Afternoon, everyone. Welcome to the next session with Immuneering. I'm Ami Fadia, biotech analyst here at Needham and it's my pleasure to be hosting the team here, led by Ben Zeskind, who's the CEO of the company. We also have Brett, the CSO, and Igor, CMO. Ben, welcome and thank you so much for taking the time to be with us today.
Thank you, Ami.
If I could just ask you to maybe kick us off with any opening remarks and priorities for the company for this year and then we can dive into Q and A.
Sure, absolutely. I should thank you and the entire Needham team for having us today. Thank the audience for joining and also remind everyone I'll be making forward looking statements so they should see our disclosures for more information. In terms of priorities for 2025, look, our goal is to help cancer patients live longer and feel better. That is really why our lead program targets MEK. Right? It is a key part of the RAS/ RAF/ MEK/ ERK pathway that drives about half of all tumors. It is a validated target. It has already been shown to help patients live longer. If you look at the COMBI-d study, when you add a MEK inhibitor in combination with a RAF inhibitor, it actually extends overall survival by six months in BRAF mutant melanoma patients. MEK inhibitors are great for patients.
They're also good business if you look alone or in combination. The four registered MEK inhibitors drove about $2.4 billion in net sales. We think that's just scratching the surface. We think there's a huge opportunity to expand beyond BRAF mutant disease, beyond neurofibromas, to really include RAS mutant disease. This dramatically expands the potential of MEK inhibitors. They've also been limited really by their tolerability, which limits their ability to combine with other treatments. That's what we've been working on. We designed 104 as a novel MEK inhibitor with the ability to target RAS mutant disease and with much better tolerability to facilitate combinations. That's why a big focus of ours has been evaluating it in pancreatic cancer. It's about 90% RAS mutant, as well as just being a huge unmet need. We started this year.
We started 2025 with clinical updates, including just an incredible ongoing case study from phase one. This is a third line pancreatic cancer patient who's been on treatment for over 13 months, with target lesions shrinking by at least 28%. We hear from the investigators that this patient’s essentially been living a normal life for the past year, which is just unheard of in that third line pancreatic cancer setting where the benchmark median progression-free survival is 2 months and even the median overall survival is 5 months. To have a patient living a normal life for over a year, we're just thrilled for that patient and what it says about 104, and it reminds me of the old fable of the tortoise and the hare. 104 didn't then come racing off the starting line like a rabbit with a really deep regression. It was slower, it was steadier.
Minus 17%, minus 24%. Slow and steady, but a really great outcome for patients. Think of 104 as the tortoise of the race. We all know slow and steady wins. We also shared at the end of the year really encouraging data from our ongoing phase 2a trial.
Yeah, maybe if you could sort of take a step back and talk about, you know, the phase 2a data and you obviously sort of highlighted the, you know, a case study there. Just more broadly across the data set, what do you believe has been sort of misunderstood about the data that you guys presented so far? Sure, yeah.
The case study was actually from phase one that I mentioned earlier. Yeah, let's talk about phase two A because the data we've shared, we believe, has been really, really encouraging. Let's start with monotherapy in second line pancreatic cancer patients. There we reported a deep confirmed partial response, a patient with a 67% reduction in target lesions. We also reported an overall response rate that's within the range of benchmarks for standard of care and, importantly, a disease control rate at 52%, which is actually right near the top end of the range of benchmarks for standard of care for disease control in that setting. We combine that strong disease control as monotherapy with truly exceptional tolerability.
If you look at our table of treatment related adverse events occurring in at least 10% of patients, we had no grade 3 or grade 4 adverse events on the table. Even if you look at any grade treatment related adverse events, the most frequently occurring one only happened in 29% of patients. And there's only five different treatment related adverse events on the list. It is just really frankly unheard of relative to any targeted agent we're aware of for this pathway. Just exceptional tolerability. That exceptional tolerability is what enables 104 to be readily combined with chemotherapy in first line pancreatic cancer. That is something other treatments have struggled with, frankly. 104 is really an exceptional combination anchor. The results we announced in combination were really quite profound, particularly for 104 in combination with modified Gemcitabine and Nab-Paclitaxel.
In first line pancreatic cancer, we saw a complete response, which is exceedingly rare in pancreatic cancer. We saw every patient that we reported in January had shrinking lesions. There is essentially, there is no left half of the waterfall plot that you typically expect. We reported a 43% ORR, which is nearly double what you would expect for the Gemcitabine + Nab-Paclitaxel alone. It is kind of right at the top end of the range of benchmarks. If you look across all the different standards of care in that setting and an 86% disease control rate, which is actually well above the top end of the range for standard of care benchmarks. Again, as was the case in that case study from phase one, as was the case in monotherapy, 104 is just a standout for disease control, again with unprecedented tolerability.
We saw similar results when we combined 104 with modified FOLFIRINOX as well. It helps to corroborate that there was disease control. There was a 2008 analysis by the Southwest Oncology Group SWOG in lung cancer that actually showed that disease control rate can be a better predictor of survival than overall response rate. If you look at the benchmarks of progression-free survival in this setting in first-line pancreatic cancer, they're all pretty dismal and they all cluster together in the Kaplan-Meier plot. That's what's available for patients. We've announced that we plan to share an update in the second quarter that includes progression-free survival. I think that's something which is coming up soon.
I think really what the market is not fully appreciating is that when you have strong overall response rate and just unprecedented profound disease control and unprecedented profound tolerability, this all suggests this drug has the potential to be a drug where survival is where it really shines, where it's the tortoise that slow and steady wins the race. I think that with the tolerability that means you can combine and patients can keep going on 104 and really benefit from the therapeutic effect.
Yeah, I like your analogy there.
Credit to Igor. Actually, our new CMO came up with that analogy. He came in with a fresh look at the data and that was his suggestion.
That's an interesting, interesting way to look at it. Yeah. Makes sense. Okay, now from your, the data that was disclosed in the phase 2a, IMM-1-104 plus combo demonstrated responses in PDAC patients with G12D mutations. Whereas when you looked at the combination with Gem/Nab, you saw sort of responses in G12V and cancer mutations. Are we reading too much into the data here or should we read too much into the data here where one combination may be more effective in certain mutations versus the others, or is this just more sort of a function of the small data set?
Yeah, I mean, look, I think we're seeing great responses with 104 across a range of different mutation types. Right. I'd remind you that the case study I talked about at the beginning, the third pancreatic cancer patient who's been on for over 13 months PFS so far in monotherapy, that patient's a KRAS G12D patient. Actually, also the second line monotherapy case study, I mentioned the confirmed partial response in second line monotherapy with the 67% reduction in target lesions, that's also a KRAS G12D. We believe 104 is clearly active, really, regardless of the specific mutation that's driving the MAP kinase pathway. That's consistent with what we saw preclinically. We'd really expect 104 to work in all tumor types that are dependent on using the MAP kinase pathway.
The variations that we've seen so far, I think to your point, really mainly reflect the N, right, kind of the number of patients at this stage. To the extent we're seeing that heterogeneity, we think it's really about the extent. It's not about the specific mutation, it's just about the extent to which the lesions are dependent on the MAP kinase pathway versus other unrelated pathways. That's why it's so important that 104 can readily combine with chemotherapy because there are plenty of pancreatic tumors that are not fully dependent on the MAP kinase pathway. Chemo can help address that, which is why we believe with the combinations we're reporting such consistent reductions in the target lesions and really kind of only seeing the right half of the waterfall plot.
Okay, now just with regards to, you know, given some of the safety concerns with that treatment, what has been your experience as you've evaluated in combination with 104 and, you know, do you anticipate that as you sort of, you know, we see data from the higher dose, the 320 mg randos, what do you anticipate in terms of the safety profile and how that would evolve.
Yeah, that's a great question. The data we've shared publicly for 104 in combination with the modified FOLFIRINOX has been at 240 milligrams. At that dose, this combination was observed to be generally well tolerated. We showed a 50% overall response rate, including with a patient with a deep PR, 100% reduction in target lesions. We think this is comparable. This 50% ORR is comparable to the 43% we showed in combination with gemcitabine nab-paclitaxel. These tend to bounce around. Excuse me a little bit, but putting 104 aside for a moment and just looking at the chemo alone, of course, gemcitabine nab-paclitaxel is a better tolerated regimen than FOLFIRINOX, and I think it's fair to say that's likely true in combination as well.
Given that the overall response rates that we've shared publicly for 104 in combination with Gemcitabine and Nab-Paclitaxel on the one hand and modified FOLFIRINOX on the other hand are kind of similarly attractive, I mean, I think if that continues, it sort of makes 104 plus modified Gemcitabine, I mean, nab paclitaxel a clear choice. Right. If you can get sort of equivalent efficacy with better tolerability. And by equivalent, I just mean to the 104 plus chemo equivalent, that makes it sort of a clear choice in terms of how we prioritize direction. I think it's also consistent with the intent of Project Optimus, where we evaluate multiple doses. I think generally our investigators have also kind of preferred the Gemcitabine nab paclitaxel. That's really what we're seeing is very encouraging.
That is what we've said has sort of already crossed the threshold where we're planning the pivotal study. Right. We've kind of already said that we're obviously subject to ongoing data and regulatory authority feedback, but we've already started planning the pivotal study for 104 in combination with the modified Gemcitabine + Nab-Paclitaxel. That is what we've said so far.
Yeah, yeah. As you think, as you sort of think about or as you plan for that study, what else do you need to do in terms of really sort of getting study started? Is there any additional data that you need to generate in the phase two, or is it really about getting the study design, et cetera, you know, aligned on with the FDA and then just moving forward with that.
Yeah, look, our phase 2a arms are ongoing. Right. We're continuing to run those studies and I think when we report data in the second quarter, that'll help to really kind of fill out the picture. Right. We've guided to the fact that that will specifically include progression-free survival data from the modified Gemcitabine + Nab-Paclitaxel in combination with 104. I think it's important to see those data. That's a question we get a lot. What's the durability? How does it look in terms of progression-free survival? That's really the next step, to share those data publicly and I think at that point we'll be able to start talking more about the details of the trial design. Certainly we've already shared kind of a preliminary schematic for the trial in our public deck.
We're certainly thinking carefully about the pivotal study.
Okay. One of our competitors, Revolution Medicines, is also sort of planning a pivotal trial in first-line PDAC later this year. How do you see this particular combination that we just sort of talked about competing potentially with their multi-RAS drug RMC-6236? You know, and you know, they've shown some very interesting data. Maybe just talk about kind of the profile that you're anticipating with, I'm sort of with IMM-1-104.
Sure. Yeah. First of all, I mean the way we see it, we're kind of all on the same team competing against pancreatic cancer. We have a lot of respect for the company you mentioned. We think they have a good option for second line patients. I think the real question is maybe how did they see their drug competing with 104 plus modified Gemcitabine + Nab-Paclitaxel in the first line setting. Given that we've already shared first line data in combination with chemo and it's quite good and it's really on the basis of that data that we've announced plans to initiate a pivotal trial. Whereas to our knowledge they haven't publicly shared any data in the first line setting yet or really demonstrated the ability to combine with chemo. When it comes to that, I think that's a distinction.
You got at this indirectly when you spoke with their CEO on Monday as part of this conference and we agree with him. He really laid out the importance of combining a targeted therapy with chemo in the first line setting. We agree with him both from a mechanistic perspective. He referenced preclinical data and because oncologists really understand the chemo and it's what's been shown to work for these patients. He described a fundamental issue of staying on trial and maintaining dose intensity, which is really key for targeted agents to keep working. That's something we've demonstrated with data. I mean, we've shared first line data. We show we can combine with gemcitabine nab-paclitaxel, deliver excellent ORR, exceptional disease control and tolerability. We've shown we can combine with modified FOLFIRINOX as well.
I think really one of the things that really sets us apart, that really sets apart 104 is the ability to combine with chemotherapy that we've demonstrated in the first line setting. That's due to the tolerability, the way the efficacy works. It's important because when you can combine, when you have good tolerability, patients can stay on drug longer. When they can stay on drug longer and have good performance status, they ultimately live longer. Look, of the two companies you mentioned, we're the only one that has shown data in the first line setting in combination with chemotherapy. It's quite good. We're proceeding with our plans for the first line pivotal study based on the data that we shared. We'll be sharing additional data in the coming months this quarter.
Maybe this is a good time to just sort of recap what data are we going to get in the second quarter, what cohorts, how many patients? Perhaps if you could sort of lay that out.
Sure. Yeah. Certainly we've guided to additional data from the phase 2a this quarter. We've specifically said that that will include initial progression-free survival data from the 104 plus modified Gemcitabine + Nab-Paclitaxel side of the paclitaxel arm. We've not guided to specific numbers of patients, but if you look at our prior update, you can see there were already 21 patients in the safety data for that arm that we shared that had the December 5th cutoff date. Now, safety is available right away, whereas efficacy takes longer. That can give you a sense of maybe the floor in terms of patient numbers that you're likely to see. We haven't really guided on other aspects of the update, but certainly with the number of patients that we're talking about and the potential for PFS data, we believe it'll be a very substantial update.
Yeah. Maybe just sort of also talk about what are the other, you know, the other cohorts that you have ongoing in phase 2A and where they're at and when we could see an update there.
Yeah, absolutely. To your point, we have, you know, we have two additional monotherapy arms. We have NRAS melanoma, and we have RAS mutant lung cancer. Right. These are both areas of substantial unmet need where having the ability to block the MAP Kinase pathway is potentially very impactful. Those are the arms we have not yet guided to when we plan to share those data. I think, again, the strengths of 104, we believe, are ultimately in its efficacy, its tolerability, and its ability to combine with other drugs. I think those are cancer types where there is certainly a lot of dependence on the MAP Kinase pathway. In fact, in melanoma, it is not just NRAS, which is where we are looking initially, but certainly BRAF mutant disease is quite common in melanoma as well.
That's an area where, you know, a MAP Kinase, you know, a MEK inhibitor actually has advantages because it's further down in the pathway.
Yeah, I mean, I guess, you know, with regards to those two indications like melanoma and lung cancer, what, you know, and there are a lot of MEK inhibitors that have been approved in melanoma and, you know, they are sort of used in combination based on kind of the data that you've seen for 104 in PDAC and you're moving forward there in a combination treatment setting. How do you intend to move forward in these two, or have you made any sort of. Or are there some early thoughts around what would make sense in terms of the development path forward in those two indications? Would it be monotherapy or is it better suited as a combination therapy?
Yeah, I think that those are decisions we'll ultimately make based on data that we've not yet announced. Right. Let's put aside the topic of monotherapy for the moment because I think that'll depend on the data. Certainly I think the trajectory that we've seen in pancreatic cancer is clear. Activity is monotherapy and then, you know, just really shining with the ability to combine. That's certainly one possibility that, you know, we're exploring for melanoma and for lung. Right. I mean, I think the just the really profoundly unique safety profile that we have for 104, you know, it's sort of, you know, regardless of what you decide about monotherapy. There's sort of not a lot of downside to exploring it in combinations as well. You have to prioritize and make decisions about what you do and when.
Certainly we look at all sorts of combinations and frankly, there's a lot of interest in combining with 104, just given the target of MAPK and given the tolerability profile that we have. Again, it's sort of up to us to kind of prioritize and think through that. Certainly we see a lot of combination therapy opportunities. We announced recently an agreement with Regeneron where we're evaluating 104 in combination with their anti-PD1 Libtayo in lung cancer. I think that's one example of a, you know, a potential combination.
Maybe that was going to be sort of the topic I moved to next. Maybe tell us where you are with that and is what line of patients you're evaluating there. And then, you know, just more broadly, how are you thinking about exploring other potential partnerships where you can explore a combination for 104 with, you know, other treatments?
Yeah, it's a great question. We haven't really shared the details publicly on that study yet. On that, I'll wait till we're ready to share more detail. Certainly I think we're thinking broadly about what all the combination possibilities are. I think given the exciting data that we've seen in pancreatic cancer, by combining 104 with the standard of care first line chemotherapies like the Gemcitabine and Nab-Paclitaxel, it makes sense that we'd be exploring other combinations and other possibilities really across a variety of different types of cancer. Because look, that's why we got in this pathway in the first place. The RAS/RAF/MEK/ERK pathway drives about half of all solid tumors. With a MEK inhibitor that works in RAS mutant disease and that's well tolerated, you really have just a very broad, vast array of potential opportunities.
That is something that we're certainly aware of and looking at broadly, but we also want to start with kind of where we're the furthest along as well, which is in pancreatic cancer and just really excited by all the data that we're seeing there.
Okay, I also want to kind of just ask a question that seems to be front and center for investors in kind of just today's world. We've seen changes at the FDA and HHS recently and clearly, you know, you are in sort of discussions with the FDA as you've, as you sort of think about your pivotal trial, et cetera. Any comments you can make around any changes in interactions that you've had with the FDA level of responsiveness and things like that.
Sure, yeah. We do not comment on specific kind of regulatory interactions, but certainly our focus as it has always been is on creating great medicines for cancer patients. Right. And executing on that mission. Right. You know, that is our focus. You know, I think the data that we announced in January certainly shows that we are making good progress on that goal. You know, great response, great disease control, great tolerability in these combinations. You know, I think we are excited to share additional data in the second quarter including progression free survival data from the modified Gemcitabine + Nab-Paclitaxel in combination with 104 in those first line pancreatic cancer patients. That is our focus and I think if we execute well on that, everything will work out well.
Sure, yeah, absolutely. Maybe just a last question, just more of a balance sheet question. You guys have sort of opportunistically raised capital in the last several months. Maybe just talk to us about, obviously, you know, we have this data that you just mentioned that's coming up soon around the corner with PFS. Beyond that you do have the other two phase 2a cohorts that are ongoing. Maybe just talk to us about the cash runway and what that could fund in terms of just flipping some of these cards.
Sure, yeah. We, you know, we've guided to having cash runway into 2026. Right. That certainly, certainly takes us well beyond the second quarter data readout that we've guided to, you know, which we've said will include the initial progression-free survival data from the 104 plus modified Gem /Nab-Paclitaxel arm. We, you know, certainly, that takes us well beyond that, you know, continuing to execute on the phase 2a trial and then from there we kind of keep all options on the table in terms of how we'd likely fund the pivotal study. There's Wall Street, but there's also pharma and we certainly have extensive interactions with a variety of potential partners. Our goal is just to keep all options on the table and ultimately find the best possible way to push forward with the pivotal study.
Because we believe if the data continues as we shared in January, 104 plus the modified Gemcitabine + Nab-Paclitaxel has the potential to really be an impactful and differentiated option for patients with pancreatic cancer. Again, to see cases like that, the third line patient who's been on for 13 months, living a normal life, if you will, that's really what we believe the potential and the power of 104 is. Everyone focuses on curing cancer and how quickly you can get this ORR, how quickly you can make the tumor shrink. That's not how most diseases have been conquered. If you look at things like HIV, like heart disease, like diabetes, they're not cured. The disease doesn't magically disappear. It's controlled in a way where it's no longer a terminal condition.
There's no cure for HIV, but patients for the most part can live long, healthy, relatively normal lives. We believe that that's a potentially very positive outcome for cancer patients. I think the case study we shared of that third line patient really gives you a glimpse into what that could look like, a tumor that's shrinking gradually, but a patient that, because of the tolerability and the activity of the therapy and efficacy, is really able to kind of live a normal life. That's, you know, that's a possibility that we, you know, we think would be a very beneficial outcome for cancer patients. You know, we think that's something you'd see in disease control. You'd see it in progression free survival and ultimately survival. You know, to make that happen, you got to have great tolerability.
You got to be able to combine with other therapies the way we're able to combine with chemotherapy, and that, you know, that could be an outcome that would be really exceptional for a lot of cancer patients.
Yeah, yeah. No, I think that's an interesting perspective that you need to be able to sort of control the disease and you don't have to, you know, we are not expecting to solve for it forever, but if we can maintain disease control rate, I think that is a win. That just sort of, you know, makes me think of a question around like the data that you're going to be presenting in the second quarter. Perhaps if you could just sort of share the forum in which you might be able to share that data, if at all, you can share that. More importantly, what data points would we get outside of EFS, should we expect maybe spider plots, patient level data, disease control rate and things like that, and any color on that?
Yeah, so we haven't guided to the particular forum yet. You know, we've historically sort of done both, right? At times we've announced data through a press release and an investor call. Other times we presented at medical meetings. You know, we haven't really provided guidance. For us, it's more about the timing of when, you know, when is the right time to share, share the data as it matures. I think that's similarly how we think about the exact contents of any given update. It's really sort of which arms is at the right time to share an update in terms of there being a clear and meaningful signal that's material. At the end of the day, that's the real threshold for these updates is, is materiality.
You know, I think we've, you know, we've shared pretty proactively as recently as January updates on what we're seeing. Certainly we're very, very encouraged by, you know, what we announced in January. I think it all compares really favorably to benchmarks and particularly to see those disease control rates be so, so high above the benchmarks, you know, with great tolerability. Again, you know, it's the tortoise in the hare, right? We think 104 is the slow and steady that, you know, we believe has the potential to really, really win the race for these patients.
Okay, we just have a couple of minutes remaining and I have one question that has come in. I guess the question is, you know, did picking gemcitabine, was it purely based on safety? With the higher 320 milligram dose, you could push to a higher activity width for combo. Is that something you'll consider if competitors like Revolution Medicines generate even higher efficacy in first line?
Again, we're the only ones that have shared data in the first line setting and it's quite encouraging. Let's just remember that we're the only ones that have showed the ability to combine with chemo, which is so important in the first line setting. I wouldn't misinterpret the fact that we've decided to move forward with planning a pivotal study that includes 104 plus the modified Gemcitabine + Nab-Paclitaxel. Don't infer from that a negative decision on the modified FOLFIRINOX. It's really to us, two independent decisions. Right. What we've said is just from the data we've shared publicly in January for 104 plus the modified Gemcitabine + Nab-Paclitaxel that we believe has crossed the threshold where it makes sense to start planning that trial.
We haven't said one way or the other around the combination with 104 and the modified FOLFIRINOX, but I will say there is this kind of, kind of old school mentality around maximum tolerated dose, right, where you just sort of dose up and dose up and dose up till you do you really make a patient very sick and then back off one. That's just, you know, that's kind of the, that's the hare, that's the rabbit, right? That's trying to run out of the gate quickly and sort of get that ORR early on. We don't think that's the right thing for patients. You know, we're big believers in the philosophy behind Project Optimus from FDA, which says, you know, don't, don't just go to the highest dose you can without seriously hurting a patient and back off.
Don't do the MTD, find the biologically right dose. You know, we think what we're seeing with 104, you know, with the data we shared in January at 320 and 240 is just really compelling. Again, trying to win the race for the long run, trying to make cancer like HIV, where it goes from being terminal to chronic. I think as a field we have to move beyond this over focus on maximum tolerated dose. For us, it's really about what's the right dose to help patients live the longest.
I just had one other quick question just with regards to the melanoma and the lung cohorts, are those cohorts currently enrolling and maybe where are they with enrollment?
Yep, they're currently enrolling. We've not shared details on the current enrollment, but they are currently enrolling. Absolutely.
Okay. All right, all right. That's all I have. Thank you so much. We've run out of time, so I'll thank everybody for taking the time to do this with us and to our listeners for taking time to join.
Thank you, Ami, always a pleasure, and thanks to everyone for listening.