Good morning, and welcome to the Shattuck Labs Investor conference call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session, and instructions will follow at that time. As a reminder, this conference call is being recorded. I will now turn the call over to your host, Dr. Taylor Schreiber. Taylor, please go ahead. Thank you, operator. Good morning, everyone, and thank you for joining. I'm Taylor Schreiber, the Chief Executive Officer and Scientific Co-founder of Shattuck Labs. During today's call, we will be providing a company update, including an interim update on SL-172154, and the introduction of SL-325, a first-in-class DR3 antagonist antibody. The press release reporting our company update was issued pre-market this morning and can be found on the investor relations section of our website, shattucklabs.com. Before we begin, I would like to remind you that today's webcast contains forward-looking statements and would refer you to our most recent 10-Q and other filings with the SEC, which are available from the SEC's website or on our corporate website, shattucklabs.com. Today's call will begin with the results from a recent interim data cut for SL-172154 in patients with higher-risk myelodysplastic syndrome and TP53 mutant acute myeloid leukemia, along with the rationale behind our decision to discontinue further clinical development. We will then introduce SL-325, our first-in-class death receptor three blocking antibody developed in-house, and provide a rationale for why we expect this agent to provide superior benefits compared to TL1A blocking antibodies and upcoming milestones for this program. I will then be joined by Dr. Lini Pandite, Shattuck's Chief Medical Officer, and Andrew Neill, Shattuck's Chief Financial Officer, for the Q&A session. Let us first turn to our interim data cut for SL-172154 in patients with higher-risk MDS and TP53 mutant AML. As you might recall, we announced updated interim data from our ongoing phase Ib studies in high-risk MDS and TP53 mutant AML in June of this year at the European Hematology Association Annual Meeting. These data demonstrated meaningful improvements in complete response rates compared to what would be expected with azacitidine alone in both cohorts. Improved response rates alone, however, are not sufficient and need to be accompanied by meaningful improvements in overall survival. Before sharing our recent interim data on overall survival, I'd like to review the latest benchmark data for what is expected in terms of overall survival for patients with high-risk MDS or TP53 mutant AML treated with azacitidine alone. As many listeners are aware from our program updates over the past year, a majority of the patients enrolled to our high-risk MDS study and all patients on our AML study have mutations in the TP53 gene and are amongst the poorest-performing subset of high-risk MDS and AML patients. At the top portion of the slide, we are highlighting the TP53 mutant high-risk MDS and AML are a continuum of the same disease. Thus, these are not discrete diseases, and there is no reason to believe that efficacy to a given agent would be isolated to one or the other end of this spectrum based solely on a difference in baseline blast count. The middle section of this slide highlights a series of benchmarks from published and unpublished studies. These tables highlight that the expected complete response rates and median overall survival for patients treated with azacitidine alone have improved over time. All cross-trial comparisons should be interpreted with caution, but should, at a minimum, be taken as examples for the range of responses which could be seen on an internal azacitidine-only control arm. As of our June update at EHA, we had not yet reached the median overall survival for either the high-risk MDS or TP53 mutant AML cohorts. We have now reached median overall survival in both cohorts and are able to have a meaningful look at where those data stand. We completed an interim overall survival analysis on September 3rd, 2024, for both the TP53 mutant AML and high-risk MDS cohorts. All but three patients in the high-risk MDS cohort have TP53 mutant disease. The three patients with wild-type TP53 are all continuing in survival follow-up. For the TP53 mutant patients, the current median overall survival is 10.6 months. With subsequent data cuts, the median could improve up to 13.1 months, but not beyond that. In TP53 mutant AML, the current median overall survival is 10.5 months. There are a number of censored patients who have not yet reached the current median, and the survival of these patients could potentially reduce the current median to shorter than 10.5 months or extend the current median overall survival to 11.7 months, but not longer. Approval of SL-172154 in TP53 mutant AML and high-risk MDS would have to be based on an improvement in overall survival. High-risk MDS and AML are a continuum of the same disease, and we must view our current data with both cohorts in mind. While the OS improvement in TP53 mutant AML is potentially meaningful, the OS improvement in TP53 mutant high-risk MDS is only slightly above the expected survival for azacitidine in recent randomized phase III clinical trials. When viewed holistically, and in light of the current sample size in a phase I clinical trial, the overall survival numbers achieved with SL-172154 in combination with azacitidine represent only marginal improvements to updated benchmark survival numbers for azacitidine in recent randomized phase III studies. We also cannot ignore the disappointing reality that, like many immune checkpoints over the past decade, no CD47 inhibitor has shown a significant and sustained efficacy signal in any indication to date. Thus, we have decided to discontinue all further development of SL-172154. While these data are not what we hoped for, they are data that we can rely on. They were generated due to a tremendous effort by our team, our clinical investigators, and as a result of many brave and trusting patients and their families. All of us at Shattuck are immensely grateful for these efforts and hopeful that other therapies will soon yield improvements for these devastating diseases. Thankfully, Shattuck has always maintained a very strong research and development capability, and we have a number of opportunities which have been part of our preclinical pipeline efforts for the past several years. These opportunities leverage the tremendous infrastructure we have built at Shattuck over the past five years, the development experience of our team, and the lessons derived from developing complex biologics. One of these opportunities is our DR3 blocking antibody. The TL1A/DR3 axis is a TNF receptor ligand pair, which has received recent clinical validation. Many listeners will be familiar with the emerging data from TL1A blocking antibodies, which have shown impressive clinical remission rates in treatment-refractory inflammatory bowel disease. Shattuck's core expertise is in TNF biology and the development of agonist and antagonists against these important immune targets. On a personal note, I have a long-standing connection to the TL1A/DR3 axis, as this was the focus of my graduate work, and I've published extensively on these targets. We are very pleased to more fully introduce our SL-325 program to you this morning. We believe that we have a first-in-class DR3 antagonist antibody, which may be more efficacious than targeting TL1A. For the remainder of the call, we will walk you through the underlying biology of the axis and then data specific to our SL-325 program. We begin with a quick introduction to the fundamental biology of this axis, because most of the discussion to date has focused on the ligand, TL1A. TL1A promotes inflammation through binding a receptor known as DR3. The only known ligand of DR3 is TL1A, so from a safety and specificity standpoint, there is no reason to believe that targeting DR3 will be unique from targeting TL1A. TL1A has a very different expression pattern than DR3, however, which prompts the consideration of whether blocking DR3 may lead to greater anti-inflammatory benefits than blocking TL1A. First, TL1A is expressed primarily by antigen-presenting cells at sites of inflammation. TL1A is turned on for short periods of time locally within inflamed tissues and is then rapidly downregulated, both at the transcriptional level and through protease cleavage at the membrane. Membrane-bound and soluble TL1A can promote a range of inflammatory responses through binding to DR3, which is constitutively expressed by immune cells, both in the blood and in tissues. In humans, a decoy receptor evolved to help quell inflammation driven by TL1A, which underscores its role in immunopathology. DR3 is not known to interact with any signaling ligands apart from TL1A. When TL1A binds to DR3 on immune cells, it provides a costimulatory signal to a broad range of T helper one, two, nine, and seventeen polarized lymphocytes, which amplify an even broader range of effector cytokines that are known culprits of many inflammatory diseases. There is an abundance of preclinical literature demonstrating that DR3 blockade may provide greater efficacy than TL1A blockade. On this slide, we show data from a mouse model of inflammatory bowel disease wherein either DR3 or TL1A were genetically deleted. In the top set of figures, the incidence of IBD was compared between IBD-prone mice that expressed or did not express DR3. This figure clearly illustrates that the DR3-deficient mice were almost completely protected from the development of inflammation in the gut. In the bottom set of figures, the role of TL1A deletion was evaluated in the same strain of IBD-prone mice. In this case, you can see that the TL1A-deficient mice were only partially protected from Crohn's disease-like inflammation in the GI tract. One potential reason for the dominant role of DR3 over TL1A in these preclinical models relates to the differing expression patterns of DR3 and TL1A in the context of inflammatory bowel disease. DR3 is expressed by circulating immune cells, and once a cell turns it on, it continues expressing DR3 for as long as that cell lives. As a result, you see relatively consistent expression of DR3, both in actively inflamed sites in the colon and small bowel and in the adjacent non-inflamed tissue. TL1A is expressed in a very different manner than DR3. In IBD patients, TL1A is only found at sites of active inflammation, but not in the adjacent non-inflamed tissue. Further, TL1A is only turned on for short periods of time and then rapidly turned off again. Patients with inflammatory bowel disease do not always have inflammation at the same sites in their GI tract, and in fact, inflammation can wax and wane in different places over time. Because TL1A is not present at sites that are not actively inflamed, TL1A-blocking antibodies have no means of retention at sites where inflammation is just beginning. It is possible that this may contribute to the disparity between the rates of clinical response and clinical remission in the emerging clinical data sets for TL1A-blocking antibodies. Immune cells co-express a mixture of co-inhibitory and co-stimulatory receptors that are activated by their ligands, expressed primarily by cells and tissues. A recent example in oncology, where the efficacy of targeting a transiently expressed ligand versus a constitutively expressed receptor, is the PD-1 and PD-L1 axis, wherein PD-1 blockade has generally proven more efficacious than PD-L1 blockade. As shown in the figures on the left, the DR3 expression pattern on immune cells is very similar to the static expression pattern of PD-1. This is in stark contrast to the figures on the right, showing the comparatively sparse expression patterns of TL1A and PD-L1 on immune cells that can be accessed by blocking antibodies in the peripheral blood. For all of these reasons, we believe that DR3 blockade may have a similar safety profile, but superior efficacy profile in indications where TL1A has demonstrated initial clinical activity. With that background explaining the rationale for targeting DR3, the receptor for TL1A, we will now turn our attention to SL-325, our DR3-blocking antibody. We've been working on this for a while now, and we are excited to be able to share more about it with you today. We've generated a very nice preclinical data package that demonstrates that SL-325 has the desired characteristics of an antagonist antibody and supports our nomination as the lead product candidate for first-in-human studies. SL-325 is the first in a series of DR3-specific antibodies in development at Shattuck. SL-425 is a half-life extended form of SL-325. Half-life extension mutations may not be as important for DR3-targeted antibodies as they are for TL1A-blocking antibodies, because DR3 is stably expressed and blockade is expected to be durable. Nevertheless, we plan to evaluate the relative pharmacokinetic profiles of SL-325 and SL-425 in non-human primates to inform this hypothesis. Another advantage of targeting DR3 stably on immune cells is that this approach avails itself to co-targeting other inflammatory receptors expressed on immune cells and which are clinically validated contributors to inflammation in IBD and other autoimmune conditions. We are exploring several bispecific combinations and look forward to sharing more about these programs in the future. SL-325 is a first-in-class opportunity as a DR3-blocking antibody. Those that have followed Shattuck for years now know that we are specialists in developing TNF receptor agonists and thus have all of the tools in place to develop both TNF receptor agonists and antagonists. We applied this expertise to the DR3 antibody project and have identified a highly potent DR3-blocking antibody, SL-325, which compares favorably to the leading TL1A-blocking antibodies and will soon enter clinical development. Identification of a very high-affinity DR3-blocking antibody was a key consideration for this program. SL-325 was selected from hundreds of other DR3-specific antibody candidates for several reasons. First, SL-325 is an unusually high-affinity antibody, measured at 1.3 picomolar by surface plasmon resonance. Second, SL-325 demonstrates a very slow dissociation rate, indicative of stable binding that may translate to long receptor occupancy in clinical studies. Third, SL-325 is entirely specific to DR3 and binds an epitope that is not shared with decoy receptor 3 or any other closely related TNF receptors. Because decoy receptor 3 provides a natural antagonist function to TL1A, Fas ligand, and LIGHT, it is important to avoid epitopes that are shared with DcR3 in the development of SL-325. In evaluating SL-325, we synthesized bioequivalent versions of other TL1A-blocking antibodies, including tulisokibart and RO7790121, formerly known as RVT-3101. This figure demonstrates that SL-325 was able to block DR3 binding to a recombinant TL1A at lower concentrations of antibody than was required for TL1A-blocking antibodies. When DR3 is expressed by cells, a majority of DR3 is present as a monomer with a smaller proportion as a dimer, and very little exists in the active state of a trimer. When TL1A is introduced, it stimulates ligand-induced trimerization of DR3, which is then capable of signaling. Thus, it was important to test whether SL-325 could efficiently block TL1A binding to cell-expressed DR3 to ensure that 325 could prevent TL1A-mediated trimerization of DR3. These results show that SL-325 was capable of blocking TL1A binding to cell-expressed DR3 at lower concentrations than TL1A-blocking antibodies, confirming efficient TL1A blockade and ligand-induced trimerization. The efficient binding and blocking activity of SL-325 suggested that it would also be capable of preventing TL1A-mediated activation of human lymphocytes. As noted earlier, TL1A is present in both a soluble and membrane-bound state, and either source of TL1A can activate DR3 signaling in humans. The figure on the left demonstrates that soluble TL1A stimulates the production and release of interferon gamma from human lymphocytes, and that this can be inhibited in a dose-dependent manner by SL-325 and also control TL1A-blocking antibodies. The figure on the right shows the same effect in an assay that contains membrane-bound TL1A. Thus, SL-325 blocks DR3 activation by either soluble or membrane-bound TL1A. TL1A-mediated activation of immune responses is largely dependent upon T cell receptor signaling. In this assay, CD3 and CD28 activation mimics T cell receptor activation, and the addition of TL1A dramatically increases the amounts of interferon gamma released by human lymphocytes in the presence of CD3 and CD28 activation. The orange bars on the left demonstrate that SL-325 does not provide any activation of lymphocytes in the presence of CD3 and CD28 activation on its own. The blue bars on the right then show that SL-325 provides dose-dependent reduction of TL1A-mediated costimulation of human lymphocytes and is capable of fully neutralizing the costimulatory effect of TL1A. The data on the prior slide is an example of the potency of SL-325 on healthy human donor lymphocytes. Patients with autoimmune diseases, including Crohn's disease and ulcerative colitis, have immune systems which are at a heightened state of inflammation. Thus, it was important to ensure that SL-325 could fully inhibit DR3 on immune cells from patients with these diseases. The experiments in this figure show that this effect translates to lymphocytes provided by patients with ulcerative colitis or Crohn's disease. In both cases, 325 was capable of fully neutralizing TL1A-mediated costimulation of IBD patient lymphocytes in a dose-dependent manner. As you have just heard, there is compelling rationale to target DR3 instead of its ligand, TL1A. While there are a number of me-too TL1A-blocking antibodies in development, SL-325 has a first-in-class opportunity to more potently block the axis through DR3 blockade. The core aspects of the value proposition for targeting DR3 instead of TL1A relate to, first, stable expression of DR3 by immune cells in the peripheral blood and in tissues. This should allow for durable DR3 blockade that is not possible with TL1A-targeted antibodies due to the transient nature of TL1A expression. Second, stable blockade should prevent inflammation from spreading from inflamed to non-inflamed tissues more efficiently than TL1A blockade, which also relates to differences in the expression patterns of DR3 and TL1A and may contribute to higher rates of endoscopic remission with DR3 blockade. Third, TL1A-specific antibodies lead to immune complex formation with soluble TL1A, which may in turn contribute to the high rates of immunogenicity that have been observed with TL1A-specific antibodies. Because DR3 is membrane-bound, immune complex formation is not expected. Fourth, from a clinical development perspective, the proliferation of TL1A-blocking antibodies will provide an increasingly significant challenge for recruiting patients whom have never received the TL1A blocking antibody, or excluding patients who have measurable concentrations of a prior TL1A blocking antibody in the blood. As a first-in-class DR3 blocking antibody, SL-325 is not expected to encounter these challenges. Finally, because DR3 is a membrane-bound receptor expressed by immune cells, SL-325 provides a scaffold upon which bispecific antibodies co-targeting other immune cell-expressed inflammatory receptors can be built. These efforts are underway at Shattuck and are expected to provide pipeline growth in the years ahead. SL-325 will begin GLP toxicology studies this month, and an IND filing is expected in the third quarter of twenty twenty-five. The phase I trial will consist of single and multiple ascending dose cohorts, with clinical data expected in 2026. With this shift in focus to SL-325, we are able to extend our cash runway into 2027 and through the phase I clinical study for SL-325. We look forward to updating investors on our progress with SL-325 and other emerging programs into 2025 and beyond. With that, we are happy to take questions. Operator? Thank you. We will now begin the question-and-answer session. If you would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star one again. Your first question today comes from the line of Joe Pantginis from H.C. Wainwright. Your line is open. Hey, everybody. Good morning. Sorry to hear of the news about 154, but also very thoughtful of you to make this decision early on versus, you know, pushing it on through later-stage studies. So first, for the new asset here, I guess two questions. First, beyond IBD, what are other possible niche therapeutic indications? Would you consider niche indications in inflammation? And I guess that sort of applies to, you know, longer-term plans with regard to BD or partnership plans and how long you may hold on to the drug. Sure. Morning, Joe. Thanks for the question. So the reason that development of TL1A blocking antibodies began in inflammatory bowel disease is because ulcerative colitis and Crohn's disease are where there's the strongest genetic linkage between single nucleotide polymorphisms and TL1A that are associated with an increased risk of IBD than in any other disease. That being said, there are increases in the incidence of both DR3 expression or some of the same single nucleotide polymorphisms in TL1A in a variety of different musculoskeletal autoimmune diseases. This includes things like psoriatic arthritis, a couple of different arthritides, even lupus. There's reports of an increased expression of TL1A-driving disease. And so this has the potential to move into a variety of other areas. One of the places that there was also early interest was in asthma, particularly severe chronic asthma. Teva ran an initial phase I clinical trial in patients with that disease, which read out negative. So, I think, you know, we'll be paying attention both to the places where genetic evidence linking TL1A overexpression to disease exists, but also some of the emerging clinical evidence from the incumbent players here. We believe that the differentiated approach of going after DR3 instead of the ligand may serve us well in those efforts. No, thanks, and just a quick follow-up, if you don't mind. So I guess in targeting DR3 versus TL1A, you're focusing obviously on the first-in-class potential here of the asset. So I'm just curious, have there been any, say, technical accomplishments that you've been able to you know, bring forward in targeting DR3 over TL1A, and why haven't others necessarily targeted it at this point? Yeah, it's a good question, and I have an imperfect answer that requires a little bit of speculation that may or may not be fully true. So as I mentioned in the beginning, I did my graduate work in postdoc with Eckhard Podack at the University of Miami. He is one of four or five labs in the world academically that had been studying TL1A and DR3 for decades. The others included Steph Targan out in California. He was the scientific founder of Prometheus. Ayman Al-Shamkhani in the U.K., Fabio Cominelli at Case Western, Richard Siegel at NIH. And there really weren't many other people. Eddie Wang, I should mention, in the U.K. as well. There weren't many other people who were studying this axis for a continuous and prolonged period of time. Targan's group, for whatever reason, decided to focus on a TL1A blocking antibody first, and so that's why that went into the clinic. And so some of it, I think, is just a vestige of the relative lack of focus that this TNF receptor ligand pair, if you compare it to things like CD40, 4-1BB, OX40, GITR. The other truth is that it is a bit harder to develop a receptor-blocking antibody than a ligand-blocking antibody, because you have to carefully engineer it so that there is no risk of residual receptor agonism. Doing that obviously is something that Shattuck has worked on understanding TNF receptor agonists and antagonists for a long time, and requires finding super high-affinity antibodies that bind particular epitopes and making absolutely sure that your lead asset lacks any ability to bind Fc gamma receptors. Those were all boxes that we checked along the way. Got it. Thank you so much for those thoughts, and good luck on the development of the program. Thanks, Joe. Your next question comes from the line of Jonathan Miller from Evercore ISI. Your line is open. Hi, guys. Thanks for taking my question. I'll echo sympathies for the 154 discontinuation, but also your congratulations on doing the right thing early. I guess I'd like to ask, on the new asset, can you walk me through your confidence that you won't need a extended half-life version like the TL1As do? You know, can you give us a little bit more color on the biology that's driving durability for the existing drugs for TL1A and what you would expect for DR3? Sure. Good morning, Jon. Thank you for the question. So I'm not saying that we absolutely would not need a half-life extended version, and that's the reason why we have made both. And we'll compare the pharmacokinetic profiles of both 325 and 425 to one another in non-human primates, and if there is a good reason to advance the half-life extended version, we can do that. However, as I mentioned, TL1A, like many inflammatory ligands and cytokines, is a transiently expressed, receptor ligand that appears on the membrane, gets cleaved, goes into the circulation, and then gets degraded. And because of that, you don't have the opportunity to have durable blockade of an antibody bound to TL1A. It will, it will block TL1A for as long as it is sitting on the membrane or for as long as it persists and as an immune complex in the serum. But those immune complexes are cleared, and that is in contrast to when you're targeting a stably expressed receptor like DR3. And another important design consideration when you're making an antibody like this is to make sure it does not trigger receptor-mediated endocytosis, which our antibody does not. And what that means is that when 325 binds to a DR3-positive cell, it just sits there, and the receptor stays blocked. And there is no downregulation of DR3 that has an antibody bound. There's no cleavage of DR3 from the membrane that has an antibody bound. As I alluded to, this is actually fairly similar to how some of the PD-1 blocking antibodies work. If you look at patients that are treated with Keytruda, it binds to PD-1, and it sits there. You can look at a patient six months after their last dose of Keytruda and find that PD-1 remains 100% blocked, and there still remains high concentrations of free Keytruda in the serum of patients. We expect that we'll find similar properties of 325, both from a receptor occupancy standpoint, a serum stability standpoint in humans, that would obviate the need to go to a half-life extended version. As attractive as half-life extension is, sometimes you encounter challenges with those antibodies. There are examples where, for example, half-life extended antibodies have higher degrees of immunogenicity than the non-half-life extended equivalents. So these are all things that we'll test, and I think it's important for us to have both in our toolbox, but it's certainly far from a given that we would want to go with the half-life extended version. That makes sense. Thanks so much. I guess one more. While we're waiting for data in 2026, I believe you said, what should we be focused on for Shattuck in the meanwhile, and is there any more news we could expect out of the ARC program while we wait for DR3? Yeah, thanks, Jon. So as I alluded to, the GLP tox study for the DR3 antibody occurs this month, and we'll expect to have news on that in a few months' time. We do not expect to have much additional data from the ARC platform. We will clean the data for 154, publish it in an appropriate time, and hopefully that can benefit others that are thinking about approaching immuno-oncology targets. As you all are well aware, this has been a frustrating decade of once-promising immune checkpoints, first requiring combination therapy to show any signal and then to have the magnitude of those signals be underwhelming. So our future pipeline efforts are focused on agents that have an expectation of early single-agent activity, and that was one of the reasons why we're prioritizing 325 and going after DR3. That is a clear expectation. We've shared an abstract earlier this year at American Association for Cancer Research annual meeting, going after an intracellular target called TRIM7 that we believe is a mediator of PD-1-acquired resistance. That program is percolating along in our preclinical pipeline and make it to lead selection sometime soon. And then we had a great collaboration with Moderna in looking at how delivery of complex fusion proteins with mRNA lipid nanoparticles fundamentally changes the exposure profile head-to-head against delivery of a complicated fusion protein as a recombinant protein. And that collaboration yielded a really nice publication with some of our oncology-directed programs. But more importantly, that collaboration really opened a door that allows us to build fusion proteins that are better Orencias or better Enbrels or better Trulicities. And so we have some exciting ongoing programs going after non-oncology fusion protein targets like that that we hope to speak more about soon as well. Thanks for the questions. Your next question comes from the line of Marc Frahm from TD Cowen. Your line is open. Good morning, everybody. This is Ernie for Mark. Thanks for taking our questions. The first one is for the data in 2036 that we're expecting. Is that in healthy volunteers, or should we also expect that data to include IBD patients or TL1A responders? Yeah. Good morning, Ernie. So the initial phase I clinical trial for this program will be a approximately 70-patient, single-ascending, followed by multi-ascending dose study in healthy volunteers. And so we'll be looking for safety, receptor occupancy, PK profile in the initial dataset from that study. And that will be a key dataset that allows us to stack SL-325 up against some of the incumbent TL1A blocking antibodies. And that study, we expect to set the stage for follow-on studies in IBD patients. Okay. Thank you. And then what kind of, like, key biomarkers are you gonna be looking into? Are those the same as what is used with TL1A's? And is there a threshold that you're expecting to hit, do you think will signal incremental efficacy over the TL1A's? Yeah. So the key difference in the biomarkers that you will look for in a phase I study are that it with the TL1A-blocking antibody, the only thing you can measure are the TL1A, the soluble TL1A and TL1A antibody immune complexes in the blood. The TL1A antibodies bind and stabilize soluble TL1A that leads to the immune complex. And you can look at the concentration at which those immune complexes accumulate as an indicator for when you've reached saturating doses. When you're going after DR3, because DR3 is stably expressed by circulating lymphocytes, you can measure receptor occupancy. And that's in addition to the PK profile, that will be the key pharmacodynamic biomarker we're looking at. Looking at the interaction between the C min concentrations that are required over time to maintain 100% receptor occupancy on those circulating cells. Got it. Thank you. That's very helpful, and good luck with the program, and thanks again for the DR3 overview. Appreciate it. Thanks, Ernie. Your next question comes from the line of Yigal Nochomovitz from Citi. Your line is open. Hi, this is Ashiq Mubarack on for Yigal. Thanks for taking my questions, and I want to echo our appreciation for the candid and disciplined nature of this update, so thank you for that. One question on DR3. Can you give us a flavor as to how aware the physician community is of DR3 as a target and maybe some of the nuanced biology and expression patterns you described? How much of an educational lift do you think you'll have to do to get patients to enroll in your study next year? Thanks. Yeah, thanks, Ash, for the call and for the question. I think, you know, the biology of the axis is very well known, and there was a lot of work academically that began in the early 2000s that defined all of the rules of the axis. And those rules haven't changed. So, you know, people at one point in time wondered, you know, "Might TL1A bind any other receptors, and might DR3 bind any other ligands?" Lots of groups, including ours, tried hard using multiple methods to probe those questions, and, you know, all of those efforts came up empty. And I think you can have a very high degree of confidence these days that this is a truly monogamous receptor-ligand pair. And so long as you build a DR3 blocking antibody that doesn't have any intrinsic effector function, i.e., it doesn't find any Fc gamma receptors, because that is a monogamous receptor-ligand pair, you expect the safety profile of TL1A blocking antibodies to predict the safety profile of DR3-blocking antibodies. By the time we go into the clinic, we will have a direct comparison there from non-human primate studies that I expect will bear that out. I think, you know, because a lot of the dialogue has been focused on TL1A, there's certainly an awareness that we need to raise that TL1A binds a receptor, and it's known as DR3, and these are the reasons why it makes sense to consider approaching the other end of the axis. But I don't think, aside from raising that awareness and educating folks on how the axis works overall, that this will be a difficult concept for folks to grasp because there are so many other examples. I've mentioned the PD-1, PD-L1 example. There's also examples with other TNF ligand versus receptor-blocking antibodies in autoimmune diseases, for example. You look at OX40 versus OX40 ligand blockers, and CD40 versus CD40 ligand blockers. And so there are class lessons there that can be applied. Okay, got it. And I'll, I have one additional quick question. And what's your level of interest in potentially partnering this program? When would that make sense? Is this something you might need help with to run a large pivotal study in a few years' time? Thanks. Yeah, I think we have to carry this forward to the next stage. Certainly getting through non-human primates, I think will be valuable for the program. It was valuable for a program that AbbVie recently in-licensed from a Chinese company with, you know, the fifth in class, probably TL1A blocking antibody. And, you know, we're ready to carry this through the phase I study as well, and I think recognition of the value of targeting DR3 will grow over that period of time. And, you know, we'd be happy to continue engaging in conversations with prospective partners there. IBD is a competitive and massive landscape, and so there certainly could be a time where having a partner helping us take this to the next stage could be helpful. Got it. Thanks very much. Thank you. Your next question comes from the line of Ethan Markowski from Needham & Company. Your line is open. Hi, guys. This is Ethan on for Gil. Thank you for taking our questions. Just a couple from us. So, you mentioned you have a DR3 bispecific in preclinical development. Do you expect it to have increased potency compared to SL-325? And if so, why not start with that program instead? Yeah. Hi, Ethan. Thanks for the question. So there's a couple reasons for it. First, the TL1A DR3 axis actually has a very high degree of monotherapy activity on its own. And the key aspect of the value proposition that we believe DR3 blockade may address is the discrepancy between the proportion of patients that have some degree of clinical response to a TL1A blocking antibody, and that sits somewhere around two-thirds of patients that are treated, and the proportion of patients that have true clinical remission, which sits at about a quarter of the patients that are treated. And we believe that more durable blockade of DR3 may close that gap between true remission and response. And so that's a hypothesis that we're excited to test in our first clinical trials. And if that bears out, then there's a huge market there. The attraction to build on the DR3 blocker with bispecifics, first of all, requires some degree of clinical experience with the DR3 blocker on its own to help us understand the exposure-response PK profile of DR3 targeting with a monospecific. And we think that could be leveraged with some other valid, clinically validated targets in IBD and also other diseases. So you could look at, you know, standard of care agents like Entyvio like IL-17-specific antibodies, IL-23-specific antibodies. There's a number of others. Realize that when you're going after a membrane-expressed target like DR3, that approach avails itself to co-targeting the receptors that are also expressed by DR3-positive T-cells for some of those validated targets in autoimmunity. So we see this as a two-step process wherein the DR3 asset will derive value on its own initially. Thank you. That makes sense. And then maybe two more quick questions. So, for 154, were there any new safety updates, particularly related to infections or cardiac adverse events? And then can you provide a little more color on what led to the termination of the collaboration agreement between you and Ono that you also announced this morning? Thank you. Sure. I'll address Ono first. You know, as callers are aware, this discontinuation of 154 has caused a painful reduction in headcount of our organization. Along with that reduction in headcount, we have to focus on the programs that are driving value for Shattuck, not programs that are driving value for other partners, particularly very early stage programs like the one we were working on with Ono. This is a consequence simply of our reduction. With the 154, no, there was no change in the safety profile in comparison to what we'd previously shared at the end of last year and at EHA. We did not see any hemolytic anemia. We did not see an increased rate of infection. We didn't see any cardiac events that we believe are related to 154, as we've previously shared. All right. Thank you for taking our questions. Thanks, Ethan. This concludes the question and answer session of the call. At this time, I would like to turn the call back over to Taylor Schreiber, Chief Executive Officer of Shattuck Labs, for closing remarks. Thank you, operator, and thank you all for joining the Shattuck Labs investor conference call to discuss company updates and strategic pipeline prioritization, with our focus on developing a first-in-class DR3 antagonist antibody, SL-325. We appreciate your continued interest in Shattuck, and we look forward to updating you on our milestones. Thank you, and have a great day. This concludes today's conference call. Thank you for participating. You may now disconnect. Have a wonderful day.