Morning, and thank you for joining us today. My name is TJ Tucker, and I'm an analyst in JP Morgan's Healthcare Group. Before I introduce you to our presenters today, I would like to call your attention to the blue button on your screen. This is where you'll submit questions that will be addressed during Q&A. With that, I am pleased to introduce the Shattuck Labs team, including Taylor Schreiber, CEO and co-founder, Andrew Neil, CFO, and Conor Richardson, Senior Director of Finance and Investor Relations. With that, I know that they are very excited to tell you a little bit about their story, so I'll turn it over to their team. Great. Well, thank you, TJ. It's my pleasure to be here to present to you on behalf of Shattuck Labs at the JP Morgan Healthcare Conference. These are my forward-looking statements. At Shattuck, we've developed a completely new class of biologic medicine that we refer to as the Agonist Redirected Checkpoint, or ARC platform. We developed this platform to accomplish a few very specific goals. What we wanted to do was to build a biologic which could block immune checkpoint targets that are relevant in immuno-oncology, including PD-1, CD47, TIGIT, and others, while simultaneously activating an important class of co-stimulatory receptors in the immune system, known as tumor necrosis factor receptors. Targets that you may be familiar with in this class include CD40, 4-1BB, OX40, and others. The structure of an ARC therapeutic is shown in the cartoon on this slide here. A few things to point out. These are hexameric fusion proteins, and one of the ways that these compounds differ from antibody-based therapeutics is that both of the functional domains, which are depicted in orange and blue in this cartoon, are derived from native human proteins and not from antibody-based target binding sequences. The reason that activating tumor necrosis factor receptors was an unmet medical need is really due to the fact that this class of receptor has a unique structure as compared to many of the receptors you might want to target with a monoclonal antibody therapeutic. That structure is shown in Panel A of the [Inaudible] slide. What's important to recognize is that all TNF receptors have to assemble into trimers, as shown in the cartoon here, in order to signal. When you think about what that means in the context of, an antibody-based therapeutic, you can realize that perhaps a bivalent antibody, shown in green here, may not be the right tool for the job. The reason for that is that an antibody could always bind two subunits of a TNF receptor, but a single antibody in and of itself will never be able to bind all three, and therefore, to cluster a TNF receptor trimer together. Simply the wrong key for the lock, the wrong tool for the job. You can pick your favorite analogy, but this is the fundamental reason why the clinical trials to date using monoclonal antibodies against this class of target have yielded underwhelming results. We wanted to get around this structural problem by building a therapeutic where the structure actually matched the structure of a TNF receptor target. That's what led us to this, ARC platform. Again, with the hexameric structure shown in the cartoon. One of the reasons why these compounds have unique activity, which I'll show you in a minute, from cancer patients, is that these compounds contain two pre-formed TNF ligand trimers. These are not conditionally active biologics. They will be able to bind and activate TNF receptors wherever they encounter them while simultaneously blocking immune checkpoint receptors. This slide provides a snapshot of our clinical stage pipeline and then a very small subset of our preclinical pipeline. We have two different molecules that are in a total of four phase I clinical trials today. The first is what we call 172154, and I'll refer to it over the course of this morning's presentation just as 154. This is a SIRPα-Fc-CD40 ligand fusion protein. This molecule is a dual CD47 inhibitor and CD40 agonist. We have a trial ongoing for patients with advanced platinum-resistant ovarian cancer, and that's where we've recently shared clinical data that I will review with you today. We have a second clinical study ongoing for patients with cutaneous or head and neck squamous cell carcinoma. We have a third clinical study ongoing for patients with acute myeloid leukemia or higher risk myelodysplastic syndrome. The second clinical stage program is 279252, which I'll refer to today as just 252 for short. This molecule is a PD-1 Fc OX40 ligand fusion protein. You can think of this molecule as a dual PD-L1 inhibitor and OX40 agonist. Similarly, we've shared phase I clinical data recently from this compound in patients with advanced solid tumors and lymphoma, and I will review that data as well today. We have an enormous preclinical pipeline. We've generated over 400 constructs from this ARC platform. One of the molecules that we've shared data on recently is a TIGIT-Fc-LIGHT construct. Unfortunately, in today's presentation, we won't have time to review that. However, I would direct you to our website where we have a presentation that was recently shared in December at the TIGIT symposia, where we lay out the mechanism of action of this construct and the reason why we believe this construct will have activity in PD-1-resistant tumors, where so far other TIGIT blocking antibodies have not. The clinical data that we'll review in a few moments provides the first clinical evidence for the ARC platform in humans. There's enormous utility in being able to look at data from two different compounds from this platform in humans at the same time in terms of being able to evaluate the safety of the platform as a whole, the ability of these molecules to bind and occupy their specific targets in a dose-dependent manner in the context of monotherapy dose escalation trials, and we also have evidence of the manner in which these compounds activate TNF receptors, including CD40 and OX40, in a manner that has not previously been seen with any prior TNF receptor agonist. This data also includes the first monotherapy antitumor activity with the 252 compound in PD-1 refractory cancer. Together, these data help to validate the ARC platform as a whole, in demonstrating that these are not only well-tolerated compounds, but that they really have unlocked the TNF receptor superfamily, in a manner that the industry has attempted to do for well over 30 years, and I'll review that data over the next few minutes. We'll start with data from the 154 compound. Again, just to remind you, the structure of this compound includes, in orange, the extracellular domain of the human SIRP alpha protein, and so this will bind and block CD47 similar to other CD47 inhibitors. The central domain of this molecule, shown in gray, contains an Fc gamma receptor silent core domain, and we selected this domain to avoid any of the cytopenias that have been seen with certain CD47 inhibitors. Where this compound differs from all other CD47 inhibitors in development is that we include this CD40 ligand co-stimulatory domain, which leads to amplification of an adaptive immune response that is initiated by macrophage phagocytosis of tumor cells. Again, we've published on this preclinically and outlined the mechanism and the head-to-head performance of this molecule relative to CD47 inhibitory antibodies. I would direct you again to our website if you'd like to review that preclinical data. The data that we've shared to date is from the monotherapy dose escalation portion of a clinical study in patients with advanced platinum-resistant ovarian cancer. The dosing schema that we've explored to date is shown in this slide. We began at a dose of 0.1 mg/kg and have shared data to date through the 3 mg/kg dose level, and the study has continued on to the 10 mg/kg dose level. As you would expect in a phase I study, these are heavily pretreated patients that have failed an average of five prior therapies. Patients eligible for the study included patients with ovarian, primary peritoneal, or fallopian tube cancers. There have been no dose-limiting toxicities to date. No grade three or greater treatment-related adverse events. Infusion-related reactions were common but highly manageable with non-steroid-containing pre-medications, and no patients had to discontinue the infusion due to these infusion reactions. Importantly, we have not seen any evidence of anemia, thrombocytopenia, cytokine release syndrome, nor liver toxicity, which are the toxicities that have hindered the development of both prior CD47 inhibitors as well as prior CD40 agonists. There's been over 30 years of clinical data with CD40 agonists, and one of the first in the clinic was a CD40 agonist antibody first developed by Pfizer and referred to as CP-870,893. This compound could not be safely dose escalated beyond 0.3 milligram per kilogram due to the observance of both cytokine release syndrome and hepatotoxicity in humans. In a publication from Pfizer, that cytokine release syndrome was associated with increases in both TNF-α, shown here, as well as interleukin 6, shown in this panel B over here. These were two cytokines that we were monitoring closely in this trial to make sure that we were not encountering the same sorts of toxicities observed with these prior CD40 agonist antibodies. What you can see here in this panel here, looking at TNF-α levels, as well as this panel here, looking at IL-6 levels, is that at doses of up to 3 mg/kg, which is now 10x the dose shown in this slide with the Pfizer antibody, we do not see any appreciable increases in TNF-α nor IL-6, and that correlates with the lack of any cytokine release syndrome or hepatotoxicity observed in these patients to date. Turning to the pharmacodynamics of this molecule, we were again looking in humans to make sure that the SIRP alpha domain was capable of binding and blocking CD47. Also looking at the CD40 ligand domain of the molecule, which I'll get to in the next slide. What you can see here in the panel on the left is that we are measuring receptor occupancy on CD47 expressed by white blood cells. Even at the first dose level of 0.1 mg/kg, there's a large distribution of the data, but we were already achieving high occupancy in some patients. As we moved up in the dosing schema now by 3 mg/kg, you can see that all of these patients have a receptor occupancy that's approaching 80% or greater. Our expectation is that at the 10 mg/kg dose level, we will achieve complete occupancy on leukocyte-expressed CD47, which is an important variable for this compound. Interestingly, at those same dose levels, we do not see significant occupancy on red blood cell CD47. This is important both from a safety perspective, as well as from an antigen sink perspective that may lead to unique dosing levels as compared to some of the CD47 inhibitors which do bind red blood cells. Turning to the CD40 side of this molecule, we were also in Panel A measuring receptor occupancy on CD40-expressing cells in the peripheral blood. The dominant cell types that express CD40 in the blood include both B cells, which are almost uniformly CD40 positive, as well as monocytes, a subset of which are CD40 positive. In both of those cell types, we observed a dose-dependent occupancy on CD40. As you might expect from the prior slide, by the 3 mg/kg dose level, we had nearly 100% receptor occupancy on CD40-positive cells in the peripheral blood. Now CD40 is an agonist receptor. Whereas with CD47, the only pharmacodynamic effect that other companies have reported is receptor occupancy. When you have an agonist target like CD40, you expect to see receptor occupancy, but then you expect to see downstream signals that target has led to immune activation. We see that in multiple forms. One of the ways that you can see that is in panel B here. We're measuring the proportion of B cells in the peripheral blood pre-dose, followed by one hour post-dose, 24 hours post-dose, and then seven days later, which is immediately prior to the next pre-dose time point. What these peaks and troughs are telling you is that pre-dose, there are a large number of CD40 positive cells in the peripheral blood. Within an hour of infusion, most of those cells rapidly leave the blood and accumulate in other tissues, including tumors, as I'll show you in a minute. Those cells slowly return to the blood seven days later. This phenomenon repeats cyclically with every dose. Another outcome that you expect if you are activating CD40 is that these cells that express CD40 will upregulate other activation markers on their cell surface. Two of these markers include CD86 as well as CD95. What we're showing you in this figure here is that there's a 2- to 3-fold increase in the density of CD86 and CD95 expression on the surface of these immune cells at doses of 1 or 3 mg/kg. One of the factors we were most excited to see was an increase in multiple antitumor cytokines following infusion of 154. What we're showing you in this slide are the serum concentrations of interleukin 12, which is a potent antitumor cytokine. The valleys here are showing you the pre-dose time point, and then the peaks are showing you the 2-hour post-dose time point. You can see there's a rapid increase in the concentration of circulating interleukin 12 in these patients that comes down at 24 hours, but not quite down to baseline, especially at the higher doses, that then returns to baseline by the subsequent pre-dose time point. Just like the cyclical movement of CD40-positive cells in and out of the central compartment, we see cyclical increases in interleukin 12 following every infusion. By the 3 mg/kg dose level, this is roughly a tenfold increase in interleukin 12 concentration as compared to pre-dose. Other cytokines that we see increase include CCL2, CCL3, CCL4, and CCL22, as well as some others. To put this in context, some of you may be familiar with efforts in the past where recombinant IL-12 therapeutics have been developed and administered to cancer patients. The concentrations that we're achieving here with this compound approach the Cmax that was reported with some of those recombinant IL-12 therapeutics. However, we are not seeing the sorts of toxicities that limited development of those agents. It was important to look within these patient tumor biopsies, both pre-dose and then on treatment, to see whether 154 was altering the immune microenvironment within patient tumors. Here we're looking at a pretreatment biopsy from one of our ovarian cancer patients. You can see in the magenta staining pretreatment, there are a number of macrophages present in this patient's tumor pretreatment. However, three weeks after the first infusion, you can see that there's a large increase in the proportion of macrophages within this patient's tumor. Furthermore, the macrophages which are present have upregulated both MHC class II, which is involved in antigen presentation, as well as CD40, which is involved in activation and co-stimulatory pathways. This is a compound that we show pre-clinically was able to bridge an innate to an adaptive immune response. In this same patient, same biopsy locations, we were able to look pre-dose at the proportion of lymphocytes, in this case CD8-positive T cells that were present in the tumor. One of the characteristics of ovarian cancer broadly is that it tends to be an immune neglected tumor, at least from a T cell perspective. You see very few T cells in this patient's pre-treatment biopsy. Three weeks later, you can see that there's an enormous infiltrate of CD8-positive T cells that are both proliferating and expressing cytolytic markers, including granzyme B. The presence of this T cell subset suggests that there has been an inflammatory response which might include interferon gamma expression. One of the sequelae of interferon gamma is upregulation of PD-L1. We are indeed able to see that in the tumor microenvironment, specifically expressed by the tumor-infiltrating immune cells. Overall, this compound has been very well tolerated. We've bridged the gap well above where prior CD40 agonists could be safely dosed while saturating both CD47 and CD40. We've seen a number of signs of both receptor engagement on CD47 and CD40, as well as signs of immune activation downstream of CD40, which of course have not been observed with any of the other CD47 inhibitors. The best response that we've observed to date is stable disease in the first 14 patients, and this is expected because this compound contains no intrinsic pro-phagocytic activity, which is essential for antitumor activity with all CD47 inhibitors. This is the reason why all CD47 inhibitors are not being developed as monotherapies, but instead are being developed in combination either with certain chemotherapies that cause immunogenic cell death, or with targeted antibodies that contain ADCP active Fc domains. Given the levels of immune activation we've already observed, we have initiated the combination strategy for this compound, and that includes initiation of a trial in ovarian cancer, actually an extension of the ongoing trial, where we will be enrolling patients in combination with liposomal doxorubicin. We've shown pre-clinically that liposomal doxorubicin is capable of upregulating the pro-phagocytic signals on tumor cells that potentiate the CD47 mechanism. In addition, we have initiated a phase I trial for patients in both acute myeloid leukemia as well as higher risk myelodysplastic syndrome. This is the area where CD47 inhibitors have been clinically validated, and we will be enrolling patients this year in both combinations with azacitidine as well as azacitidine plus venetoclax. We're excited to see the data come in over the course of the year from these combinations and see what this unique pharmacodynamic profile translates to as compared to any other CD47 inhibitor from an overall response and response duration standpoint. Turning to the second clinical-stage molecule, SL-279252. This again is a hexameric fusion protein with a similar structure to SL-172154, but with different functional domains. In orange, we use the extracellular domain of the human PD-1 protein. This domain will bind and inhibit PD-L1 or PD-L2. Again, we selected an Fc gamma receptor silent core domain in the middle of this construct. In blue, we include an OX40 ligand domain which will bind and activate OX40 expressed by CD4-positive T cells. The data that we've shared to date is from the monotherapy dose escalation portion of our trial. We have shared data through the 6 mg/kg dose level and have continued to treat patients at 12 and 24 mg/kg. These are heavily pre-treated patients, the majority of which are both PD-1 refractory and PD-L1 low or non-expressers. The predominant cell types or tumor types that have been enrolled to date include ocular melanoma, adenocarcinoma non-small cell lung cancer, and gastric adenocarcinoma. This compound has also been very well tolerated with no dose-limiting toxicities to date. The most common treatment-related adverse events included maculopapular rah and low-grade infusion reactions. The dominant pharmacodynamic signal that we've observed in patients treated with 252 to date includes the rapid margination of OX40-positive, CD4-positive T cells from the peripheral blood within an hour of infusion. This is showing you the proportion of CD4-positive, OX40-positive cells that leave the blood post following the first infusion or following the first infusion on the second cycle. The proportion is corresponding here to the measured concentration of 252 post-infusion. What you can see from both of these graphs is that following the first and second cycle, the magnitude of margination of CD4-positive OX40-positive cells continues to escalate. This tells us that we have not yet maximized the pharmacodynamic effects driven by OX40 and is part of the rationale for continued dose escalation. We have also collected both pre- and on-treatment biopsies from the patients enrolled in this study. This is an example observed in many patients where there are low levels of CD8-positive T cells and NK cells in the pretreatment biopsy. Where three weeks later in the on-treatment biopsy, we see heavy infiltration of this tumor by both CD8-positive cells that are expressing the cytolytic marker granzyme B as well as natural killer cells. We have observed initial antitumor activity in patients that were enrolled at the higher doses with this construct. This includes a confirmed partial response in a patient with ocular melanoma who had previously failed both PD-1 and CTLA-4 inhibitors, which lasted greater than one year. We also had stable disease in 12 subjects, including five subjects for greater than 24 weeks. We also had an unconfirmed partial response in another patient with vulvar melanoma. This was another patient who had previously failed both PD-1 and CTLA-4 inhibitors, where the target lesion ultimately regressed completely, but unfortunately, this patient developed a brain met, which is the reason it's considered an unconfirmed partial response. To put the dosing levels into context with where PD-L1 inhibitors are approved, including drugs like atezolizumab, the data we've shared to date is through 6 mg/kg. PD-L1 inhibitors are approved at doses of between 10-15 mg/kg. The 12 mg/kg dose, which is currently enrolling, is the first dose, which is roughly dose equivalent to the approved PD-L1 inhibitors. We are interested to see what happens at that dose level and whether we've maximized the pharmacodynamic effects driven by OX40 at that dose level. Again, 252, similar to 154, has been very well tolerated. We've seen linear PK through doses of 3 milligrams per kilogram and then nonlinear PK at 6 milligrams per kilogram. Yet another reason to continue on. We've seen dose-dependent receptor occupancy and engagement of OX40 and initial antitumor activity in PD-1 refractory cancer patients. In summary, we've now shared clinical data from the first two different ARC constructs in patients. It's important for any new platform to demonstrate safety, and it's especially important in our view to show that for multiple molecules from a new platform. For you to be able to compare and contrast the immune effects of activating OX40 versus CD40 with these two different compounds. We've seen that these molecules have saturated their targets in a predictable dose-dependent manner and have led to pharmacodynamic effects driven by OX40 and CD40, which have not been reported with prior TNF receptor agonists in the past. We see that there's evidence not just of immune activation in the periphery, but also within on treatment tumor biopsies. Dose escalation is continuing with both of these molecules to reach a recommended phase II dose. We believe that these data as a whole help to validate the hypothesis which drove generation of the ARC platform in the first place. We've been able to activate TNF receptors in a unique manner, and that opens up a number of additional opportunities with other ARCs from our platform. We talked a bit about our TIGIT-LIGHT construct. We also have a number of 4-1BB ligand-containing constructs in development and are closely monitoring some of the other 4-1BB agonists that are being developed today. Over the course of 2022, we will expand clinical development, both in terms of other ARCs as well as expanding the footprint of our existing trials. I've alluded to some of the ways we have already planned to do that with the 154 molecule. This will create multiple shots on goal from both our existing molecules and new ones entering the clinic. Shattuck is in an extremely good position to continue executing on this plan with roughly $290 million in cash and cash equivalents on the balance sheet as of the end of the third quarter of last year, which funds operations and these clinical plans into the second half of 2024. I'd like to thank you for your interest in listening to this presentation, and we certainly look forward to continued engagement with all of you in 2022. Thanks very much. Thanks so much, Taylor. Really appreciate the presentation, and very excited obviously about the prospects for Shattuck and the team. We'll go ahead and turn it over to Q&A for the questions that we received from the audience. The first one being you recently shared data at the SITC 2021 conference. What do you believe is the most compelling data from your recent SITC data disclosures for SL172154 and SL279252? Whether that be the data in total or just individual pieces of that data, whatever you find the most compelling. I think, as I tried to allude to in the presentation, our industry has attempted to target TNF receptors using antibody-based therapeutics, be they monoclonal, IgG-based, or even bispecifics, for over 30 years. This has been an elusive goal, where the clinical data has underwhelmed and where development of these agents has been hampered by a combination of toxicity as well as this atypical bell-shaped dose response curve, which has made it hard to try to hone in on this Goldilocks zone of picking a dose that you could bring into future development. We believed that by targeting TNF receptors with a drug which matched the structure of those targets, that we would be able to dose escalate and maximize the biology of these targets in a way that antibodies have not been able to do, and hopefully to do so safely. The safety sequelae of some of these agents is not fully understood, but has been associated with the need for antibodies to have Fc gamma receptor binding domains on them. We believed in that hypothesis, and certainly the data to date indirectly support that that may have been one contributor to why those agents encountered tox. You know, I truly believe that these data suggest that hexameric drugs like ARCs can unlock this important class of immune costimulatory receptor in a way that we've tried to do for a long time and which has led to phenomenal antitumor activity in many preclinical models. It just hasn't been able to translate. That's important for OX40 and CD40, but it's important more broadly for the platform because, you know, there's another 17 or so TNF ligands that tickle immune responses in different ways that might be worth exploring. For sure. No, I think that's a great point. In addition, I guess in how you were talking more broadly about the platform, as you kind of continue to advance in the clinic, how do you think about business development opportunities for the ARC platform, maybe domestically and potentially internationally? Sure. You know, so this is a broad platform and we will never be able to develop, you know, the 400 or so compounds we have in our preclinical pipeline. Some of those targets may be of interest to other parties. Of course, this is a show me world, and I think, you know, leveraging those sorts of partnerships to other molecules requires the sort of data that we've now shown that the platform is well-tolerated and actually unlocks these targets in the way they were designed to do. I think there are pieces of the platform that, you know, we don't yet have in our visible pipeline that could be interesting to other parties. We intend on retaining value of our lead clinical constructs, and that includes commercial rights to those advanced commercial constructs. You know, that being said that there may be ways of augmenting or accelerating clinical development through collaborations with larger companies, especially as we get into registration-directed studies with SL-172154. Another molecule we didn't talk much about is the TIGIT-Fc-LIGHT construct. That's a molecule that will be co-developed with PD-1 or PD-L1 inhibitors. There might be similar collaborations that are worth considering with that construct as we move into the clinic. We also actually have another platform which we haven't even discussed, which is a Gamma Delta T-cell engager platform, where you know, early-stage partnerships with some of these constructs are possible. Partnerships take time and resources. We'll do it selectively, and fortunately, we're in a position where partnerships are attractive from the value they bring in clinical development, more so than the capital due to our existing balance sheet. That's perfect. I'm glad you mentioned, you know, kind of this internal pipeline, however many targets that you do kind of have in your back pocket. Are we going to see any additional ARCs in the clinic in 2022? Or if so, are the ones that you highlighted in the presentation, is there anything that you're particularly excited about for clinical development in 2022? The answer is yes, you will see another compound in the clinic. I think there's not a very low-risk bet on what that might be. You know, but there's a number of targets that we're excited about. You know, I alluded to the fact that early-stage partnerships might be unlocked by, you know, some of the clinical data we've seen to date, but our strategy as a company up to this point has been to move compounds into the clinic toward validated IO targets with at least one side of the molecule. We've always said that perhaps we'd be willing to take more risk with a novel compound, especially a novel TNF ligand, once we saw that the construct performed in humans as it was designed to do. I think, you know, the breadth of opportunities we have in front of us is only expanding, based on what we've seen to date. That's great to hear. Just one final question. You did say your, you know, cash position and cash runway. Are there any, kind of factors that could cause the cash runway to, like, deviate? Andrew, you wanna take that one? Yeah, sure. I mean, of course, as Taylor said, you know, we have a tremendous breadth of opportunities in front of us. You know, so of course, we're always evaluating levers on both the cash in and cash out. You know, we could, for example, expand clinical development activities in 154 beyond what we've currently described that, you know, may or may not impact the cash runway. We would only do so in ways that made good sense. As it relates to 279252, you know, I think we've set a pretty high bar for success for that program. You know, currently, we're not budgeting to take that molecule beyond the dose escalation portion of 12 and 24 mg/kg. You know, we would expect to see and hope to see, you know, a 20% overall response rate in order to advance that program. I think if we do, that's a huge win for Shattuck, but is not currently baked into the cash runway scenarios, which would be very easy for us to fund in other ways. Awesome. Well, I think that we are running up on time here, but we really appreciate you all being here today. Very excited about the prospects with the company, and hope that you guys get to enjoy the rest of the conference. Great. Well, thank you all very much for tuning in, and happy 2022. Thank you for having us. Thank you.