Okay, very good. My name is Dan Schmitt. I am the President and CEO of Actuate Therapeutics. I really appreciate you taking the time out of a very busy, hectic, completely filled schedule to make time to meet with us tonight. This is a KOL discussion focused on the Phase II top-line data that was presented this afternoon by Dr. Deva Mahalingam on the Actuate-1801 Part 3B study in first-line treatment of metastatic pancreatic cancer. The trial represents a major milestone in our development of elraglusib, we are really honored to have four world-renowned clinical leaders in GI oncology here with us to provide their perspectives and insights. Before we begin, the lawyers, don't go away, even though you'd like them to. It is now my pleasure to introduce our panel. Dr. Colin Weekes, immediately to my left, is Director of Pancreatic Research at Massachusetts General Hospital and Associate Professor at Harvard Medical School. His research focuses on early drug development and targeting the tumor microenvironment in pancreatic cancer. He is also leading a trial with elraglusib in combination with FOLFIRINOX in metastatic pancreatic cancer. Dr. Devva Mahalingam is a Professor of Medicine and GI Oncologist at Northwestern's Robert H. Lurie Cancer Center. He directs the Clinical Trials Office and the Developmental Therapeutics Unit, where he leads early-phase research across GI malignancies. He is also the principal investigator in our Phase II Part 3B trial and was the presenter in the main session today. Dr. Rachna Shroff is a nationally recognized expert in pancreatic and biliary cancer. She co-chairs the SWOG Hepatobiliary Subcommittee. She led ASCO GI 2024 as the chair and is the national PI for SWOG 1815. Last but not least, Dr. Tony S aab is the David F. and Margaret T. Grohne Professor at the Mayo Clinic and Chair of Hematology and Medical Oncology in Phoenix. He leads GI cancer research across the Mayo Clinic Cancer Centers and co-chairs several national committees focused on hepatobiliary cancers. Please join in in welcoming all four of our panelists. I am really proud to have them here. Thank you. What I would like to do is, this is a fireside chat. I try to make it as conversational as possible, but I would like to begin with Dr. Weekes and ask him to provide an overview of the pancreatic cancer treatment landscape, existing treatment regimens, and his experience with elraglusib. After that, we will have Dr. Mahalingam discuss the Phase II Actuate-1801 Part 3B study and the results that were presented this afternoon. Following that data review, we are going to open it up to the panel with Dr. Shroff and Dr. Saab, who will share their perspectives on the data and how elraglusib may ultimately fit into the treatment paradigm. After those discussions, we will open it up to the floor for any questions that you may have. Dr. Weekes, the floor is yours. All right. Hello, everyone. I think what I would like to do is just sort of outline in general sort of how we think about pancreatic cancer, and that stems from patients who have localized disease all the way to metastatic disease, which is what we're going to talk about ultimately. In patients with localized disease, we sort of break those down into resectable versus borderline resectable and locally advanced. Right now, it is somewhat controversial in terms of what chemotherapy we use in that setting. The two real chemotherapies that we use are either nab-paclitaxel plus gemcitabine or FOLFIRINOX. There's most recently NALIRIFOX, which is, I think, just a fancy version of FOLFIRINOX. I think for most of us, we think about FOLFIRINOX and NALIRIFOX sort of similarly. I would also say that I think that when we think about treating these patients, it's really sort of two therapeutic paradigms, either sort of gemcitabine nab-paclitaxel or a FOLFIRINOX paradigm. I think what's beginning to come out is that we have these different molecular subtypes of pancreatic cancer, and those patients may respond differently to different types of these chemotherapy regimens. I think if I'm talking to my patients about it, I'll say, okay, there's male and female pancreatic cancer cells, and the cancer tumors are an amalgamation of these male and female cells. It may be that, say, the female cells respond to chemotherapy or FOLFIRINOX better than, say, the male cells. What we also know is that sometimes these cells can transition from male to female, and that process is called epithelial-mesenchymal transition, EMT. That's one of the ways that elraglusib works, by inhibiting EMT. In addition to that, elraglusib potentially also alters the immune function. We saw today in the presentation that we see an augmentation of CD8 positive T-cells and then the release of granzyme B from those T-cells. That demonstrates that, in fact, not only are the T-cells present, but they're actually active in killing cells. That's the importance of that piece of information that was presented today. Then in addition to that, elraglusib, it potentially targets the proliferative pathway, which is shown by its ability to inhibit NF-κB. It functions in many ways in pancreatic cancer. I think that's important in terms of pancreatic cancer because pancreatic cancer, if I was to cut that tumor open, it would look very different than, say, if I cut a lung cancer tumor open. If I cut a lung cancer tumor open and look at it, what I'm going to see is lung cancer cells only versus in pancreatic cancer, what we see is an amalgamation of cells. The paucity of those cells are actually the tumor cells. We also see what are called cancer-associated fibroblasts, and there's also called the desmoplastic reaction, which is the stroma or the concrete of the tumor. All those things are active in pancreatic cancer. It turns out that elraglusib potentially targets all of those different components of the tumor. I think that's one of the unique things about elraglusib as a drug for pancreatic cancer. As you said, I have experience with FOLFIRINOX. I've been doing clinical trial FOLFIRINOX over the last couple of years. I think what I've sort of come to the conclusion from that experience. Now that study is a small study, so it's a total of 60 patients, and it's randomized to receive FOLFIRINOX. We were also using a drug called losartan, which is a blood pressure medicine. We think that losartan alters the function of the stroma, and so that's why we're doing that. It also alters, potentially, the whole EMT process. You're asking the question, if we give elraglusib with FOLFIRINOX, do we alter the EMT process and do we maintain cells in an epithelial state where they'll respond to FOLFIRINOX? I think the interesting thing for us in that study is we do have some incredibly long responders who have done really well on that study. These patients had very high burdens of disease to begin with, and they did very well. All the patients that we took care of on that study. It's a much smaller study, so 50 patients total, where all the patients that we studied on that study had eye or vision changes. Their vision changes lasted for just about 24 hours, and then they were fine after that. That wasn't anything that was permanent. These are patients who were on study for, some of them, for two years and really didn't have any problems. I don't see it as a sort of an inhibitory toxicity of this particular drug. I think the question really then becomes, which one of these pathways do we go down in terms of drug development? I think both pathways are valid. I think the control arm for one study versus another, I think there's a question out there about that. I think from my perspective, you want to do a control. The control arm should be whatever the arm is that you're combining the drug with. You're asking that question, right? Does that drug improve this chemotherapy, FOLFIRINOX? Or does that drug improve the chemotherapy, nab-paclitaxel and gemcitabine? I think the real importance of this study, at the end of the day, and then I'll be quiet, is if you think about pancreatic cancer drug development. Now Excuse me. FOLFIRINOX was studied in 2011. I think nab-paclitaxel and gemcitabine was around 2013. It's been quite some time since we've had anything that says it improves outcomes for patients with these chemotherapy backbones, despite a lot of negative trials, right? We could fill this room with negative trials. I think that's really the importance of this study is that we're, for the first time, seeing an overall survival benefit. The magnitude of that benefit, I think, is actually substantial. That's how I think about this study. Given what I know in terms of my experience with patients with FOLFIRINOX, I'm really quite excited about what we're seeing with this drug in the context of chemotherapy. With that, I'll be quiet and I'll pass it on to the rest of the team. Dr. Mahalingam, some very compelling data was presented today. We have your slides here if you want to refer to any of them. From your experience, before we get into the data, what are some of the biggest challenges that you see patients facing as they go into first-line treatment? What are the current limitations of the alternatives they have right now? I think in general, when patients presented metastatic pancreatic cancers, usually they are, I would say about a third of them are already symptomatic because of the disease burden that they have. A lot of them have lost weight, poor nutritional levels because the pancreas is really part of your kind of absorption of food. Can we get the microphone turned on, please? I think the challenge is, the first question we are often asking is, are they a candidate for treatment versus symptom management versus nutritional support? There's a lot of things that goes in when someone initially presents. If they are usually a candidate for treatment, we are kind of deciding whether we want to treat them with one of the two chemo backbones that Colin just mentioned, the FOLFIRINOX chemotherapy or the gem-nab-paclitaxel chemotherapy. I think there is possibly a selection bias, especially in community practices, where patients may want to lean a little bit more to the gem-nab-paclitaxel because they feel it's easier as opposed to the FOLFIRINOX, where maybe some of the toxicity profiles are a bit harder for kind of perhaps older patients and frailer patients. There's certainly a selection bias in there. Generally, when we think about the patients, we're trying to figure out what regimens. On top of that, we're then trying to see if there's a regimen, is there a clinical trial that we can add them onto as well. In this trial, by way of background, this started as an early phase study. As it developed and we went into pancreatic cancer, we allowed a flexibility of patients to come in. We didn't really restrict who could come in. I suspect that's part of the reason why. You're seeing a little bit of the depth early in the study, I think that the drop kicks in, then you start seeing this kind of slowing down of the progression, which is why the survival benefit is seen later. When we did the early trials with elraglusib, we saw hints of something. These were patients who were all refractory to multiple lines of treatment, we started seeing complete response in melanoma. That said, maybe there's an immunomodulatory function going on. As we developed the drug and came into an earlier line, in this case, in the first-line setting, then we can appreciate that survival differences that we may not have appreciated if someone is in the third-line pancreas, for example, where the survival is usually less than six months. I think that's really the journey of the drug and how we kind of think about trials in general. I'm surprised. I can tell you when I started the study, we as clinicians, we want to see response and shrinkages of tumor. When we start seeing patients that are still in the study one year on, we're going, "What's going on here with this treatment?" That's my little spiel on that. Yeah. Please. I would also say that in the FOLFIRINOX-treated patients, if you look at most of the trials that are out there for pancreas cancer, it's going to be nab-paclitaxel and gemcitabine because it's very challenging to combine with FOLFIRINOX. Most of the studies that we see with FOLFIRINOX, they actually don't make it because of the toxicity associated with the combination of the drugs. In my case, with my study, what I've really actually been really pleasantly pleased with is it's very tolerable in terms of combination with FOLFIRINOX. What we see as patients go along, they actually feel back to their normal self, at least in my study. I think I've been pleasantly surprised, as long as we hear data about that experience as well. Colin, when you say they feel back to their normal self, is that different than what they would have normally been on the FOLFIRINOX? Yeah. FOLFIRINOX is challenging. I'm not saying patients are not having toxicity associated with FOLFIRINOX. They are. What I have appreciated many times is patients saying to me, "I'm able to do the things that I was able to do before I was diagnosed with cancer." They really feel like they're getting some of their lifestyle back. When you look at their partners, which is really what I think the telltale thing in this conversation, when you look at their partners, their partners are elated because they have their spouse back. I think that's something that I find very encouraging with this. Excellent. Devva, in terms of your phase II data, we have a few slides. Are there any ones that you want me to pull up or you would like to direct and sort of run through? Because not everybody was at the presentation today. If there's any highlights that you think are important that the audience here has access to. This is a multi-center effort, so I want to thank all of the people on stage that enrolled patients onto this study. Let me just start with the mechanism of action. That's the first thing, right? It's been a while since we have kind of come up with a new drug with a kind of different mechanism of action. It's not only pancreatic cancer, but just to have a drug that can target a protein called GSK-3 beta itself is unique. It has been attempted before, I think there were two key drugs that came before this, but pharmacokinetically, it was just not as good because of shorter half-lives and poor tissue distribution and rapid clearances. This drug came in and tried to hit a target that we know has kind of proven effects across multiple pathways. We only listed about four or five targets here, but there are multiple kind of regulatory targets in normal cells. In cancer, obviously, when you inhibit it, you kind of see all these things that this has been shown in laboratories and also pre-clinical data. We see this kind of pro-apoptotic signals that are increasing cell proliferation. Colin referred to the EMT, and this is really relevant in pancreatic cancer as well as the fibrosis down there because pancreatic tumors are usually fibrous tumors, and we can't even get drugs penetrated into the tumor. The question is whether it's allowing more chemo to penetrate into the tumor as well. Ultimately, this is obviously the thing that I think probably helps that survival curve, that survival benefit we're seeing is the T-cell and the NK cell activation in tumors. Usually a hard cancer for immunotherapy to even work in the first place. I think the key thing with this study is that this is a first-line study that we saw an improvement in overall survival. We also started seeing things like neutropenia in the patients. The question is, why were the patients getting neutropenia? I think Andrew obviously summarized it well, is that the assumption is that elraglusib has a regulatory role in hematopoietic stem cells. It does actually help proliferation of cells. Some of the older agents, you actually see a neutropenia, that means the stem cells are trying to regenerate. When you come in with chemo, it causes more of that neutropenia. In essence, we did not see any of this kind of toxicity associated with neutropenia, such as febrile neutropenia and sepsis. That was one of the things we noted. The twice-weekly regimen was obviously something that had been developed as a drug when we opened it, that should we do a weekly regimen or a twice-weekly regimen because of potentially the half-life of the drug and the pharmacokinetics. We realized that the weekly regimen would surpass compared to the twice-weekly regimen. We ran the study. I think the only other thing I would say here is, let's go to the Kaplan. This is the main slide. As you can see in the modified intent-to-treat population, we see the improvement in survival but as I pointed out in the thing is we see this sharp decline in the first two months in about, I say on average, about 15% of patients between the two arms. We see this actually, we're starting to see a lot of this in pancreatic cancer trials where we see this early drop-off probably because the patients have a poor biology, and we're starting to see a lot of things about basal subtypes which are a lot more aggressive, and they tend to perhaps drop off a little bit earlier. You start seeing the Kaplan-Meier curves diverge and stay separated. I think that's when the drug starts hitting you. I think we have a slide. I don't know whether it's after this. Let's just say we assume that a patient can at least complete the first cycle. We selected the patients. We have maybe a little bit more stringent. Remember I said we were not as stringent in the trials and in our patients that were enrolled. If we can be a little bit more stringent, I think we will. You put it at the end? Okay. This is a slide at the end that he added in. Yeah. Anyone who's kind of completed one cycle, that's all we want is one cycle. Then we looked at the analysis in a different way. You can see in the red there that the median overall survival then steps up to about 12.5 months. The 8.5 is actually what we saw in the MPACT study with their overall survival as well. We are kind of seeing this difference again of approximately three months. I think anytime we see a three-month, I think the discussion had said that. Four months, yeah. Four months. Sorry, my math, I'm tired. Four months in this thing, but anything above three months I think would be kind of significant. Obviously, this is just an analysis that we are doing to see if we can account for that rapid decline in a group of patients. I think we are looking at the data because when we look at our data now, I think that's being pulled up right now, Andrew, right? We see a lot of patients with low albumin. If you look at the NAPOLI-3 trial, they had a cutoff of three in terms of the albumin because this is actually, albumin has been shown to be a good marker in terms of survival as well as tolerance to treatment as well, because some of the toxicities can be more pronounced as the patients are frailer with the lower albumins. If we can benchmark that to the NAPOLI trial, I would say that we would have also another way of preventing this kind of early decline that we see with our trial that perhaps we didn't see with the NAPOLI trial as well. I think this is a nice slide because it's important to show the mechanism. We know it hits different targets. We know we can get cytokine levels on all patients. These cytokine levels would suggest that the drug is doing some sort of an immunomodulatory function to the T cells. We can see that at least some of the cytokines, the CXCL2, would suggest that in the elraglusib only cohort, we see this kind of improvement in overall survival with the high CXCL2 at baseline, but not in the GnP arm. Obviously the tissue sample that we saw. This patient, as a reminder, did not get a response. That's stable disease, right? He went on on study for over 20 months. You can see on the far right figure here, you see all the infiltrations of the T cells and the granzyme B positive cells suggesting activated T cells, as well as the CD56 positive natural killer cells. The other thing we noticed was a decrease in MDSCs, myeloid-derived suppressor cells, which is actually bad in the microenvironment. I think that the drug helps clear that as well. I think we need to do kind of more work in this in looking at tumor analysis on what we have. I think like this suggests that the mechanism may lead to what we are thinking as tumor reprogramming of the immune microenvironment. I leave it at that. That would help. No, I think that's very helpful. I think the data is very compelling. If you equilibrate, so the non-MD on the ZIAS, you look at a more restricted patient population to sort of compare and contrast to the other major studies. All of a sudden, the delta and median OS improves, the hazard ratio goes down, clearly the effect of the drug is being shown. Yeah. We obviously, as a physicians, we don't like to compare between trials because it's not a good idea to do that. Yeah. We have a comparison, at least between our own patient population that we enrolled in the randomized study, I think that should be the take-home message. We can certainly do a little bit better by trying to be a bit more stringent as we do a registration type trial in the info. It's the double-edged sword of running a randomized control trial just so you have a control, then they say, "Well, how do you compare it to another trial? Yeah. Right? It's always a bit of a challenge to make sure that the data is represented in the most scientifically rigorous way. I think from my perspective, the data speaks for itself. Rachna, your patients, you had patients on the trial. Can you give us a little bit of perspective on what you saw in the trial and what's your takeaway on the data you're seeing here? What's the meaning of that? I will say, I think because I was able to see a number of patients that were on this trial and see, I mean, first of all, I think there's also something to be said, this was kind of already alluded to, that it's not easy in pancreas patients to just add more therapy on. I mean, definitely with FOLFIRINOX, but even with gemcitabine/nab-paclitaxel. I think what was really great is that there wasn't necessarily, I mean you showed the data at your presentation, there really wasn't anything that made it complicated to be able to put patients on this trial and offer them this drug, which I think is really, really important because the point that was made earlier, pancreas patients are really. It's a complex disease and there's so many facets to their care and how they do That has nothing to do with the drug that we're giving them. So I think the ability to give them something that doesn't necessarily add to cumulative toxicity is really important. I also think that looking at that patient population that was able to get the first cycle is really key. Colin and I were looking at that data just before we got on stage, and we were saying, "I mean, that's really meaningful and impactful." Yes, that absolutely was not statistically designed to look at that specific patient population. You take all of that in terms of the data purity component of it. I think at the end of the day, in the real world and in the clinic, there are patients across the spectrum in terms of bad players and bad biology, and all of them are getting FOLFIRINOX or gemcitabine plus Taxol. I mean, that is the real-world statement. At the same time, when you then account for what is probably that initial drop-off, that bad group of patients that perhaps had a lower albumin or had other poor prognostic types of things that make them the more aggressive biology or the type of patients that would've just done poorly, unfortunately, regardless. Then you take out that noise, if you will, and you look, I mean, then you really see, I think, the magnitude of the impact of the drug and what it can potentially do, and I think that's the punchline to me. This is something that, I don't want to put words in your mouth, but I've been in oncology for 20 years as well, and I look at the profile of this drug and what I'm hearing from the data today, both in terms of, this is all about patient care, right? We have this almost benign, I don't want to overblow it, but we have patients who feel better. They do have some toxicity, additional toxicity, but not dose-limiting or treatment-limiting, and with a significant outcome in terms of their overall survival. Tony, weigh in here, shoot some holes in this. What did you see in your patients? Give us your perspective on elraglusib and the potential for where you see this going in the treatment of pancreatic and maybe beyond. Yeah. One has to start with, as you've heard, pancreas cancer is the toughest nut to crack. It is a tough one. We all see these patients, quite a few of them, and we know how tough it is to actually get them through treatment and get them to live beyond the one-year mark. We certainly are doing much better today than we were before, but we're not even close to any other GI. This is the only cancer that's still in the single digits. I mean, depending on what you look at. It's about 8%, some would say 12% five-year survival. No other cancer is there. This is the cancer that desperately needs improvement. Going to this, it's a balancing act. There's no effective therapy that doesn't add a little bit of toxicity. It doesn't exist. It's not supposed to exist because essentially you're modifying something in the system. You will see a little bit of toxicity, added toxicity. That has to be balanced out. I think one of the problems with how we measure toxicity is we also don't account for the time the patients spend on treatment. Sometimes when treatments are more effective, you're spending more time on chemotherapy, and so you see some cumulative toxicity later on rather than earlier on. These would be related to the chemotherapy. That's not a bad thing. These are things we can control as long as they don't impair the quality of life of patients. The same thing with your experimental agents. When you add an experimental agent to a standard therapy, you don't want to see the toxicities from the standard therapy get amplified to the point where the patient cannot go through the treatment. At the same time, you don't want to have the toxicities that essentially make it difficult for the patient to even be able to go on that experimental treatment. Here we're not seeing that significant added toxicity that would be concerning for us to say, "This seems like a go." This is a go. The patients are able to. When we're talking about feeling better, and you can't quantify that on a clinical trial. This is something that, as we see patients in clinic, my patient comes in the door, and we're sitting there talking, "Gained three, four pounds. I'm feeling better. I'm doing more things. I'm able to go back golfing." In Arizona, there's a lot of golfing. All these things, this is what we hear from our patients, and that happens in the first month of treatment. Before even I see the scan, I'm like, "Wow, this looks like this patient's going to do well." To the point where you're bringing that first cycle, patients that are able to get that first cycle, it is so predictive that if those patients are able to go through the treatment as we want them to, as we hope they do, these are the patients that do the best. Yes, there are certain characteristics here that, if you adjust for a little bit more, the numbers, the delta will continue looking more favorable. Of course, you don't want to do that. The point of it is that one of the, as again, Rachna and others have alluded to, is you don't want to compare to other studies at this point in time. You created your own control. This patient population is very heterogeneous. Every study looks different if you look at the control arm. That's why you have a control arm, to make sure you adjust for the patient population you're enrolling on this study. The direction in survival is actually pretty impressive. In pancreas terms, this is a big differential. The tail of the curve that's forming actually is even more impressive. The fact that you have doubling of the landmark survival is pretty impressive itself. Now, I will tell you historically, when we used gemcitabine many, many eons ago, you would never see a patient reach the three years mark or the two years mark. When gemcitabine and nab-paclitaxel or ABRAXANE came through, we were excited about the fact that about 5 plus% of the patients were able to survive 3 plus 5 years. This sounds crazy, right? You're thinking, okay, how does that make sense in today's world? This is in pancreas cancer. That's a lot of improvement already. Now we're seeing this lift further up. Of course, the main question is, when you look at the data, when you look at our individual patients, we were seeing these results individually from patient to patient. It's important ultimately to see the data that is presented today. The data definitely confirms these things we're seeing, like, okay, we're seeing responses in both, but those patients that are going on elra are actually staying on longer, and they're living longer than we expect them to. That data confirms it. The study confirms it once you're done. This makes sense. If you look at the world we live in today, the world of immune therapy, immune modulation, you see a little bit of a disconnect between how many more responders you're seeing, those that flip that waterfall plot down, versus how long they're surviving. If you look at liver cancer, you look at biliary tract cancer, you see sometimes those curves staying close together, and then they start opening up at the end, and that's the immune therapy effect. That's the immune modulation effect, which is leading patients to live longer because now the immune system around their cancer is healthier, is able to actually maintain or check or keep the cancer in check. This is what we're seeing here as well. I think, ultimately, when we observe in clinic, all of us, as we treat those patients, we see the individual patients doing as well, it's so good to see this actually, this data coming out with the control arm and these curves looking as good as they are, and that stay starting to really look favorable in terms of survival. I think that overall, this sums up my impression of the individual and the data from the trial. Yeah. It's remarkable to hear. Well, I guess it's not remarkable to hear that in different situations, such as Colin's, who's got it on the backbone of FOLFIRINOX, or the rest of the panel that has it on the back of gem ABRAXANE, is reporting sort of the same phenomenon, where patients feel better. Not only are they doing better, they're feeling better with the drug in tow. Go ahead. I'm just going to add on what Tony Saab said. I think it's really important to think about the fact that Can you hear me? Yes. Okay. I think it's important to think about the fact that because the cancer is so complex, there's not one drug that's going to be the end-all be-all for this disease, okay? I think what this drug does, and the safety profile we're talking about, it now lends for combinability. It becomes a platform that you can add to, right? If you think about the RAS inhibitors, for example, that are coming, right? You can think about how you can potentially add this to that. We've sort of touched on the immune system, right? If you look at pancreas cancer drug development, immunotherapy has not worked in pancreas cancer. Maybe we have some hints that there's a backbone here that you could potentially add on to. I think these are all important things to think about is that at the end of the day, I think there's a platform here that you can build upon that we didn't have that platform, I think, prior to what we saw today. Absolutely. May I add to that? I think these are building blocks, we can continue to amplify on these building blocks. Once you start modulating the environment around the tumor, it's a winning proposition for pancreas cancer. Again, that's another one of the toughest nut to crack is that tumor microenvironment in pancreas cancer and how all the immune therapy, previous immune therapy, more traditional immune therapy studies have failed. That's because you had that fortress just around these cells that you cannot penetrate. Now, as you actually start modulating that environment and invite those favorable cells, now then you can start thinking about these combinations. You establish that first platform, you add onto it, but not to undermine the fact that already by itself, it's already lifting up, at least that's what we see on the study. We're already lifting up the capacity of these patients actually to survive. That's a positive study. For me, I don't know about you guys, but I can't recall the last really positive study that we've seen in pancreas cancer since NAPOLI-3, which really didn't change the landscape much, just stacking on more chemotherapy and we'll hit that cytotoxic wall. This is one of the, if not the first, biologic modified immune-based therapy that biology and immunology together in this, that essentially drove the study to be positive. We haven't seen that for a long, long time in pancreas cancer. You don't typically see the type of curve, the type of event No. That kind of relatively quick separation and durable separation. That's not a typical overall survival curve Yeah. In the world of pancreas cancer. I think that it's notable. Especially when you look at that efficacy evaluable after four weeks population, even that hazard ratio, that's not a hazard ratio we see Yeah. In pancreas cancer. Starting with a five. Yeah. Right? Exactly. We're usually happy with 0.7, 0.8. Those speak volumes for the fact that in the world of pancreas cancer, those are notable things, I think. In terms of combinability, we've got two trials. We've got a pilot trial or a small three-arm trial that you're running with FOLFIRINOX. I think this is an exceedingly reasonable size trial for potentially a pivotal trial. This is 50% of the phase III trial, size-wise. Yeah. This is half a phase III trial. That's one of the largest phase II randomized trials. Absolutely. On record. Yeah. You're well powered. You're very well powered. Good. In terms of other drugs coming, we know that there's a lot of visibility to the RAS inhibitors. We know that there's been some preclinical research or at least mechanistic understanding that those two, the RAS inhibitor with a GSK3 inhibitor may be combinable and potentially synergistic. How do you see those two and any other new drugs coming to the fore, and what should we be looking for to combine LRO with? You mean you do have a study that's looking at an immune checkpoint inhibitor plus elraglusib, right, and that paclitaxel? It's in the drafting stage, yeah. Oh, okay. It hasn't hit the first patient yet. Oh, okay. I'll let him talk about it. Yeah. I was going to say that I think that the low-hanging fruit would be obviously in terms of checking to see if the kind of modulating the immune microenvironment there with checkpoint inhibitors is what I think Colin was referring to. I think that trial is going to be an ongoing trial, right, Colin, is that the one you're talking about? Yeah, there's one in draft. In draft, yeah. That's obviously another, to see if that would add anything more in terms of the overall survival. I think the RAS inhibitors are certainly of interest. We have seen preclinical data that would show that the two drugs could work just based on the docking proteins and where the RAS, especially the RAF proteins are hitting the GSK inhibitors. I think we could kind of see if that would add more in terms of not just response, if we see a lot with the RAS inhibitors, but also survival. We know that the RAS inhibitors could also be limited in terms of the duration of response and whether this could add in more in terms of survival as well. As well, was there anything else, Dustin? I would say also with the RAS inhibitors, I meant the EMT, so the RAS inhibitors, EMT could be important for that process. Yeah. The MAP kinase pathway, which is what RAS targets, its engagement with GSK3 is also very important in EMT. You could potentially see how combining those two drugs might even further augment the conversation around EMT and potentially overcome resistance to the RAS inhibitors in patients who don't have the particular EMT phenotype that the RAS inhibitors would work in. There's many ways to think about how you can combine this with RAS inhibitors for different things. There's other drugs, too. What else would you raise? As you know, we are very excited about what we're seeing for patients right now with these backbones. Obviously, there's other combinations or potentially other histologies or subtypes. Where should we be looking at as next steps for putting this drug out? We always talk about risk-benefit to the patients. In this study, we show clear significant clinical benefit with minimal clinical risk, I would say. Where else do you think this would be applicable? You mean outside of pancreas? Is that what you're thinking? Any other histologies or any other patients that you see the first line metastatic pancreatic if there I think within pancreas cancer, any of the patients who have localized disease, I think these combinations potentially make sense in that setting. I think this conversation about EMT is important for other GI malignancies as well. I think now you have evidence that it's combinable, you could think about looking at the other GI cancers, colon cancer, gastric cancer, biliary cancer. I think there's many places, even if you're thinking about combining RAS, lung cancer becomes also a setting where RAS inhibitors are important in terms of disease modifying. Yeah. Thinking about the multifaceted mechanism of action, I actually think there's a broad swath. Yeah In which you could think about this. To your point about combinability, regardless of the chemo backbone or whatever the combination is that is being used, say gastric cancer or biliary cancer, whatever, I think that EMT component as well as the immunomodulatory effects, I think those two things right there make a number of different tumors, definitely within GI, but even probably outside of GI as well, reasonable. If you think about this as your playground, right? You've already shown a proof of principle that your playground seems to be safe and seems to be effective, and you have to confirm that. I wouldn't undermine the fact that as standalone right now, you have enough justification to move to the next level of confirmation. That doesn't mean that you don't also think about your opportunities, because now you've shown a proof of principle where one, you have an agent that adds value, significant value to patients, which you hope to confirm even further with larger studies. At the same time, start creating a path to the future, whether combining with RAS inhibitors, with other immune-based strategies, whether you expand so you start building around your safe and effective playground. I think you already have quite a bit to move forward to the next level, but at the same time also start thinking strategically about, all right, the RAS inhibitors, they make a lot of sense to combine all that. IO-based therapy or even all these, right? Because they all modulate different aspects of the immune system. This is creating a positive milieu. It takes it from a very negative milieu to a very positive milieu. You create a playground where you can actually work with multiple different options, including stacking multiple options on. The two don't necessarily have to essentially go stacked up one on top of the other. They can all go in parallel, and they should, because ultimately, if you think about it, even with the RAS inhibitors, we're not achieving more than 20%, 25%, maybe 30% if you want to really go with this vision of an imagination of a response, and many of these responses are not durable in pancreas. In others, maybe, but in pancreas. There's a big challenge in pancreas that remains even with the most promising elements. That's why I think, as you said, as Colin said, you can't just think about one strategy. One strategy right now, this is a valid and valuable strategy to move forward with. You start thinking about the other building blocks that are going to come. What about IV versus oral? Weekly seems fine. Oral would be optimal if you can move to an oral formulation. It certainly is optimal. It will make it easier on the long run because, you think about the long-term benefits of this agent, right? Because it seems that the benefits continue long term. You think about strategies where chemo can drop and you continue with your agent. This is where an oral agent would make it even more attractive on the long, long term, right? Because that's what you're aiming for. When you start thinking about combinability with other strategies, when you start thinking about the other area where EMT becomes even more important is in the early stage of the disease, where you can actually improve significantly the likelihood of these patients to survive their cancer. Today only, 30%, maybe 20%-30% do survive their cancer. Actually, perhaps less than that. You can change the whole landscape in the earlier stages. This is just the beginning. To Colin's point, great minds, I like to think, I was going to ask the oral question as well, because I'm not sure if everybody's aware, but we do have an oral development program, we've got a lead formulation that's this tablet that shows greater than 95% bioavailability in preclinical testing, which is something that we are bringing along for further development. I think that the earlier-stage patients and longer duration of treatment in a home setting certainly is attractive on all the right levels. Remember, a lot of these statistics are transient and happen early. There is a long-term potential. We're not seeing any long-term issues with this agent. We do see them with chemo. We're not seeing them with elro, which makes it ideal for a long-term strategy. Even one can think that as it is a modulator as well, that you can go across multiple lines of therapy. You don't have to stop it if gemcitabine/ABRAXANE stops working. You can move to the next treatment and change your chemo but continue the elro. To that point, right, the trial that I have open right now is patients get FOLFIRINOX for six months then go on maintenance 5-FU plus the elraglusib, then when the tumors grow back out, they go back onto FOLFIRINOX and elraglusib. What I can tell you is that we see that in the maintenance therapy alone, it's maintenance elraglusib plus 5-FU. We are seeing patients continue to have response in that setting. Then when they do grow back out, we also see the reintroduction of response. To Tony's point, it is feasible to do. Yeah. I'm open to opening it up to the audience if there's any questions. I guess my first question is, all right, if we were to stack these out and we wanted to do the next studies, should we be looking at first locally advanced, or should we be doing more metastatic work? If you had to send in a note, Rachna, what would be the next step for you? Where would you like to see this in your What patients are coming in that you say, "Wow, I'd really like to have them on elra? I think the localized patient population is a really important population to the point around EMT and the way that this drug works. I think, again, just speaking to the fact that it's a tolerable regimen and that sort of thing, I think locally advanced is a really complicated field. Just the definition of and what the approach is, I think it's hard to do a really clean study when you're looking at a drug in terms of understanding what the right and meaningful endpoint is there, without trying, again, kind of factoring in the heterogeneity that comes into that population. I would say probably more in the localized that is potentially operable, whether that be resectable, borderline resectable. I think that's a really interesting space to look at because of the way that this drug works. Devva, in your practice, you've done a great job with us. I think the low-hanging fruit is obviously to move this into a registration-type trial in the frontline setting in pancreatic cancer, with the kind of strategy of deciding you're going to need over 500 patients for this study. What kind of eligibility criteria would you want to include to allow and prevent that kind of early drop that we saw? That's the first thing you're going to invest your dollars in doing. Tony mentioned the building blocks. The building blocks would suggest maybe start bringing this early on in pancreatic cancer treatments early. The second building block is that some of the trials that you all are already talking about, where you would add an immunotherapy to the things that are already established to see whether this adds anything more. That building block can go across multiple histologies. It's just a matter of where you want to put your resources. I'm sure many investigators will be reaching out to you guys to say, "Can we run investigator-initiated trials in the States?" I already have hounded Andrew there with multiple already. Money, obviously, that's going to dictate how you're going to do these trials, and who you're going to partner up with as well. There is no shortage of people knocking on the door right now. I would say, I totally agree with the early disease setting. That's, I think for me as an investigator, that's where I think it's important. I think as a company, the important thing is to do the registration trial. I would actually also focus on FOLFIRINOX, because as I said before in this conversation, their drugs have not been combinable with FOLFIRINOX. Some of the agents that we're talking about have overlapping toxicity with FOLFIRINOX. A lot of just MAP kinase pathway inhibitors are going to have GI toxicity, which is common toxicity for FOLFIRINOX. If you can carve out a space where you have a drug that combines with FOLFIRINOX, then that's a space that you're going to own. Then I would take that and do all these other things that we're talking about. You have to get this agent to the patient. Your strategy has to rely first on a registrational strategy, which means that this is how you get it to the patients. Otherwise, this drug will not be accessible to the patient, ultimately. If these, there's no reason not to believe that these trends will continue, then that's an added value again to patients in the near future if this study goes and runs, again, as you're building all these other pieces and putting them in place. The landscape in pancreas cancer is needed. If you look at any other cancer, there are 20 million competing studies at the same time. Pancreas cancer, good luck to find one. The space is empty. You can open it wide. The RAF inhibitors are trying to rush into it, but they're not even close yet. They'll talk about first-line, changing that first-line landscape. You got to hit that biology early and hit it hard. That's the only way you're going to make a big difference in patients' lives. That what we continue to see across all these malignancies is that, yes, you can see a lot of benefits for agents being tested later in lines, that biology in first line, it matters the most. A lot of patients lose the opportunity to see another agent, half of them, after the first line, then it goes downhill very quickly from there. This is why you need to really hit hard at the beginning. That's a great opportunity, actually. This is a rare positive study in pancreas cancer. Good. Yeah. Mike Warrior has the microphone. Is there any questions? I'll ask one from an analyst that wasn't able to attend, a member of the past in the group. Albert Lowe at Craig-Hallum. What portion of first-line patients do you treat with gemabraxane versus FOLFIRINOX or NALIRIFOX? What portion of these patients do you think would be good candidates for the elraglusib combination? I'll take this one very quickly. If it's on a clinical trial, it doesn't matter. If my clinical trial has gemabraxane, that's the standard of care for all the patients. There's no frankly good data. I'll get to the NALIRIFOX issue, there's no good data that suggests that FOLFIRINOX is any better than gemabraxane outside the BRCA1, BRCA2, which is a very small proportion of patients. They're pretty similar. That's across the board, whether you're here, in Japan. In Japan, in fact, they favor gemabraxane over FOLFIRINOX. It's a wash. I really don't think that that's frankly an issue. It used to be a few years ago, people were very much entrenched into one camp or the other, the data starts coming, including real-world evidence suggesting, "You guys, get over it. Chemotherapy is chemotherapy. It's all the same. It doesn't add much value anymore to the patients. Let's move on. NALIRIFOX, interesting. Study was positive. I was part of that study. It was positive, slightly positive. I'd say marginally positive, but very tough regimen to tolerate, and that's why it hasn't picked up. If you look at the market in the U.S., NALIRIFOX is less than 2%, if not less than 1% of the overall market. That's because it's sheer torture for patients, frankly. Anybody else with a different perspective? In academic institutions with experienced investigators, I think there is a balance. I think there's a mix between the two regimens, with some nuances about which one they would lean towards to. In community practices, I think there's a lot more gemcitabine nab-paclitaxel than in the academic setting because they feel it could be better tolerated. I think just depending on where you are, it balances out to about 50/50, I would say. Then there are many patients who don't, are not able to get a combination treatment, are just on single agent gemcitabine or single agent FOLFIRINOX as well. You have to keep that into mind as well. Some questions. Chris? Thanks. Chris from Capital Markets. First, congrats on the data. Just a couple of questions. First, for Dan, when do you plan on exploring sort of a biomarker strategy? We saw some potential biomarkers here today, and what could a registrational study look like? For the panel, in this data set, we've kind of seen a lower median OS, slightly lower median OS than what we've seen in historical studies for the control arm. Does the data here today kind of explain some of that? You mentioned low albumin. Something I noticed was a high CA 19-9. Does that adequately explain that? Lastly, for Dr. Mahalingam, we saw there was one slide with a biomarker of a CXCL2. Do we have the exact numbers for the median OS in that biomarker subset? Do you want to take that? I'll take the first one. I think that we do have a biomarker strategy in development. Some of that was presented in a poster this afternoon. That was very well attended, by the way. In terms of a registration study, I think that that is dependent on our discussions with the regulators and asking them, in light of this data, what would be required. We have mapped out the options from a full phase III to sort of more of a confirmatory trial. We want to talk to the regulators and see what they're thinking, particularly in the light of the kind of compelling data that's been shown here today. I mean, from the company perspective, I ask the question, how long should you hold this away from patients who really need it to do a 200 more patients? We'll have those discussions, and it'll be an agreement between us and the FDA and EMA. Next is the question- The control. The control. The question about the control arm or the control itself, that other control. That's one of the most dangerous exercises in feasibility, is to actually compare studies, different studies to each other. That's one of the biggest weaknesses in having single arm studies, because they all look quite fluffy. They look great, and they fail when they go to the phase III. Some of them don't as much. That's why having a control arm, especially in pancreatic cancer, is very important, because it controls for the patient population that's included in the trial. Because that's a very heterogeneous patient population. Algorithm can explain part of it, selection bias. Some people like FOLFIRINOX better. Perhaps they picked patients in that early phase of the study that may not fill the perfect bill. At the end of the day, all what matters is that delta. That's what you measure yourself onto. You're not picking the winner, right? Like you do with a single arm study. You're flipping a coin, kind of, half a coin, I guess. You're flipping a coin to pick who goes here and who goes there. You have no control over it. That's the cleanest way to actually have a signal. The only clean comparison here is between arm A and arm B. That's the only comparison that's valid, frankly. Yeah. I mean, I would just even add to that in the way that modern day drug development happens and just the necessary speed with which companies have to move to be able to try to stay ahead of the game, as well as also make sure that they're getting their drugs out to their patients. More often than not, we see a phase I study that potentially has a signal, then turns into expansion and becomes a single arm study, and we all get really excited. I think to Tony's point, I mean, I really actually give this study kudos for doing a large randomized phase II trial, because, I mean, it takes a lot of work, and it takes a lot of investment and a lot of resources, financial as well as others, to be able to do it. To his point, it is the only way that we who treat this cancer every day can look at this and say, "This actually means something." I think that's really impactful because we have that clean control. To your biomarker question, I think that this is still very exploratory, so I can't give you immediate, because that was just one of the cytokines we looked at, and we are saying that if you have a higher level, it's associated with an improved survival only in the elra-GnP arm and not the GnP-only arm. We're looking at a subgroup within a subgroup of one biomarker, right? We do see multiple biomarkers that are in that trend, and I think as we get more of the data analyzed, it might be easier then to start looking at kind of true survivals and things. Maybe someone else, maybe Taylor might know, because I know she was doing some of this machine learning stuff as well. Did you see, was there a survival? Was there an actual median overall survival that you saw, in terms of the CXCL2 data? There's patients with rank CXCL2. The level is different. Yeah There is a exclusive biomarker. We are pulling out patients who have 500 patients and over 500 patients. Once you pull out those patients by the biomarker, the patients that are CXCL2 low actually mirror the control. It's even being populated with patients that have a biology that will respond to these drugs. The run of biomarkers is definitely signal, with biomarkers that will really enrich for a given, either a biomarker or pull out the patients that have that really long time for all these groups. Oh, thank you. Right now I'm using machine learning and multivariate models to actually try to combine those and improve on what we see with CXCL2. I think there is some really complicated signals there, and we can improve on that. Even just with CXCL2 alone, we're seeing a really clean biomarker. I did cross-validation to basically see if you randomly sample this patient cohort, is it a stable signal? Because I think that's the problem with a lot of machine learning analyses is, you look at your cohort, you make the machine learning or mathematical model, and then it looks great, but you reapply it, and then it's like, okay, well, that doesn't really necessarily translate. We did this cross-validation study to make sure that it was a stable result, and CXCL2 is rock solid. The hazard ratio across all these different cross-validation folds was solid. Even looking back at some of our phase I data, we similarly see these cytokine signals. I think it's really conveying, you can look at a patient, look at their immune environment and say, are they a patient that is going to have an anticancer effect when you add that GSK3 inhibition? You can kind of encapsulate what does that patient's immune system look like at that time, and is GSK3 inhibition the right kind of perturbation to push them towards anticancer effects? Thank you, Taylor. We have RK. Go ahead. This is RK from A couple of quick questions. Talking about safety, there were a couple things that popped up. Visual impairment. You're going to have to speak up a little bit. I'm having a hard time hearing you. Sure. There were a couple of safety measures, safety issues that popped up in the presentation. Visual impairments and the rates of neutropenia. Are these a real impediment in terms of adoption or these things could be taken care of with certain prophylactic therapy that it should not really impact anything? Let's start with the visual disturbances, as we call it. It's more an irritation because the GSK3 beta normally has a signaling pathway in the rods and cones of the eyes. We see just a color and light changes perception that are usually transient. I think it's also to do with the Cmax of the drug, so the concentration of the drug as it hits the peak, which is why it's usually transient. In most cases, I think it just lasts a few hours. Patients usually describe it as a lightening or darkening of the room or something like that. I do not see that as an impediment in terms of, for patients that is. Right? The neutropenia was, we just noticed more neutropenia, but as we did the trials, you can see it never translated to febrile neutropenia episodes because that's really what will kind of impact the patients in terms of things. Every time they come in for their weekly check, we are seeing the neutropenia levels. Patients were coming in and said, "Oh, I feel fine." All the physicians tend to do is just maybe adjust the doses of chemo along the way as they are treating the patients just to balance out for the neutropenia. I would say in my study to answer those questions too, we do see patients having visual changes. It's like a blue or black hue that their vision is, and that lasts for like, I've had patients up to 24 hours, but so they get chemotherapy one day, the next day they wake up and it's gone. It does persist over time, but it's not a thing that sort of alters their lifestyle. I agree with the neutropenia, that can be managed. The second question from me is on the PFS data that we saw today, it was similar between the two arms. Were there any observations in terms of quality of life which would tell you that even though it's the same, the quality of life is better, especially with elra+GnP? Yeah. In the trial, if someone progressed for whatever reason, even if it's a small lesion that maybe popped up on a scan, that's a progression. Right? Clinically, the patient is doing well, but we have to follow study protocols. I don't think in the study we allowed for patients to go on, what we do in a lot of the immunotherapy trials, we'll say, "Okay, you can keep going beyond what we call progression." I think that's what we're seeing with the immunomodulatory signal is that patients are actually getting this kind of post-progression benefit. We had patients who actually had progressed and then decided not to get second-line treatment and said, "No, 50% of patients get second-line therapy." We saw them living at 10 and 12 months on, they were kind of sitting around for 6 months, not getting any treatment but still surviving. That's a choice that a patient can make, right? I think that I saw that in patients where they were clinically well. But by protocol they all study. Thank you. I'm Phil Winter, I'm a physician. I have a question to the company. Did you consider, obviously, unfortunately, it's pancreatic cancer, there will be a lot of progressors. Would it make sense to re-challenge with elra, and did you consider adding an exploratory cohort maybe to a pivotal trial so that it could be maybe line agnostic eventually as you read out the pivotal trial? My second question is maybe for the whole panel. As you scale up in the path with obviously some of these chemotherapy trials, the pivotal trial, what are your prescriptions for a pivotal trial here as we expand to more patients, more sites? Obviously, you mentioned we're already 50% there in terms of patient population, but what are some of the pitfalls that we should consider, maybe enrollment criteria or something to replicate the benefit we're seeing here? Are there any threats to potentially making it smaller here? Thank you. I'll just start. The last latter question, I think the site selection is really important because I think you want to have sites that, if you're using, let's say FOLFIRINOX as your chemotherapy backbone, they have experience with managing patients on FOLFIRINOX or gemcitabine, right? There's nuances to both of those things. I think you want to have, it's been shown if you take patients who have Whipple surgeries for pancreas cancer, right? It's been shown that the amount of Whipple surgeries that a place does, the better the outcomes are and the less deaths are associated with that. I think the same thing applies here, right? We're talking about metastatic disease, but the more experience that the center has, and it's not just the doc, it's actually the nursing staff, all the ancillary staff that goes into taking care of those patients. The more experience that that center has with this disease population, the more likely the outcome's going to be more closer to the truth, right? It's going to be a greater estimate of the truth, right? I think in this particular study, you see that when you eliminate those patients at the first, the initial tail that falls off, right? When you eliminate those patients, you have an outcome that looks pretty promising, right? How do we get to eliminate those patients? That's where the study center, choosing your sites, that's how you eliminate those patients that fell off initially. Because I'm going to pick true. If you say that patients have to be ECOG 0, 1, 2, or 3 to go on to a study, right? There's an objective way to do that, but it's really subjective, right? It's what I say ECOG 0/1 is, right? If I say, "Okay, well, I just want to see if I can just push this patient on the study," they're truly ECOG 2, but I said they were 0/1, right? That ECOG 2 patient that I said was 0/1, that's the patient that falls off in the first part of the study. You really want to be selective about who's doing the study, right? Also, you want to have experienced investigators like him who says, "Okay, we see neutropenia, but what does it really mean?" Right? You understand that maybe neutropenia is present, but it's not the rate limiting step in this conversation. Whereas if you have a non-experienced leader of a trial, that stuff gets sort of muddied as well. I think you just got to be very careful about who you select to do your study. Sometimes having more sites to be fast isn't the right thing to do, right? I think in pancreatic cancer, that really is the case, where we've seen if we were to go over all the studies of pancreatic cancer where there's muddied water, it's because it's a number of sites that do a certain thing. Like we were talking about locally advanced disease. If you look at those studies, they're a mishmash of outcomes, and a lot of it is because they wanted to do these things quickly, so they had a lot of sites that don't know how to take care of pancreatic cancer patients, and then you get outcomes that you can't really replicate. You say, "Okay, well, I don't know what to do with this information." I think it is really important about being selective and not too much, right? Right. A mismatch of sites with a mismatch of patients, right? Well, I think it's experience is what I'm really saying. I think it's a good problem to have. With this data, even if we are required to do a registration-type trial, I think there will be a lot of interest globally to be a participant of this trial. That's the first thing. As a physician when a patient comes in to see me, I'm thinking of putting them on a trial, I know that they are on the fence, right? Ultimately, I'm looking at the patient and he's saying, "Please give me hope. I want to try and get into this trial." I'm going to try and get that patient into the trial, which is where the subjective nature comes in. Ultimately, we want to give the patient the best option, even if we might think that it's kind of iffy, right? I think you're going to see this in the global trial, and the only way you can control things is to play with the eligibility criteria and be stringent where you can with some flexibility. I think that's going to be how we design the protocol, how we kind of put the right language in, and then let it be. This is like letting a global trial, you're going to see the differences. You're right, you need to pick the global trial in institutions that have higher volumes of pancreatic patients so that they know how to manage these patients as opposed to the odd one here and there. Yeah. That's an interesting point, right? Like, it's not been thought about, right? To you saying that we could try and get a sub I think this is something that Colin has talked about with his trial, where even after a break of the chemo, the elraglusib continues, and then the chemo comes on. Whether we would re-challenge, there's no data to support re-challenging of elraglusib if someone has progressed kind of clearly on elraglusib. To your point, I think Tony mentioned it earlier, is whether you could just keep elraglusib going, even if you bring in another chemo backbone in the second-line setting to see if that improves survival as well. Hi. This is Kareri Coleman from Claire Street. Thanks for all the insight and for taking my questions. Just a couple from me. What minimal magnitude of OS benefit or OS difference would you like to see when we move from this study to a bigger trial? The second one, it was discussed since it has an immunotherapy effect with a longer tail in terms of survival, which we have also seen in PFS, but here we are seeing the effect most prominent in the OS. Is there any reason why that is specifically in the OS metric alone? If you have seen any similar patterns with any other drugs before? Thanks. I'll maybe take the second question first with the tail end, right? We've seen it with checkpoint inhibitors for start with, for example, one of the trials that is now, if you look at the KEYNOTE-048 trial, which is a head and neck cancer trial, in that trial, the randomization was pembrolizumab with fluorouracil and cisplatin versus cetuximab, which was standard of care before that. You could look at the data and you'll see that the overall response rates and the PFS were comparable between the arm, the pembro added the kind of tail end. We kind of saw that in the checkpoint inhibitor world where you get this kind of post-progression survival, if you could say. There are other trials in lung cancer, the KEYNOTE-042 and the CheckMate-577. There's so many numbers I can't remember, even in the second-line trials, we're seeing the same patterns, improved overall survival and things. We're seeing this in kind of immunomodulatory kind of things, that's what I think we were trying to get at with this trial, is maybe we're seeing the tail end because of that. I think your first question was to do with, what was it again? The minimum magnitude of OS benefit that you would like to see. I think three months, I think we were close. We were three months on that thing. Yeah, three months. I think even the discussants even said anything at three months, and the difference would be both significant and meaningful in pancreatic cancers. That would usually translate with a hazard ratio kind of less than 0.7. The three months corresponds to the trial overall at this point, and the trial's still ongoing. The four months corresponds to those patients who could get beyond one cycle of treatment. Again, to, I think it was Tony and both Rachna were saying, there hasn't been a major advance in this area. These are major advances. Even the three months is a major advance. Yeah. I mean, it really is. I'm gonna give one last question. One more question. Uh-oh. Just a hypothetical, maybe. If this drug were to be available to you tomorrow, what% of patients would you give it to initially? Are there any patient population whom you would avoid giving it, this combination, based on its risk-benefit profile? Thank you. Based on the data, never mind whether you have to fall far enough, but at least now we have the gemcitabine/ABRAXANE data, I would give all my patients gemcitabine/ABRAXANE with this drug because of the survival benefit that we see. I'm waiting to see Colin Weekes' data, which I think would come up probably in front end. If it needs far enough to do the same thing, that would be great. In terms of, I would be happy to add that to either chemotherapy arm if it can heed the tail end survival go longer. I may not heed the PFS on the kind of more responses or anything like that, if the patient is going to live better and do better chemically without any additional side effects, then I think I can convince the patient to do that in whichever arm I pick to do. Me? Yeah. I would give it to every patient. My study is done enrolling. It's a much smaller trial, it's not going to be like this. Based upon what I've seen, I would give it to all patients, I'm actually currently developing studies for neoadjuvant studies with FOLFIRINOX combination. I'm all in. I'm a little bit biased, I guess. All right, Chris, you're the last man standing, my friend. Go ahead. Chris Moose, Capital Markets again. Thanks for letting me ask one more question. For the patients who can get to at least one full cycle of treatment where you had that four-month difference, has any analysis been done into what's enabling those patients to get to that point? What's the difference between the safety population and the one-month population, that delta of patients? Is it the albumin or have we done anything? As we talked about, very subjective on how we put people onto the trial, right? You have this group of patients, there could be other factors. We know that there's certainly a certain subgroup in pancreatic cancers that are highly aggressive, highly resistant to the current standard chemotherapeutic agents. I think that's certainly one of the population that we see the drop-off. I think the other one is just performance status. Patients are usually, when they come in, have declined from where they were, even very quickly. Usually, over a space of three to six months, they have had weight loss, symptoms related to their cancer, I think that accounts for some of the patients who would start off and then decide a few weeks in that, "I don't know whether I can do this chemo and I just want to come off the study." They would decline very quickly. We've seen all of that, there's no way of kind of figuring out who that is upfront, apart from being more stringent about patient selection. That's the only thing. Thank you. Very good. Well, thank you. I think we've run our time tonight. I appreciate everybody, your time and attention, and the time and attention of these gentlemen who have more than enough appointments to take care of. Appreciate your support and the fact that you're using elraglusib and taking care of patients. With that, we're going to wrap up and bid everybody good night.