Good morning. 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. Instructions will follow at that time. As a reminder, this conference call is being recorded. I will now turn the call over to Shattuck's Chief Financial Officer, Mr. Andrew Neill. Please go ahead. Thank you, operator. Good morning, everyone. Thank you for joining. During today's call, we will be providing a company update, including clinical data from the phase I clinical trial of our potentially first-in-class DR3 blocking antibody, SL-325. 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. I would refer you to our most recent 10-Q, our most recently filed corporate presentation, and our other filings with the SEC, which are available from the SEC's website or on our corporate website, shattucklabs.com. I am joined on today's webcast by Dr. Taylor Schreiber, our co-founder and Chief Executive Officer, Dr. Lini Pandite, our Chief Medical Officer, Dr. Suresh de Silva, our Chief Scientific Officer, and Dr. Michael Choi, our VP of Clinical Development. We will start with results from the phase I trial of SL-325 in healthy volunteers, including safety, pharmacokinetics, pharmacodynamic, and immunogenicity data from all 72 participants enrolled in the study across all dose levels in the single-ascending-dose and multiple-ascending-dose cohorts. We will introduce SL-846, our lead bispecific product candidate and a potentially first-in-class bispecific antibody providing dual blockade of TL1A signaling through DR3 and IL-23 signaling through the IL-23 receptor. We will make a few closing remarks before opening up the floor for questions. I will now turn the call over to our CEO, Dr. Taylor Schreiber. Thank you, Andrew. We are very excited this morning to be able to share the results from our phase I trial with SL-325. SL-325 is now the first antibody to generate clinical data for blockade of the TL1A receptor, known as DR3. As you all know, we have seen clinical proof of concept for several TL1A blocking antibodies in ulcerative colitis and Crohn's disease with better efficacy than TNF inhibitors, integrin inhibitors, or IL-23 inhibitors. This raises the potential for therapies in the TL1A/DR3 axis to become leading medicines in a market predicted to exceed $40 billion in global revenue. In addition to ulcerative colitis and Crohn's disease, aberrant signaling through the TL1A/DR3 axis is thought to contribute to other rheumatologic and dermatologic inflammatory diseases. We believe DR3 blocking antibodies may provide superior efficacy to TL1A blocking antibodies for two reasons. First, a best-in-mechanism immunogenicity profile. Second, more durable inhibition of the TL1A/DR3 axis because DR3 is a more stable target than TL1A. We've now completed our phase I clinical trial of SL-325 in healthy volunteers with these key findings. First, SL-325 was well-tolerated across all doses, with a safety profile consistent with the TL1A antibody class. Second, a single low dose of SL-325 is expected to block TL1A binding for over three months, potentially enabling extended dosing intervals at volumes compatible with convenient subcutaneous dosing using an auto-injector pen. Third, there was no evidence of DR3 agonism. Finally, only 3.7% of participants developed anti-drug antibodies, suggesting a best-in-mechanism immunogenicity profile. The TL1A/DR3 axis is fairly straightforward in the sense that TL1A is the only known signaling ligand for DR3. TL1A does not cause signaling through any other receptors. This means that both TL1A and DR3 are on equal footing from a specificity standpoint. TL1A is initially expressed by antigen-presenting cells as a membrane-bound protein. The extracellular domain of TL1A can be cleaved, which produces a soluble form of TL1A that can be measured in the blood. DR3, on the other hand, is always a membrane-restricted protein. SL-325 does not bind decoy receptor 3. As a result, there is no risk of immune complex formation with SL-325. This has very important implications for the immunogenicity risk of SL-325 relative to TL1A-blocking antibodies, as we will touch on further in a moment. Here's a quick snapshot of our current pipeline. In addition to SL-325, Shattuck is also developing a half-life extended equivalent antibody known as SL-425. We are very pleased today to introduce our first DR3-directed bispecific antibody, SL-846. 846 leverages the emerging biology of the TL1A/DR3 axis with the known clinical efficacy of the IL-23 class in a format that may avoid the immunogenicity issues we have seen with other TL1A-directed bispecifics. We will share more on 846 later in the presentation. As we just noted, TL1A is found both as a membrane-bound protein in tissues and as a soluble protein in human serum. This creates two sites of action for TL1A-blocking antibodies. In IBD patients, the desired site of action is to achieve TL1A blockade at sites of inflammation in the GI tract. However, TL1A-blocking antibodies also bind to soluble TL1A in the blood, resulting in the formation of immune complexes. All of the TL1A-blocking antibody developers with reported clinical data have used soluble TL1A as a biomarker for dose selection of anti-TL1A antibodies. They have all shown that the concentration of TL1A in the blood increases by two to three logs immediately after treatment with TL1A-blocking antibodies. These results demonstrate that anti-TL1A antibodies function by converting low concentrations of free TL1A to very high concentrations of immune complexed TL1A. Immune complexes are a well-known cause of immunogenicity for therapeutic antibodies, especially anti-TNF antibodies. The root cause of immune complex-mediated immunogenicity for anti-TNF and anti-TL1A antibodies is similar because both TNF-alpha and TL1A are homotrimeric proteins found in the blood. Published and emerging data have shown that both neutralizing and non-neutralizing anti-drug antibodies to TL1A-blocking antibodies leads to a loss of exposure and a loss of efficacy at the induction time point in IBD patients. We expect that this dynamic may be exacerbated as treatment continues into maintenance. Because the mechanism of immunogenicity is similar for anti-TL1A and anti-TNF-alpha antibodies, and the possibility that ADA might limit efficacy over time, we took a look at existing data for IBD therapies with low and high rates of ADA to see if any correlations could be drawn. Many clinical trials in IBD use re-randomization designs, which obscures the actual numbers of patients benefiting from a therapy. The plot here shows whether the absolute number of patients in clinical remission increases or decreases from induction to maintenance. Strikingly, with both TNF and TL1A-blocking antibodies, there is not a meaningful increase in the number of patients in clinical remission over time, and some studies have shown an erosion over time. In contrast, non-immunogenic drugs like JAK inhibitors or drugs with low rates of ADA, including IL-23 inhibitors, show a conversion of patients from clinical response to clinical remission. This results in significant increases in the total number of patients in clinical remission over time. These results have significant implications for the overall commercial opportunity for SL-325, with a potential for accumulating efficacy from induction to maintenance. That would mean that in the real-world setting with a non-immunogenic therapy, patients could potentially r emain on SL-325 for years. O O ne of the differences between TL1A and DR3 is that DR3 is constitutively expressed, but TL1A is not. Several of the original studies on the TL1A/DR3 axis showed that one of the most potent inducers of TL1A expression by antigen-presenting cells is exposure to immune complexes. Given the unusually high concentrations of immune complex to TL1A in patients treated with TL1A-blocking antibodies, we hypothesized that these immune complexes could stimulate a feedback loop, resulting in increasing levels of TL1A expression. To test this, we conducted experiments examining whether immune complexes between a sequence equivalent of tulisokibart and soluble trimeric TL1A could also directly cause an increase in TL1A expression. As expected, these preclinical studies showed that exposure of human monocytes to tulisokibart TL1A immune complexes caused over a 70-fold increase in production of TL1A within a six-hour period. Although these studies were conducted with tulisokibart immune complexes, the data suggest this phenomenon may not be unique to tulisokibart and may apply more broadly to other TL1A-blocking antibodies. This phenomenon, together with high rates of ADA, may be co-conspirators that have driven the selection of the very high doses of TL1A-blocking antibodies that are being evaluated in multiple ongoing phase III clinical trials. It is now my pleasure to turn the call over to Dr. Lini Pandite, Shattuck's Chief Medical Officer, to walk you through the results from our phase I clinical trial. Lini? Thank you, Taylor. This slide shows a schematic of the design of the phase I clinical trial for SL-325 in healthy volunteers. This trial included six single ascending dose levels and three multiple ascending dose levels. Eight participants were randomized 3:1 to either SL-325 or placebo for a total of 72 participants enrolled. The demographics of the enrolled participants were well-balanced and typical for a healthy volunteer study. We designed this trial to establish the safety and tolerability profile of SL-325 and to establish the dose and the dosing schedule for SL-325 in subsequent phase II clinical trials. In addition, we also designed the trial to investigate the risks associated with targeting DR3 and to evaluate the attributes of SL-325 that could differentiate from TL1A antibody class, including evaluation of immunogenicity, DR3 receptor occupancy, and residual DR3 agonism. SL-325 was well-tolerated in both the single ascending dose and the multi-ascending dose cohorts across a wide range of up to 30 milligrams per kilogram. No serious adverse events occurred, and all treatment-related adverse events were mild and grade 1. The most common treatment-related adverse event was mild headache, which occurred in 15% of participants who received SL-325. The headaches were transient and resolved in less than 24 hours. One participant experienced a mild infusion-related reaction after receiving the second dose in the 10-milligram per kilogram multi-ascending dose cohort. The symptoms resolved within 10 minutes and without therapeutic intervention. The participant was diagnosed with strep throat the following day. Although subject remained ADA negative, the third dose was not administered. Overall, the safety profile of SL-325 was very consistent with the TL1A class across all doses. A key challenge in developing a blocking antibody to a TNF receptor, including DR3, is to engineer the antibody appropriately to remove any risk of residual agonism. This challenge is likely one of the reasons why the first generation of antibodies all target the ligand TL1A. DR3 agonism in healthy participants would be expected to cause rapid and dose-dependent proliferation of lymphocytes, including Tregs, within five to eight days following stimulation of DR3. We carefully monitored for any evidence of T cell proliferation, serum cytokine increase, and evidence of a change in activation status of lymphocytes in treated participants. We observed no evidence of lymphocyte proliferation, no evidence of changes in serum cytokines, or changes in markers of cell activation status in any participant who received SL-325. We are very pleased that these data generated in human participants confirm our previous findings, including both in vitro and in non-human primate studies, that SL-325 is a pure DR3 blocking antibody. As we expected, there was no increase in the level of serum TL1A in any participant. The PK profile of SL-325 showed dose proportional increase in Cmax and AUC across all dose levels, and an accumulation ratio of approximately 1.64 to 1.75 with biweekly dosing. Steady-state clearance was consistent across all dose levels. The estimated terminal half-life is approximately 16 days. In designing SL-325, we intentionally selected a very high-affinity antibody that does not cause internalization of DR3. We measured DR3 occupancy of SL-325 by testing for any evidence of TL1A binding to cells in the peripheral blood samples that we collected from study participants. Human data now shows that complete DR3 occupancy was achieved even at the lowest dose of 0.1 milligram per kilogram. A single dose of 0.1 milligram per kilogram SL-325 provided complete inhibition of TL1A binding to DR3 for over one month. By the 1 milligram per kilogram dose level, SL-325 completely inhibited TL1A binding to DR3 for three months. These data surpassed our expectations and indicate that extended maintenance dosing intervals via subcutaneous administration using an auto-injector pen are expected to be possible for SL-325. I will now turn the call back to our CEO, Dr. Taylor Schreiber. Thank you, Lini. In sharing our phase I immunogenicity results for SL-325, our goal is to be transparent and to explain the questions that investors should ask when presented with an ADA% or a qualitative description of ADA rates. ADA assays are customized for individual therapeutic antibodies, and each assay has unique performance parameters. Reporting ADA% without disclosing these parameters impedes interpretation of ADA results because every ADA assay has a dynamic range. The lower bound of that dynamic range is well understood and relates to the ability of an ADA assay to detect low-titer ADA. This is known as the sensitivity of the assay. The upper bound of ADA assays is poorly understood and is a parameter known as assay tolerance. This parameter defines the maximum concentration of a therapeutic antibody in a serum sample that does not interfere with the ADA assay itself. The FDA has written articles on this topic, surprisingly, only 25% of monoclonal antibodies were found to have adequate assay tolerance in the ADA assay at the time of BLA submission. The impact of inadequate assay tolerance is the potential for high rates of false negative results, particularly at higher doses of a therapeutic antibody. This may also be the source of the widely held belief that somehow higher doses of antibodies reduce immunogenicity. The ADA assay that Shattuck developed for SL-325 is highly sensitive, with a lower limit of detection at 5 nanograms per ml. This assay also had a high level of drug tolerance and returns valid results so long as the serum concentration of SL-325 at the time of analysis is below 160 micrograms per ml. We analyzed ADA across multiple time points, which is particularly important at the higher doses to allow for the concentration of SL-325 to fall into the dynamic range of the assay. Testing in this manner ensures valid assay results for each participant. Only two out of 54 SL-325-treated participants were found to be ADA positive. This provides a composite ADA rate for SL-325 of 3.7%. In the two ADA-positive subjects, ADA remained low titer and had no apparent impact on PK or RO. SL-325's ADA rate of 3.7% is significantly better than the published composite rates of ADA from the anti-TL1A antibodies in phase I clinical trials. As you can see on the slide, these composite rates range from 48% to over 80% for certain anti-TL1A antibodies. Additionally, we believe that these composite ADA rates may be understating the actual ADA burden of these antibodies, given the possibility that inadequate drug tolerance at the higher dose levels could contribute to false negative results. In summary, the data collected in this phase I trial have answered the key questions we set out to address, demonstrating that SL-325 was well-tolerated with no evidence of DR3 agonism and positioned as a potentially best-in-mechanism antibody by virtue of achieving durable physical blockade of TL1A binding and a superior immunogenicity profile. We are now poised to move SL-325 into phase II development. I am pleased to introduce Dr. Michael Choi, our VP of Clinical Development, to outline the phase II study of SL-325 in Crohn's disease. Michael? Thanks, Taylor. In Q3 of this year, we expect to initiate a large, double-blind, multi-dose, placebo-controlled study of SL-325 in patients with moderate to severe Crohn's disease, which we have named RECEPTIVE-CD1. We will examine SL-325 at multiple dose levels in comparison to placebo using a treat-through study design. The primary endpoint is endoscopic response at 12 weeks, with a secondary endpoint of clinical remission at 12 weeks. We expect to enroll a total of 174 patients randomized evenly between the three arms, and all placebo patients will be offered high-dose SL-325 following the 12-week induction period. Flat phase II doses were derived from a quantitative systems pharmacology model, which predicts that over 95% TL1A signal inhibition is expected throughout the dose interval, even with the lowest dose. We are now also very pleased to introduce SL-846, our lead bispecific product candidate, a potentially first-in-class DR3 and IL-23 receptor blocking antibody. I will turn the call over to Dr. Suresh de Silva, our Chief Scientific Officer. Thank you, Michael. There are three potential strategies to leverage TL1A DR3 inhibition as the preferred backbone of future combination therapies in IBD. DR3-directed bispecific antibodies, multi-antibody co-formulations, or TL1A-directed bispecific antibodies. A summary of some key considerations when selecting amongst these formats are summarized in the table. The recent DUET study results highlight the elevated clinical trial complexity and cost when developing an antibody co-formulation, wherein dose ranging is required for each individual antibody and where powering against an active comparator can be challenging. In addition, if the high doses of anti-TL1A antibodies advance to phase III studies are required to maximize efficacy, this will introduce feasibility challenges with subcutaneous injection that are likely to be compounded in multi-antibody co-formulations. Two TL1A-directed bispecific antibodies have been tested in clinical trials, AMG 966 and RG6730. In both cases, nearly 100% ADA were observed in all healthy participants after a single dose at all dose levels. In each of these cases, up to three TL1A bispecific antibodies can bind to each circulating TL1A trimer, and the other Fab domain is then free to bind the second target. Although these immune complexes may actually be smaller than the immune complexes created by TL1A-directed monoclonal antibodies, they are clearly still highly immunogenic. The preclinical data for these programs was considered compelling. However, there is no preclinical assay that predicts the risk of immunogenicity secondary to immune complex formation. In many ways, the emerging efforts in developing TL1A bispecifics is similar to what was once thought feasible for TNF-alpha-directed bispecific antibodies. Unfortunately, all of those efforts ultimately failed due to immunogenicity concerns, and the early data sets for those programs may serve as a warning for continued efforts with TL1A bispecifics. We developed SL-846 to avoid both the immunogenicity and clinical trial complexity issues that challenge the development of TL1A-directed bispecifics or co-formulations. One half of SL-846 is nearly identical to SL-325. Thus, the DR3 binding and immunogenicity characteristics of SL-325 would be predicted to inform the clinical performance of SL-846. We paired DR3 blockade with IL-23 receptor blockade for multiple reasons, including the existing clinical proof of concept for anti-IL-23 therapeutics and the known co-expression of DR3 and IL-23 receptor by immune cells, which offers the potential for binding in cis for SL-846 without introducing immune complex risks derived from binding soluble trimeric proteins. SL-846 was also engineered to lack any ability to bind Fc gamma receptors and also contains a YTE mutation for half-life extension. SL-846 was rigorously tested in a wide range of preclinical binding and potency assays using a number of benchmark controls, including risankizumab and etrasimod. Across these preclinical assays, SL-846 performed equal to or better than sequence equivalents of these clinically validated benchmarks. As a result of these data, SL-846 was advanced to chronic GLP toxicology and PK studies, which are now underway. Taylor? Thank you, Suresh. In conclusion, SL-325 has checked all of the initial boxes with regard to safety, immunogenicity, lack of residual DR3 agonism, and DR3 saturation at low doses. In addition, the duration of complete TL1A blockade has exceeded our expectations and provides the potential for extended dosing intervals through highly durable receptor occupancy. As promising as the emerging data has been with TL1A-blocking antibodies, SL-325 provides a clear opportunity to capture additional efficacy through a superior immunogenicity profile, potentially at dose levels that are expected to be compatible with a self-administered subcutaneous auto-injector pen. It will be an exciting year ahead as SL-325 moves into the RECEPTIVE-CD1 trial, which we expect to be the definitive phase II trial in Crohn's disease, allowing us to select an optimal dose to study in phase III. We are equally excited about SL-846 for a variety of reasons, including the validated biology of both the TL1A and IL-23 axes and the opportunity that this opens for Shattuck outside of IBD. Chronic toxicology studies for SL-846 are already underway, and we expect to share initial data from this toxicology study, including safety and immunogenicity data, later this year. I'd like to close by thanking the Shattuck team for their hard work over the past year to complete the phase I trial in a highly rigorous manner, and especially the participants in the study who enabled collection of the data that is now in hand. With that, we are happy to take questions. Operator? Great. Thank you, Taylor. At this time, we'll be conducting a question and answer session with our speakers. To our analysts joining us live, please use the raise hand feature to indicate you have a question. Please hold for a brief moment. Our first question comes from Yasmeen Rahimi at Piper Sandler. Please go ahead, Yas. Hi. Good morning, team. Congrats on the outstanding data, really congrats also on the nomination of a very smart bispecific construct. Two questions. One is maybe help us understand how you're thinking about the two doses selected in your phase II-B Crohn's study for SL-325. Also, given the data you shared that lower ADAs drives greater efficacy, how are you thinking about powering for that Crohn's study? Then maybe a third last question in relations to the new bispecific is how do you think about durability for that novel construct given what you showed today? Thank you again for allowing us to ask our questions. Great. Thanks, Yas, for the question. On the dose selection question for the phase II study, as Michael mentioned, we've performed an extensive quantitative systems pharmacology analysis based on the data that we have in hand, and this takes into account the affinity of the antibody to DR3, the receptor occupancy, and PK data that we collected in the phase I. Then it also takes into account the differences in DR3 expression between healthy volunteers and subjects with IBD, both in the peripheral blood and the gut. What we're looking at here is really addressing two questions. The first is that there is the potential, in my opinion, the likely potential, that maintaining full receptor occupancy for the duration of the dosing interval is the requirement that will lead to maximal efficacy. As we now know, this can be achieved at very low absolute doses, probably at infrequent intervals. The low dose is going to be aimed at answering just that question and maintaining trough concentrations throughout the dosing interval that are expected to exceed the trough for full receptor occupancy. That is a dose that would be certainly able to be administered in a low volume subq auto-injector. The high dose is taking into account the historical learnings for other approved antibodies in inflammatory bowel disease, where the targets of all of those antibodies undergo rapid rates of turnover in the tissue. This includes TNF, IL-23s, α4β7s. Because of that high rate of turnover of the target, the antibodies all have to get dosed at gross excess to the dose required for target saturation. That's so that they maintain a high gradient of antibody from the blood to the tissue and keep tissue concentrations high. We'll test that high dose as well, just to definitively address, or I should say, eliminate the risk that we have underdosed this antibody in the phase II. We expect that answering those questions will give us, as Michael said, the potential to select a single dose to advance into phase III studies. On your second question on the powering, if you look at recent meta-analyses in Crohn's disease, those analyses will tell you to assume that 13% of the patients on your placebo arm will achieve endoscopic response at 12 weeks. We have assumed that a higher percentage of placebo patients achieve endoscopic response, that is simply to provide a little bit of conservatism to the study design. On the other hand, we've powered for at least a 20% improvement in endoscopic response versus placebo. There too, 20% is not what we expect. We expect blockade of DR3 to lead to higher rates of endoscopic response than that. We hope that these design decisions have given us a bit of conservatism on both ends of the study. To your last question on SL-846, the target profile here is full blockade of both DR3 and IL-23 receptor, just as what we've just observed in the phase I study with SL-325. Suresh mentioned that both DR3 and IL-23 receptor are frequently co-expressed by the same lymphocytes. We know that the density of IL-23 receptor is less than the density of DR3. The absolute dose levels that we've now shown to be required for achieving DR3 occupancy are expected to exceed the dose levels required for concurrent blockade of IL-23 receptor, and should also lead to expected low doses to saturate both targets. Thank you so much. Thanks, Yas. Yes, thanks for the questions, Yas. Our next question comes from Prakhar Agrawal at Cantor Fitzgerald. Please go ahead. Hi, good morning, and thank you for taking my questions, and congratulations again on the excellent data. Maybe first on the bispecific, given what we have seen on the immunogenicity side for DR3 monotherapy, what does it mean for immunogenicity for your IL-23 bispecific now? What preclinical data will we get later in the year that could have implications for immunogenicity in humans? Then I had a follow-up on the monotherapy. Okay, great. Thanks, Prakhar. First of all, just as was the case with 325, because 846 is binding two receptor-restricted targets, there's no risk of immune complex formation with 846. As Suresh mentioned, because half of the antibody is 325, it's possible that the learnings about the immunogenicity for 325 partially inform the risk of immunogenicity with 846. With 325, many folks may remember that we had a 9% rate of ADA in monkeys, and now a 3% rate of ADA in humans. We'll be sharing that ADA rate of 846 in the second half of this year, and it's possible that whatever we see in monkeys will also over-predict the ADA rate that we see in humans. Got it. On the monotherapy, as you think about the Crohn's disease phase II trial, could you just remind us why you think that targeting DR3 could show differentiated efficacy in Crohn's? Will the induction period be enough to show that differentiation? Or because of your lower ADAs, you'll need some of the maintenance data to make a compelling case for differentiation versus TL1A? Thank you so much. Yep. Thanks, Prakhar. We've looked at the published data for afimkibart, and in the data supplement for their The Lancet Gastroenterology & Hepatology paper, in the data supplement there, they showed that ADA alone were providing a relative reduction in efficacy at the time of induction that crunched the numbers there, and it converts to about five to eight placebo-adjusted percentage points of clinical remission loss at the time of induction. That's a m eaningful delta just at induction that could be captured here. We were really struck by looking at the absolute patient numbers that go from induction remission to maintenance remission across the different IBD drug classes to see just how clearly the high ADA and low ADA medicines differ from one another. Given that the TL1A DR3 axis seems to be upstream of the IL-23 inhibitors and is analogous in some ways to how the JAK inhibitors are interfering with effector immunity, we would expect that a low ADA drug like this would lead to a potential doubling of the absolute number of patients in remission from induction to maintenance. We think benefit could be seen at induction, but then only grow over time. Thank you. You're welcome. Thanks for the questions, Prakhar. Our next question comes from Umer Raffat at Evercore ISI. Please go ahead, Umer. Hi, guys. Thanks so much for taking my question, congrats again. Maybe a couple of questions here, if I may. First, Taylor, would you remind us, is this a cell-based assay? Is it a functional assay, or is it a ligand assay, the five nanograms per mil sensitivity that you were referring to? The second one is, as we think about sort of the indication pot ential here, obviously there's a GI indications, but I also wondered if there's other indications where there's a bigger discrepancy between DR3 expression and TL1A. For example, HS. I was thinking out loud, maybe there was possibilities of going quite rapidly into those indications right away and not just limit to UC Crohn's type of thing. I'm curious how you think about that. Thank you, Umer. The ADA assay is a pretty typical bridging assay format. It's not a cell-based assay. It's an electrochemiluminescent ELISA-based assay, where that five nanogram per mil sensitivity threshold was identified and same thing, the 160 microgram per mil drug tolerance threshold. Happy to answer if you have any follow-ups there, just to get to your second question, we're very much looking forward to Merck sharing data on the HS indication later this year. We're also looking forward to, obviously, the range of other indications with TL1A readouts coming. Really across the board there, the TL1A data have been great at the time of induction. I expect that will still be the case just further highlight that if immunogenicity does not impact efficacy, this class may really continue to be viewed as a backbone of a few combo therapies across indications. HS is definitely an interesting one. Merck, many people may be aware, shared an interesting poster at EA DV last year where they were looking in HS lesions at the relative abundance and localization of both TL1A and DR3. In that presentation, they showed that just like in IBD, DR3 is much more abundant than TL1A in HS lesions. They also provided correlations that it was the amount of DR3, not TL1A, that correlated with inflammatory cytokines such as TNF, IL-1, and IL-17s, all of which are known to be key contributors to disease pathology in HS. Pairing with IL-23 in indications like that and others where TL1A, DR3 are likely contributors to inflammation could lead to meaningful breakthroughs in those really difficult-to-treat diseases. Thank you very much. Thanks, Umer. Yes, thanks for the questions, Umer. Our next question comes from Joe Pantginis at H.C. Wainwright. Please go ahead, Joe. Hey, guys. Good morning, and thank you very much for this very extensive data set here that ho pefully really defines the path forward. First, if I could just look forward for the phase II study, what are your plans right now of targeting bio-naive versus bio-experienced patients or looking to have a split? And then similar to Prometheus Merck, even though it wasn't Crohn's disease, are you looking to enrich for any TL1A biomarkers? Great. Thanks, Joe, for the question. Michael, can I turn it over to you to give some of the details there on the phase II? Sure, Taylor. Joe, good questions. First of all, enriching for TL1A within our cohort, we are not going to do that. We're going to just basically go with the Crohn's patients who are moder ate to severely active. Regarding your question about the bio-naive versus bio-experienced, we are going to basically have a nice split between the two cohorts so that we'll have probably about 50%-60% bio-experienced and the rest being bio-naive. Great. Thanks for that. For the current data and then also looking to the future, you really, I think, have allayed a bit of a fear here with regard to the chronic DR3 blockade and the data you showed with regard to lack of impacts on Tregs and all the cytokine profiles that you looked at. Based on these data and your preclinical tox data, do you ha ve any potential concerns or what are your thoughts for much longer-term dosing on impacts of any of these immune components? That's a great question and a question that I think the field is still learning about. The data that we have in hand in inflammatory bowel disease, and this will be a bit of a scientific answer, but the data that we have in hand in inflammatory bowel disease clearly shows that in a disease like that, where the antigens that are driving inflammation are always present, that Tregs are no longer playing a role in suppressing autoreactivity in the gut, and it's really the effector arm of immunity that you would like to interfere with. I do wonder, is the reason why duvakitug, as Teva's TL1A antibody, failed in asthma b efore it succeeded in IBD, was that in any way influenced by the fact that asthma is not driven by antigens that are always around? It's a seasonal or environmental antigen-driven disease. Therefore, the interplay between effector immunity and regulatory immunity may not be the same as it is in IBD. I would have t he same concerns about something like atopic derm. There's certainly a number of indications where the offending antigens are always present, just like they are in IBD, where this axis is likely to be very important. Thank you very much. Thanks, Joe. Yes. Thanks for the questions, Joe. Our next question comes from David Nierengarten at Wedbush. Please go ahead, David. Hey. Thanks for taking the question. I had one speculative question. Just if you had any opportunities or thoughts on maybe an investigator-sponsored study or looking at biomarkers in patients who have not responded to a TL1A. I know, obviously, it's an experiment from a clinical trial, but I was just curious if you had any thoughts, and if there was any utility in taking a look at those patients in an exploratory study in the future. Thanks. David, that's a really great question. It is definitely something that we are thinking about. If participants in TL1A trials had initial benefit and then ultimately failed due to ADA, so long as the ADA that are generated to anti-TL1A don't cross-bind other antibodies, you might expect them to become respon sive to something like 325 in the same pathway. It's not on the roadmap today, but that's a study that makes, I think, a lot of sense. Great. Thanks. Thank you. Thanks, David. Our next question comes from Marc Frahm at TD Cowen. Please go ahead, Marc. Hi. Thanks for taking my questions, congrats on the data today. Really impressive. Maybe just back to the idea of additional indications beyond Crohn's. I guess, makes a lot of sense to translate UC from Crohn's, for going beyond outside of IBD, how much are you willing to maybe test some indications before phase II proof of concept is available from other TL1A programs? How much do you want to wait for that proof of concept? Also, do you think you can translate the dose directly across to any of those indications and maybe go straight to phase III, just like in UC, or are you going to need phase IIs, you think, anywhere outside of IBDs? Thanks, Marc, for the question. This axis is now being investigated in a bunch of indications where the translational biology makes sense, right? We'll get data from systemic sclerosis soon. Later this year, we'll see data for RA, psoriatic arthritis, maybe a little bit of axSpA, HS. We'll get AD next year, liver diseases thereafter. I think we're in a situation here where there's almost, in my opinion, no chance that we don't see a signal in a couple of those other indications. We won't see signals in all of them, we will in some. That could double or triple the market that is addressable with this class of drug. We can be confident now that SL-325 is the least immunogenic of the drugs being tested in the TL1A-DR3 axis. That should lead to higher efficacy anywhere the TL1As provide a signal. Because of that, I think we're in a position where we don't have to deploy risk capital ahead of some of those early studies providing clinical proof of concept for the axis or not. That is the strategy that we will stick to, at least for the time being. Apologies, Marc, you had one other question, I thought. Just on the ability to potentially translate dose, or do you think you need kind of rigorous phase II dosing for each other therapeutic area? I think we've now identified a pretty narrow dose range that is likely to drive efficacy, I still think most regulators will ask us to do some amount of dose exploration in phase II before moving on to phase III. I don't think that'll be the case in IBD. I think the dose and schedule that we identify in phase II in Crohn's will layer to what we study in phase III in ulcerative colitis. Probably not so much in derm and rheum indications. Okay, thank you, congrats again on the data. Thanks, Marc. Thanks for the questions, Marc. Our next question comes from Joey Stringer at Needham. Please go ahead, Joey. Hi, good morning. Thank you for taking our questions. A data question on slide 12 for the DR3 agonism data. Does this include data from the three MAD cohorts, and does that DR3 agonism data look similar to the SAD cohorts? Then can you speak to the formulation work that you've done for SL-325, the sub-Q delivery? Is the formulation currently optimized, or would you need to do additional work, potentially for an auto-injector presentation, depending on what the phase IIb data tell you? Thank you. Thanks for the good questions, Joey. Thank you. On Slide 12 on the DR3 agonism studies, the data that are on that specific slide came from the single ascending dose cohorts. We have the exact same data from the multiple ascending dose cohorts, and the data look exactly the same, and there were no changes in serum cytokines, no increase in serum TL1A, and no change in proliferating lymphocytes following repeated dosing. I think we're in good shape there. On the formulation side, we have developed a sub-Q formulation for 325. Concentration of that formulation is 150 mg/mL. That allows flat dosing in a 2 mL volume sub-Q auto-injector up to 300 mg or less. As you can see from the receptor occupancy data, lower doses than that are expected to provide durable blockade for at least three-month intervals. Right now, we know that the formulation we've developed has acceptable concentration and viscosity parameters. We also have accelerated stability for that formulation that predicts a two-year shelf life at four degrees. That sort of checks all the boxes for what you might want with a sub-Q formulation. The plan there is to run a phase I IV versus sub-Q bioavailability study while the phase II study in Crohn's Disease is proceeding, using that data to convert to the sub-Q formulation in phase III. Great. Thanks for the questions, Joey. Our final question comes from Yigal Nochomovitz at Citi. Please go ahead, Yigal. Hi, guys. Thank you very much. Congrats on the very strong results. I was just curious with regard to the antibody itself. Obviously, you've shown excellent immunogenicity and as well the no agonism on the receptor. I'm just curious as to the structure of the antibody and whether the same or different features of the epitopes are driving that strong profile with low immunogenicity and no agonism. Thank you, Yigal. I think there are sort of two separate issues. As Lini alluded to, one of the key challenges in going after DR3 and not TL1A is that because DR3 signals, every DR3 antibody can potentially cross-link two DR3 subunits, and you need to carefully discharge the risk that that causes tickling of the cytoplasmic domains of those two subunits and residual agonism. Finding the right antibody there requires the right mixture of a unique epitope, tuning the affinity appropriately toward that epitope, and removing any evidence of Fc gamma receptor binding. If you get any one of those things wrong, then a blocking antibody can be converted to a partial or full agonist antibody. This was something that we spent a lot of time on over the years. Shattuck's history for a decade now has been understanding TNF receptor biology. I think this was something that we were uniquely suited to do. Sorry, Yigal, second part of your question? Yeah, I was just curious. Oh, immunogenicity, sorry. Yeah. That's a bit of a different issue. There's two things you can do to reduce the risk of immunogenicity, and pre-clinically, all you can really do is to use a variety of tools and vendors that are out there that are looking at the primary sequence of your antibody to identify any potential binding to MHC residues. We did that. Everybody does that. If you don't get a low value there, you should pause and re-engineer. In this case, none of those pre-clinical assays give you any sense of what your risk of immunogenicity is if your antibody causes immune complex formation, and that's why I think we're seeing some of what we're seeing with the TL1As. In this case, there is no risk of immune complex formation. Once you answer those sequence-based liabilities, which we now have, that's the full story. Thanks. Just my quick follow-up was, I was just curious as to why you selected to go with Crohn's first versus UC first, because I think frequently the first indication is UC as opposed to Crohn's. Is there a specific reason for that choice? There's a few reasons. First of all, the translational link between Single Nucleotide Polymorphisms in TL1A and the risk of Crohn's disease has always been much stronger than the association of TL1A SNPs and ulcerative colitis, even though we now have clinical proof of concept in both indications. Secondly, we think through both the single-arm tulisokibart Crohn's study and the controlled duvakitug Crohn's study, there is clinical proof of concept now for Crohn's, just as there is in UC. In addition, if you get a strong signal in Crohn's disease, you talk to most KOLs, they will tell you, "Okay, if a drug works there, it's going to work in UC. We don't necessarily treat UC datasets in the same way." Finally, we really haven't spent any time on the call talking about this, but the other reason beyond immunogenicity to believe that DR3 could be a better target than TL1A, is that it's much more stably expressed. You might expect more durable, persistent blockade to lead to greater efficacy in diseases that had more foci of inflammation. That is certainly more so the case in Crohn's disease than in ulcerative colitis, starting there may give us a dataset that gives us a glimpse into that second part of the value proposition here. Thank you. Thanks, Yigal. Yes, thank you for the questions, Yigal. This concludes our Q&A 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. Thank you all for joining the Shattuck Labs investor conference call to discuss the first-in-human clinical data for our lead DR3-blocking monoclonal antibody, SL-325, an introduction of our DR3 by IL-23 receptor bispecific antibody, SL-846. We appreciate your continued interest in Shattuck, and we look forward to updating you on the milestones ahead. Thank you. This concludes today's conference call. Thank you for participating, and you may now disconnect. Have a wonderful day.