Immuneering 3rd Annual Guggenheim Healthcare Innovation Conference

Ben, welcome. Thanks for having me, Paul.

Sure, absolutely. Again, I am Ben Zeskind from Immuneering. Just to remind everyone, I will be making forward-looking statements today, so see our disclosures for more information, and thanks again to the Guggenheim team for having us. We started by asking a simple but profound question, and the question is, can you create a cancer treatment regimen that would have long survival, outstanding quality of life, and do it in all comers? I think the data, and we will talk more about the data today, the data from our phase II study shows that that is possible, right? I think that answers it with a resounding yes, right? We have 17.3 months median OS in first-line pancreatic cancer, with great tolerability and really strong weight stability and gain numbers.

The phase III that we have underway now, the MAPKeeper 301 study, that is going to be the definitive answer to the question. But why is this a profound question? It is a profound question because to date, there has really been a trade-off between how broadly a cancer drug works and how well tolerated it is. For instance, if you look at RAS inhibitors, we are not a RAS inhibitor, we are a MEK inhibitor, and we will talk about that. But if you look at RAS inhibitors, you can either go wide with a pan-RAS approach, but then you end up with some pretty gnarly side effects, or you can go narrow to a mutation-specific approach, like a G12D inhibitor, where you have fewer side effects, but it is a smaller population of patients that you target. So there is this trade-off, broader population, more side effects, narrower population, fewer side effects.

What we did with the Deep Cyclic Inhibition technology is we basically created a new technology that breaks that trade-off, that creates the potential that you can have your cake and eat it too. You can have an all-comers population in MAP kinase-driven cancers, like pancreatic cancer, and you can have outstanding tolerability. So that is really our matcha goal, and I think that is what the Deep Cyclic Inhibition technology is designed to do, is to provide long survival with outstanding quality of life in all comers. I think the data we have shared to date suggests that we are on track for that.

Yeah, it is a great question. This is not your grandfather's MEK inhibitor. So, MEK, just to remind everyone, MEK is in the same pathway as RAS, but it is downstream. So the pathway goes RAS, RAF, MEK, ERK. So, in theory, MEK has always been a really exciting target because it is sort of downstream at the narrow point of the funnel. It is hard to mutate around. That is why you almost never see a MEK mutant cancer. But the first-generation MEK inhibitors were really pretty disappointing, frankly. Even though they showed a substantial improvement in overall survival. So the COMBI-d study showed that adding a first-generation MEK inhibitor could extend survival. So they are validated clinically. MEK is a validated target clinically. MEK inhibitors are also validated commercially.

In 2025, there were over $3 billion in sales for MEK inhibitors in combination with RAF inhibitors, as well as monotherapy. MEK's a target that's validated clinically, and it's validated commercially. But the challenge with first-generation MEK inhibitors was that they were limited to a narrow population of patients, and they were poorly tolerated. On that trade-off that I talked about earlier between the breadth of the patients and the quality of life, they actually didn't do very well on either one. I think that's why MEK got a bad name. They were limited primarily to patients with BRAF mutant disease, and they had a lot of tolerability challenges with rashes and diarrhea, things kind of similar to what you see with pan-RAS inhibitors.

When you inhibit this pathway continuously, whether it's at RAS or MEK, you get a lot of the same toxicities. That was the first generation of MEK inhibitors. What happened was Neal Rosen at Sloan Kettering, in his lab, they figured out why the first-generation MEK inhibitors were only working in BRAF mutant disease. Based on their findings, scientists at Chugai were able to make a second-generation MEK inhibitor, which actually worked in RAS mutant disease as well as RAF mutant disease. That kind of expanded the population of patients that could potentially benefit, but it still had all the same tolerability challenges. I mean, we're talking about very high rates of rash and diarrhea and other side effects.

What we did with atebimetinib is we figured out how to engineer out, with the Deep Cyclic Inhibition, a lot of that toxicity, how to dramatically improve the tolerability, cut the rash rates to one-third of the original levels, engineer out two-thirds of the rate of rash, and so forth. That's really what makes atebimetinib unique as a third-generation MEK inhibitor, is that it's applicable to the broader set of patients, both BRAF and RAS mutant patients, but with tolerability that's really shown to be excellent in the trials that we've run so far. I think for anyone who's interested in understanding this trajectory, we actually just published a really nice paper in Cancer Research. It was actually featured on the cover of Cancer Research a couple weeks ago. I'd encourage everyone to check that out if they haven't seen the paper.

The journal also published a really nice spotlight commentary by independent investigators that I think really helps put this into context as a third-generation MEK inhibitor. The title of that spotlight was "On the Quest for New Sources of Therapeutic Index." I think that's a good way to think about what we've been doing. We've been on a quest for new sources of therapeutic index, and I think the Deep Cyclic Inhibition technology enables that.

Yeah. This is data that we presented at ASCO this year. Dr. Peter Vu from UC San Diego presented it in an oral session at ASCO at the annual meeting. This is for 55 first-line pancreatic cancer patients treated with atebimetinib in combination with chemo. As you pointed out, 17.3 months median overall survival we reported there, which is among the highest median overall survival numbers that we are aware of in any phase II and first-line pancreatic cancer. Importantly, I know there is a lot of excitement around RAS inhibitors. No RAS inhibitor has shown a median OS as high as 17.3 months in any setting in pancreatic cancer. Let me repeat that. No RAS inhibitor has shown a median OS as high as 17.3 months in any setting in pancreatic cancer. That is really important. Let us get back to our goals that I mentioned at the beginning, right?