All right. Well, thank you everybody for joining us. Our conversation with Shattuck's CEO, Taylor Schreiber. Thank you so much for coming down to Miami and braving Florida for our conference. My pleasure. Let's start with a high-level view as we head into the end of 2023 into 2024. Obviously, you've had a ton of recent news. You've had some meaningful advances that we've waited a long time to see. How are you viewing the new year, and what should we be focused on as we enter 2024? Yeah. I mean, a few things. It's-- I think we're in the midst of a defining time for the field, understanding whether CD47 is a valid target in oncology or not, both in solid tumors and heme. And, you know, the elephant in the room, obviously, is what happened with magrolimab in the ENHANCE, in the ENHANCE-2 trials. And we probably won't know the answer to that question, at least, you know, from the horse's mouth, until EHA of next year, is my guess. Mm-hmm. You know, what is disclosed there, I think will be important for a lot of folks who have seen the recent ALX data and, you know, are intrigued by the fact that there appears to be a signal there in a controlled study, albeit with a small n. Clearly, durability will be something that we also learn more about from evorpacept in around the same time period as we learn more about ENHANCE and ENHANCE-2. And I think our data, you know, coming in the midst of both of those evolving stories, will certainly be helpful here. Because what we recently reported was that in the initial cut of the Doxil combo study in patients with platinum-resistant ovarian cancer, we have some early responses. And Doxil, historically, depending on whether you're looking at the AURELIA study, which had an 8% response rate, or the JAVELIN study, which is more recent, that had a 4% response rate, whichever one you prefer, the response rate for Doxil is low. Mm. You know, if we can triple or quadruple that, that's a good start, and if that, by the second quarter of next year, evolves into a five plus month durability of response, that will be meaningful. You know, in conjunction with that, we have data coming at ASH. The abstract for the data that will be presented at the meeting itself is out, and this was a study that was performed in patients with relapsed refractory AML or high-risk MDS, mostly TP53-mutant patients. There was a SL-172154 only control arm, and a SL-172154+ AZA arm, and we had a monotherapy responder in a TP53-mutant AML patient who had failed 7+3, had failed FLAG, had failed venetoclax, responded within the first cycle, then went on to hematopoietic stem cell transplant and is disease-free today. It's one patient, but that's unusual for a patient like that, and it's certainly an important outcome for that person. So, the full body of that data will come out at the presentation on December 11th at ASH, and then we'll follow it up shortly after with a look into our frontline expansion cohorts in both TP53-mutant AML and higher-risk MDS. We've tried to set high benchmarks there. Mm. The initial look will be at CR rates, and then that data will also... Both of those cohorts are now fully enrolled, and so those data will also mature through the first half of next year. So, we can dissect each one of those pieces, but, just to sort of lay out the landscape, I think between learning what happened with magrolimab and ENHANCE and ENHANCE- 2, ALX's data maturing, our data maturing, I think, there's an opportunity for the field to understand, you know, what are the engineering challenges of building a CD47 inhibitor that can preserve efficacy without some of the toxicities that have been seen. Well, we're certainly gonna get deeper into both the ASH abstract and the AML MDS and the recent ovarian data. But, let's start with that CD47 space in general, which you keep referring to. Obviously, magrolimab disappointments, ALX, as you say, looking supportive, but maybe a little mixed. Can you talk about how your approach is different from those other CD47s or from a standard CD47 mab, whether it's Fc component or not? Sure. So the first agents, magrolimab being one of them, are all antibodies that block CD47 and have an Fc domain on them that has a different level of Fc gamma receptor engagement. Before magrolimab, Forty Seven had an IgG1 antibody that had a high degree of Fc gamma receptor engagement. That was discontinued due to cytopenias. Magro seemed to solve some of those cytopenias issues, at least when those trials are run at phase I centers, where physicians are ready to transfuse. It seems like that became a bigger issue in a larger randomized study. So where evorpacept and SL-172154 differ from all of the prior CD47 inhibitors are that those are the two agents that were specifically designed to lack any Fc gamma receptor binding. And that was a design choice that we both made out of the expectation that that would eliminate the dose-limiting cytopenias that have unfortunately still been seen with magrolimab. Where SL-172154 differs from evorpacept. So both SL-172`154 and evorpacept are Fc fusion proteins. Evorpacept is a dimeric SIRPα Fc fusion protein. SIRPα-Fc-CD40L domain is a competitive inhibitor to CD47. Where SL-172154 differs is that it is now a hexameric fusion protein that has a SIRPα- Fc- CD40 ligand domain. And the addition of CD40 ligand, this is a TNF ligand, it's a co-stimulatory ligand that activates the macrophages that are engulfing tumor cells in the setting of CD47 blockade. Preclinically, what we showed is that by adding that immunostimulation domain to a CD47 inhibitor, you had higher frequency of responders, and the durability of responses was greater than with a CD47 inhibitor alone. And so that's the thesis that we are now testing in our trials. And so two major differences here: one, the valency of your CD47 axis blockade, and the other being this immunostimulation. Correct. Can you see the impacts of these differences in, well, certainly, you mentioned it's preclinical data, but can you see these in patients? Can you see markers in PD that convince you that the immunostimulation is doing its job, that you're seeing superior CD47 axis blockade through the valency? Yeah. You can. So we've shared data from the dose escalation portion of our phase I trial in ovarian cancer, and some of the data from the AML-MDS patients is in the abstract. But, with the CD-- with all CD47 inhibitors, the primary pharmacodynamic marker that has been monitored in the past is simply receptor occupancy on CD47. Is your drug binding a cell that expresses CD47? That's all that's seen. When you add CD40 agonism to the picture, you expect to, first of all, see the drug binding to cells that express CD40, and we've shown that. But when you actually activate CD40, that leads to really potent concentrations of serum cytokines coming up, which you can measure. The dominant cytokine that comes up within a few hours of CD40 activation is IL-12, also known to be a very potent anti-tumor cytokine. You also see things like MCP-1, MIP-1 α, MIP-3 α, a variety of other macrophage-driven and macrophage-activating cytokines that come up in the blood. And so we saw those things in a dose-dependent manner in the phase I dose-escalation studies and used those markers to pick the appropriate dose to bring into the expansion studies. You also see that your CD40 expressing cells, which are B cells and monocytes in the peripheral blood, rapidly leave the blood and distribute into tissues. And so those were all good signs that we were actually activating CD40. Then now, none of the other CD47 inhibitors reported a monotherapy response in a relapsed refractory AML patient. You never want to make too much of one patient, but, you know, could that be a canary in the coal mine that CD40 agonism is now adding something in terms of efficacy? Makes sense. Let's start with the AML-MDS and circle back on that ovarian that you mentioned. This is obviously where the other CD47s got the most early attention. This is where some of the initial responses were reported. And in your ASH abstract a couple weeks ago, you started to see some responses. You mentioned a monotherapy response in that relapsed patient, but you also started to see some clinical activity in the azacitidine combo as well. So can you orient us as to where you are in the process in AML-MDS, and what we should be expecting to see in the full data set at ASH? Yep. So I'll start with the full data set at ASH. So we enrolled 19 patients in the monotherapy group at 1 mg/ kg, 3 mg/ kg, and 6 mg/ kg of SL-172154, and then 18 patients in the azacitidine combo at the same dose levels. So all that full body of data will be included there, patient profiles, any adverse events, receptor occupancy, serum cytokines, waterfalls on blast reductions, bone marrow biopsies, where we were looking for evidence of SL-172154 binding to tumor cells in the marrow. All of that will be included. The data cutoff for that abstract was May 25th, and we had already moved on at that point in time to enrolling in the frontline expansion cohorts. And so in the TP53- mutant AML expansion cohort, these are our frontline patients. The initial cohort size there was about 10 patients. The protocol gives us flexibility to over-enroll a little bit. And then the frontline high-risk MDS cohort, initial size was 20 patients. And both of those cohorts have now been fully enrolled, and these are both diseases where bone marrow biopsies are first done at one month on treatment, and then, depending on which disease you're talking about and which physician, you know, at monthly or three monthly intervals thereafter. And so we'll provide as much data as we have on, you know, what is the complete response rate in those frontline patients, and then, you know, other safety data as well for those folks. Typically, ASH, presentation data cutoffs can be as late as November, or even into December sometimes. So fair to say you'll have five, six months more data than the abstract contains? Correct. Yeah, from the dose escalation. Excellent.... So really a much more mature data set with a lot more patients in it, potentially? Yeah. Excellent. You've always been very good at providing clear bars for success and bars for taking compounds forward. What are you looking for internally, at ASH and maybe in the expansion cohorts, the mature expansion cohorts, beyond to bring this compound forward? Yeah. So, you know, as I said, any activity in a relapsed refractory patient is potentially interesting. In the frontline cohorts that will come just on the heels of ASH in a company-sponsored event, in the TP53-mutant AML cohort, the complete response rate to azacitidine alone is less than 10%. And so in those folks, you know, we're looking in that group, magro AZA had a CR rate of somewhere between 30%-33%. And so we don't, we don't want to beat magro just on safety. We want to beat magro on CR rates as well. And if and only if you have an encouraging early CR rate, do you have a chance of having a good response durability. and so that's why we're trying to set those high bars for early CR rates as well, in hopes that that will mature into good response durability in the first half of next year. In the high-risk MDS cohort, most of the patients we've enrolled have also had TP53 mutations. And so the study that clinicians continue to cite there is the Aprea study. Mm. Where the CR rate for azacitidine alone was 22%. And so, you know, we want to be double that, in early study, for the same reason, to then have a chance of, having good response durability, you know, six to 10 months later. And, we're excited to, you know, be at a time where we're finally talking about clinical data. Well, we're excited to hear it. Let's, before we run out of time, let's make sure we talk about the recent ovarian data as well. We just saw initial data from that phase I cohort with liposomal doxy, as you mentioned. Only 11 patients in that update, but you did have three responses, which, as you mentioned, for a later-line doxy combo is very encouraging. So, you mentioned briefly an appropriate comp being in the single digits for doxy alone. Magro showed essentially nothing in ovarian. So do you expect the same from other CD47s without immunosuppressive activity that also lack Magro's liabilities? Or do you interpret Magro's failure in ovarian as being related to challenges dosing and keeping patients on track? I think Magro's failure in ovarian is because avelumab is not a good combo partner, more than it was anything else. And, you know, like, only two patients that they enrolled in that cohort were actually PD-L1 positive. They actually had a response in one of those two patients. You know, if they had combined with PLD, might they have or an antibody-drug conjugate, I think they might have seen something different, you know, tox considerations aside. Mm. I hope that that's one of the lessons that collectively comes in the first half of next year from ALX's data and our data is a reinforcement of some of these early lessons that the field learned because of the good work that was done by Forty Seven and then Gilead in helping to define what mechanisms combine well with a CD47 inhibitor. Makes sense. So, sticking with the Doxil combo in later line ovarian here, what's your bar for the next update next year? And, what's the opportunity in later line doxy combo, given how the PROC space has evolved? Yeah. So the bar is, you know, we need to maintain greater than a 25% response rate, and if and only if that comes with a greater than five month duration of response, is it interesting? And, you know, we're gonna know that quite shortly here, and if we see that, we will double that cohort size. And if the response and response duration holds up in a 40-patient cohort, that would then form the basis of potentially the first registration-directed study. That'd be a huge win for us, because of the low activity of Doxil. And one of the goals in that next dataset would be to demonstrate that those response parameters hold up in ADC-experienced patients. And, you know, then you could move toward a fairly broad label in the PROC setting. You know, there's earlier line opportunities in combination with ADCs that could come along as well. Right. Well, this is the other combo that you're running here with ImmunoGen's drug in folate receptor alpha-positive patients. How do those patients differ from the more unselected later line population? And, maybe just briefly, what's your bar for success on top of ImmunoGen? Yeah. Patients are have less aggressive disease. So more than 80% of the patients in the PLD combo are primary platinum resistant. In MIRASOL, they had 13% primary platinum-resistant patients, so, you know, that in and of itself is a pretty large difference. The bar in the FRα high patients is very high. They had a great response rate, decent response durability. We're looking to extend response durability in the FRα highs. And we're looking to bring both the response and response duration in the FRα low and mids up to at least what is seen in the current ELAHERE label in the highs. Makes sense. And just in the last few seconds here, current cash runway guidance is to year-end next year, so you've got to be looking at some possibilities to help extend that runway, assuming you get positive data from some of these studies and are contemplating expansions and the expansion cohorts. What are the options that you have for runway extension at this point? What are most appealing to you, and what do you view as the key drivers of interest from possible strategic partners, whether on CD47 or other platform molecules? Yeah. So there, there's a variety of conversations that have matured nicely on some of the preclinical parts of our pipeline that aren't very visible right now, but I think could be quite helpful as we move through the clinical datasets. And, you know, we've got a steady parade of data coming now through the middle of next year, and I think we'll be engaging with investors frequently along the way there. Clearly, it remains a tough market, and clinical data is what makes the difference here. So we'll be looking to bring other folks into the story along the way, and, you know, I think if we hit on duration, that's a big deal from a strategic engagement standpoint. Certainly. Certainly. All right. Well, we are unfortunately out of time, but thank you so much for joining me here in Miami at our conference. Thank you, John. All right.