All right. I think we're going to get started on our next session. We are excited to welcome from Immuneering CEO Ben Zeskind and Igor Matushenski. Guys, please take it away.
We want to thank you and the entire Jefferies team for having us today and remind everyone we'll be making forward-looking statements. Please see our disclosures for more information. We aim to help cancer patients outlive their disease. In other words, we want to help cancer patients live longer and longer and longer and longer until eventually they live so long that they no longer die of cancer. Our long-term goal is to make cancer a chronic disease rather than a fatal one. That is a big goal. We have data already from phase I that we've shared publicly that gives a glimpse into how that might be possible.
It's also a bit of an unusual goal, right? Everyone's always talking about curing cancer, conquering cancer, war on cancer, right? There's this idea that you just have to attack the tumor and destroy it as quickly as possible. You know that's OK. There's nothing wrong with that. We think that there actually might be a little more subtlety required. Actually, by shrinking the tumor slowly but steadily, that ultimately might be the way to help patients live longer. You know it's actually, in some ways, a more realistic goal. If you look at most diseases, whether it's diabetes, heart disease, HIV, they haven't been completely cured. They've been controlled. They've been made manageable so that, in general, patients no longer die from them. That's really been our approach to cancer. You know that's also informed our priorities, right?
What are our goals? Really, our first goal in developing our programs is durability. We want patients to live longer. We want to maximize overall survival. We care less about how quickly the tumors shrink. We care more about how long the patients live. We want the patients to live longer and longer and longer. We want to maximize overall survival. The second key goal, which is equally important, is tolerability. We want patients to live better. We want to minimize adverse events. Frankly, we think in oncology the bar here has been set too low. You know, most cancer therapies talk about the number of grade three adverse events, right? A grade three adverse event generally means a side effect so serious that the patient could end up in the hospital.
That's how low we've set the bar in oncology, that as long as patients don't end up in the hospital, it's considered acceptable. We just don't agree with that. We don't think it has to be that way. We think cancer patients deserve better. We think it's possible to make drugs that are both more durable and better tolerated when it's a design goal from the start, as it has been for us. The way that we do that is really through an approach that we call outpacing cancer. Again, you don't have to conquer the cancer. You don't have to outsmart it. You don't have to kill it. You just have to outpace it. You just have to change faster than it's able to change. You have to adapt with your treatment faster than it's able to adapt. That's how we've designed our treatment.
I'll walk you through how we did that and the data we've announced publicly so far showing the effectiveness of that approach. Really, our initial focus has been on our lead program, IMM-1104. It's in phase IIA. We're combining it in the first-line setting in pancreatic cancer with modified gemcitabine nab-paclitaxel. We'll tell you more about that today. First, how's it working in the clinic? What are we hearing from our investigators? One of the things we hear from our investigators is the impact of IMM-1104 in my practice has been nothing short of transformative. Nothing short of transformative. You don't hear the word transformative very often from oncologists, let alone from pancreatic cancer docs. That's what we're hearing from our investigators. The question is, why? What's so different about our approach?
What's so different about how this drug is working in the clinic? It comes back to the durability and the tolerability and what a unique experience and unique set of outcomes that that creates for the patients. We'll walk you through that. Just keep that in mind. Transformative. Not our words, our investigators. How do we achieve durability by outpacing cancer? What does that mean? How is that different from what's come before? Virtually everyone making targeted cancer therapies, and really most cancer therapies more generally, is focused on sustained inhibition. Most therapies are designed for sustained inhibition. They're designed to shut down the pathway 24/7. It's kind of a natural initial reaction, right? There's this thing inside the patient that could kill them. You just kind of want to hit it as hard as you can, right? That's the initial instinct.
That initial instinct might be leading the field astray. We believe there's a better way. Because when you hit it as hard as you can in a sustained way, when you inhibit this signaling pathway 24 hours, we have these signaling pathways for a reason. When you inhibit it 24 hours, the cancer cells adapt. They adapt. They develop resistance. You're selecting for cells, for clones that are resistant to the therapy. You can see that in the diagram at the bottom. A lot of targeted therapies, it's kind of the same story over and over again in targeted therapy. You see therapies that do a really good job at first at shrinking the tumor, 50% shrinkage in the tumors, great overall response rate. It's not sustained. It may be you see it for a couple of months.
You start to select for the resistant clones. Ultimately, you end up with a larger and more resistant tumor. In a disease where one of the hallmarks of the disease is a high mutation rate, providing sustained inhibition, where you're basically suppressing the pathway 24/7, is a recipe to shrink tumors quickly but temporarily. This is kind of what most therapies do. You've seen it in BRAF mutant disease. You've seen it with mutation-specific KRAS inhibitors. You're seeing it even with Pan-RAS kind of approaches. Sustained inhibition shrinks tumors quickly but temporarily. We're taking a fundamentally different approach to achieving durability by outpacing cancer. Our therapies are designed for deep cyclic inhibition, deep cyclic inhibition. That means that they pulse faster than the cancer can adapt. They change. Our therapeutic changes faster than the cancer is able to adapt to it.
The result of this is that the tumors shrink slowly but durably. You can see it there in the second picture. Maybe the tumor only shrinks 20% at first. You're not selecting for resistant cells in the same way. You're able to control it. You're able to kind of hold it in check. Over time, you whittle away at it. It's really slow and steady wins the race here. Slow and steady wins the race. That's how we designed our programs. That's what the clinical data that we've reported publicly really shows. This is how the deep cyclic inhibition works. Again, the goal is to shrink tumors slowly but durably. This, we believe, is the future of cancer treatment.
This is how you help cancer patients live longer and longer and longer and ultimately outlive their cancer with durability and tolerability. This is the durability that we see. Our first deep cyclic inhibitor, our lead program, is called IMM-1104. It targets MEK in the MAP kinase pathway with the goal of essentially outpacing the cancer, adapting faster than the cancer can adapt to really help patients live longer. As many of you probably appreciate, the MAP kinase pathway is altered or inappropriately activated in a majority of cancers. This is a pathway that has broad applicability to many different types of cancer. For us, pancreatic cancer is really just the beginning. It is an important place to start. The reason is the vast majority of pancreatic cancer, 97%, are driven by the MAP kinase pathway.
It is sadly an incredibly lethal disease, about 51,000 deaths in 2025. This is an area where helping patients live longer is an urgent need. That is our goal. Our goal is to help patients live longer and longer. That is really what we are working to accomplish. MEK, as a target, has already been shown to help extend survival. If you look at the COMBI-d study, which was in BRAF mutant melanoma patients, they treated with just a RAF inhibitor in one arm. In the other arm, they added a MEK inhibitor in combination. Just the addition of a MEK inhibitor in combination with that RAF inhibitor added six months of overall survival, six months of overall survival from adding in a MEK inhibitor.
This is a target that's already been validated, already been shown to help patients live longer, which is our goal. What's been the challenge with the existing MEK inhibitors? They've been limited mainly to BRAF mutant disease or neurofibromas. They've been very, very toxic, very, very challenging to tolerate. Those are really some of the goals that we set out to correct with our approach, our deep cyclic inhibition in creating IMM-1104. It's a novel composition of matter. It's a new MEK inhibitor. We created it in-house. We didn't in-license it from somewhere. It's a new car, not a used car. It really works by inhibiting the MAP kinase pathway at the level of MEK in this cyclic way, this deep cyclic inhibition that we talked about. How's it working?
How does this kind of slow and steady approach look in the clinic? Let me talk to you about a patient from our phase I that really demonstrates the durability that we're trying to achieve. This patient, as of our last public update, has had a PFS of over 13 months. This is a patient with third-line pancreatic cancer, meaning they had progressive disease with FOLFIRINOX. They had progressive disease with a gemcitabine-containing regimen. They started our trial with a baseline, just a terrible, monstrous tumor burden of over 18 centimeters worth of tumors, 18 centimeters worth of tumors in the third-line pancreatic cancer setting. The expectation for that patient, the median PFS is only two months. The median OS is only five months in that setting. Yet, look what happened with this patient.
On the plot here on the right, the four different colored lines are the four target lesions. The black line is the sum of longest diameters. What you can see is we did not shrink the tumors slowly. We did not shrink them quickly. We shrunk them slowly. That is what we want. We shrank them 14%, 17%, 22%, 25%. It bounced around a little, 23%, 24%, 28% as of the last 28% reduction in the tumors as of the last public update. Over 13 months on treatment, the patient has had improved quality of life on the instrument that we use. They have gained weight. They have seen reductions in their KRAS mutant ctDNA, dramatic reductions in their levels of CA 19-9, which is a blood-based biomarker of pancreatic cancer tumor burden and survival. Really just an incredible set of numbers.
Behind the numbers, the most important thing is we hear from the investigator that this patient has been living a normal life, living a normal life for over a year with third-line pancreatic cancer. That is unprecedented. This is what we believe is possible when you shrink tumors slowly, not quickly, when you shrink them with the durability and the tolerability that we've designed into 104 with the deep cyclic inhibition mechanism that aims to outpace cancer. We believe this kind of a profile gives us a glimpse into a future where cancer could be a disease that's not fatal. Cancer could be a disease that's chronic, that's managed, that patients can live with rather than dying from. That's been our goal from the start, is not kill the tumor, kill the tumor, kill the tumor, but focus on preventing the tumor from killing the patient.
This kind of durability, we believe, is really unprecedented. It's great to see for this patient and more generally, over 13 months in third-line pancreatic cancer, just remarkable. Now, how do we achieve the tolerability? I talked a lot about how we achieve durability through the deep cyclic inhibition mechanism, how we achieve the durability by not driving resistance the same way that sustained inhibition does. How do we also achieve the tolerability, which is kind of the other half of what you need to really make cancer into a chronic disease that patients can live with for a long time as opposed to a fatal disease? We have the MAP kinase pathway for a reason other than for cancer to hijack it. Let me say that again. We have this pathway for a reason. It plays an important role in healthy cells.
The role that it plays in healthy cells, the proliferative signaling, it's transient. It's intermittent. It says, "Grow and divide. Grow and divide," right? It's spaced out, "Grow and divide." When you have cancer cells, when you have oncogenic mutations that turn those healthy cells into cancer cells, the proliferative signaling goes from transient to sustained. Suddenly, this signaling pathway is telling the cells, "Grow and divide, grow and divide, grow and divide, grow and divide, grow and divide." It's sustained. It doesn't stop. It's always on. It's nonstop. What's the way to fix that? What's the way to fix that when you have a signal that's constantly telling the malignant cells to grow and divide?
The approach that everyone else has been doing, sustained inhibition for decades, the approach in oncology, is to basically reduce that signaling as much as you can and do it 24/7, make drugs with long half-lives, shut down the pathway 24/7, maintain occupancy. Unfortunately, because of the toxicity of that, you can really only suppress the pathway to a certain extent. For instance, the MEK inhibitors that have come before really are only able to get up to around their IC50 values. They're only able to suppress the pathway by about 50%. The pathway is still saying, "Grow and divide, grow and divide." It's a little quieter, right? It's about half the volume. But it's saying, "Grow and divide, grow and divide, grow and divide, grow and divide." You're not completely suppressing the cells, the malignant ones. You're hurting the healthy cells.
You're hurting the healthy cells, which no longer get that full grow and divide signal. That, we believe, is why you see such poor tolerability with most targeted agents, most sustained inhibitors. It doesn't have to be that way. It doesn't have to be that way. We believe patients deserve better. Patients deserve to feel almost like their pretreatment cells, as one of our investigators described our therapy. How do we do that? We do that through deep cyclic inhibition. What we're able to do is essentially through these pulses, this intermittent inhibition, we're able to get up well above our IC90 value, meaning we can suppress the pathway more than 90%. We do that for several hours a day through our PK. We have approximately two-hour half-life in humans and fast-binding kinetics. It's not just the drug concentrations.
is also whether they are suppressing the pathway. The combination of that, we believe, is essentially restoring the full transient signaling to healthy cells. We are giving the healthy cells back the pathway the way they need it. That drives fewer adverse events. This is just a fundamentally different approach. We believe it is the right one because, look, cancer is not an infectious disease, right? It is not a bacterial infection. It is not some bug that came from outside that we just need to squash and kill. Cancer is us, right? It is our own cells that are just turned up too much. They are getting that, "Grow and divide, grow and divide, grow and divide, grow and divide," signal all the time.
Rather than trying to squash them and destroy them, and you just get resistance and you end up destroying the healthy cells as well, instead, if you can just help them slow down, "Grow and divide, grow and divide, grow and divide." You just got to slow them down, slow down that signaling. That is ultimately, we believe, how you can achieve durability and great tolerability. That is the design. How is that working out? Let's look at some of our phase I data, actually phase II data as monotherapy in the second-line setting. What you can see is this drug is extremely well tolerated. This is your typical table of treatment-related adverse events observed in at least 10% of the patients. What is not typical about the table is how empty it is, right? You see there are no grade 4s. There are no grade 3s in the table.
You can count on one hand the number of grade 2s in any category. Even just the number of categories, the fact that only five categories clear that 10% threshold for treatment-related adverse events is highly unusual. We believe this profile has the potential to be best in class. We believe it's dramatically better than anything else we've seen for this pathway or certainly more generally. We've had KOLs describe this as placebo-like tolerability. If anyone's seen a better tolerated drug, let me know. We certainly haven't. That is by design. That tolerability has a number of advantages, right? The first is patients feel better. They want to take your drug. In some ways, that's the most important. Patients live better. They're not only living longer, but they're living better lives, more normal lives. The second advantage is this maintains performance status.
Performance status is highly associated with survival. If you can maintain patients with better performance status, that actually feeds into the other goal of durability. The tolerability feeds into the durability through performance status. The third advantage of this kind of tolerability is combinability. We can combine this drug readily with almost anything. We have shown it already in the first-line setting in pancreatic cancer where we readily combine with chemotherapy. I will show you some of those data in a minute. We readily combine with chemotherapy. We recently announced an agreement with Regeneron where we are assessing 104 in combination with their anti-PD-1 Libtayo in lung cancer. We believe that is really just the tip of the iceberg. There are so many ways to combine this drug. That is not a given.
Frankly, there are a lot of therapies out there that are struggling to combine in terms of the tolerability, struggling to combine with chemo and with other agents. That is just a real advantage of 104 and of this deep cyclic inhibition approach more generally. Tolerability drives durability as well. In phase I, what we really showed was that 104 monotherapy has activity, it has durability, and it has tolerability. Now we are in phase IIA, and our primary focus is on evaluating 104 in combination with modified gemcitabine-nab-paclitaxel in first-line pancreatic cancer. What is the molecular rationale for that combination? One of the other interesting things that we showed in phase I, and this gets back to the idea of not driving resistance. If you look at acquired alterations, these are acquired alterations, new mutations or other alterations that occur over the course of treatment.
If you look at that for more typical sustained inhibitors, you see all kinds of new mutations in the MAP kinase pathway. For instance, if you look at a G12C inhibitor, you see new mutations in G12D, G12V. What we see is very few acquired alterations in the MAP kinase pathway. We are not driving resistance in the MAP kinase pathway to the same extent as sustained inhibitors. What we do see, though, are acquired alterations in other pathways unrelated to the MAP kinase pathway. That is the beauty of the combination with chemo because the chemo, the gem nab, can help mop up some of those non-MAP kinase pathway resistance mechanisms. At the same time, the MAP kinase pathway is a resistance mechanism for the chemotherapy.
There's a really nice synergy there that we showed preclinically last year at AACR, where you can see that gem nab does well relative to the untreated tumors. 104 does even better. It is really when you combine them that you see this dramatic flatlining of the tumors. The tumors are flatlined. We ran this study out 60 days. Most people will show you mouse studies that are just out a couple of weeks. We ran it 60 days to really assess and demonstrate the durability. That's our key goal, durability and tolerability. You see it here. We took this combination into patients. It is really important because pancreatic cancer is tough. The standard of care options for first-line pancreatic cancer, they have a six-month survival of only 67%-76%. Just think about that for a minute.
That means that a quarter of the patients in first-line pancreatic cancer pass away within a quarter to two-thirds, really, pass away within the first six months of treatment. This is a disease that's in urgent need of therapies with more durability and better tolerability. That is what we intend to bring to patients. Our phase II is evaluating the impact of IMM-1104 plus the modified gemcitabine-nab-paclitaxel on survival. We've got an update in Q2, which is in the next few weeks. We said that's going to include survival data from over 30 patients. We're very excited for that update. What we've talked about publicly so far from that arm, you can see here. This is 1104 plus the modified gem nab in first-line pancreatic cancer. You can see we have a patient with a complete response, which is exceedingly rare in pancreatic cancer.
In the MPACT study, the phase III study for gemcitabine-nab-paclitaxel, the chemo that we're combining with here, there was one complete response out of 431 patients. One out of 431. We have one in the first seven. Again, we believe that's a big part of the design, how we design this drug, the deep cyclic inhibition, not driving resistance, having that ability to kind of make lesions completely undetectable. You can see the waterfall plot is kind of missing the left half, if you will. For the chemo alone, the disease control rate is about 48%. You'd expect kind of a whole left half of that waterfall plot that we're just not seeing here. Overall response rate, 43%, disease control rate, 86%. All this is as of the December 5th data cutoff. It's interesting.
Disease control rate has actually been shown to be a more powerful predictor of subsequent survival in a number of different papers and analyses. It gets back to the theme that we started with. If you can control the tumor, right, you don't have to shrink it too fast or too much. Just shrink it, chip away at it, slowly but surely, reduce those tumors, help patients live longer. Durability, tolerability, overall survival, those are our goals. I think the data we've shared publicly is all very encouraging in that regard. This is the tolerability for that combination in first-line pancreatic cancer, again, data that we shared in January. Again, extremely well tolerated, particularly for a combination with chemo. This is about giving patients that durability and the tolerability so they not only live longer, but they live better. What are the benchmarks, right?
We've talked about that we'll be sharing survival data in this update coming up in the next few weeks. Here we've plotted the three standard of care treatments for first-line pancreatic cancer, NALIRIFOX, FOLFIRINOX, and gemcitabine-nab-paclitaxel. You can see that it's pretty dismal, right? I mean, it's very sad for these first-line patients that these are the options they have available. You can see just plummeting curves there. That's kind of the current set of benchmarks. Similarly, in progression-free survival, it's not much better. You see rapid progression in a good number of patients on all three of these benchmarks. It's just important for people to appreciate the benchmarks going into our updates that we have coming in the next few weeks. With our data update in January, we quoted Dr.
Bakhayesab at the Mayo Clinic, who's been a member of our SAB for quite a while. Immuneering phase IIA data in first-line pancreatic cancer are very promising. If current trends continue, the combination of IMM-1104 with modified gemcitabine-nab-paclitaxel may provide improved efficacy and tolerability in the first-line setting where patients continue to urgently need better options. In addition, having a MEK inhibitor that appears to be as well tolerated as IMM-1104 may provide new opportunities for patients with different types of cancer. I think it's important to zoom out. Pancreatic cancer is where we're starting, but the MAP kinase pathway drives the majority of all cancers. We believe the breadth of opportunities for this drug are incredible. For IMM-1104, there's potential across so many different types of cancer in so many different combinations with the durability and tolerability that we're seeing.
We've started planning our global randomized pivotal trial. This is in the first-line setting in pancreatic cancer to evaluate IMM-1104 with the modified gemcitabine-nab-paclitaxel randomized against standard of care chemotherapy. We've guided to this starting next year, and we're really excited to have this in planning. We talked about the pancreatic cancer really just being the start. We've announced an agreement with Regeneron in lung cancer, as I mentioned. We've guided to sharing this updated data in the second quarter, quite soon. With that, I want to thank you all for listening.