developing our pipeline was we set out to try to address those two things in a new way, in a unique way, right? How do you selectively target the malignant cells relative to the healthy ones in a unique way? And then, you know, 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 earlier this year.
Yep.
Can you just remind us what you saw?
Sure, yeah, and that was in March of this year, and you know, the first thing we saw is that 104 was well-tolerated. Look, this was the endpoint, right? Phase I, this was the goal, the endpoint of the study, and it wasn't just well-tolerated, you know, we believe it was uniquely well-tolerated. You know, 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, you know, 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 know, you can count on one hand the number of Grade 2s in the table and you know, a modest number of Grade 1s as well. So, you know, if you look at, say, any grade, a 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. But that, 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?
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, you know, 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, and 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 to, you know, to if the highway's 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, you know, it helps, right? If you block a lane of the highway, you're gonna get a traffic jam, but eventually, the tumor kinda gets to that blockage, and it switches lanes, it goes around it.
You know, what these companies saw and published was that with G12C inhibitors, the tumors would acquire alterations in other, you know, other KRAS mutations, KRAS G12D or G12V, or they'd get an NRAS mutation or, you know, BRAF, excuse me, mutation. These were the ways that tumors were getting around the G12C inhibitors. The acquired alteration data that we shared in March showed not one single acquired alteration in any RAS gene. So what does that tell us? 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 acquired alterations in other pathways unrelated to the MAP kinase pathway. And so what that told us is that, you know, the tumors were being. They couldn't change lanes on the highway. They had to do what 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, in that we were achieving this goal of sort of having the broad activity across the MAP kinase path. We 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, you know, we saw shrinking lesions in about half the patients. You know, even though most of them were pancreatic cancer, 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? You know, did the magnitude of lesion regressions vary by indication?
It's a good question. You know, as we talked about at the time in March, you know, the majority of the patients on the phase I were pancreatic cancer patients, more than 60%. So, you know, I don't think we had the numbers in other cancers to really, you know, draw conclusions around that. But certainly, you know, encouraging to see, you know, multiple lesions in multiple patients shrinking by a third or more. You know, 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, y ou know, the tumors basically getting off the highway and going to the train station. So with those acquired alterations and what you saw, you know, what effect do those compensatory pathways have on the ultimate tumor regressions that you saw? Like, and how do you think about the fact that, you know, yes, it, you know, 104 is forcing the tumor to change its methods, but then, y ou can maybe just talk a little bit more about how you're thinking about all of that.
Yeah. No, that's a great question. And look, it's important, right? Because, you know, in these patients who are in the later line setting, that, you know, that probably limited the, you know, kind of the scale of the regressions that we saw, we believe. And why was that? Well, you know, 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, you know, it's essentially .
When you have patients who have been through multiple lines of mutagenic chemotherapy, you're buying them train tickets and ferry tickets and, you know, a trip to the airport. You know, it's creating additional ways for the tumors to get around. So, you know, what we said in March is, you know, the design of the phase II-A is very different. First of all, you know, response is an endpoint, so it's designed to look at this. But you know, we're moving into earlier line patients, who have been through fewer rounds of mutagenic chemotherapy. And then we're also, in two of the arms of the phase II-A, combining with, you know, sort of standard of care agents.
And I think that, you know, that's a big difference that helps, we believe, to sort of block, you know, block the ferries, b lock the train station.
How does the MAP Kinase Pathway dependence vary across indications or lines of therapy? I guess, where do you see the best opportunity for your approach?
Sure. Yeah, look, I mean, we're excited about all five arms of the, you know, the phase II-A for various reasons. You know, I think it's, you know, certainly, the earlier you are in treatment, you know, we believe the more dependence there is on the MAP kinase pathway. So, you know, I think that's important. You know, 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, you know, 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 two of them, you know, you see a very strong tumor growth inhibition that's very durable in these animal models. You know, and that, and we had in the AACR poster as well, you know, kind of the molecular underpinnings for that, right? Which is that the pathways that you know, every drug has pathways that tumors use 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. You know, particularly the gemcitabine paclitaxel data was just really a very nice flat line in that animal data. You know, we said at the time, and it's the case today. I mean, that's one of the arms of our phase II-A. That's active. Yeah.
Now, in the past, you've talked about your interest in colorectal cancer for 104, you know, such as in combination.
Yeah.
Are you still planning to pursue colorectal in the phase II-A? And maybe just talk about your interests in that indication.
Yeah, absolutely. So it's not one of the arms of the phase II-A right now, but we certainly remain very interested in colorectal cancer. Particularly, so what our preclinical data shows in colorectal cancer, and we've shared this previously, is combinations there are really sort of the optimal approach. So we you know absolutely believe 104 ultimately has great potential in colorectal cancer as a combination therapy. But you know with the phase II-A, you sort of only have so many arms and so many you know resources to pursue, so we selected the five arms that we did as higher priorities.
You talked a little bit about combinations with 104, but m aybe if I can just dig into that a little bit and ask a couple questions?
Yeah.
So, you know, you've talked about different types of combinations, such as vertical, immune modifying-
That's right.
O rthogonal, orthogonal mechanisms of action. So how do you think about different types of combinations? You know, what magnitude of improvement would you expect to see with each, and, and how are you prioritizing combination development?
Yeah, great, great question. I mean, you know, as you know, our phase II-A has two arms that are in combination, both in first-line pancreatic cancer patients with standard of care chemotherapies. One's with gemcitabine and nab-paclitaxel, the other's with FOLFIRINOX. So clearly, those. You know, we have prioritized the, you know, the top priority combinations, given that we're already testing them clinically. But, you know, we have encouraging animal data with quite a few other combinations. You know, you alluded to some of them. Between 104 and 415, our other program, you know, we have encouraging data with immuno-oncology agents, with G12C inhibitors, with RAF inhibitors.
So there's really quite a few possibilities that the animal data is telling us have potential and warrant further exploration. But, you know, 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 a 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 path, you know, KRAS, RAS, RAF, I think it's the tolerability of 104, you know, we believe is favorable. So that opens so many doors for assessing possibilities.
You know, I believe that's one of the reasons we're able to do the combinations we are in phase II-A. And it, you know, we really believe. We're big fans of the FDA's Project Front Runner, 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 the earlier lines, even to frontline, first-line patients, even if that means doing it in combination with standard of care, right?
And our, t hose two arms in the phase II-A, I think, are very well aligned with the philosophy of Project Front Runner, which, you know, again, we think is very, very thoughtful. And so that, you know, 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've talked about different types of combinations, but, y ou know, one that I wanted to ask about was the combination of like PD-1, CTLA-4. You know, what kind of data have you generated in that, you know, with that combination, and, and how does that inform your combination strategy?
Yeah, I mean, it's certainly one of the combinations of interest. You know, 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, you know, we saw certainly you know, improvement by adding in our drugs to the IO therapies. So it's a, it's certainly one of the areas of combination that we're very interested in exploring further.
That data from your phase II-A, you know, that's expected this year.
Yes?
What should we expect to see, and, and what do you need to see to consider it good results?
Yeah, great, great question. It's a key, key question. Look, we have, we have five arms of the study, right? We, we started in March, we said that. You know, and, and each, each of the arms of the study is important for a, for a different reason. You know, I will say we're, the ACR data we share, the animal data, we, 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, these chemo agents in the, in the animal studies. So I think that warrants emphasis. And, you know, 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 II-A. In terms of benchmarks that you asked about, look, you know, the nice thing about these arms is that there are clear benchmarks, right? We know how the chemotherapy performs alone, right? If you, you know, if you look at gemcitabine and paclitaxel, for instance, right, there's the phase III MPACT study, right? It's 23% ORR in that study. Mostly PRs, by the way. There's only 1 CR out of 431 patients. You know, the disease control rate in that study was 48%. So, you know, that's what that chemo does alone, right?
If you look at FOLFIRINOX, there's similar benchmarks from the phase III studies, right? About a third 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? There's also a tolerability component to all of this. So, you know, and the other arms as well, there's clear benchmarks based on standard of care. That's the advantage of a phase II-A study where the endpoints include ORR, right? There's clear benchmarks for showing how a drug, whether alone or in combination, differs from what's currently available for patients.
Now, maybe if I can ask a question on two words that you said.
Yeah?
You indicated in 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?
Yeah, we haven't really guided more specifically to that. So I think I would just, I'd say stay tuned. You know, in terms of the number of patients, right, I think you know, our attitude has always been, you know, when there's a clear signal, we talk about it, right? And I think that can you know, 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.
Okay. Yeah.
Could you provide an overview of the program?
Sure. Yeah, so 415 is 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, you know, what we're doing is we're hitting the tumor with a very high concentration, a very high free fraction Cmax of drug, you know, 20-60 times 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 zero drug trough. And what we found through our early research is that, you know, 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 of 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 easygoing, right?
They can have a shorter and more intermittent level of 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 underwater for more than a couple minutes. They can't go along without this sustained high level of MAP kinase signaling. Whereas the healthy cells, they need the signaling more the way a person needs hydration, right? A couple hours without a drink of water, you're fine. 5-6 hours, you get pretty thirsty. It's really not till 24 hours that it's a medical situation.
So, 104 and 415 are both designed to exploit that difference, to take it to, you know. And what we showed with 104, in the March data update and the PD data, was that we're, you know, we're essentially shutting down the MAP kinase pathway, right? We're above the IC 90, for, you know, kind of 2-3 hours each day, depending on the dose. And so that's a lot of time for a tumor to be without its air supply, if you will, right? But we give the pathway back by the end of the day, and that's, you know, that's really helpful, we believe, for the healthy cells. So that's the deep cyclic 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 a faster cadence. So it's designed to be given twice a day in humans, whereas 104 is once a day in humans. And you know, based on our preclinical data, that difference in cadence has an effect on you know, the particular mutations 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 and mutations in either RAS or RAF, whereas with 104, it was only RAS. I shouldn't say only RAS, that's pretty, still pretty broad, right?
It was any RAS mutation. So, you know, I think that's one of the key differences with 415, is this faster cadence of deep cyclic inhibition, which makes it twice daily.
Now, you highlighted the differences and talked about how, y ou know, the differences in, you know, potential tumor types or, that you could use between 415 and, you know, your other program.
Yeah.
But, based on your preclinical data, you know, which tumor types specifically seem most promising from the early data that you've generated?
Yeah, there's a number of them, so I wouldn't wanna list all of them. But, you know, 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, encorafinib, in a 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 know, you saw this nice tumor growth inhibition, but then it flattens off, and then eventually, in the animal model, 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 know you have this resistance developing, where the tumor finds a way around, and if you look at the literature for RAF and MEK inhibitors in combination, often the way the tumor gets around it is by an NRAS mutation, for instance, so what we, you know, what we theorized is that 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 combine 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 seven-day drug holiday, where we stop treating altogether, the tumor doesn't grow much, and then it you know 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, you know, we also gave them a seven-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 encorafinib, and it knocks them back down.
So it, you know, to us, it supported the hypothesis that, you know, 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? You know, 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. You plan to report data from the phase I/II-A study by year-end. You know, what should we expect to see?
Safety, tolerability, PK, and PD, right? So you know, 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 II-A ? Can you just talk about, like, what you would consider, like, you know, good results? And, I don't know, to the extent that you can, you know, how many patients' worth of data might you have?
Yeah, I mean, I think we would need to see a good safety. We would need to see PK kinda as intended or as designed, and PD showing effective pathway suppression. So basically meeting the endpoints that are laid out for the study.
And then for the II- A, how many tumor types would you expect to explore in parallel? Maybe can you just talk a little bit about the II- A or your current thinking on that?
Yeah, I mean, I think it's early to talk about the II-A, given that we're still in the phase I. But, you know, in phase I, you know, 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, you know, we're open to a variety of tumor types. That being said, you know, I think everyone, the sites are familiar with our preclinical data, and they're generally sites that kind of focus on the tumor types that you know 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, you know, is that potentially gonna 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 questions: Could you just remind us of your cash position and the runway?
Sure, yeah. 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 2025. I think it is worth noting, you know, 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. We'll, we'll leave it there. Thanks so much for your time.
All right. Thank you, Jeff, and thanks, everyone, for listening. Appreciate it.