Good morning and welcome to the Shattuck Labs Investor Call and Webcast. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentation. As a reminder, this call is being recorded and a replay will be made available on the Shattuck website following the conclusion of the event. I'd now like to turn the call over to your host, Taylor Schreiber, Co-founder and Chief Executive Officer of Shattuck Labs. Please go ahead, Taylor. Thank you, Tara. Good morning, everyone, and thank you for joining. I'm Taylor Schreiber, the Chief Executive Officer and Scientific Co-founder of Shattuck Labs. We are excited to provide an interim safety and efficacy update from our Phase 1B portion of our clinical trial, combining SL172154 with azacitidine in frontline TP53 mutant AML and higher-risk MDS patients. Throughout today's call, I will refer to SL172154 simply as 154 and to azacitidine simply as aza. The press release reporting top-line results was issued pre-market this morning and can be found in the Investor Relations section of our website, shattucklabs.com. Before we begin, I would like to remind you that today's webcast contains forward-looking statements and would refer you to our most recent 10-Q and other filings with the SEC, which are available on the SEC's website or on our corporate website, shattucklabs.com. On today's call, we are joined by Dr. Naval Daver, a professor and director of the Leukemia Research Alliance Program in the Department of Leukemia at MD Anderson Cancer Center. I will briefly introduce the mechanism of action and clinical development overview for 154, and then turn the call over to Dr. Daver. Dr. Daver will review the data from the phase 1b dose expansion cohorts, combining 154 with aza, in patients with TP53 mutant AML and higher-risk MDS, shared today at the European Hematology Association 2024 Congress. Following our prepared remarks, Dr. Daver and I will be joined by Dr. Lini Pandite, our Chief Medical Officer, for the Q&A segment of the call. Although many of you are familiar with the structure, as a reminder, 154 is a dual-sided fusion protein. It contains three functional domains, each of which contribute in different ways to 154's emerging clinical profile. First, the SIRP alpha domain, shown in orange, binds to and inhibits CD47 on tumor cells, removing the don't-eat-me signal required to enable macrophage-mediated phagocytosis. An Fc domain, shown in gray, was included to stabilize 154, and importantly, Fc gamma receptor binding was eliminated in 154 to avoid anemia and other cytopenias. Third, 154 contains two trimeric CD40 ligand domains, shown in blue, to activate antigen-presenting cells and enhance efficacy. 154 has now emerged as the leading CD47 inhibitor in AML and higher-risk MDS. This can be explained by comparing the functional characteristics of 154 to prior CD47 inhibitors. Like most prior CD47 inhibitors, 154 binds CD47 specifically and with high affinity. The central Fc domain of 154 was designed to lack any Fc gamma receptor binding. It is now clear that CD47 inhibitors that contained an active Fc domain encountered dose-limiting anemia and other toxicities in clinical development, which led to their discontinuation. These data are being shared for magrolimab at the EHA conference this year, and the results are similar to a number of other Fc-active CD47 inhibitors that were discontinued previously, including TTI-621. Finally, the CD40 ligand immune agonist domain differentiates 154 from all prior CD47 inhibitors. This function led to improvements in efficacy in preclinical studies, and we believe that we are now beginning to see the clinical differentiation that this domain may provide. There are several steps involved in 154-mediated anti-tumor activity. First, the SIRP alpha domain of 154 binds to CD47-expressing tumor cells, disabling the don't-eat-me immune checkpoint signal. Those tumor cells must be decorated with an eat-me signal for macrophages to come along and phagocytose the tumor cells, however, and this is the reason that CD47 inhibitors must be administered in combination with other agents. In AML and higher-risk MDS, tumor blast cells upregulate these eat-me signals following exposure to aza. These two events are necessary to initiate tumor cell phagocytosis, and this is where the mechanism of all prior CD47 inhibitors stops. 154 is unique in also providing the CD40 immune-activating signal. This was included in the design of 154 because although macrophages initiate the immune response, anti-tumor activity and efficacy is mediated by T cells, and 154 is the only agent in the class that links an innate and adaptive immune response in this manner. Thus, by inhibiting CD47 and blocking the don't-eat-me signal while simultaneously activating CD40 on macrophages, the dual immune-activating mechanism of 154 has the potential to elicit an anti-tumor response with faster kinetics and greater durability than blocking CD47 alone. Recent clinical updates from other drugs in the CD47 class may now be highlighting the differentiating features of 154, particularly the CD40 agonist domain. In frontline higher-risk MDS, a recent study reported a 15% complete response rate for patients treated with a SIRP alpha Fc fusion protein in combination with aza. The prognostic features of the patient population treated in this study were more favorable than the patients treated with 154, a SIRP alpha Fc CD40 ligand fusion protein, yet to date we have observed nearly triple the complete response rate. Another recent study in platinum-resistant ovarian cancer patients reported zero objective responses when patients were treated with a SIRP alpha Fc fusion protein in combination with pegylated liposomal doxorubicin. This patient population was very similar to the patients treated with 154, yet we have observed a 19% objective response rate to date. Across these two studies, the main difference between 154 and the other SIRP alpha Fc fusion proteins is the CD40 ligand domain in 154. We reported profound pharmacodynamic effects demonstrating CD40 activation in our dose escalation clinical studies of 154, and similar pharmacodynamic effects have not been reported for any prior CD47 inhibitor. These pharmacodynamic effects may have utility in future studies in differentiating responders from non-responders and explaining the superior efficacy profile that is emerging for 154. With that, it is my pleasure to introduce Dr. Naval Daver. He is a distinguished clinical investigator with a focus on molecular and immune therapies in AML and myelofibrosis, and is a principal investigator on more than 25 ongoing institutional, national, and international clinical trials in these diseases. Naval has published more than 450 peer-reviewed manuscripts and is on the editorial board of numerous hematology-specific journals. Naval, please go ahead. Hello, and it's a pleasure to join you for this discussion. Here, I'm going to be presenting updated data and focusing on additional results from the two frontline dose expansion cohorts where 154 is being conducted and combined with azacitidine in patients with previously untreated TP53 mutated AML or high-risk MDS. So building on the previous dose escalation trial, 3 milligrams per kilogram was the selected dose for 154 in these dose expansions. So first, let's start with the frontline TP53 AML cohort, and it's important to highlight that TP53 mutated acute myeloid leukemia remains an area of highest unmet need in newly diagnosed acute myeloid leukemia. There have been a lot of efforts over the last 10-15 years to develop therapies that can improve the outcomes, but unfortunately, in spite of these efforts, we have not been able to have an improvement in the response rates or overall survival, or even the ability to get these patients safely and effectively to allogeneic stem cell transplant. Historically, the expected response rates, so CR rates with TP53 mutated frontline AML, are about 10%-20%, and there is a lot of interest to use mutation-agnostic therapeutics such as immune checkpoints, bispecific antibodies, CD47 strategies, as we believe these may be able to target TP53 in spite of the resistance to multiple genomic and cytotoxic and epigenetic therapies. So at the data cutoff, there were 21 treated patients with TP53 mutations or deletions with poor prognostic disease characteristics. As you can see, out of the 21 treated patients, 91% had complex cytogenetics with TP53 mutation or deletion, and 67% of these patients had what we would consider to be a secondary AML or a therapy-related AML arising from treatment of a prior malignancy or a prior myelodysplastic syndrome, which in general is considered to be an additional high-risk factor among the TP53 mutated patients. So in general, this would be considered to be a population enriched for what is considered high-risk TP53, especially the patients who have associated complex cytogenetics, which in this study was the majority of patients, as well as those who have secondary therapy-related AML. It appears that very few of these patients are going to be among the lower-risk TP53 AML because those patients often do not have associated complex cytogenetics. So in general, quite a high-risk real TP53 AML population. We're now looking at the safety and tolerability profile in this frontline TP53 mutated AML population. Here you see that infusion-related reactions, or IRRs, were the most common of the 154-related treatment emergent adverse events. By addition of dexamethasone to the pre-medication regimen, the incidence and severity of these IRRs has been reduced considerably, and we have not observed a grade 3 or higher IRR after the administration of dexamethasone pre-medication, which has been good. Importantly, there was no evidence of any hemolytic or destructive anemia, which has been a major issue for other CD47-targeting agents that have a more active Fc domain. The grade 3 or 4 adverse events that were reported in 7 patients as possibly related to 154. There were 4 deaths due to adverse events, including sepsis in 1 patient, pneumonia in 2 patients, and cardiac arrest in 1 patient. The Grade 5 event of cardiac arrest was previously reported in December 2023. This event occurred in a patient with a history of significant cardiovascular disease, including prior myocardial infarction and coronary artery stents, hypertension, and other adverse risk factors, including comorbidities, uncontrolled AML, recent arrhythmia, as well as recent use of amiodarone for the arrhythmia and hypokalemia. The observed infusion-related reactions were clearly related to 154 and were manageable with the use of dexamethasone on the day of infusion. Aside from these events, the adverse events which have been observed to date are largely consistent with what I would expect to see from azacitidine and more broadly for patients with TP53 mutated AML, who tend to be at a higher risk for all-cause mortality, including deaths from infection as well as cardiovascular events, regardless of the therapy delivered. As of June 4, 2024, data cutoff, the objective response rate was 43%. Importantly, 29% of the patients achieved a complete remission, 5% of the patients achieved a complete remission with incomplete hematological recovery, and 10% achieved a partial response. For the 6 patients with the CRs, minimal residual disease assessed by flow cytometry and next-generation sequencing is ongoing at this time. Initial data demonstrates clearance of the TP53 mutant subclones by next-generation sequencing in some of these patients. 24% of the patients proceeded to allogeneic transplant after achieving a response following 3-7 cycles of study drug treatment. Some of these patients were taken into transplant after achieving a PR or CRi, and it is possible that these patients would have gone on to achieve a CR if additional cycles of therapy were given prior to the transition to allogeneic stem cell transplant. It is encouraging to see that 154 in combination with azacitidine can achieve MRD negativity in this very high-risk TP53 mutated frontline AML and can also safely bridge patients to transplant, and in general, seems that we are able to get more patients to transplant in this TP53 mutated AML than historically has been seen with other regimens for such a population. We're now looking at a relative blast reduction from baseline for these 21 patients who were treated in this frontline TP53 mutated AML cohort. It is encouraging here to see that consistently we are achieving blast reductions in this poor prognosis, high-risk subgroup, and approximately 50% of the patients who had stable disease with blast reduction in December have actually matured and gone on to achieve a complete response. These preliminary efficacy results are highly encouraging, especially given the complete response rate benchmark for aza as monotherapy in frontline TP53 mutated AML is approximately 10%-11%. Now we're looking at the time to response and duration of treatment for patients in this frontline TP53 mutated AML cohort. The median duration of CR, overall response rate, and OS have not yet been reached. As you can see in the figure, there are several patients who are still on treatment. Additional follow-up will be needed to assess the duration of these endpoints, and this is currently ongoing for the patients still on treatment. The median time to achieve objective response and the complete response were 2.1 months and 3.1 months, respectively. So this basically suggests that we do need to persist with treatment and that responses can improve over time and can progress from an initial response to a complete response with continued therapy. Blast reduction had been observed in most of the patients with stable disease, and some of these patients may further improve if we are able to give additional cycles, and we hope to see also improvements in peripheral blood counts, including platelets and neutrophil count with time, as has been seen with some of the patients who have stayed on treatment for longer durations. On this slide, we are looking at the hemoglobin change from baseline over time for all patients, which shows a general improvement in hemoglobin coincident with the achievement of response on treatment over time. So consistent with the lack of hemolysis, patients did not require hypertransfusion at study entry to achieve a specific hemoglobin threshold before initiating the dosing of 154. The median baseline hemoglobin was 8.1, and significant drops in hemoglobin were actually not observed following administration of 154, which has been shown on this graph. Also of note, 154 was not associated with interference in blood cross-matching resolution and did not require extended cross-matching or molecular genotyping of RBC. These issues were associated with magrolimab and did create issues with rapidly having access to appropriate blood units for transfusion when needed. Overall, these data show that there was no significant drop in hemoglobin from baseline, which I think has been a concern in the CD47 field, and it is good to objectively outline that this was not an issue with 154. Four of the 13 patients who were RBC transfusion dependent before starting treatment actually went on to become RBC transfusion independent, for an RBC transfusion independence rate on treatment of 31%. Now we're going to shift gears and go to the frontline high-risk MDS cohort. This cohort has completed enrollment as of the end of 2023. Again, it's important to highlight that patients with high-risk MDS, which are usually defined as patients with the intermediate high or very high-risk IPSS-R score, have limited treatment options. azacitidine has been the treatment that has been approved and used for the last 20 years for these patients. There have been many efforts to develop combinations and doublets, but thus far, unfortunately, none of these have been able to show clear superiority or improve the response rate or survival as compared to azacitidine monotherapy. Median survival for these patients tends to be between 12-24 months, and there is an ongoing effort to try and find novel targets, including CD47 SIRP alpha and other immune targets that may improve the outcome for this population that has really not had any change in their treatment or improvement in the last 20-25 years. Here we're looking at the demographics and disease characteristics for the 24 treated patients in this frontline higher-risk MDS cohort. It's notable here that a very high proportion of these patients had a TP53 mutation as well as complex karyotype therapy-related MDS. Now, this is something that we do see in some of the studies, such as CD47 SIRP alpha studies, because people want to find good options for the patients with TP53 mutated, but it's really important to highlight that this is a much higher proportion of TP53 mutation than would be seen in general in frontline high-risk MDS, where the expected rate of TP53 mutation deletion is about 20%-25%. So it's important to note that this was overall quite a poor prognosis, even among the high-risk MDS, and a lot of these patients tend to be resistant to standard frontline therapeutic options and often tend to have a limited survival in the current landscape with treatments. We're now looking at the safety and tolerability profile in this previously untreated frontline higher-risk MDS. Overall, infusion reactions were the most common, 154-related treatment emergent adverse events. Importantly, there was no evidence of hemolytic anemia also in this frontline MDS cohort, and there was generally an acceptable safety and tolerability profile, as is shown here. Grade 3 or 4 adverse events that were considered to be possibly related to 154 did occur in 10 patients. Infusion-related reactions occurred in 3 patients. Febrile neutropenia occurred in 2 patients. All of the other grade 3 and 4 events occurred in 1 patient each. The grade 5 adverse event related to sepsis was considered by the investigator to not be related to 154, but likely related to the underlying disease. The grade 4 myocardial infarction occurred in the setting of sepsis in a patient with coronary artery disease, hypertension, type 2 diabetes. In the setting of sepsis, there was evidence for demand ischemia in this patient. As previously noted, the presence of relevant cardiac antecedent history is the main risk factor for developing cardiac events, to our knowledge, at this time during treatment. As in the TP53 mutated AML cohort, the IRRs were an adverse event that were considered clearly attributable to the 154. These were manageable with pre-medication steroids on the day of infusion, and the randomized control study in high-risk MDS that is currently ongoing enrolling patient will further clarify the 154 safety profile. However, this time, the adverse events, aside from the IRR, are consistent with what I would expect to see in frontline higher-risk MDS patients who often have underlying comorbidities, and especially given the large proportion of these patients have underlying TP53 mutation. Those patients are also prone to more significant cytopenias and other comorbidities than those who do not have TP53 mutation. Here we're looking at the efficacy as of data cutoff, April 23rd, 2024. Overall, the objective response rate was encouraging at 67%, with a complete response rate of 42%. It's important to note that of the 10 patients who achieved CR, 9 patients actually had abnormal cytogenetics at baseline, and 6 of those 9 patients achieved a cytogenetic CR, which is a very good sign and higher than what would be expected with single-agent azacitidine. 8 of the 10 CR patients also achieved MRD negativity by flow cytometry, which is also encouraging and higher than we would expect with standard frontline therapy in higher-risk MDS. Additionally, 3 patients who achieved a marrow CR plus hematological improvement also went on to achieve MRD negativity by flow cytometry. The preliminary results from NGS analysis do show clearance of TP53 mutation clones in 4 of 5 patients who achieved CR, and in 2 of 3 patients who achieved a marrow CR. 3 patients in CR have been bridged to allogeneic stem cell transplant after achieving a CR. In general, overall, these response rates, including the overall response rate, CR rate, as well as cytogenetic CR and flow MRD negativity, are quite encouraging and better than what has been published or seen with single-agent azacitidine-based approaches in such a high-risk TP53 mutation complex cytogenetic enriched population. We're now looking illustratively at the maximum blast percent reduction from baseline in bone marrow blast, again using the April 23rd, 2024 data cutoff. Notably, 14 of 24 patients achieved a CR or marrow CR. The CR rate was 42%, which is a double of what has been historically observed in patients treated with azacitidine alone, and especially in a population enriched with TP53 mutation complex cytogenetics. Maybe even lower CR rates would be expected often in the range of 10%-20%. So the 42% does look encouraging, although at this time numbers are small, and we want to continue to build on this experience. We're now showing the time to response and duration of treatment for the patients in this frontline high-risk MDS cohort. Median duration of CR, overall response rate, and overall survival have not yet been reached. The further follow-up is needed and is ongoing at this time. Important to note that the median time to achievement of the overall response and complete response was one month and 3.6 months, respectively. Blast reductions and hematological improvements were observed early on in treatment, and the swim lanes here show that three patients achieved CR were then eventually bridged to allogeneic stem cell transplant. On this slide, we show the hemoglobin change from baseline over time for all patients, which shows an improvement in hemoglobin coincident with the time to response. Consistent with the lack of hemolysis with this agent, patients did not require hypertransfusion prior to study entry to achieve any pre-specified hemoglobin threshold. Median baseline hemoglobin change was minus 0.7 gram per deciliter. Significant drops in hemoglobin were not seen after treatment with 154 in this patient population. Also important to note that 154 is not associated with interference in type and cross-match and selection of blood units. We did not require RBC genotyping or extended cross-type match. These are all issues that were associated with another CD47 antibody magrolimab, and it is good to see that this has not been an issue. So blood units are readily accessible and can be matched if needed with the 154, which had been an issue with the magrolimab. So overall, I would say this looks like a good profile without a concern for significant anemia or drop in hemoglobin. Seven of 13 patients who were RBC transfusion dependent prior to initiation of treatment actually went on to become RBC transfusion independence for a 54% RBC transfusion independence rate, which is actually quite encouraging. So overall, what we can see is that the landscape has evolved significantly over the past few years, and data presented today will hopefully help establish a reemergence and resurgence in enthusiasm for the CD47 targeting field. 154 especially does demonstrate evidence of immune activation through CD47 blockade, as well as concomitantly through CD40 activation. Overall, the safety profile, in my opinion, is acceptable in combination with azacitidine and very similar to the general safety profile seen with single-agent hypomethylating agents such as azacitidine and decitabine. Importantly, there were no evidence of hemolytic anemia requirement for hypertransfusion or extended cross-type matching or molecular RBC genotyping, which helped to differentiate 154 from prior CD47 inhibitors, which were mired with many of these problems. Given TP53 mutant high-risk MDS and TP53 mutant AML are diseases with particularly poor prognosis in areas of highest unmet need in the treatment landscape of MDS and AML, the trending response rates and reductions in bone marrow blasts are extremely promising, and we are excited also to see that a number of these responses are maturing from marrow CR to complete remission, as well as transfusion independence over time, advocating the need to continue treatment for patients on the 154 after initial reduction in the blast percentage has been observed. Overall, I'm optimistic about the growing clinical data set that supports the therapeutic potential of 154 in combination with azacitidine for these patients with frontline high-risk molecular unmet need MDS and AML. With that, I'd like to conclude my portion and hand over the call to Dr. Schreiber for the final comments. Thank you. Thank you, Naval. Looking back to our last update in December, approximately 50% of the TP53 mutant AML and higher-risk MDS patients who had stable disease with blast reductions have since achieved complete responses. This places our current complete response rates well above what has been shown for azacitidine alone. We are encouraged by the proportion of patients who have achieved minimal residual disease and been bridged to hematopoietic stem cell transplant, as these variables have been shown in multiple studies to predict longer overall survival. Importantly, the safety profile of 154 continues to be manageable. As you just heard from Naval, infusion-related reactions are a clear adverse event, which is mediated by the immune agonist CD40 ligand function of 154, and the implementation of steroids on the day of treatment is a mitigation step that is familiar to hematology oncologists, where T cell engagers, antibodies like daratumumab, and CAR T therapies are well established. We believe that the other adverse events which have been observed are attributable to azacitidine and also comorbid diseases in a high-risk MDS and TP53 mutant AML patient population. This slide provides an overview of where we have been and where we are going in the development of 154 in AML and higher-risk MDS. As is typical these days, we are unlikely to follow a traditional clinical development path with distinct phase 1, 2, and 3 clinical trials. Higher-risk MDS, and in particular TP53 mutant AML, are areas of very high unmet medical need, where clinical results like the ones we are generating could open accelerated opportunities for registration. We are pleased to have enrollment underway in a randomized controlled dose optimization study in patients with frontline high-risk MDS. We expect the data from this study to address Project Optimus at FDA and also to provide the first controlled data to further clarify the safety and efficacy of 154 in combination with azacitidine compared to azacitidine alone. We are also planning a randomized study for patients with TP53 mutant AML, which will be controlled against a physician's choice between azacitidine alone or in combination with venetoclax. This is an appropriate control in this patient population because venetoclax has not been shown to improve overall survival in TP53 mutant AML patients beyond the roughly six months observed with azacitidine alone. Together, we expect these studies to provide safety and efficacy data, which will be supportive of a registrational study in AML and higher-risk MDS. We expect that discussions with regulatory agencies, including potential accelerated studies, to take place in the second half of this year. We look forward to engaging with the investment and partnering community further as the data from the current studies matures and is soon complemented by these controlled data sets. Before we conclude today's call, I would once again like to thank the patients and their families that have participated in the clinical development of 154 to date, Dr. Daver, and the rest of the clinical investigators, our investors, and the entire Shattuck team that have enabled the progress shared today. With that, we are happy to take questions. Operator? Thank you, Taylor. Please hold for a brief moment while we pull for questions. So our first question comes from Joe Pantginis at H.C. Wainwright. Please go ahead, Joe. Hi everybody. Good morning. Thank you for taking the questions and congratulations on these increasingly differentiated data. So a couple of points I'd like to discuss with Dr. Daver, if you don't mind. So first, Dr. Daver, I want to go off your point about a therapy that has the potential to be mutation agnostic and then sort of funnel that down to the patient demographics and look at, say, the pure erythroid subtypes and what you would expect to see normally in potential responses or not here and anything else that might stick out to you with regard to the underlying demographics and karyotypes. Great. Thanks for the question, Joe. Dr. Daver, why don't you go ahead with that? Naval, looks like you're in for a really good. Yeah. So no, I think it's a good question. And TP53 mutated disease is already very high risk and difficult to treat. But I mean, among those, those who have the erythroid leukemia tend to also have a higher resistance even among TP53. So historically, basically nothing works at all in that group. I mean, even with Aza-Ven, the true CR rate in an erythroid population in our experience is probably less than 10%-15%. And with intensive chemo, a lot of those patients actually have early mortality in the first 60-90 days from myelosuppression and toxicity. So I mean, I think that's a very, very difficult subset that I wouldn't necessarily focus on, but it is a population you will get as part of the TP53. I think the key factors in this population are that these are all what we call the real TP53 because they have either high VAF or associated complex cytogenetics. And data both from our side and Moffitt has shown that those are the patients who really have a poor outcome driven by TP53. There are some TP53s monoallelic with low allelic burden without associated complex cytogenetics that could do reasonably well. But when we look at these patients, that is not the group. So these are kind of the real high-risk TP53. And to see CR rates in excess of really 20%, which is what you get with Aza-Ven, is quite encouraging. Of course, numbers are small, but if we continue to see good CR rates, true CR rates with durability, anything beyond 25%, 30%, 35% in frontline MDS or AML over time, then I think this will be very, very impressive. No, that's very helpful. Thank you very much for that. And then I guess the two-pronged question here about the profile of the asset here. And I guess, obviously, there's just such sensitivities about the CD47 AE profiles and talks of others. So I'll ask it two different ways. First, how do you feel these data can start to have broader impact in driving physicians away from sort of the basket thinking, the CD47 talks of others, and then sort of pushing the envelope because everyone's going to be so ultra-focused here? Now that the company's adding dexamethasone for each infusion to alleviate the IRRs, what is the potential risk, if any, that dex could sort of mute any potential immune response from the CD40 component? Or is that something you don't even consider? Yeah, I think the first one is very, very, very important. And I think many who have been in drug development for many years know that this is actually not uncommon at all to see that the first drug on a particular pathway doesn't work. We've seen this actually with FLT3 inhibitors that people forget. Let's start in the first randomized study done in 2004, 400 patients, completely negative. It was supposed to be a FLT3 inhibitor. And then, of course, now we have 4 FLT3 inhibitors approved and in common use. And people tend to think FLT3 inhibitors always work. We've seen the same with BCL2 inhibitors. 3 of them didn't work before venetoclax came along, and now everybody feels BCL2 works. So I think a lot of times it's not about the pathway. A lot of these pathways are relevant. There's excellent comprehensive preclinical data suggesting how they're important, and it's often about the specific drug. And I think this may be the case here. I still very much feel that, like FLT3 and BCL2, CD47 is a relevant target. I just think we have to find a drug that has a good mix of benefit-risk. With magrolimab, we'll be showing a lot. I'm actually at the meeting right now, and we're going to be showing data. Some of it was shown today by David Sallman. Tomorrow, I'll be presenting. It really was the toxicities that kind of pretty much removed any chance of success because we were seeing twofold higher discontinuation within the first six months. And this even led to less patients being able to make a transplant from the aza-magrolimab. So really, the toxicities caused such a high discontinuation and inability to make a transplant that even if there was an efficacy component, it could not be overcome. So I think if a drug does not have that toxicity profile, the discontinuation rates are similar to what you would see with the control arm, then actually there should be a good chance to see efficacy. So that's where so far it looks like we're seeing encouraging activity with the SL-172154, but we have to keep building on that. The DEX, I'm not too concerned about. I mean, there's a lot of data now from immune checkpoints, CAR T-based therapies where we are giving DEX very routinely, and it doesn't really seem to mitigate efficacy. So I'm not too worried about that. And in reality, we do have to do it because we did see some infusion reactions, some of which were significant. And I think it's kind of more important to maintain that safety at this point by avoiding them. Thank you very much for the answers. Thanks for the questions, Joe. So our next question comes from Jon Miller at Evercore ISI. Please go ahead, Jon. Thanks so much for taking my question. And I'll echo Joe's congrats on the great data update. I'd like to start on the cardiac signal. Obviously, last year, we saw a grade 5 death, a cardiac death. The abstract showed a grade 4 MI. You touched on this briefly, but I would love to hear Dr. Daver talk about whether this is potentially a signal of a cardiac and incipient cardiac tox, if there's anything that concerns you about seeing multiple cardiac signals on this trial, and if there's any plan to monitor this more carefully moving forward. Great. Hey, Jon, thanks for the question. Dr. Daver, back to you. Yeah, yeah. It's a great question. And definitely, as you probably imagine, we've spent a lot of time looking at those two events and talking to the investigators and kind of the steering committee of investigators who've been working on this. It's really hard to say for sure, but one of those patients really had a lot of pre-existing cardiac history, stents, arrhythmia. If I recall, I think pacemaker was on 3 or 4 cardiac medications. Of course, anemia is still a part of the disease itself, even though it doesn't seem to be worsened by the treatment here. It's still something we, of course, see in MDS AML with routine hemoglobins of 7.5, 8.5, even on presentation before starting trial treatment. So one of them, after looking at everything, the investigator as well as myself and other members of the steering committee kind of said that this was really something that is happening in a normal course of MDS, older patient, multiple cardiac history, and hard to really specifically associate with a drug. The other one, though, I think there was a little more concern. It happened a little bit early after the infusion reaction. So we did report that. We haven't seen it now with many patients treated after that. We haven't implemented any significant changes in management guidelines or routine echo or EKG enhanced monitoring. So I think we have to keep an eye on it. But overall, we haven't seen other cardiac events, even of grade one, two, or lower severity. So I think at this point, there's not a high level of concern, but it's definitely something we'll have to keep an eye out for. I'll just add a little bit to that quickly, Jon. Thanks, Dr. Daver. In the setting of the second patient, I think as Dr. Daver mentioned during the presentation, it was also an event that occurred secondary to sepsis. That's a relevant additional variable in that patient. For all those listening, it will come as no surprise that FDA and other regulatory agencies have a heightened state of awareness to follow the safety profile of all CD47 inhibitors. The way that we see this as a company developing a CD47 inhibitor really comes in the form of information requests. We received a comprehensive information request from FDA back in February immediately after magrolimab was put on full clinical hold. So all of these events have been shared with FDA. Obviously, at that point in time, the efficacy data was inferior to what we have today because we just didn't have as much follow-up. So there haven't been any events like this that have happened since, as you can see in the current data. So we as a team certainly agree with Naval and the other investigators that we need to be mindful of this. But in general, the AEs that are related to 154 do seem to be concentrated on IRRs. Thanks, Jon. Yeah, that's a great call. Thank you very much, Taylor. I'd love to maybe then switch gears and ask a question about efficacy. Obviously, we've seen some patients that you were previously tracking that weren't in CR eventually became CR patients. It takes several cycles to achieve true CR for both relapsed AML and high-risk MDS patients sometimes. Do you have any sense at this update of patients that you are tracking currently that you think could potentially convert with continued follow-up? And how did those patients that you were tracking at ASH last year that could potentially convert? How did those patients fare in this updated data set? Yeah, thanks for the question, Jon. So when we look back at the patients that had stable disease with blast reductions in either the TP53 mutant AML or MDS cohorts that were shared in December, about 50% of patients that didn't at that point in time have an objective response developed an objective response over the subsequent months. And that's a phenomenon, as Dr. Daver outlined, that is secondary to the fact that it takes time. You might see blast reductions quickly in these patients, but it takes time to then see the full hematopoietic compartment come back in the peripheral blood with a median time to CR of around 3.5-4 months. And so there are some additional patients that we're monitoring in both cohorts today. I think there's 4 patients in the high-risk MDS cohort and another 3 patients, at least in the TP53 mutant AML cohort, that fall into that same bucket where there are blast reductions that have occurred. In some cases, there are 1 or 2 lineages that have started coming back up in the peripheral blood, and they're still on treatment. So we'll keep following these folks over time. Makes sense. Thanks so much. And then I guess just to get a little more color on timing that you were talking about the next steps at the end of the presentation there, could you just remind us how you view the cadence of updates on those registrational trials and when we could expect to see or potentially registrational trials, I should say, those randomized trials, when we could expect to see first to look at data there? Yeah. The randomized controlled study in high-risk MDS just began enrolling patients. We're providing guidance that will give the next update on that study in the second half of 2025. That guidance is heavily based on the fact that we just began enrolling patients. We do expect enrollment to be brisk. Internally, we expect that most or maybe even all of those patients could be enrolled by the end of this year. That would be great and may provide an opportunity for an earlier look. But at this point, we'll say second half of 2025 on that data. Then we'll have full responses, and we expect we'll have overall survival data in a mature state from all current patients sometime in the first half of next year. Thanks very much. Thanks, Jon. Thanks for the questions, Jon. Our next question comes from Yigal Nochomovitz at Citigroup. Please go ahead, Yigal. Hi. Thank you very much for taking the questions. I had one for Dr. Daver if you could help sort of contextualize this data in MDS and AML. And the prior question just referenced OS. So I'm just wondering if you could comment on how predictive you see these current response rates and CR rates with respect to translating to a better OS down the road, especially obviously given the company is now pursuing the randomized studies with OS readouts. Thanks. Great. Thanks, Yigal. Dr. Daver, back to you. Yeah. No, I think, I mean, it's always a tricky question. I mean, I'm not going to say it's definitive that a CR rate will translate to OS, but it is probably the best historic indicator as well as the best regulatory indicator that the FDA has used. And if anything correlates with OS, especially in frontline MDS, it is CR. It's not CRc and CR plus mCR or CR MRD negative, any of those. So I mean, yeah, I think it's a good sign. And in general, unless we see any late toxicities or any reason to expect that these CRs are not as durable as historical CRs, which I don't really have any reason to think or believe, that should translate into OS. And I think we're just going to have to wait and see. Now, I think the other question, of course, is, will the CR rates hold with time, right? And that's something that we have seen with, for example, magrolimab, that initially the CR rates looked high, but with time, they didn't look as good. So that's something we'll have to explore. And we're already going to get an earlier idea of this with the magrolimab, I mean, with this drug than magrolimab because we're doing a randomized effort very early on with the Aza/SL-172154 versus azacitidine, which the FDA also wanted to kind of look at. So I think that that small randomized phase 1b portion should give us a lot of information to build confidence or not before going into large registration study. Okay. Thanks. And then just for one specific question, I think in one of the slides, you referenced the benchmark for aza monotherapy in high-risk MDS CR, about 22%. Obviously, I assume everyone saw the abstract for ENHANCE where they showed a 33% CR rate. I'm just curious if you could comment on that and whether you see that as a relevant number or not in terms of thinking about a benchmark. Yeah, yeah. So yeah, so the benchmark of 22% was only for TP53 mutated. And that really comes from the aza APR study where, if you look, which is the most contemporary study that had aza alone for TP53 mutated in a specific subset. And there, it was 33% for the aza APR CR rate versus 22% for aza placebo in TP53 mutated. The ENHANCE, of course, is all comers. And we're looking into that subset data and response rates. But I can already tell you that the CR rate in TP53 in ENHANCE with aza magrolimab is going to be lower than the 33%, which was for all comers. So I think that 20%-22% true CR rate in TP53 frontline high-risk MDS is probably a very good and contemporary number. Okay. Thank you. Thanks for the questions, Yigal. Our next question comes from Gil Blum at Needham. Please go ahead, Gil. Hi, good morning and good afternoon to everyone. Thanks for taking our questions as well. So maybe a first one, a slightly different angle as it relates to the side effect profile. Is there a potential that the infections and sepsis that we saw could potentially be drug-related considering the immune activation mechanism of the drug? What gives you reason to believe it isn't? Thank you. Hi, Gil. I'll maybe start, and then Dr. Daver can chime in on anything that I miss with his perspective. The CD40 agonist side of this compound certainly provides immune co-stimulation. If you think about the conditions in which CD40 ligand gets turned on in the normal biology of our immune systems, it's in response to infections. And the native role of CD40 ligand is actually to help the presence of an infectious pathogen, not somehow cause one to be present. So if anything, you'd expect having CD40 ligand on board would help you clear any undetected infections that that patient had rather than causing one to erupt. So we simply don't see any means by which 154 could increase the possibility that somebody became susceptible to an infection. But let me turn it over to Dr. Daver and see what he would add to that. Naval, you may be on mute. Yeah. Oh, sorry. Yeah. Yeah. I I mean, I don't know. I mean, I think the answer is we cannot say for sure, but we see sepsis in patients with high-risk MDS and TP53 mutated AML frontline, absolutely. In fact, TP53 mutated, and there's a lot of biological data as well, impacts not just the blast population resistant to traditional cytotoxic and HMA therapy, but it also impacts T cell function and NK cell function, potentially other immune components. We see the risk of infection, early mortality, sepsis, autoimmune complications all tend to be higher in TP53 mutated compared to non-TP53 mutated. This is across therapies with Aza-Ven. The early mortality is more than 20% in TP53 compared to 5%-7% in non-mutated, similar for chemo. I don't find anything numerically or in severity, the sepsis numbers outside of what I would expect in a TP53 mutated frontline MDS AML population. I guess I don't biologically know, but if anything, if it's an immune-stimulating agent, it should protect against sepsis. We don't expect any immune dampening. So I would say I don't know biologically for sure, but it doesn't look to me as it's adding an immunosuppression component causing more than expected severity or frequency of infection at this point. Okay. Thank you both. That's very helpful. And Dr. Daver, now that I have you, I have a question regarding the durability that we're seeing emerge here. In your practice and practical experience, how does this compare to what you would normally expect in this patient population? At least it looks like you have quite a few patients who are responders greater than four months in the TP53 AML and over six months for the MDS portion. Thank you. Yeah. Yeah. I mean, I think in general, six months is kind of the benchmark that we think of for TP53 mutated frontline patients as being a good durability or better than what we can get. With Aza-Ven, for example, we know the duration of response is about four months. This has been pretty well shown in the VIALE-A subset analysis for TP53 mutated. It's very short, four to five months. But the follow-up is short and the patient numbers are small. So it's always hard to say conclusively that this is going to be what it is eventually. But at this point, yeah, six months in TP53 mutated is very, very good, four to six months. I think we just need to continue the follow-up and see. Excellent. That's very helpful. And maybe a last one for you, Taylor. As it relates to evidence for T cell activation, are we collecting additional data from these patients to kind of showcase that given the CD40 portion of this and the potential for adaptivity? Thank you. Yep. Thanks, Gil. We are. As many folks will remember in the dose escalation studies, we did fairly comprehensive immune monitoring and saw dose-dependent receptor occupancy, dose-dependent margination of CD40 expressing B cells and monocytes in the peripheral blood. We saw staining of 154 on T cells, blasts, and myeloid cells in the bone marrow of these patients, and very large increases in a fairly broad profile of peripheral cytokines. I can tell you that there are already some correlates that are emerging in a responder-non-responder analysis with some of those biomarkers that come up even within a few hours of the very first dose. If some of those things hold, where there's a biomarker that you see on two hours post-treatment that predicts with some degree of certainty whether that patient develops a CR three and a half months later, that could be very helpful in the next stage of development. And so we'll look forward to updating folks on that as the data set grow over the coming months. All right. Thanks for taking our questions. Thanks for the questions, Gil. Our next question comes from Marc Frahm at TD Cowen. Please go ahead, Marc. Thanks for taking my questions and congrats on the update today as well. Maybe a little bit more forward-looking. Taylor, as you're enrolling these randomized and opening these randomized cohorts now, just kind of what are you setting internally as kind of the bar, the separation that you want to see to justify kind of moving forward from those? And then also with the planned kind of regulatory discussions later this year, what are the kind of key unanswered questions or things that you want to kind of solve for with regulators in terms of thinking about pivotal designs? I mean, is it really just selecting dose, or are there other kind of nuances about the patient population and things like that that we should be paying attention to? Yeah. That's a really good question, Marc. There's a few angles to this. So first of all, we've been looking early on to, in TP53 mutant AML, try to be roughly double the CR rates of what you'd expect for azacitidine, roughly double what you'd expect in terms of the proportion of patients that get bridged to transplant, as Dr. Daver mentioned, because achieving those early milestones gives you the greatest degree of confidence that you will also be superior at a later point when the OS data are mature. In high-risk MDS, we take a similar view. If the true CR rate for aza alone is in the low to mid-20s%, then being north of 40% is a very good place to start. Especially amongst those CRs in both populations, if you're achieving true MRD negativity by flow or next-generation sequencing, then large deltas in the setting of MRD negativity may be grounds for discussion with regulators about potential routes to an accelerated approval in MDS. We don't have certainty on that yet, but it's at least a trend that if it holds, I think will be a topic of discussion. In AML, it's not as important whether or not CR rates and CR rates in the setting of MRD negativity are the basis for accelerated approval because OS is so short in patients treated with azacitidine or Aza-Ven in those same populations. So we'll have an end-of-phase 1 meeting at the end of this year with FDA, and there may be some interactions ahead of that that would really be the first time we can have a true discussion with regulators on what the path to approval might be. But we do expect that it will, as I alluded to, it will probably not be a traditional phase 2 and then phase 3 trial on the heels of the existing studies. There could be a phase 2 with an interim look based on CR rates, at least in the MDS population, and then a longer look at OS as it matures. We'll see. We'll have to have those discussions at that point in time. Dr. Daver, I don't know if you'd add anything to that or not, but that's how we're reviewing it. No. I think that's generally true. I think CR and then OS are kind of the two key regulatory points, at least for MDS. So once we get more data from some of the randomized subsets, I think it'll put us in a better position to discuss that with them. I think that's really helpful. I'm going to have to jump off. I have a talk here actually at EHA soon. So thank you all very much, and hope to talk more in the future. Thank you so much, Dr. Daver. Just to make sure I'm 100% clear on one of your comments there. Just when you're talking about accelerated approval path in terms of MRD, that would be driven entirely by a subsequent phase two, or whether it's called a phase two or a phase three trial kind of interim readout, not off of this randomized, correct? Yeah. Due to the degree of unmet medical need in this population, I think we should avoid making dogmatic statements about what regulators will or will not want to see. But I think the conservative assumption should be that the data from these randomized phase 1b cohorts will lead to a phase 2 study with registrational intent. Thanks. Very helpful. Thanks for the questions, Marc. So our final question comes from Kaveri Pohlman at BTIG. Please go ahead, Kaveri. Yeah. Good morning. Congrats on the results, and thanks for taking my questions. So my questions were mostly for Dr. Daver. I'll ask some of them. Just to put things in context, when comparing this 154 trial versus ENHANCE and a prior trial, can you tell us how comparable is the TP53 mutant patient population and their baseline characteristics between these trials? Sure, Kaveri. Well, I've been hogging the mic, so we'll let Lini take that one and Dr. Daver's instead. So that's a really good question, Kaveri. We've been looking at the TP53 allelic status, and we've been comparing it to what we know of the prior data. And we do have more patients with, in fact, all of our TP53 mutant patients in the AML cohort are multi-hit. And in the MDS cohort, from the data that we have, more than 80% are multi-hit. In fact, it's a very high percentage that are multi-hit. So that is actually very different from what was shown, what has been shown, at least in the public domain for APR-246. We also have, just as Dr. Daver said, these are patients with complex karyotypes, or very high percentage of patients with complex karyotypes in our patient population. So it appears in a nutshell, it appears that our patient population in this study has worse characteristics for TP53 than what has been in the public domain. Yeah. And we may get more details on the ENHANCE trials today and tomorrow. The proportion of patients that had TP53 mutant on ENHANCE is more reflective of the general population, 20%-30%. And that suggests, at least to me, that the mutation characteristics and karyotypic characteristics may also be more reflective of what you'd see in a general population. Great. Thank you for the questions, Kaveri. So this concludes our Q&A session for today. I'll now turn it back over to Taylor for closing remarks. Great. Well, thank you to the team for all the, to the Shattuck team for all the work that has gone into generating these results. Thank you to Dr. Daver and all of the rest of the clinical investigators that have gotten us to this point. It's clearly taken some grit to work through the history of the CD47 space. As you heard from Dr. Daver, this is not about the target. This is about the specific drug and the characteristics of that drug. We certainly hope that these data for 154 continue to mature in a way that establishes it as the leader in the space at this point. We really appreciate all of our analysts for joining the call today and for the great questions they provided, as well as to the investors and others in the audience who joined. We look forward to engaging you with each of you individually in the coming days and weeks and to providing further updates later on in the year. Take care, everyone.