Good afternoon. I would like to welcome everyone to the Aptose Biosciences Clinical Update and Data Review, in conjunction with the European School of Hematology, ESH, Sixth International Conference. At this time, all participants are in a listen-only mode. After the speaker's remarks, there will be a question-and-answer session. Joining me on today's call are Dr. William Rice, Chairman and CEO, Dr. Rafael Bejar, Senior Vice President, Chief Medical Officer, and our special guest and key opinion leader, Dr. Naval Daver from the MD Anderson Cancer Center. I will now turn the call over to Dr. Rice, Chairman and CEO of Aptose Biosciences. Please go ahead. Thank you, and good morning, all. Today, we're coming to you from the European School of Hematology Conference being held in Estoril, Portugal, and it's my pleasure to welcome you to our clinical update and KOL data review for Aptose's lead agent, tuspetinib, that's being developed for the treatment of patients with relapsed or refractory acute myeloid leukemia, or AML. To contribute their expertise to the discussion, today we are joined by two KOLs, Dr. Naval Daver and Dr. Rafael Bejar. Dr. Naval Daver, our featured KOL, is Professor and Director of the Leukemia Research Alliance and Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas. As a reminder, Dr. Daver is the lead investigator on Aptose's APTIVATE trial of tuspetinib, and he's a renowned hematology clinical investigator, recognized for significant achievements and the development of novel treatments for AML patients. In particular, as the architect of targeted doublet and triplet combination therapies to deliver lasting responses and overcome mechanisms of drug resistance. Dr. Daver has published more than 150 peer-reviewed articles, serves on the editorial boards of numerous hematology-focused journals, and serves as a featured presenter of groundbreaking data at national and international conferences. Also joining us today is Dr. Rafael Bejar. Dr. Bejar serves as our Chief Medical Officer for Aptose and continues to serve as an Associate Professor of Clinical Medicine at the UCSD Medical Center, and we're very proud to call Dr. Bejar one of our own at Aptose. So, gentlemen, it's a pleasure working alongside both of you, and we thank you for joining us today. As for our agenda, I first will provide a brief background on tuspetinib. Next, Dr. Bejar will present clinical findings with tuspetinib, administered as a single agent to relapsed or refractory AML patients, and then he will present the most up-to-date clinical findings with the tuspetinib plus venetoclax, or tus-ven drug combination, inclusive of our preliminary data from the most recent data cut of last week, taken on October 23. Afterwards, Dr. Daver will be available to answer your questions, to provide insights into current as well as future treatments for AML, and to discuss how tuspetinib can fit into those treatment strategies. So first, let's begin with the overview. Tuspetinib, or TUS, as we often refer to it, is a once daily oral kinase inhibitor. It already has demonstrated robust single-agent activity and an excellent safety profile as a treatment for relapsed or refractory AML. Because it's a kinase inhibitor, we're often asked: Does it inhibit FLT3? And indeed, it does. It's a very potent inhibitor of both the wild type and the mutant forms of FLT3. But it's actually much more than a mere FLT3 inhibitor. It was designed also to inhibit the SYK kinase, the JAK1/JAK2 kinase, so the JAK-STAT pathway, RSK2 of the RAS-MAPK pathway. And so tuspetinib was designed to be a multi-kinase inhibitor, to simultaneously suppress multiple oncogenic signaling pathways and have broad activity across many subpopulations of AML. But it was also designed to avoid hitting safety kinases, thereby allowing the tuspetinib to have a strong safety profile. So collectively, this makes tuspetinib a multi-kinase inhibitor, but not a dirty kinase inhibitor. It's also this unique kinase inhibition profile that has allowed us now to extend beyond AML and to move into the larger indication of MDS. But this is important for us, but let's park the MDS discussion for now and move back to the AML. I believe that most of us are aware that the treatment paradigm in AML has shifted toward venetoclax-containing combination regimens, and this has been a remarkable event for patients, giving them longer life expectancies. But it also has a bit of a dark side, because we're seeing an emerging wave of venetoclax failure patients that are very difficult to treat. And by the way, I'll often refer to the ven failure patients, venetoclax failure patients, as ven failures. So what does this have to do with tuspetinib? Well, it turns out tuspetinib's safety, efficacy, mechanism of action, and convenience properties make it an ideal drug for combination therapy. Plus, tuspetinib directly targets the mechanisms that AML cells use to create drug resistance to venetoclax. This means that TUS may mechanistically resensitize ven failure patients to venetoclax, and that tus-ven may successfully treat these ven failure patients. It also means that we may have a potential accelerated approval path for the tus-ven doublet in prior ven failure patients. So today, you'll see data readout from the October 23rd data cut that was taken last week. You'll see all the preliminary data, both the source verified as well as the preliminary data that Dr. Bejar will be presenting today. But it's also important to know that we're gonna have additional data readouts and events in the days, months, weeks ahead of us. As for the TUS-VEN doublet, we will take an additional data cut at the end of November so that we could present these data at the ASH conference in December, and Dr. Daver will actually be presenting much of those data with us... also for the TUS-VEN doublet. Now, we'll continue to collect data on these patients that are dosed, as well as additional patients, and so that we're able to provide a bit more of a perspective on the duration of response as we go into the first quarter and second quarter of 2024. And then beyond the doublet, we're also planning a triplet study in which we combine tuspetinib with venetoclax, as well as HMAs, to treat frontline newly diagnosed AML patients. We're planning on a pilot study in frontline patients for the first half of next year, and that's a very important study for us. We wanna see the data. We know what large pharma wants to see the data, so that's important for us. Likewise, we do plan to extend beyond AML into the higher-risk MDS patients, as well as CML, CMML patients, and we're positioned well to begin dosing those patients during the fourth quarter of this year. So much ahead for us. So let me just focus now, drill down a little bit on the recommended Phase II dose of tuspetinib. It's 80 mg as the recommended Phase II dose as a single agent. We've seen that it's been highly active across diverse subgroups of AML patients. These are relapsed/refractory AML patients and those patients with highly adverse genetics, including FLT3, TP53 mutation, RAS mutations, and others. In patients who are naive to venetoclax, we've had very strong, overall response rates. Overall patients, 42% CR/CRh rates. In patients with FLT3 mutations, 60%, and in patients with FLT3 wild type, approximately a 30% response rates. Again, CR/CRh, and this, it's very challenging for a kinase inhibitor to have activity in both FLT3 mutated as wild type, and so this is a real differentiator for tuspetinib because it has strong activity across the board in these patients. But I also wanna point out that as we rose above the 80 mg dose level in our dose-escalating trial, the response rate unexpectedly changed midway through the phase I trial. As you can see in the table, as we dosed through 20, 40, and then up to 80 mg of tuspetinib as a single agent, the response rate there was approximately 35%, and those were CR/CRh. But then, as we began to dose escalate higher, and as you can see in the 120 mg dose level there, the response rate was 19%. So this created a cloud of confusion for us internally, for investigators, and also for investors. But fortunately, that cloud has been lifted as we learned more about the patients. And it turns out the patient population that was enrolled at those higher dose levels, 120 mg and above, was a completely different patient population. As you can see in the table, at 120 mg, over 80% of the patients now were VEN failure patients, whereas at 80 mg, it was only 30%. That's responsible for the decrease in the response rate at the 120 mg dose levels. In fact, in the U.S. this year, we've seen over 90% of the patients coming to our trial have been VEN failure patients. It's known that these patients are much more difficult to treat and have dramatically lower response rates to single-agent therapies. But the good news is there's a silver lining to this cloud around the venetoclax failure patients. Although venetoclax, when it's administered single agent to these patients, would have very little, if any, activity, we have learned that the addition of venetoclax to tuspetinib jumps the 19% overall response rate, as you can see in the table, up to 44%, demonstrating that the TUS-VEN doublet can solve the problem. So how is it that tuspetinib can do that? Well, it turns out that tuspetinib directly targets pathways involved with resistance to venetoclax. Although venetoclax targets BCL-2, the resistance mechanisms occur in multiple other pathways, and it turns out that by shutting down those additional escape pathways, tuspetinib may resensitize those prior VEN failure patients to venetoclax. So we'll see what it looks like on the right side of the slide here. So as you can see in the plasma membrane of the AML cells, you have the receptors. Those receptors then activate the cascade, signal transduction pathways that are inside the cells, and those pathways then promote the growth and proliferation of the cell. So clearly, in AML cells, you know, you see those pathways upregulated. Then over on the right side of the slide, very far right of the slide, in parallel, we have pathways that govern the cell death. And of course, AML cells want to avoid cell death. How do they do that? Well, very often they upregulate the BCL-2. So that's why patients are treated with the venetoclax to inhibit the BCL-2 and allow cell death to occur. But over time, as you treat patients with venetoclax, the AML patients develop just a panoply of mutations that occur in the other pathways. The FLT3 becomes mutated. KIT, the KIT receptor becomes mutated. We see mutations in JAK as well as STAT pathway and the RAS MAP kinase pathway. So all of these then lead to enhanced growth and proliferation signals, and that also increases the MCL-1, that then prevents the cell death from occurring. So what happens when we introduce tuspetinib? It directly inhibits the FLT3, the mutated forms of KIT, it inhibits directly the SYK, as well as the JAK kinases and the RSK in the, in the RAS MAP kinase pathway. And consequently, it reduces the MCL-1 expression levels, and that allows the cells to die. So this is concept. Do we have really any true clinical data to support that? Yes, we do. We've been dosing patients with the TUS-VEN doublet all year in our APTIVATE trial. There was expectation that we have, by this time of the year, we would have dosed 30 patients. We're actually at 49 patients now, as of this week, that have been dosed with tuspetinib, and that's been driven by investor enthusiasm. There's a lot of data on this slide, but I'm gonna focus your attention to the area that's encircled by the green box. We've been taking data cuts August 1, September 1, and then August, excuse me, October 23. As we went through this, we had more and more patients that became evaluable. First, it was 10 patients, then 15, and now, as of October 31, 31 of the 49 patients have reached the evaluable state. In the patients who have failed venetoclax previously, you can see across the board, we're maintaining a 44% response rate. Yes, we have activity across the board in patients, wild type FLT3, mutated FLT3, but the most remarkable point here is that these VEN failure patients are responding to the TUS-VEN, TUS-VEN doublet. I also wanna point out that many of these patients were just dosed in the last 2-6 weeks in September, October, so they're very early in their treatment, and we expect the responses to continue to mature as we go through the coming months, and Dr. Bejar can speak more about that in his section. I wanna have just one more slide here. I'll just point out, if you see the, the blue bar that indicates venetoclax and HMA in frontline therapy have a 66% response rate. But then, over time, the patients are failing that frontline therapy. Many patients are getting treated in later lines of therapy, and when patients fail the venetoclax, the disease is highly refractory to salvage therapy. In fact, it's in the range of 4%-15%. So we and it's because we're triggering all these additional pathways that make it difficult for other drugs to be active in these patient populations. So we absolutely need an improved therapy for these VEN failure patients, and tuspetinib VEN combination has shown already to be safe and active in these patients. With that, I'm gonna turn it over to Dr. Bejar. Dr. Bejar? Thanks, Bill. So I'll talk about the clinical experience with tuspetinib to date. I'll start with tuspetinib as a single agent, where we've already demonstrated substantial single-agent activity and a very favorable safety profile. As you know, we had an end of phase 1 meeting with the FDA that led to the selection of a recommended phase II dose of 80 milligrams once daily and confirmed that all potential registration paths remain available. Then, I'll talk about the APTIVATE expansion trial that began earlier this year, where we're treating patients with tuspetinib both as a single agent, but more importantly, with tuspetinib in combination with venetoclax for the first time. And I'll share with you data from that that shows that we continue to have a very safe, favorable safety profile and increased activity, as Dr. Rice just mentioned. Finally, I'll summarize by talking about the impressive response we've seen with tuspetinib and venetoclax, particularly in that prior VEN AML-treated patient population, and how most of these patients are now actually prior VEN patients with that are coming to our study. This may give us the opportunity for an accelerated approval development path, I'll talk about at the end. Let's start with our experience with tuspetinib as a single agent and just do a quick recap. We began with a first-in-human study doing dose escalation at 20 milligrams, going all the way up to 200 milligrams. At every dose level where we saw signs of activity, we explored it further by adding additional patients at those dose levels, and you can see that we explored the 40 milligram, the 80 milligram, the 120 milligram, and the 160 milligram dose levels. We saw signs of clinical activity, including CRs, at each of those different dose levels, and importantly, despite a large number of patients treated, saw no dose-limiting toxicities. In fact, there was only a single dose-limiting toxicity in the study that occurred at 200 milligrams, 2.5 times higher than our recommended phase II dose. The take-home message for this is that we saw responses in a broad array of patients, as I'll show you, including patients with very adverse mutations. Let's talk about the safety of tuspetinib as a single agent. I think it has been impressive to date. You see the table on the right there from our September first data cut that shows that tuspetinib has been very well tolerated. Importantly, we haven't seen side effects that might be common to other tyrosine kinase inhibitors, including no signs of QTc change or QTc prolongation, no drug-related non-hematologic severe adverse events, and no drug-related deaths or discontinuations of drug due to adverse events related to the drug. We've not observed differentiation syndrome, and as I mentioned, no dose-limiting toxicities all the way from 20 mg to 160 mg dose level. The one dose-limiting toxicity, 200 mg, occurred in a patient with high exposure that had a phenotype of muscle weakness, but importantly, not muscle damage. They had no rhabdomyolysis or no muscle breakdown, no elevations in muscle enzymes like CPK. Overall, tuspetinib has a very favorable safety profile that avoids some of the typical toxicities seen with other targeted agents. Now, let's talk about the activity of tuspetinib as a single agent. This waterfall plot shows the greatest reduction in bone marrow blasts compared to baseline for patients treated at a variety of different dose levels shown in those different colors. You can see that more than half of the patients treated had some reduction in their blasts, and many had complete reduction of their bone marrow blasts. This includes patients with prior FLT3 inhibitors, as shown by the little red triangles over the top there. As you can also see, that many of the responses came at 80 mg dose level. As Dr. Rice mentioned earlier, as we increased the dose level, we saw that the patient population had begun to shift. We're seeing more and more patients that had received prior venetoclax, and as we saw, the response rates were a little bit lower in that patient population. This is encouraging data nonetheless, because it tells us that if we can combine with another active agent, we might see greater reductions in blasts and greater responses, which I'll show you has been the case. When you break down the waterfall plot by the mutation status of the patients, you can see that the FLT3 mutant patients maybe have a slightly greater sensitivity to tuspetinib, not surprising, given that they've mutated one of the critical paths that tuspetinib targets. But there is substantial activity, even in the FLT3 unmutated or the wild type population, that I think differentiates tuspetinib from many of the other agents that are out there. So now let's talk about the responding patients on tuspetinib single agent. This swimmer's plot shows those patients over time. I want to make a couple of key points about this. First, the point that I just made about how patients without FLT3 mutations can respond, and several of our responders were in that category, but also how these responses evolve over time. You can see that patients with leukemia who have low blood counts often have an initial response that may be a complete remission with incomplete hematologic recovery. But as you can see, these responses that get checked over time can evolve and can improve, despite continuing dosing of tuspetinib, meaning that without any dose interruptions, the patients can see the counts improve and the quality of these responses get better and remain in a good state for a long period of time, as we've seen with a couple of long-term responders that did not go to stem cell transplant. That said, several of our patients did have early responses and were able to move to stem cell transplants that offer the best option for long-term survival with patients with relapsed/refractory AML. Another question that we get about tuspetinib as a single agent is: how does it compare to other existing agents? It's a difficult comparison to make because these agents were approved at a time when the landscape for treatment of AML was slightly different. Importantly, it didn't have a lot of patients receiving prior FLT3 inhibitors and didn't have a lot of patients, or any patients, that received prior venetoclax. However, we do have some patients that we think we can make an apples-to-apples comparison with. So, for example, if we take our FLT3 mutated relapsed/refractory AML population, identify those patients that were treated with tuspetinib at a recommended phase II dose, we see that we had five of these individuals, and three of them had a CR or CRh, a really excellent quality response. If you compare that to the experience with gilteritinib in its phase III registrational trial, treated at its commercial dose, the CR/CRh there, as adjudicated by the FDA, was 23%. So I think we are as good, if not numerically better, despite small numbers, than gilteritinib in that target patient population of ven-naive, FLT3-mutant AML patients with relapsed disease. However, we think we're if we look at the FLT3 wild type population, again, looking at those ven-naive patients treated at a recommended Phase II dose, we see substantial and respectable activity in that patient population, with two out of seven patients achieving a CR or CRh. Whereas in the early phase studies of gilteritinib, the only time that we really, they really treated FLT3 unmutated patients, the response rate was essentially zero for the CR/CRh responses. Meaning that really tuspetinib has activity in a patient population where gilteritinib seems to not have as much activity, and in that sense, makes it a better agent for those patients. Other important development work that we've done with tuspetinib shows that we're marching towards our registrational study. One of the key things that we needed to do was a food effect study. This is important because before this, we were limited to dosing tuspetinib in the fasted state. When we wanna combine tuspetinib with other agents, sometimes you would like to be able to take them at the same time. So, for example, venetoclax must be taken with food. So we did this fed versus fasted study that confirmed that there isn't any significant difference, no clinically significant difference in exposure, when you give tuspetinib as a single agent in the fed state versus the fasted state. This will give us the flexibility to remove any fed versus fasted requirements for tuspetinib. So with that, let me move on to talk about TUS and then in the expansion trial, where we give the two drugs in combination. I'll start with the safety profile, again, with the September first cutoff, where we treated a large number of patients with a TUS-VEN combination, and compare that to our experience with tuspetinib as a single agent, as I've shown you earlier in the prior slide. The important message here is that we have seen no unexpected or new safety signals that have arisen from the TUS-VEN combination. The combination is well tolerated. Importantly, we've seen no further increases of QTC prolongation, we've seen no differentiation syndrome, and no drug-related deaths. If you look at the table on the right, you'll see the one thing we do observe is a slightly higher rate of cytopenias and slightly higher rate of febrile neutropenia, which I would say is still favorable compared to other venetoclax-containing regimens, like HMA-VEN, and VEN-GIL, gilteritinib in prior studies, where the published febrile neutropenia rate is 40% or higher. Other studies we've done with the combination, when you look at the relative exposure of the two drugs when given in combination, the dose exposure of tuspetinib when given in combination with venetoclax is essentially unchanged, comparing it to when it's given as a single agent, meaning that we don't have to worry about any dose adjustments of tuspetinib when given in combination. The reverse also seems to be true, that when we look at venetoclax exposures, they're very similar to what you would expect if venetoclax was given as a single agent, comparing it to published data where venetoclax was given at the same dose. However, this data collection is ongoing, and we'll do further analysis down the road. But at the moment, it looks like there's no need to make large adjustments of the venetoclax dose when these two drugs are given in combination. It gives us the freedom to follow the label for venetoclax in our clinical studies. Now, I wanna summarize the activity that we've observed in the TUS-VEN doublet and compare it to what we've seen with tuspetinib as a single agent. So this table highlights the response, the overall response rate for both of these different ways of giving tuspetinib. As a single agent, you'll see that our response rate in the ven-naive population was quite good, 34% response rate overall, which was even higher in the FLT3-mutated population, 55%, and respectable in the FLT3-unmutated population that was ven-naive, of 22%. But as we mentioned earlier, the ven-pretreated patients had lower response rates. This is a very difficult-to-treat patient population with any agent, particularly a single-agent drug. However, when we combine tuspetinib with venetoclax in our doublet study, even the prior ven-treated patients have an excellent response rate. We have a 44% overall response rate. That's even higher in the FLT3-mutated population. We saw five out of nine patients achieve an overall response, and 38% in the FLT3-unmutated. This is a really promising result for this combination therapy that has been well tolerated to date and gives us the opportunity to pursue the combination as a potential registrational strategy in this difficult-to-treat patient population. Here is a swimmer's plot of the responding patients to the TUS-VEN doublet. This looks somewhat similar to what I showed you earlier for TUS as a single agent, but I'll point out some key differences. First, we see that a lot of these patients, the vast majority, have a V in that third column, reflecting the fact that they have seen prior venetoclax. Several of the patients also have an F, reflecting the fact that they've seen prior FLT3 inhibition. And like with tuspetinib as a single agent, many of these patients have a FLT3 unmutated status, while we have seen many, ITD and TKD mutant patients here as well. The other difference is that there is greater myelosuppression with the combination of venetoclax, as you would expect, with the addition of a myelosuppressive agent, and that right now, because of our rapid accrual in the last 2-6 weeks, the data are still early. So we hope to give you additional updates on this at ASH. In fact, the data accrual has been quite quick over the last few months, where in August, we only had 5 patients on that swimmer's plot. That was updated September 1st, and now with our October 23rd data cut, you can see the great addition of additional patients there. So again, at ASH, we'll give you some more additional data with greater follow-up to better understand the quality and the nature of the responses that we've seen in the TUS-VEN doublet. So now I wanna give you a preview of where we're headed with the combination therapy. As we showed you, we had a successful end of phase I meeting with the FDA in the middle of this year, where shortly after we launched the APTIVATE tuspetinib single-agent arm for relapsed/refractory AML. We've since launched the APTIVATE TUS-VEN doublet, which will continue probably into the first or second quarter of 2024. We'll gather all the data required to understand exactly how the drug is performing and how we will need to fashion a potential registrational study of TUS-VEN in prior VEN-AML, prior VEN-AML-treated patients. It'll be a study that will include the potential for accelerated approval based on the response rate, but will be powered for overall survival. So the study itself, like the ADMIRAL study, can serve as a full approval study. In the meantime, we'll also be expanding the indications for tuspetinib. We'll be opening an arm for relapsed/refractory higher-risk MDS and for and CMML patients with refractory disease. This is important, I think, because many of the pathways that we've seen activated or mutated in patients with AML that have responded to tuspetinib are also active in patients with higher-risk MDS and CMML. So we're interested to see what kind of activity we'll see in this greater patient population. And I think most importantly, we are going to be combining tuspetinib with venetoclax and HMA as a triplet therapy for newly diagnosed, untreated patients with AML. So we hope to launch sometime in the middle of 2024. That development will begin shortly after ASH. So we have a large program ahead for tuspetinib, both as a single agent and in combination with venetoclax, and additional data to share with you at ASH. But now we'd like to step back and take the opportunity to answer some of your questions. So with that, I'll pass it back to Bill. Oh, thank you, Raf. All right, so as we're gonna enter into the Q&A session so that everyone is able to ask questions to Dr. Daver. And as the operator is doing the questions for Dr. Daver, I wanna ask you a question at first. So could you please describe for us this VEN failure patient population? As they enter your clinic, how sick are they? What is their reservoir of normal bone marrow function, and what is their expected life expectancy without salvage therapy or with current salvage therapies? Yeah. Thank you, Bill and Raf, for the discussion question. So as you said, the HMA-VEN, as well as other VEN-based therapies in the frontline setting, have been really important for our patients and have improved response rates and survival, which is good, but we are seeing a number of patients relapse, especially post HMA-VEN. We see that the median duration of remission is about 14-24 months. So in about 2-3 years, we're now seeing close to 50%-70% of these patients relapse. And what has been shown by our group, as well as others, is that at the time of relapse, these patients tend to be very different from their frontline presentation, with enrichment of mutations, including FLT3, TP53, RAS, MAPK-involving mutations. They tend to be very resistant to standard therapies that usually do not cover these mutations well. The response rate that has been published by our group, as well as others in the relapsed/refractory setting, post HMA-VEN, is around 15%-18%, CR/CRi, with whatever regimen you may use, cytarabine-based, other HMA combinations, targeted therapies. The median survival in our publication, this was in Haematologica from MD Anderson a couple of years ago, post HMA-VEN was about 2.8 months. Two other groups have also now published similar data at about 2 months. Really a very difficult population, less than 20% response rates and about 2.5-3-month expected survival. So really a big unmet need, probably the biggest unmet need, I think, today, in the AML relapsed/refractory setting, to find something that can give us good response and outcome, as well as good tolerability, because as you mentioned, these patients also tend to be quite myelosuppressed, and we need to have a regimen or combination that does not cause very severe myelosuppression. Okay. Thank you, Dr. Daver, for giving us the characterization of this, this emerging patient population. Now let me turn it back over to the operator for questions. Thank you. At this time, we'll begin conducting our Q&A session. As a reminder to our analysts in the queue, please raise your hand to indicate you would like to ask a question. With that, we'll kick it off with our first question from Matt Biegler at Oppenheimer. Hey, guys. Can you hear me? Yes. Yes. Hey, thanks for walking us through this. ... Data, nice update. I'm just wondering, I'm thinking ahead maybe to the front line here. Is there any way that you can leverage some of the recent FDA guidance under Project Front Runner? And if yes, how is that kind of shaping how you're thinking about designing a trial that maybe you can get into the front line setting? Thanks. I can start. Yeah, I think that the Project Front Runner does provide us some guidance about how to bring therapies to the front line earlier. I think this- Yeah -treat the most sick and the most relapsed and most refractory patients first with an agent before you can bring it to the front line, can really prevent drugs from making it that don't have that kind of activity. Now, fortunately, tuspetinib does have the single-agent activity that we have been able to show in these highly relapsed refractory patient populations, but I think our greatest interest is to put it in that front-line setting, and we'll be, we'll be moving forward with that as quickly as possible. We should ask Dr. Daver. He's pretty much the architect of the triple combinations in front-line therapy. Dr. Daver? Yeah. No, absolutely. I think, you know, there is a huge unmet need in the front line as well. You know, it was just another meeting we were chairing in London, and one of the comments that came out is that HMA-VEN has kind of become a crutch in a little way to the development of new treatments, because people have become complacent, which we should not be, because the three-year survival is only 23%, for older unfit with HMA-VEN. So I think there's a huge recognition now that we need to improve on that, and triplets are really the front runners there. And I think, you know, if we can leverage that, there may be potential ways in discussion with the FDA. They are looking more at true CR, as well as MRD, potentially for certain molecular subsets to look at early approval, maybe even potentially single-arm approval. So of course, we have to generate the data, but yes, I think with this triplet, especially looking at the profile of tuspetinib, with less amount of suppression, single agent showing better responses than what we had seen with gilt in salvage, as well as wild type activity, I definitely think we should think about potential rapid frontline triplet approval paths. That makes sense. And then in the salvage setting, which I guess is kind of where we're going for, what we're going for immediately, what kind of powering assumptions are you thinking for that doublet over, you know, standard? Or actually, what even would be standard of care? Would it just be like best supportive care? Like, what are you kind of thinking for the design of that trial to get this drug approved? Thanks. No, that's a great question. I think if you look at the options that patients have, in terms of standard of care, so today, after they've failed or been failed by venetoclax, there aren't a lot of things that are out there. There are some intermediate chemotherapy approaches. Some of these patients may be eligible for chemotherapy, so that could be one of the options. I think this would be run very similar to the ADMIRAL study, where you have a short list of potential therapies that one could give, absent the experimental therapy, and the physician would have to select, prior to randomization, which one they would treat their patient with, and the patient would be randomized, and they would receive that therapy. I don't know, Dr. Daver, if you have additional thoughts about the options that these patients could receive. Yeah, I mean, I think this is probably, in the FDA's perspective, a huge unmet need, so a post-HMA then population. And I think, yeah, there is no standard of care. I mean, there's nothing... The NCCN gives us a whole list of different options you can use, cytarabine, HMA, hydroxyurea, palliative care. But yeah, I think it would be very much what Dr. Bejar is saying, that we would use the TUS ven, and we would give a list of five of the regimens people use, knowing that none of them really have more than a 15%-18% response, because unfortunately, there is nothing that is there. And the endpoint here probably would be something like CR and OS. I think this could be not a very large randomized study, especially if we continue to see the data we are with a potential early approval path. Thanks again. Thank you for the questions, Matt. The next question comes from Sumit Roy at Jones Trading. Good morning, everyone, and congratulations on the really solid data. I guess the swimmers link kind of shows the difference between relapsed refractory treatment and second-line it markedly improved. A quick question on that is none of the patient in the ven combo trial are going through HSCT. Is that a good sign or a bad sign? Is it availability of donors, or you just give us some color? Oh, I just think it's early. I, you know, the decision to transplant a patient after treatment, well, first it takes some time to do, and then ideally, you wanna transplant them when they have a low level of disease. So it takes them a bit to get to that point. So I think it still is a possibility for some of these patients. Got it. On the febrile neutropenia front, are these patients getting treated prophylactically with GM-CSF, or how is the management going, and how much of a concern is there? Yeah, so febrile neutropenia is very common, obviously, in relapsed refractory AML populations through a variety of agents. I think that this doesn't really stand out, I think, as being abnormal or unexpected for this patient population. The protocol doesn't require any form of prophylaxis. It really defers the institutional standards for that. But perhaps Dr. Daver could put this into context for us. Yeah. No, I yeah, absolutely. I think that's a great question, and febrile neutropenia or neutropenia itself is probably the key side effect that we would be looking for in the salvage combination with ven. And, you know, looking at ven gilt that we published, I was the lead author and JCO, we did see significant febrile neutropenia rates. The regimen is very effective, but had more than a 65% febrile neutropenia. And even HMA ven doublets when used in salvage after intensive chemo, our group has published multiple times, the expected febrile neutropenia rates are closer on 55%. The 26%-27% febrile neutropenia here with the TUS VEN, granted it's early, but does look like it's lower than what we have seen with VEN gilteritinib or HMA, and VEN in salvage, and could become an advantage if we continue to see that over time. ... Got it. Thank you again for taking all the questions. Thank you, Sumit. Thank you. The next question comes from Joe Pantginis at H.C. Wainwright. Hey, everybody. Good morning. Thanks for taking the questions. I wanted to continue on that theme with regards to febrile neutropenia. So obviously, you're quoting the rates in the, you know, other trials, whether it's with HMA or gilteritinib or what have you. So I guess I wanted to ask the question, for the planned first-line setting, you know, how you're gonna be looking to hopefully mitigate the febrile neutropenia, since you'll be combining with HMAs? And then, secondly, any color you can add with regard to, you know, those on the call and beyond, the underlying mechanism of action, why TUS is having what appears to be significant impact in the FLT3 wild type? Thanks a lot. Yeah, those are excellent questions. So I can address the first part a little bit, and then I'll have Dr. Daver comment. Since a lot of what we're doing is really based on his experience, putting these drugs together in first-line combinations. I think whenever you combine agents that bring toxicity to the table, you do have to do some dose adjustment. And I think that that's one of the things that we'll keep in mind, that the label for HMA ven is quite aggressive, where it's 28 days of venetoclax for a 28-day cycle if you follow it exactly. But I think the reality is we're realizing that you need to reduce the venetoclax dose substantially in order to be able to get these patients to have significant count recovery. However, in the triplet study that we would propose, we would do something akin to what we're doing in the doublet, where we have patients have a bone marrow examination early on in the process. If they've cleared their blast, then we would hold the venetoclax to give them more time to recover. So it would be a little bit more of a dynamic dosing strategy. And we would, of course, be open to reducing the doses of the drugs if need be, in order to combine them. That'll be part of what we learn about in our triplet pilot. But I think that you That is the key point. I think being able to manage the cytopenias and the other side effects of the agents when you put them in a combination is really important, 'cause if you don't get that right, getting patients into remission they can't tolerate isn't gonna be successful. So, Dr. Daver, can you share some of your experience? Yeah, absolutely. And as you mentioned, you know, we've pioneered many of the triplets, and these are moving forward. And the key issue here, of course, over the last four years, and we're working very closely with the FDA as well as other large cooperative groups, is mitigating myelosuppression. Nobody really doubts that if you combine biologically active drugs, you're gonna get better activity. This has been shown very well by multiple myeloma, lymphoma, ALL, over the last decade. So the key usually is optimally reducing it, and if you have a drug that does not have cumulative myelosuppression, that is a big advantage. So our approach has usually been to do an early marrow, somewhere around day 14 or 21, which the FDA has actually agreed on multiple other frontline triplets, to gate the stoppage of venetoclax. Once you've achieved either a remission or a marrow ablation hypocellularity, we all agree that there's no point in giving ven if your day 14 or 15 marrow shows that you have already achieved clearance of the disease, and then you need to stop and allow count recovery. This would probably be one approach, and with this approach, with other triplets that we have shown, the HMA ven with CD123, HMA ven IDH, HMA ven and other FLT3 inhibitors, the myelosuppression has actually become quite manageable, with count recoveries now below 35 days for all of these triplets, which is actually in line with what you get with doublet HMA ven. I think with the TUS, which, at least in salvage, what we're seeing with maybe less febrile neutropenia, less profound myelosuppression, this could get even better. The second thing, which I think is a very good question, is: Why is this working in the wild type? This is always a question we have with many different TKIs, and often, many years later, we start realizing that we may have just been focusing on one pathway of interest, like FLT3, but there's other targets. I think with TUS, it's really interesting to see that it actually targets four or five of the major common resistance pathways to ven. These are FLT3, RAS/MAPK kinase, JAK-STAT, TP53, and MCL-1. These five are probably 90% of VEN resistance pathways, so, that may be, to some degree, good coincidence, and maybe to some degree, the way the drug was designed, but this may really be why we're seeing very nice activity in combination with VEN, and we'll have to see how that pans out in the frontline setting. Yeah. Very much. Yeah. Thank you, Daver, Dr. Daver, for that. I wish I could have said it so eloquently. Thank you. Next question. The next question comes from Greg Renza at RBC. Hi, guys. It's Anishan for Greg. Congrats on the continued progress, and thanks for taking my question. Just on the ESH posters and the 2,000-fold increase in sensitivity of tuspetinib-resistant cells to venetoclax, just wanted to ask how you might be able to leverage these findings and translate them to the human population with regards to the clinical care regimen in terms of dosing, timing, et cetera. Congrats, and thanks again. Thanks. We'll have, Dr. Bejar address that one. Yeah, thanks for mentioning that. We didn't talk about it in the slides, but we do have a poster here at this meeting that highlights some preclinical data, where we created tuspetinib-resistant lines by exposing them to tuspetinib for a prolonged period of time. And then we went to see what other things are they sensitive to, or how their sensitivities change. And the key finding is that these lines that have become resistant to tuspetinib are now 2,000-fold more sensitive to venetoclax than they were at baseline. That, I think, speaks to how these two drugs work in concert. And the way we might leverage that clinically is what we're doing with the tuspetinib combination. Namely, that if the mechanisms that lead to TUS resistance are then more sensitive, more sensitizing to venetoclax, putting these two drugs together could slow or prevent the emergence of that TUS resistance. So we think it's an important from that standpoint. And I think in general, combination therapies that have very different mechanisms of actions offer you that opportunity to avoid the development of resistance. And that's, that'll be something that we explore in our patients as we go forward. ... Great. Thank you. Thank you. The next question comes from John Newman at Canaccord. Hi, guys. Good morning. Thanks a lot for the very detailed data update. I just had two questions. The first one was, I'm just curious as to how you're defining venetoclax failures. I'm just wondering, what portion of the venetoclax failure patients progressed on prior venetoclax versus maybe discontinued, they couldn't tolerate the drug? Second question, just a simple one. On the durability, it looks like you're measuring that in the number of cycles. If that's correct, just curious as to the length of the cycle. Thanks. Yes. So for the tuspetinib doublet, we are measuring it in terms of cycles. There's a little bit of flexibility in the cycle length, as we will allow the cycle to be extended if patients need more time for count recovery. But cycles are on the order of 28-56 days at the most. Most probably on average, closer to 42. And then I would ask Dr. Daver if he could comment on the first question. Yeah, sure. Yeah. I, I... You know, for VEN failure terminology, which is being used before, but even much before the tuspetinib studies, it's basically refractory and/or relapse. You know, if they had never achieved a CR, CRi, CRh, which is about 20%-25% or so of HMA VEN frontline, that's refractory. Of course, relapse is those who achieved a CR, CRh, CRi, and then relapsed. We don't see too many patients who just come off VEN because of intolerance. A lot of it is because we are—we and many others have now, through our publications and others, have become familiar with the reduction of VEN duration. Yeah, that VEN failure really is efficacy failure definition, more than intolerance. That's our experience with the study participants. Most of them have, you know, seen a substantial amount of prior VEN HMA. It's not a single cycle or something of that nature. Great. Thank you. Thanks, John. We have, I think, one more analyst in the queue. The question will come from Li Watsik at Cantor Fitzgerald. Hey, good morning. Thanks for taking the questions. I just wonder if you can comment on the CR, CRh rate for the doublet, and whether you believe you can perhaps get approval based on the CRc rate. Also, looks like the two CRs occurred in the wild-type patients. Wondering, why do you think that's the case? Do you think it's mostly driven by their prior lines of treatment, or they're more likely to respond to the doublet, so they get a deeper response? Yeah, that, that's a great question. So I, I think it's early and that these responses evolve over time, just as they did for tuspetinib as a single agent. So we... I don't think I can make a strong comment about what the eventual CR, CRh would be. I think if you are looking for accelerated approval, it does have to be on that basis. I haven't seen a lot of flexibility from the FDA about accepting responses that are other than CR, CRh. And then for the, the second half of your question about- Sure ... you know, why do we only see the full CRs in the patients without prior venetoclax? I think that may have something to do with the bone marrow reserve of patients who have been through venetoclax. I don't know, Dr. Daver, if you have any insight into that. Yeah, I think it's hard to say, you know, exactly the mechanism there. I think among the wild type, there is activity because of the many different kinases that are being targeted, as we mentioned, RAS/MAP kinase, JAK2, SRC, that may be playing a role there. I'm not really sure. I think the numbers are too small right now to know for sure. But to the previous part of the question, I do think there is a potential for CR, CRh, or CR, to be an endpoint in salvage studies in highest unmet need with no standard of care. This is kind of exactly the three or four things the FDA would look for to consider single-arm approval. So I do think that if we continue to see that, but also has to have a durability component. So if you have a good CR, CRh, along with the durability component in salvage, much beyond what can be shown by contemporary publications and controls for that similar population, this is definitely something that we could discuss. But we do need to get more durability data there. Yeah. Do you think that the patients with prior venetoclax exposure have a different hematopoietic reserve? Is it harder for them to recover counts in subsequent therapies? I think, yes. I mean, in general, the relapse patient population tend to have heavy prior treatment and more burnt-out marrows, kind of the general term we use. But I also think they tend to be enriched with mutations like TP53 and RAS/MAPK, which also stunt hematological recovery. So I think it's probably a combination of those factors. Okay. All right. Well, I believe we've hit our time limit now. So let me just thank all of the attendees, the listeners here, for joining us today. But a really special thanks goes out to Dr. Daver. And so taking time away from your practice, your research, your family, to be here with us today, we appreciate it so much. So a special thanks out to you. Let me hand it over to Raf. Yeah, let me echo that. Naval, thank you so much for joining us today. Your insight is extraordinarily helpful, as it has been helping us navigate this drug through its clinical process, and we look forward to working with you further. Yeah, absolutely. Thank you. Yeah, same here. I'm very excited to continue. And I will say, you know, the data, as we get more and more patients, is looking more and more robust and, and more and more confident. So I'm very hopeful next year we'll really have some forward inroads with the data. Well, thank you for the comments. Yes, we always hear it takes more patience and more time, and so that's, that's what we're doing. All right, well, I'll turn it back to the operator now, but thank you so much again, Naval. We appreciate it. Operator? Thank you, ladies and gentlemen. This concludes today's conference. You may disconnect your line, and have a wonderful day.