Good morning. Welcome to the last day of the 41st JP Morgan Healthcare Conference. Hope you have all enjoyed the conference. My name is Ting Zhang. I'm from the JP Morgan Healthcare Investment Banking team. It is my great pleasure to introduce this session's speaker, Taylor Schreiber, CEO of Shattuck Labs. Without further ado, I'll pass it over to Taylor. Thank you, Ting. Good morning. It's my pleasure to be here to present Shattuck to you. Thank you to the organizers of JP Morgan for the invitation to present the 2023 Healthcare Conference. Doesn't look like this is advancing. Okay, there we go. These are my forward-looking statements. Shattuck is a clinical stage cancer immunotherapy company. We have two compounds, both from the ARC platform, that are in a variety of Phase I clinical trials right now. I'll tell you about where we are and what to expect this year from those trials today. We have a second platform, which is in the preclinical stage of development that is a series of gamma delta T-cell engagers. We'll also touch on that platform. As of September 30, 2022, we had roughly $185 million in cash and cash equivalents, and that is expected to carry the company well into the second half of 2024 and beyond a number of key clinical readouts this year. Shattuck in total has about 108 employees. We have a footprint in both Research Triangle Park, North Carolina, that's where I'm based, that's where we have research and development operations, internal manufacturing, clinical quality and regulatory teams are all based in North Carolina. We also have a footprint in Austin, Texas. This is a corporate office for us where accounting, finance, legal, and HR functions are based. Here's a snapshot of our current clinical pipeline. The lead compound we call SL-172154 or 154 for short. I'll be telling you about the four different studies that we're currently running in patients with platinum-resistant ovarian cancer, acute myeloid leukemia, and higher risk myelodysplastic syndrome. The second program I'll touch on is SL-279252 or 252 for short. This is a PD-1 inhibitor and OX-40 agonist in a Phase I clinical trial for patients with advanced solid tumors and lymphoma. Let's start with the agonist redirected checkpoint or ARC platform. We designed this platform to accomplish a set of very specific goals. First of all, we wanted to build molecules that on the one end could block a variety of different immune checkpoints, including PD-1, CD47, TIGIT, and others. Importantly, we wanted to build a molecule that could also activate an important class of immune co-stimulatory receptors that fall within what's called the TNF superfamily. This includes, in total, 19 different receptors, of which the ones you're most likely to have heard about are CD40, 4-1BB, OX-40, and others. Accomplishing these two goals with one drug led us to think outside the typical antibody scaffold. A cartoon of an individual molecule of an ARC is shown in the cartoon on the right, and what you can see is that this is a hexameric fusion protein. Now, the reason that that hexameric structure was a desired property for us relates to the fact that tumor necrosis factor receptors, including CD40, all have to assemble into a trimer in a cell membrane in order to signal. That trimer is illustrated in panel A of this figure. Our industry has attempted to harness the biology of TNF receptors for nearly three decades, and by and large, the clinical efforts to do so have utilized monoclonal antibodies. As you can see in the cartoon in panel B, monoclonal antibodies are bivalent drugs, so each of the two arms of an antibody can each bind an individual TNF receptor. That means that a single antibody can always bind two but never bind all three of the necessary subunits to cause TNF receptor signaling. This structural mismatch means that you have to cluster multiple antibodies together in order for more than two binding domains to be in close proximity to one another. It turns out that that's a very inefficient process in humans, and it leads to both the toxicity that has been seen with nearly every clinical trial with a CD40 agonist or a 4-1BB agonist that occurs at low doses above a roughly 0.3 mg/kg and manifests as a combination of liver toxicity and cytokine release syndrome. The second problem with this structural mismatch is that it creates a bell-shaped dose response curve. That's been reported again in nearly every clinical study with a CD40 or 4-1BB agonist antibody. What we believed is that, by building a hexameric drug that contains two preformed TNF ligand trimers, that that would overcome both the toxicity limitations and the pharmacodynamic limitations that have been encountered with these antibody-based drugs. Let me pivot to the clinical data where I believe, you'll see that these hypotheses have now been borne out. The lead clinical program, as I mentioned, is 154. This is a CD47 inhibitor and CD40 agonist. Some of you in the audience may be very familiar with CD47. For those that are not, this is commonly referred to as the macrophage "don't eat me" signal. The leading compound in the field is a drug that was developed by a company called Forty Seven, referred to as magrolimab. In the bottom left here, we're showing you some of the exciting data that was generated when magrolimab was combined with azacitidine in patients with TP53 mutant AML. What you can see here is that the vast majority of patients had an impressive reduction in the percentage of bone marrow blasts when they received this combination. It's important also to note here that while this drug, magrolimab, and all CD47 inhibitors block the macrophage "don't eat me" signal, that in and of itself is not sufficient to drive efficacy. That's the reason why magrolimab and all CD47 inhibitors have been combined with other agents, in this case azacitidine, because when those, in this case, AML blasts, are stressed with a drug like azacitidine, that causes upregulation of pro-phagocytic signals. It's that mixture of blocking the "don't eat me" signal and providing the pro-phagocytic signals that ultimately drive responses to this entire class of therapy. Magrolimab is not a perfect drug. In early 2022 it was put on clinical hold because it causes, in some cases, very rapid and deep anemia, destructive anemia in patients that are treated. That can become particularly problematic as the clinical footprint for an agent like this broadens into centers that are not used to dealing with that sort of anemia. That clinical hold was thankfully lifted. Nevertheless, you can also see that the durability of responses that are seen in patients that do benefit from an initial response, certainly leaves room for improvement. That's exactly what we're trying to achieve with 154, by not solely relying on CD47 inhibition, but by designing in the CD40 agonist function in the molecule. In the cartoon in this slide, the orange domain is the extracellular domain of the human SIRPα protein. This will bind and block CD47. The gray domain in the middle is an engineered Fc that was selected to lack Fc-gamma receptor binding activity to avoid some of those cytopenias seen with other agents. Where 154 differs from all other CD47 inhibitors in development is inclusion of these two CD40 ligand trimers on the other side of the molecule shown in blue. In 2022, we completed the monotherapy dose escalation study in patients with platinum-resistant ovarian cancer. Ovarian cancer was selected as the first tumor type to study SL-172154 because of any solid tumor, it expresses the highest amounts of CD47, and it's also known to be a heavily myeloid-enriched tumor. Those tumor-resident myeloid cells are the target cell population, both for the CD47 and the CD40 side of this molecule. We moved to the top dose of 10 mg/kg, which in and of itself is significant because, as I mentioned earlier, these CD40 agonists have had a lot of trouble dose escalating beyond 0.3 mg/kg. We did not see any evidence of destructive anemia. Again, we attribute that to the lack of Fc-gamma receptor binding activity in the core of the molecule. Infusion-related reactions were common but manageable. Overall, the 10 mg/kg dose was defined as the maximum administered dose, but not the maximum tolerated dose. We did not see a good reason to go higher than 10 mg/kg because of some of the pharmacodynamic data I'll show you next. First of all, we were looking in patients to see whether the two targets of the molecule, CD47 and CD40, were becoming saturated as we moved through successively higher doses. What we saw is that by the 3 mg/kg dose, both CD47 and CD40 were fully saturated. If you look at other CD47 inhibitors, receptor occupancy on CD47 is the primary pharmacodynamic finding that's been reported. Beyond that, we wanted to show evidence that we were actually activating CD40. What the graph on the left is showing you is first of all, in peripheral blood, roughly 100% of B-cells and roughly 40% of your monocytes express CD40. When those cells are activated by CD40 agonists, they rapidly migrate out of the blood within an hour of infusion, and you can measure this. The graph on the left is showing you that as we move up in dose, and by the time we reach the 3 mg/kg dose, roughly 95% of the CD40 expressing cells in the peripheral blood, rapidly migrated outward. The next question became, as we moved from the 3 mg/kg dose to a super saturating dose of 10 mg/kg, would we maintain that maximal plateau in pharmacodynamic activity? Would we see that inverted bell-shaped dose response curve that's been seen with every prior CD40 agonist in the clinic? The results are very clear. You maintain that maximal plateau. The next pharmacodynamic marker we were looking at is the release of a number of serum cytokines. The graph on the right is showing you the fold increase in IL-12 concentrations in the peripheral blood following infusion of SL-172154. You can see a clear dose-dependent effect that begins to reach a maximal plateau by that 3 and 10 mg/kg dose level. We're showing you fold change here in terms of absolute concentrations we are reaching in the range of 2,500 - 4,000 picogram per ML IL-12 concentrations, and those are well into the range of the C-max that have been observed with prior recombinant IL-12 therapeutics. Of course, IL-12 is known to be a potent antitumor cytokine. Beyond IL-12, we're seeing increases in IP-10, CCL2, CCL4, CCL22, and other cytokines and chemokines, all of which supported this conclusion that we could now safely dose escalate a CD40 agonist through complete receptor occupancy without encountering toxicity and without encountering the bell-shaped dose response curves that have limited the ability of prior agents to fully engage the pathway. We then moved, last year, the 3 mg/kg dose into two different combinations in patients with platinum-resistant ovarian cancer. The first is a combination with pegylated liposomal doxorubicin, which is one of the standard of care chemotherapy agents used in this population. There's an enormous body of evidence for Doxil showing that it has an expected overall response rate of 10%-12% in this population. We've also studied Doxil in preclinical studies and shown that Doxil stresses ovarian cancer cells in a way that potentiates the mechanism of CD47 inhibitors. We expect that these two mechanisms will be synergistic in humans, and we're aiming for an overall response rate of 30% or greater in this initial patient cohort. The second combination is with a drug that is a Folate receptor alpha antibody drug conjugate that recently received accelerated approval by ImmunoGen called mirvetuximab soravtansine. This agent received approval for patients whose tumors express high levels of Folate receptor alpha. It did not receive approval in tumors that expressed low or medium levels of Folate receptor alpha. We worked with ImmunoGen on a series of preclinical studies to explore this combination, and the data on this slide are showing you a human macrophage phagocytosis assay, where we selected three different human tumors that express on the far left, high concentrations of Folate receptor alpha, medium or low amounts of Folate receptor alpha to mimic those three patient buckets. The orange bars are showing you the ability of mirvetuximab on its own to induce phagocytosis. What really stands out in this analysis is that as you look at the medium and low expressers, particularly the low Folate receptor alpha expressers, there's very weak induction of phagocytosis in those tumor cells, which correlates with the clinical experience with mirv. When you look at the red bar, this is the combination of mirvetuximab with SL-172154. Regardless of the concentration of Folate receptor alpha expression, you see that those two agents potentiate the activity of one another. These are two combinations we're very excited about in this platinum-resistant setting. We were able to move that 3 mg/kg dose immediately into those combinations, so we're not expecting any further dose escalation within these combinations. With the liposomal doxorubicin, we're expecting to have 10-20 patients worth of response data by the middle of this year. As I mentioned, aiming for that 30% response threshold. With mirvetuximab, we're expecting to have about 40 patients worth of data by the second half of this year across that Folate receptor alpha expression. We're looking to roughly double the response rates, with each of those FR alpha expression buckets that have been previously reported by ImmunoGen. Beyond the ovarian study, we also began a clinical study in patients with acute myeloid leukemia or higher risk myelodysplastic syndrome last year. This trial has the staggered parallel, dose escalation portion that you can see on the slide. We began at 1 mg/kg monotherapy, then went to 3 mg/kg monotherapy, and then began the 1 mg/kg plus AZA cohort. We are expecting that the 3 mg/kg dose will very likely be the dose in Heme, just as it is in solid tumors. We will be reporting initial data from the dose escalation portion of this trial, which is being conducted primarily in relapsed refractory AML and higher risk MDS patients in the first half of this year. That'll be somewhere north of 20 patients worth of data. Move quickly into those dose expansion cohorts, which will take place in the frontline setting. There we'll be enrolling patients with frontline TP53 mutant AML in a combination with azacitidine, where we believe the azacitidine alone is expected to have a complete response rate somewhere in the range of 22%, and we'll be looking to double that complete response rate in the 154 combination. The second bucket is with frontline higher risk myelodysplastic syndrome patients, again, in a combination with azacitidine. There's been some discussion as to what the expected monotherapy complete response rate is in this patient population for azacitidine alone. Our view is that you should expect azacitidine to have a complete response rate of roughly 30% in these patients. We'll be looking for a response rate closer to the 50% threshold in combination with 154. We'll expect to have initial data from these frontline azacitidine combination cohorts in the second half of this year. It's a data-rich year for 154 for us. I've just walked through the readouts that are coming in the first half, the middle of the year, the back half of this year, and I hope set clear expectations for the response thresholds that we are looking for. Our second clinical program is SL-279252. This is a PD-1 FC OX-40 ligand fusion protein. We reported data through the 6 mg/kg cohort for this molecule in November of 2021. Through that dose level, 252 was very well tolerated. We enrolled primarily PD-1 experienced subjects. At that 6 mg/kg dose, we did not yet reach that maximal plateau in OX-40-driven pharmacodynamic activity. We also were just barely starting to see nonlinearity in the pharmacokinetic profile for 252. It's worth mentioning that PDL-1 inhibitors, which is what 252 is, are approved in the range of 10 mg/kg-15 mg/kg. For all of those reasons, we continued dose escalating to the 12 and 24 mg/kg cohorts, which are maturing right now. This is a tough patient population. These are all PD-1-experienced patients. We are looking for roughly a 20% overall response rate or greater in one of these last two cohorts to justify further development of 252. We did in those not initial data release through 6 mg/kg, see evidence of antitumor activity in patients that were enrolled at 1 mg/kg or greater. That included a patient that was multiply checkpoint refractory that had a partial response, and another patient that had an unconfirmed partial response who was also multiply checkpoint refractory. As I said, this is a difficult patient population, and we've set a high bar here accordingly. I also wanna touch briefly on the second platform that we've developed internally at Shattuck, which is a series of gamma delta T- cell engagers. Some of you may be familiar with gamma delta T- cells. This is a cell population that really sits at the nexus between our innate and adaptive immune system. These cells attracted quite a lot of interest recently, as a result of a publication in 2015 in Nature Medicine. What those authors were attempting to do is to look at the immune infiltrate of many different immune populations across 25 different solid tumors and ask which of these immune infiltrates provides the most significant positive overall survival prognostic value out of different immune cells. What they reported is that the frequency of gamma delta T- cells in all 25 of these solid tumors did provide that best predictor of overall survival. That painted a picture that perhaps this small but highly cytolytic population of T- cells may be important for antitumor immunity. After that, in 2020, it was reported what the actual entity that the gamma delta T- cell receptor recognizes actually is. In the panel on the left here on the bottom, I'm showing you a gamma 9 delta 2 T- cell. These gamma 9 delta 2 cells represent roughly 90% of the gamma delta cells in the peripheral blood and roughly 50% of gamma delta cells in most other tissues. The way that these cells recognize a target cell is when two different Butyrophilins on the surface of that target cell form a heterodimer. This heterodimer between Butyrophilin 2A1 and 3A1 typically forms when that target cell is metabolically stressed, there's an accumulation of phosphoantigens in that cell, and those phosphoantigens tickle the cytoplasmic domain of those two Butyrophilins to bring them into proximity. That provides signal 1 to the gamma delta T- cell receptor. Something that we published last year is that, if those gamma delta T- cells don't also receive a signal 2, which can come either from CD28 ligands or NKG2D ligands, then after they provide an initial kill, they will rapidly undergo activation-induced cell death, just like alpha-beta T- cells. This is something that's important to keep in mind, with some of the emerging biologics, in this field. Nevertheless, we believed that a fusion protein might be a particularly attractive way of displaying a butyrophilin heterodimer on the surface of a target cell, particularly if we could anchor that heterodimer on that target cell surface with an antigen-specific scFv domain. This is the structure on the left of molecules from what we call a GADLEN platform that achieve those goals. These compounds are roughly the size of a monoclonal antibody and are highly modular, where we can flip out the scFv domains at will to approach the same antigen with a bivalent construct or different antigens with a bispecific construct. One of the initial compounds that we made as proof of concept binds to the CD20 antigen that's commonly approached by CD3-based T- cell engagers. This is data from a study where we infused mice with a mixture of human peripheral blood mononuclear cells that contained a low percentage of human gamma delta T- cells as well as human B- cells. In the graph in the bottom left in blue, you can see that this is showing you the level of engraftment in these mice of human B- cells. In red, this is a specificity control where these mice were treated with a GADLEN that targets the CD33 antigen, which is not expressed by B- cells. In green and purple, we're showing you a low dose and a higher dose of what happens to B- cells in mice that are treated with the CD20 GADLEN. What this is showing you is that you can have greater than 99% depletion of that B-cell pool, and this occurs within six hours. It occurs at effector-to-target cell ratios where you have 1 gamma delta T- cell for every 50 B- cells, and it occurs without requiring the resident gamma delta T- cells to proliferate. This is serial killing that occurs rapidly. We also completed a non-human primate study last year that demonstrated the same dose-dependent effect in monkeys. Important to mention as well that this is entirely specific. You don't see any depletion of non-CD20 expressing B- cells. In monkeys that treated at doses up to 25 mg/kg, which was the highest dose we reached in the study, there was no evidence of cytokine release syndrome. This creates a therapeutic opportunity for solid tumors, we think, which has been difficult for CD3-based T-cell engagers. This is an exciting year for us. There we have a steady parade of clinical data where we think 154 may have an opportunity to show the potential of CD47 inhibition in solid tumors for the first time, and also show what CD40 ligand may be able to add beyond what you can expect for a CD47 inhibitor alone in acute myeloid leukemia and higher risk myelodysplastic syndrome. We're in a good place as a company. As I said, we've got cash safely through these readouts this year and well into the second half of 2024. It's an exciting time for us to leverage this platform further to demonstrate clinical proof of concept with efficacy in multiple indications this year, and to expand our clinical pipeline beyond the ARC platform with the first compound from the gamma delta T-cell engager platform. Thank you for your attention. We look forward to engaging with many of you over the course of the year, and sharing data along the way. Thank you, Taylor, for the terrific presentation. We will now open it up for questions. As a reminder for our audience, please feel free to raise your hand if you're joining us in the room. For our audience joining via webcast, please feel free to submit questions online. I'll kick it off. Hi, Taylor. You had touched on the ARC platform. Could you maybe walk us through how it allows you to address biology differently than the traditional bispecifics, and how does it differentiate? Sure. It really boils down to the structure of these molecules. There's a number of efforts these days to make bispecific antibodies where one arm binds to a TNF receptor, there are CD40 by 4-1BB bispecifics that are in development. There are CD40 by FAP bispecifics in development. What those agents are relying upon, I'll just use the CD40 by FAP as an example, is that FAP antigen density will be high enough in a tumor so that many of those free CD40 Fab domains are clustered closely to one another, so that if a CD40 expressing cell wanders into that environment, that those approximated Fab domains will be able to bring together a trimer of CD40 on a cell surface. The story with these bispecifics has been the same from a toxicity and bell-shaped dose response perspective as the original story with the two-armed regular monoclonal antibodies. You know, in that case, there's still cross-linking that has to occur. It's just through FAP rather than Fc-gamma receptor binding. What I hope I've convinced you of today is that when you have a hexamer that binds CD40 and engages CD40 independent of those cross-linking requirements, that it skips the toxicity that seems to be mediated by accumulation of those compounds on Kupffer cells in the liver. It also enables you to fully occupy and engage the CD40 receptor without that bell-shaped dose response. Thank you. With regard to the GADLEN platform, could you maybe explain to us a little bit further on what is different in terms of a gamma delta T- cell versus a alpha-beta T- cell, and why is it showing advantage? gamma delta T- cells are somewhere between 0.5% and 5% of our total CD3 T- cell pool. CD3-directed T-cell engagers will activate all T- cells, including, you know, the 95% of alpha-beta T- cells, as well as the 5% of gamma delta T- cells. just in terms of the mass of T- cells that are being activated by CD3 engagers, there's an enormous number of, an enormously higher number of T- cells that are engaged with that sort of agent than would be engaged with a Butyrophilin 2A1 3A1 heterodimer. The other difference between activating gamma delta T-cells with a Butyrophilin heterodimer and activating all T-cells with a CD3 agonist, is that all of those alpha-beta T- cells also have a T-cell receptor that recognizes a specific antigen. In all of us, we contain partially self-reactive T-cells that could generate autoimmunity in any one of us, but are held in check by regulatory T- cells. When you activate all of those cells with a CD3-based engager, then they are active, and they will then be able to recognize that self-antigen that they might be reactive with. That recognition mechanism underlies much of the autoinflammation that has been seen with CD3-based engagers. gamma delta T-cells do not express a antigen specific, at least in the traditional context, T-cell receptor. They only recognize these Butyrophilin heterodimers. In one sense, T-cell activation with a CD3 agonist gives those T-cells really two sets of eyeballs, activation by CD3, and then recognition of whatever their natural antigen happens to be, which is not the same case with gamma deltas. Thank you. Now you had shared a full map of upcoming catalysts. Looks pretty exciting in terms of SL-172154 plus liposomal doxorubicin plus AZA and plus MIRV. Question is, have you already put in place a plan for commercialization down the road as well as manufacturing of these products? I'll address the manufacturing question first. We've made enormous strides through our internal manufacturing efforts with SL-172154. We're very comfortable that we're able to manufacture SL-172154. It's likely that the ultimate cost of goods of SL-172154 will be, you know, maybe 1.5x what you expect for a typical mAb, but not likely to be any higher than that. This is an agent that will from a manufacturing perspective have mAb like properties. We feel good about where we are there for future development. With Doxil and Mirv, there are, you know, likely slightly different commercial opportunities there. With Doxil, clearly this is a non-selected population in the platinum-resistant setting. A strong signal with Doxil could quickly be transitioned to potentially all platinum-resistant patients. Strength of the signal there also could put us in a position to move forward in the treatment paradigm. Mirvetuximab is clearly making an effort to move forward in the treatment paradigm already. With mirvetuximab, if we're able to broaden the base of responders to folate receptor alpha low and mid patients, you're doubling the pool of patients that could benefit from a drug like mirvetuximab. That's important already in the platinum-resistant setting. If you can move that combination forward in the treatment paradigm, obviously there's then the opportunity to capture quite a few more patients who could benefit from the combination. Thank you. In terms of on the business development or the financial front, will you provide some kind of plans for this year, given there's a lot of catalysts coming up? Sure. You know, we certainly believe that all of the clinical data that's coming has the opportunity to show, as I said, activity of a CD47 inhibitor in a solid tumor in a convincing way for the first time, because that benchmark response rate for Doxil is both low and well-known. You know, I think that will be exciting for folks if we hit that 30% overall response rate or greater in that population, and most importantly, important for patients. The ARC platform as well as the GADLEN platform have spawned a large number of other molecules. It's certainly always been on our radar to consider monetizing some of those non-core assets. It's certainly possible that that's part of the series of catalysts that come our way this year. Thank you. Just wanted to see if there's any final questions from the audience? Okay. Looks like we're on time. Thanks again, Taylor, for the presentation, and thanks everyone for joining us. Thank you, Ting.