Okay. Good morning, everyone. Thanks so much for joining us. My name is Sara Nik, Vice President of Equity Research at H.C. Wainwright, and I cover Cantargia with a buy rating. In today's session, we'll be discussing IL-1RAP as a therapeutic target in pancreatic cancer and the case for nadunolimab. For decades, treatment of pancreatic ductal adenocarcinoma, or PDAC, has been defined by cytotoxic chemotherapy, but 5-year survival in the metastatic setting still hovers around only about 3%. In recent years, the field's attention has turned to where the real treatment resistant lives, the dense inflammatory stroma that wraps a tumor and shields it from therapy. Nadunolimab, Cantargia's anti-IL-1RAP antibody, is mechanistically distinct and, as we'll be discussing today, goes after that inflammatory stroma directly in a way that could potentially complement modalities that have recently been showing promise in PDAC treatment, including RAS-directed therapies. With that, I think we're set up for a very interesting and timely discussion. Just by way of outlining our talk today, we'll be first setting the stage on the landscape of pancreatic cancer and the biology of the IL-1/IL-1RAP axis in the tumor microenvironment. We'll also be digging into the clinical data on nadunolimab and wrap up with the current competitive and strategic landscape, how nadunolimab specifically fits into the evolving treatment paradigm and what that path forward could look like. I'm delighted to introduce our two experts today, both from the University of Miami's Sylvester Comprehensive Cancer Center. First, we have with us Dr. Jashodeep Datta, a surgeon scientist and the DiMare Family Endowed Chair in Immunotherapy and Associate Professor of Surgery, specializing in gastrointestinal and hepatobiliary malignancies. He serves as the Associate Director of Translational Research at the Sylvester Pancreatic Cancer Research Institute and co-leader of the GI Site Disease Group. His research focuses on the tumor immune microenvironment in pancreatic cancer, which really places his work at the heart of today's topic. He earned his MD from Vanderbilt, completed his general surgery residency at the University of Pennsylvania with a postdoctoral fellowship in tumor immunology, and trained in complex general surgical oncology at Memorial Sloan Kettering. We are also joined by Dr. Peter Hosein, a board-certified medical oncologist and associate professor of medicine and co-director of the GI Cancer Site Disease Group at Sylvester. His clinical and research focus is on GI cancers, with a particular emphasis on pancreatic cancer, and he leads an active program of clinical trials testing novel combinations, including immune targeting and stroma-modulating approaches. He has served as principal investigator on numerous phase I and II trials in liver and pancreatic cancer and as co-investigator on national phase III studies. He completed his internal medicine residency and his hematology oncology fellowship at the University of Miami/Jackson Memorial Hospital. Drs. Datta and Hosein, thank you both so much for joining us today. Thank you for having us. It's a pleasure to be here. Yep. Maybe to start, to just get right into it and orient our audience and set the stage for our talk today, could you each give a brief overview of your practice? I know I gave a bit of an intro there, but specifically the PDAC population you treat most often, and maybe within that, roughly what proportion present as resectable versus locally advanced or metastatic? Dr. Datta, we can start with you. Yeah. I am a hepatobiliary and pancreatic surgical oncologist. I operate on patients oftentimes with a lot of complex problems in and around the pancreas. My practice is really driven by patients who come to our center for second and third opinions for unresectable, potentially borderline resectable pancreas cancers. From the vantage point of where I see patients, almost three-quarters of patients have what we call some involvement of blood vessels in and around the pancreas, so they're borderline resectable or locally advanced. A smaller fraction of our patients are what we call resectable. That's my practice. Of course, we see a larger group of patients in the metastatic setting as well. I operate on these patients following, typically, systemic treatments with chemotherapy and potential novel combinations. Okay, Dr. Hosein? I am the oncologist who is the quarterback on the team, usually taking care of patients from the time of diagnosis all the way through. The vast majority of people with pancreatic cancer are diagnosed with advanced disease. More than half of patients who come in already have metastatic pancreatic cancer. I also see patients with localized pancreatic cancer because most of those patients require chemotherapy either preoperatively or postoperatively. A big part of my practice also is clinical trials and bringing novel treatments to these patients at all stages, newly diagnosed, patients who are referred in later down the line for second opinions. I see the entire range. Great. Maybe building on that, the PDAC treatment landscape is clearly at an inflection point today with the recent RASolute 302 data for Revolution Medicines' divarasib being, I would say, arguably the most meaningful overall survival advance we've seen in metastatic PDAC in a long time. Against that backdrop, where do you both see the biggest remaining unmet need now sitting? Dr. Hosein, we can start with you. Yeah. Immediately We need access to RAS inhibitors for all the patients, and that is happening. There's expanded access for daraxonrasib coming, and hopefully, there will be an FDA approval soon, maybe sometime this year. That will be likely in the second line. In other words, patients with metastatic disease who have had chemotherapy upfront would be then candidates for a RAS inhibitor as a second line or beyond. Access is the first problem that we have, and millions of people around the world and thousands of patients in the United States are trying to get their hands on these promising drugs. As a community who studies pancreatic cancer, what we are trying to do is to move the RAS inhibitors further up the line, so bringing up into first line so there are trials ongoing. In localized patients, preoperatively, postoperatively, also trials are ongoing in that space. I believe in the next few years, RAS inhibitors will be incorporated into every stage and every line of therapy. That will open up opportunities to look into what should we do if somebody has been exposed to a RAS inhibitor and develops resistance, because it's known that most patients will develop resistance. In the RASolute 302 study, the average time to development of resistance was approximately eight months. Even though this is a very promising treatment, and I would say it's not arguable, but it is the biggest advance that we've ever had in pancreatic cancer. The truth is that this will help a lot of people and help them to live longer and better quality lives, but there will still be a big unmet need in patients who have developed resistance to that therapy. We haven't seen that many patients developing resistance yet because the drugs are now getting into patients. In a year or two from now, that's going to be the biggest problem that we have. Yeah. I'll piggyback on that and say that we're all incredibly excited. Our center, as well as many others, have been at the vanguard of putting patients on these studies. We're learning the lessons from these trials. I think I want to emphasize the fact that while this is a massive advance, it does not solve the problem of pancreas cancer, either in the metastatic setting and perhaps as we move these therapies further into the earlier lines of therapy in the earlier line settings. It does give us a new backbone, a new foundation to study the biology of pancreas cancer and to move the needle even further, and sets up a new set of questions. Like for example, why do some patients not respond initially? For the vast majority of patients who respond, why do they develop resistance? Beyond looking at the cancer cell alone, RAS is a driver of the cancer cell program. Beyond the cancer cell alone, what are the microenvironment-derived features making this pertinent to this call? The stromal features, the myeloid biology features that limit the durability of these RAS therapies. I think that's the next step in the field. Okay, great. I guess building on that a little more now that we see how you see the field advancing with RAS inhibitors as a potential new backbone for treatment, what kind of potential modalities do you see this really opening up in the next phase of treatment? Maybe Dr. Datta, we can continue with you. I think the critical features are understanding what happens at the level of the cancer cell and then what happens at the level of the microenvironment. I think it's important for people on this call to understand that whether it's in the localized setting or in the metastatic setting, if you cut across a pancreas cancer sample, a small minority of that population is actually tumor cells. 80% of a pancreas cancer, let's say in the pancreas itself, is comprised of other cells like stromal cells, fibroblasts, myeloid cells, immune cells that promote immunosuppression. That's the vast majority of the tumor mass. That scaffold is very important because it's not just a bystander. There's a lot of signaling happening. Again, coming back to the question of RAS inhibition and this new therapeutic backbone on which we can innovate, I think it opens the door for combinations for this adaptive resistance that I talked about. How do we bring in therapies that modulate, remodel the stroma? How do we bring in therapies that mitigate, reduce the inflammatory signaling from that myeloid compartment that we've been talking about? How do we bring in therapies that rewire the metabolism of the tumor? Then all of this to see if the holy grail of durable responses in solid tumor is to deploy immunotherapy. Can we then prime the tumor in such a way that perhaps it creates a good environment for immunotherapy to work? All of these are the combinatorial questions that I think come up. Thank you. Maybe Dr. Hosein, for you, just speaking of your experience now, how satisfied are you with the current first-line regimens that are available, and does the emergence of these RAS inhibitors now change how you'd think about optimizing that setting? Absolutely. I would have to put my satisfaction as very dissatisfied with the current available frontline therapies. We have chemotherapy, which have been around for approximately 15 years, that the regimens that we use commonly now, FOLFIRINOX, Gem/Nab/Paclitaxel, more recently, NALIRIFOX. These treatments are very heavy, take a big toll on patients, lot of side effects, and work sometimes, but it comes at a high price. We see some patients who derive benefit, but we definitely need to improve on chemotherapy. We now have a path forward with that. Many of the trials now for the first-line therapy, the first option when somebody's diagnosed, are incorporating RAS inhibitors. In fact, there are trials ongoing right now with chemotherapy plus RAS inhibitors in the first-line setting, and even chemotherapy versus a RAS inhibitor without the experimental group, without chemotherapy. There's a trial ongoing with daraxonrasib only as a first treatment for metastatic pancreatic cancer versus chemotherapy or chemotherapy plus daraxonrasib. You can imagine if that's a positive study with daraxonrasib winning that as monotherapy, then it would be really a paradigm shift if a new patient with pancreas cancer comes in and you say, "Okay, we can give you a pill instead of giving you heavy chemo." That would be very different. Just to take a step back and look at the overall landscape, I think we have to relearn everything. A lot of the work that we are doing from a preclinical standpoint in the laboratory and from a clinical standpoint, everything has to now be reimagined through the lens of a RAS inhibitor, because that inevitably is going to be a part of the treatment throughout. Even what Josh was mentioning about stromal modulation or looking at metabolic pathways or trying to incorporate immunotherapy, all those things now have to be built on a foundation of RAS inhibitors. I think that the landscape shifted so much a few weeks ago when the data were presented at our national meeting. When people talk about paradigm-shifting data, this is a classic example. Yep. Thank you. Dr. Datta, anything you'd want to add to that, or? I think Dr. Hosein covered all of the bases. I think the one other piece to add to this is, of course, we're talking about the largest bucket of patients, which is patients who present with metastatic disease. I think it's worthwhile to talk about there's a huge arm of our field that's trying to improve early detection of pancreas cancers, and we've seen some small shifts in earlier diagnosis, patients presenting with more local disease. If you look 20 years ago, 80% of patients were presenting with metastatic disease. That number is closer to 65%, 70%. We're seeing more and more patients. Of course, we're going to move the needle in the metastatic setting with RAS inhibition. Also thinking about how we can manage the patients whom we can cure. I think it's worthwhile to talk about those patients, too, because while, again, the standard of treatment is surgery and chemotherapy in that particular setting, with or without radiation, it's important to also understand what's happening in the biology of those patients. I think it's compelling to think about, and we'll talk about that later in this call, compelling to think about designing studies where we're combining rational, targeted combinations of RAS inhibitors, chemotherapy, with or without these biologic drugs, such as the one that we're discussing today, nadunolimab, perhaps earlier in the disease setting, so we can understand the biology and also help increase the rate of cure. I think we want to cure patients. That's our job as oncologists, whether surgical or medical. That setting is very important as well to think about. No, thank you for that. Thank you both for that, the overview of the landscape and the unmet need that we're still currently facing, even with these paradigm-shifting advances. Now, I'd like to move to the underlying biology that we touched upon briefly before, specifically looking at the IL-1RAP biology and the tumor microenvironment. For you, Dr. Datta, moving to the IL-1RAP, IL-1 signaling pathway, how prominent is that in PDAC in the tumor microenvironment, specifically relative to other signaling pathways? Is it a primary driver of progression and immune suppression, or is it one of many? Yeah, I think to do this, I'd like to present some slides while I'm talking. I hope you can see my slides on the screen here. I think the biology of IL-1 is fascinating. Yep For many on the call, you might recognize the name David Tuveson. David Tuveson was a past president of the AACR and had a seminal discovery back in 2019, which was published in "Cancer Discovery" that you can see on the screen, where his group showed that IL-1 signaling derived from the tumor cell can actually promote this concept that we describe now as stromal inflammation, which is a confluence of multiple things. It's a convergence of how fibroblasts that, again, I talked about 80% can be fibroblasts and immune cells in the tumor microenvironment, all suppressive, working together in these networks. There is inflammation in that network, and that ongoing inflammation actually reduces the efficacy of chemotherapy, immunotherapy, and now we believe also RAS inhibitors. There are multiple inputs of IL-1 signaling that we've learned since that time. Our group, as you see with the PMN-MDSC, which are basically myeloid cells, these are immunosuppressive myeloid cells, along with other groups, have shown that these all converge on IL-1 signaling. When you ask the question about whether IL-1 is just one of many, well, it is one of many, but we think that it is really one of the most dominant ones because there are so many cellular inputs, as you can see here. You don't really need to understand the specifics of the signaling, but what you need to understand is that all of these inputs converge onto IL1RAP, and IL1RAP is the common denominator between all of the receptors that receive inputs from IL-1 signaling. They propagate those signals, further creating pro-inflammatory circuits, immunosuppressive signals, and it just keeps this circuit going in the pancreas tumor microenvironment, so much so that it can actually bypass the dependence that a cancer cell has on its own signaling pathways, such as KRAS, and we will talk about that in a second. I think it's also important to understand from the perspective of IL1RAP, that for the longest time, people thought that IL1RAP signaling, and this I am showing you is a conglomeration of multiple patients with pancreas cancer that have been coalesced in this atlas called the NCI HTAN atlas. Each dot is a single cell, and the color actually shows the expression of IL1RAP, and you can see it's expressed quite interestingly in multiple cellular compartments, just like I was showing on this cartoon. One of the things that we found is that it's expressed mostly in these myeloid cells and these fibroblasts. When we looked and asked the question of the treatment resistance, which is so important, again, thinking about even patients with localized cancers or metastatic cancers getting first-line chemotherapy at this point, which is still standard of care. We find that the expression of IL1RAP in multiple compartments, including tumor cells, the stromal fibroblast cells that I talked about, and then the immune and myeloid cells, were all increased in patients who had chemo-resistant biology. Again, the details are not important, but I think the importance is the biology of IL-1RAP, where it's expressed. It's very widely expressed in the microenvironment of pancreas cancer, and particularly in those suppressive myeloid cells, and generating these networks of myeloid stromal communication. All right. Thank you. That was a very helpful intro and background. With that, what do you consider to be the most compelling preclinical data supporting IL-1RAP as a viable therapeutic target in PDAC, including for an antibody, anti-IL-1RAP antibody like nadunolimab specifically? I would start by saying that the folks at Cantargia, who we've been collaborating with scientifically for several years, and now we're moving some of the concepts into clinical trials, they've actually had a very robust discovery pipeline working with investigators both in Europe and in America to understand the biology of IL-1RAP. From our vantage point, when we discovered these data, where the expression of IL-1RAP was not just in the tumor cell, and I would say that that has been the prior focus of the efforts, is understanding what's happening at the level of the tumor cell. When we discovered these data that I showed you on the previous slide, we went back to the trial that you discussed and described very early in the call, the CANFOUR trial, which they had run in Europe, and I suspect you might be talking about that a little bit more. The trial that they ran combining nadunolimab with chemotherapy. We asked them to look at the duration of response of patients, and how it correlates with the expression of IL-1RAP in the myeloid compartment and the stromal compartment, the two compartments where we were now discovering that IL-1RAP actually makes a huge impact. Guess what? IL-1RAP expression, very similar to tumor cell IL-1RAP expression, actually stratified patients into survival. Those with high IL-1RAP expression actually did better on the drug with chemotherapy. We've generated a lot of data. Again, the details here are not important, but what we've done is we've treated genetically engineered mice, meaning mice that spontaneously develop pancreas cancers that very closely mimic human pancreas cancers, and we've treated them with nadunolimab. We found, again, this is a wheel that shows how the signaling between the myeloid compartment and the fibroblast compartment is changing with treatment. We find one of the strongest pathways that we are seeing downregulated as a result of nadunolimab treatment in the preclinical setting is the IL-1, IL-1RAP signaling pathway here that's highlighted in purple. Taking it one step further, I had mentioned, and I introduced the concept of, well, perhaps modulating all of these myeloid stromal networks in the pancreas microenvironment, in addition to RAS inhibition, can maybe make immunotherapy work better. Ultimately, we want T cells to kill cancer cells, and that actually promotes durable survival in many patients with solid cancers. Well, we see that with nadunolimab. This is actually in patients with paired biopsies pretreatment and posttreatment. What we see very interestingly is that all the green stuff, all those little green cells, those are the suppressive myeloid cells that you see pretreatment actually get significantly reduced posttreatment and vice versa. The T cells that you don't see much of here, which are in pink, they actually traffic to the pancreas tumors following treatment, and these cells actually tend to be more effective, as we've shown in our preclinical data. This is in patients, this is in our preclinical systems, where we've shown that a specific pool of T cells can be invigorated by this treatment that can make immunotherapy more effective. We have a new publication in press, that should be released soon. These are the exciting preclinical data. I will say one other thing. These genetically engineered mice that develop spontaneous pancreas cancers, and this is a specific one that we use called the PK model. These are highly aggressive tumors. We have not seen monotherapies work in this particular model. When we treated these mice with nadunolimab, the mouse version of nadunolimab, the preclinical version, we saw some very impressive responses in the pancreas. These mice develop tumors at four and a half weeks, and they're universally dead by six and a half weeks. We saw very significant regressions of tumor with singular treatment with nadunolimab. We've done multiple combination studies, and this is now published, where we combined nadunolimab with what is considered standard of care at this moment, which is chemo plus minus immunotherapy. We saw here, as you see in the blue curve compared to the purple curves, the pink curve is actually just nadunolimab alone. It's the blue curves compared to the purple curves where we see a strong separation in a very hyperaggressive mouse model of pancreas cancers when you combine nadunolimab with chemo and immunotherapy. These are the preclinical data that I think really give us excitement that this is not just another additive signal, that there is something happening at the level of the signaling that we are actually remodeling to make standard therapies and immunotherapies work better. We believe that these data can be extrapolated to explain the resistance to RAS inhibition, and those studies are ongoing. Okay, great. Thank you for that. Maybe expanding on that a little bit further before we turn to clinical strategy, could you describe a bit more how you think about IL-1RAP blockade in the context of RAS inhibition? Are they complementary to each other? You touched on this, but maybe expand a bit more on the mechanistic rationale for potentially combining them. I'm glad you brought that up, and I have a slide on this just following this, but I'll just set the background. We have some incredibly sophisticated ways of understanding this. I showed you some single-cell biology, et cetera. Now we're trying to understand this in patients as well. We're developing the appropriate collaborations that we need, both with Revolution Medicines and other major players in the field on the pharmacology and on the biotech side, but also with academic partners to understand this. This is not exactly data from daraxonrasib, but this is also another pan-RAS inhibitor. This is publicly available data from a Boehringer Ingelheim compound called BI-2493. This was published in "Science Translational Medicine" and in collaboration with one of our partners in New York. We've gotten access to this data. Just as an example of the synergy, the question that you asked between RAS inhibition, just take this as a sort of a broader RAS inhibitor foundation and IL-1RAP. I want to coalesce the biology that you saw in previous slides with what I think will be really a slam dunk combination. This is the single-cell data in the untreated setting, and you see multiple different groups there. These are all different cells in the microenvironment. That's not really important. I want you to see what happens early on with treatment. Those myeloid cells that I talked about, they start emerging early in treatment. Remember, these mice are responding to this treatment. At endpoint, meaning when the mice stop responding to treatment, they're becoming resistant to treatment, we see a massive emergence of those myeloid-derived suppressor cells that I talked about, if you remember from those human patients, where we see significant expression of IL-1RAP. Guess what? We see significant emergence of the cells, but more importantly, we see the expression of IL-1RAP in those cells at resistance. Of course, this is correlative, but we believe from all the data that we've seen, all the signs that we've generated, and the signals that I think we are seeing in some of the early experiments that we've run, that these combinations can actually be synergistic, not just additive. What we are doing is we are understanding this at the level of the biology and tackling the biology of resistance. As I mentioned, and as Dr. Hosein mentioned earlier, all of these patients are going to become resistant to the treatment. There may be a few patients that have durable responses, but by eight months or so most patients are developing resistance, and we believe that if we unlock the biology by doing studies like this and then validating these in patient samples, we will be able to find the optimal combinations. In our case, we truly believe that IL-1RAP in the myeloid compartment is going to be a strong determinant of that resistance. Oh, thank you for that. That was a comprehensive setup and definitely a compelling foundation to build upon the clinical strategy. Now, let's turn to clinical development for the last portion of our talk today. As we mentioned previously in the prior phase I/IIa CANFOUR study, Cantargia did show that although IL-1RAP seems to be a marker for poor prognosis in pancreatic cancer, high IL-1RAP expression was actually linked to better outcomes in patients when treated with nadunolimab plus gemcitabine plus paclitaxel with a median overall survival of 14.2 months and a one-year survival of 67%. Now, as they are advancing nadunolimab in light of recent landscape developments, the company is currently mapping out several positioning paths for nadunolimab in metastatic PDAC, which I'll outline a couple of here. First, in the near term, looking at combining nadunolimab plus RAS inhibitors in the second-line setting in patients that have progressed on first-line chemo. Also looking at the first-line setting in a combination with RAS inhibitors on the thesis that we discussed that IL-1RAP blockade can both enhance efficacy and really counteract that resistance that could limit RAS inhibitor durability. A third potential in the longer term would be nadunolimab plus chemotherapy in the second line for patients progressing on first-line either RAS inhibitors or chemotherapy. Maybe to you, Dr. Hosein, given the different development paths being considered, which of these do you find to be the most compelling in your view, and why? Yeah. As I mentioned at the start of the meeting, it is very likely that daraxonrasib will be approved in the U.S. this year in a second-line setting. That will be a foundation to build on. In other words, if we are doing combination studies, the FDA-approved standard in the near future will be a second-line RAS inhibitor. I think that would make it relatively easy from a strategic perspective for any company to combine drugs with the RAS inhibitor, starting in the second-line setting. For example, if you wanted to do a frontline study, you will go to the guidelines and go to the FDA and say, "Well, what is the standard in the frontline setting?" Then you have to build on that. Now, the standard second-line option will be daraxonrasib likely in the near future. That will be the foundation to build on. If you're doing combination studies, it will be likely daraxonrasib plus something else. Eventually, if you want to go to a registrational pathway, likely there will have to be some type of randomized study with daraxonrasib as a control arm. I think the fastest pathway to development now would be to combine in the second line and show safety data to begin with, and of course, efficacy. If you can demonstrate biologically that you're delaying resistance to the RAS inhibitor, then that would be potentially valuable to move forward into a larger study. Eventually, I think that looking at second line chemotherapy plus experimental drugs like nadunolimab in patients who have gotten RAS inhibitors in the frontline would be appropriate, but we don't have RAS inhibitors in the frontline yet. The trials that are ongoing now will take at least another year or two to read out, even though the pace of development here is incredible. From the time we participated in the RASolute 302 study and we enrolled patients last year. In one year, the study accrued very quickly, read out as being positive, and will likely go to the FDA soon. That pace of advancing is very quick. It's possible that we may see it come into the frontline possibly within the next year or two. A second-line trial after having a RAS inhibitor in the frontline is something that can be evaluated later on, but that's not really standard because most patients coming into second line now would not have received a RAS inhibitor unless they got it on a clinical trial, and those are a small minority of patients. In terms of kind of charting a strategy to capitalize on the developments now, I think a second-line combination study makes perfect sense. Thank you for that. With that, Cantargia is planning to initiate a phase I-B/IIa study targeting either Q4 of this year or first quarter of 2027, actually combining nadunolimab with RAS inhibitors in the metastatic PDAC patients who have progressed on first-line standard of care. The company so far has guided that the primary focus will be on safety, tolerability, and exploratory endpoints, looking at inflammatory immune and microenvironment parameters. With that, again to you, Dr. Hosein, to start, given the core hypothesis that we've discussed, that blocking the IL-1/IL-1RAP axis can relieve that immunosuppressive tumor microenvironment driving RAS inhibitor escape. In your view, is the study design as it's currently outlined sufficient to demonstrate a biological effect? Absolutely, yes. The key is, as Cantargia has done in their previous study, is to be very thoughtful and proactive about collecting the tumor samples and the blood samples that we need to answer these questions. Of course, if we're doing a single arm study with a RAS inhibitor plus nadunolimab, we probably will not be able to make conclusions about the effectiveness above the RAS inhibitor only. You'll be comparing with historical controls, which is a little bit difficult to do. We should be able to see biologic readouts from biopsies or from blood samples during the treatment. Cantargia has demonstrated the ability to execute trials like that in the past. If that is done, I think we should be able to see the contribution of nadunolimab in that setting and could lay a foundation for future research. Dr. Datta, anything you'd like to add to that? I think it's important to mention for this audience, and I think both Dr. Hosein and I touched on this, that the data, yes, while daraxonrasib has a different pharmacology, it's a tri-complex inhibitor. It inhibits the more active form of RAS in the GTP bound phase, et cetera. The pharmacology is fascinating and spectacular. I think we should take a step back and look at the lessons that we've learned from other solid tumors where RAS inhibitors have played a major role already. For example, lung cancers with G12C mutations, for example. If you look at the data, and if you compare that with what we know in pancreas cancer, I think a few signals emerge. One, obviously, the responses are different in pancreas cancer compared with some other solid tumors. Number two, it's interesting to note that while a majority of the resistance that happens in some of the other solid tumors, and even in other GI cancers that are non-pancreas, to RAS inhibitors happen still at the level of the cancer genome, at the level of the cancer cell, such as RAS reactivation or RAS amplifications and other types of things. Something to do with reactivating the same pathways that that drug is trying to block. In pancreas cancers, I think what some signals are emerging from studies done by Andrew Aguirre and other folks, is that a lot of the resistance may be driven outside of the cancer cell. I touched on this concept earlier, that the microenvironment in pancreas cancer is so dominant and so pervasive and creates so many of these inflammatory networks, it can bypass the dependency that the cancer cell has on RAS signaling. Hit the RAS pathway as much as you can is absolutely the next best step, but you have to think beyond that. I think to put what Dr. Hosein said in perspective, and to answer your overall question about do you think this is a rational strategy, absolutely. Because of the data that we found, that IL-1RAP signaling is such a dominant mechanism in the microenvironment, and we have early data to suggest from the preclinical studies that emergence of IL-1 signaling in the microenvironment is a mechanism of resistance to RAS inhibition. Combining these makes a lot of biologic sense, but now you're tackling the cancer cell, and you're also tackling what's outside the cancer cell. I just wanted to piggyback one thing also to give a little bit of a big picture overview here. There are conceptually different arms of the immune response, Josh is the card-carrying immunologist here. From a, not a lay perspective, but from a slightly different simplistic view of this, there are some tumor types like melanoma, for example, where you can sprinkle a PD-1 inhibitor and just a little touch of immunotherapy, and patients will have dramatic responses. That same drug will have zero response in pancreas cancer. It's not only unblocking the immune checkpoint, but this immunosuppressive microenvironment is an untapped area that has not been targeted by any treatment so far. Having a clinical-grade antibody, which is what Cantargia has, in a space where there isn't too much going on, but we know that this is one of the keys to unlocking resistance in pancreas cancer, not only to immunotherapy, but to chemotherapy and maybe RAS inhibitors as well. That is very valuable because there are many people who think about doing things that can target the tumor microenvironment and to relieve this suppressive phenotype of the tumor, but don't have drugs that are this advanced in development, right? This drug has already been through phase I, has already shown some signal in pancreas cancer, and I think this is a natural progression to continue the development of the drug. Again, it's not trivial that this is safe to give in human patients, right? We know about the toxicity profile, and it does not overlap significantly with the toxicity profile of a RAS inhibitor. Even when you combine with chemotherapy, maybe there's a little more leukopenia or neutropenia, which is dropping off the white cells, but that is easily manageable nowadays with supportive care. Having a drug which is ready to go in the clinic to be able to layer on to existing treatments and new treatments like RAS inhibitors, I think is a combination which is sort of a win-win that it will allow it to move quickly through development if we see the signal that we believe that we will see when a trial like this is done. Again, targeting the myeloid environment or the immunosuppressive nature of the pancreas cancer has not been successfully done to date. This is a strategy that the company is taking and that we are involved in the science that underpins that approach. We are really strong believers that this is the way that we will crack the resistance and the very unfavorable behavior of pancreas cancer in general. We are very optimistic about approaches like this, and that's the reason why we are talking to you here today. No, thank you for that. No, that's definitely solid, bringing together all the different facets, based on the clinical data that they've already shown and the rationale for combining the study, the assets moving forward. Maybe one last point on this, you mentioned the signals to be looking for, given that the study, they've shown clinical data in the CANFOUR study before, but in the context of the study that they're going to be initiating in the coming months, given that this particular phase I-B/IIa will have a small N to start. What exploratory signal or even preliminary would give you even further conviction that this combination is worth advancing into a larger registrational study? Let's start with you, Dr. Hosein. Yeah. I think we might be able to see a signal of longer duration of therapy. Really the proof of concept will be in the translational research that will go alongside the study. We know from the RASolute study what the benchmark is for the time on therapy for RAS inhibitor. In a small study, you might be able to beat that, but it will still be a little bit difficult to conclude that it's superior unless you do a randomized study. Again, coming back to it, that's why it's so important in small studies to get good biospecimens, collect biopsies, collect blood samples, to be able to look for proof of concept that resistance is being averted or delayed and maybe even in RAS subtypes. Most of the patients in the RASolute study had KRAS G12D or G12V, maybe in some of these uncommon RAS subtypes like Q61H, for example, if we're seeing responses there. That could also tell us that there's some synergy between these treatments and allow us to be able to move it forward. Dr. Datta. I was going to just comment that the interesting data that Cantargia has published on the post hoc stratification from their CANFOUR study, which showed the higher tumor cell expression, I kind of referred to that earlier, I think lays the groundwork for the subsequent studies, particularly this one that's in conception and hopefully deploying in the near future of combining daraxonrasib with nadunolimab because some important questions are, can we detect these signals in the blood as opposed to having to do invasive biopsies? There's a huge explosion of ctDNA techniques. We're working with multiple companies as well as developing our own homegrown technologies to do this. The other question is, well, does the initial setting, meaning does IL1RAP expression both in the blood and in the tissue initially when patients are starting RAS inhibitors, does that make the difference or is it on treatment emergence of IL1RAP? Getting those paired samples, like I showed you in previous examples from our data along with Cantargia, I think is going to be very important as we design that clinching large registrational pathway. Again, to piggyback on what Dr. Hosein was saying, that we've been very thoughtful about developing the infrastructure here to do studies like this. I think Cantargia is very much like-minded in the way that they think about understanding the biologic underpinnings. I think that's going to be key because if we can understand those pieces in different compartments, blood, circulating tumor DNA, tissue, at the level of single cells, then we're going to be able to really unlock the potential of this combination. If you just throw everything in together and don't study it, nothing's going to work. Oh, absolutely. No, that's very helpful. Maybe one of the last things I wanted to touch on today, was actually the neoadjuvant and surgical perspective, and potential for nadunolimab. Dr. Datta, for you, from a surgical vantage point, do you see that there's a potential neoadjuvant or perioperative setting where nadunolimab's stromal remodeling mechanism could be particularly valuable? Well, it's funny you mention that because we've been developing one in conjunction with Cantargia for now seemingly forever. It's really coming to fruition. Big picture from a translational perspective, I believe the neoadjuvant setting is arguably the most important and informative place to test this, understand this biology. Like-minded centers like ours, and this is very hard to do and painstaking to do, we get biopsies before and after treatment in the neoadjuvant setting. Remember, these are patients that we're trying to cure. These are patients that we are trying to treat early to eradicate their microscopic micrometastatic disease to make surgery more impactful. We're learning what's happening before treatment and at the time of surgery. We have a short window, about four to six months or so, where we can really understand what the treatment is doing. Imagine if we could get that on every single patient that we study. We've been doing that. We've done over 100 patients where we understand what's happening before and after at our center, and I know there are other centers out there. I believe that that's the best setting to understand it. If you think about the endpoints, now we can craft and think about creative endpoints where we can get early readouts of that signal that we see at the level of the translation. We are developing a neoadjuvant study with Cantargia, another company that's providing us a PD-1 inhibitor, where we are combining At this moment, the standard of care is chemotherapy followed by surgery. We are combining chemotherapy with nadunolimab and a PD-1 inhibitor in two different cohorts and understanding what's happening before and after treatment, followed by surgical resection to see, again, as I've mentioned very early in the call, we are trying to cure more patients. The neoadjuvant setting allows us to innovate, allows us to understand the biology, allows us to try novel therapies with a thoughtful infrastructure, and potentially can help us cure more patients. Cantargia has been an incredible partner in supporting that initiative to understand this. Remember, the continuum, even though localized patients might be a little bit different from patients with metastatic disease, understanding the biologic continuum is also going to be important. The lessons we learn in the neoadjuvant setting can also perhaps apply to how we think about this in the metastatic setting, and how we can think about the combination of RAS inhibitors, for example. Oh, that's very exciting. Looking forward to seeing how this could be applied and help across the treatment spectrum for these patients. Well, thank you both so much for your time today. Maybe to close, I'd pose this to both of you, of course, while acknowledging that this is still very early days. What gives you optimism or the most optimism about targeting IL-1RAP in PDAC? And maybe, again, taking this big picture a bit further, where do you see nadunolimab and IL-1RAP blockade more broadly fitting into the treatment paradigm? Let's start with you, Dr. Datta. Sure. Yeah. My optimism comes from the convergence of three or four things. One, the strong biologic rationale for why IL-1RAP signaling and disrupting that signaling is important. I think everybody on the call can see that. It is one of the dominant pathways in pancreas cancer that promotes why pancreas cancer is so different and why it's so bad compared to other solid tumors. I think we have now, as Dr. Hosein was alluding to, large amount of clinical evidence that the drug is safe to give, it can be given effectively, and that we can learn from what happens before and after the drug. Then, building on years of work in our laboratories in conjunction with like-minded folks, the preclinical rationale for these combinations, whether it's standard chemotherapy or in the era of RAS inhibitors, combination with RAS therapeutics, and how the plausibility of those combinations gives us hope for the future. I think that's where my optimism comes. I think if you really think about the way that we are developing IL-1RAP signaling, it's going to be one way for us to not just test the biology, but it's also going to be ways for us to select patients for certain types of therapies, monitor responses, and then more importantly, guide rational combination strategies that will move the needle for our patients. Of course, this is a huge victory right now, but we can't just rest on our laurels. We've got to think about the next wave and the next generation of therapies. Dr. Hosein? Yeah. Thank you. I think there's tremendous opportunity still. We started off by talking about the unmet need. There's an opportunity that predated the RAS inhibitor era and will still remain now, which is that the real nut to crack is the resistance that is created by the tumor microenvironment. We know that the immune checkpoint inhibitors, the PD-1 and CTLA-4 inhibitors, have been widely successful, but we have not had a myeloid checkpoint inhibitor. Really that's not maybe the right term for this drug, but thinking about it as targeting this really bad programming that the tumor has to try to overcome that is a tremendous opportunity that we have with this drug and other strategies that we can finally have something that we can go after that resistance mechanism. That is a reason why immune checkpoint inhibitors don't work in pancreas cancer. In following this line of investigation, not only could synergize with RAS inhibitors, but also with PD-1 and CTLA-4 drugs, which the holy grail has been in every single cancer to try to get immune checkpoint inhibitor to work or, quote-unquote, "immunotherapy" to work in general, right? I think there's tremendous opportunity for us to take that forward in pancreas cancer now. To me, that's the thing that has me most optimistic. I appreciate that. Again, thank you both so much for your time today and for all of your insights and perspectives. They're very helpful in laying the groundwork, and awareness as nadunolimab begins, again, its next phase of clinical development in pancreatic cancer. Thank you also for everyone for tuning in and joining us today. Please feel free to follow up with any questions you may have. Have a nice day