Hello. Welcome to the Aptose Biosciences clinical update and data review conference call and webcast. At this time, all participants are in listen only mode. If anyone should require operator assistance, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Dan Ferry of LifeSci Advisors. Dan? Thank you, operator. Good morning, welcome to the Aptose Biosciences conference call and webcast. Earlier today, Aptose issued a press release relating to this clinical update and data results being presented today at ASH. The news release, as well as related SEC filings, are accessible on Aptose's website. Joining me on today's call are Dr. William G. Rice, Chairman, President, and CEO, and Dr. Rafael Bejar, Senior Vice President, Chief Medical Officer. Dr. Naval Daver of MD Anderson Cancer Center, Global Lead Investigator for tuspetinib phase I phase II trial, will be joining us for the question and answer session. Before we proceed, I would like to remind everyone that certain statements made during this call will include forward-looking statements within the meaning of U.S. and Canadian securities laws. Forward-looking statements reflect Aptose's current expectations regarding future events, but are not guarantees of performance, and it's possible that actual results and performance could differ materially from these stated expectations. They involve known and unknown risks, uncertainties, and assumptions that may cause actual results, performance, and achievement to differ materially from those expressed. To learn more about these risks and uncertainties, please read the risk factors set forth in Aptose's most recent annual report on Form 10-K in SEC and SEDAR filings. All forward-looking statements made during this call speak only as of the date they are made. Aptose undertakes no obligation to revise or update the statements to reflect events or circumstances after the date of this call, except as required by law. I will now turn the call over to Dr. Rice, Chairman, President, and CEO of Aptose Biosciences. Dr. Rice? Thank you, Dan. Good morning, all. Welcome to the Aptose clinical update and data review being held concurrently with our data release at the 2022 ASH annual meeting. We thank you for joining us. You'll see that we are thrilled to roll out the clinical data from our programs. We also recognize that many among us are very busy here at ASH. We will be respectful of your time. On our agenda today, I will first introduce our clinical-stage molecules, tuspetinib, also known as HM43239, and luxeptinib, also known as CG-806 or just Lux. I'll provide our view of the future medical and commercial applications of tuspetinib. Dr. Rafael Bejar, our Chief Medical Officer and resident KOL, will review our exciting clinical data for tuspetinib. After which, I will quickly review our new findings and future activities with Lux. Finally, we'll move into the Q&A session. Dr. Bejar and I will remain available during the Q&A session to answer questions, but more importantly, we'll be joined during the Q&A session by Dr. Naval Daver, the Global Principal Investigator for the tuspetinib phase I/II trial in AML and a recognized KOL in AML therapies. Be certain to take advantage of the access to Dr. Daver and prepare your questions with regard to combination therapies, response rates, safety profiles, and those responses, responsiveness for targeted agents. Most of you know that Aptose is a precision oncology company, developing a pipeline of oral kinase inhibitors for the treatment of life-threatening hematologic malignancies. Our earlier stage molecule, luxeptinib, shown on the bottom left in red font, is a lymphoid myeloid kinase inhibitor in phase I development. Today, I'll briefly remind you of the complete remission, or CR, delivered by Lux in an AML patient. I'll report a new CR from our B-cell trial with Lux. We'll underscore our ongoing studies with our new oral G3 formulation of Lux. The majority of the time will be spent on tuspetinib, our lead agent and potent inhibitor of the SYK, JAK1, JAK2, and FLT3 kinases. tuspetinib is once-daily oral tablet for the treatment of AML. Dr. Bejar will review findings from 60 patients enrolled in our phase I trial and will feature the safety profile and single-agent CRs across multiple dose levels and across a diverse collection of mutationally defined AML populations that harbor a wide assortment of adverse mutations. He'll describe the profile of tuspetinib that we believe positions tuspetinib to become the drug of choice for physicians to address the needs of AML patients. He will mention our APTIVATE expansion trial just initiated to collect data on enriched patient populations when treated with tuspetinib as monotherapy or in combination with venetoclax. First, I'm gonna present one slide that outlines what we believe are the greatest needs among AML patients and our belief that tuspetinib can address these needs and lead to a billion-dollar-plus commercial act success. The first need is to identify a safe and highly active drug to add to venetoclax and hypomethylating agents as a triplet combination that can place frontline patients in an MRD negative complete remission without prolonged myelosuppression or toxicities, and can be active in FLT3-mutated and FLT3 wild-type patients, as well as in unfit and fit populations. The second need is to have a highly safe drug for maintenance therapy. Once a patient achieves a CR through induction therapy or a stem cell transplant, the desire is to get them into an MRD negative CR and keep them there to prevent relapse. This will require a very safe and effective drug that is active on FLT3-mutated and FLT3 wild-type AML. The third need is a superior FLT3 inhibitor to safely and potently treat FLT3-mutated patients that already have been failed by other FLT3 inhibitors. The FDA recognizes the need for a highly safe agent that inhibits FLT3 better than current agents, but is more than just a FLT3 inhibitor and can act on other targets and other pathways to serve these patients with no approved therapies. Based on the safety profile, the ability of tuspetinib to potently inhibit FLT3, JAK1, JAK2, and SYK, and the ability of tuspetinib to deliver CRs in FLT3-mutated and FLT3 wild-type patients with other adverse mutations, we believe tuspetinib can best serve all of these needs and deliver medical successes and commercial successes. Now Dr. Bejar will present the data that give us this confidence. Raf? Thanks, Bill, it's my pleasure to talk to you today about the clinical activity of tuspetinib in our phase I/II study. I'll start with focusing on emerging clinical PK and safety data and why this could be a potentially superior AML therapy. Let's begin by talking about the status of the trial as it stands as of October 6th, where we have completed what we're calling part A or dose escalation on the left, taking patients from 20 mg all the way up through 200 mg once daily. The study is designed in such a way that we can then explore additional patients at those dose levels and show signs of activity. We began to add additional patients, not only at 80 mg but also at 120mg and 160 mg. We've now gone back and added additional patients at the 40 mg dose level to better understand the PK characteristics, safety, and exposures that we encounter in the patient population. As you see on the right, we've achieved clinically meaningful responses, including complete remissions at all four of these dose levels. None of these patients at the 40 mg- 160 mg dose levels have experienced a dose-limiting toxicity. In fact, there's only been one dose-limiting toxicity in the study to date that occurred at the 200 mg dose level, which I'll talk about briefly. On the right are shown the number of efficacy-evaluable patients treated at each of these different dose levels. As you can see on the next slide, we break down the number of patients treated at each dose level, identified by whether they were the total number dosed, evaluable for safety and efficacy, as these definitions are slightly different. Here we show a slide from our ASH poster that demonstrates the exposures achieved at the different dose levels. On the left are shown the exposures after the first dose is given over a period of 48 hours, and on the right are shown a 24-hour period of exposure that occurred somewhere in the middle of Cycle 1, close to where the patients would be at steady state. The key findings from these data are that the 120 mg dose level, shown there in light blue, achieves a slightly higher exposure than the average exposure of patients in the 80 mg dose level, shown in green. For this reason, we have selected the 120 mg dose level as our go-forward monotherapy dose, since it puts more patients above that minimum threshold that we think is required for response, even though we've seen substantial activity even at the 80 mg dose level. This next slide highlights the areas where we think tuspetinib is clinically active at the molecular level. We see here in this diagram that there are multiple different signaling pathways that are driving leukemic cells to proliferate and grow, and that several of these are directly inhibited by tuspetinib. This is really much more than just a FLT3 inhibitor. While it does inhibit FLT3 in all of its mutant forms, including the wild-type form, we also see substantial activity against other important signaling pathways. This includes the mutant forms of the c-KIT receptor, as well as downstream signaling pathways involving JAK1, JAK2, and subsequent STAT signaling, direct inhibition of the SYK intracellular kinase, and even perhaps activity downstream in the RAS pathway on RSK1 and RSK2. These are pathways that can converge at the nucleus to drive proliferation. Inhibition of just one or a couple of these may not be sufficient to provide long-term control of disease. I'd like to highlight two different aspects here that we can go in and actually do some pharmacodynamic testing in the patient population that we've treated. This includes looking at phosphorylation of FLT3 as well as phosphorylation of STAT5. That's shown here on this next slide. These are plasma inhibition activity assays, both for phospho-FLT3 on the left and phospho-STAT5 on the right, where you see increasing inhibition of phosphorylation with increasing exposure. This is true both in FLT3 mutant and in FLT3 wild-type patients, denoted by the different colors of dots. In blue are shown the range of exposures that were achieved at steady state in those individuals that had a response. You can see that the responses began at a very low level of 0.15 micromolar, well before even we have complete saturation of inhibition of our targets, suggesting that this combination of multiple pathways is converging to help achieve a response in these individuals. We'll look at the patient profile in the study treated to date. This is a slide that's taken from our poster as well. The key take home messages from here are that these patients, with an average age of 61, comprise a wide range of AML patients. They include slightly more than half that are FLT3 wild type, with the remainder being FLT3 mutant. These patients are very heavily pretreated. They received on average 2.7 prior lines of therapy, meaning that on average, patients are coming to us even after third line of therapy. The types of therapies that patients received are quite varied. They have more than 70% of patients that have received prior cytotoxic chemotherapy. 60% of patients have received a prior hypomethylating agent, and 50% of patients have received prior venetoclax before coming onto our study. More than a quarter have had a prior stem cell transplant, and among those patients that have a FLT3 mutation, half have received a prior FLT3 inhibitor. Again, very heavily pretreated patient population with great unmet medical need. This slide summarizes our safety in the phase I/II study to date. It shows that tuspetinib is very well tolerated. While patients with acute leukemia often have adverse events, only 20.3% of patients experience a drug-related adverse event, the majority of which were Grade 1 or 2. The most frequent drug-related adverse events were diarrhea in 11.7% of patients and nausea in 8.3% of patients across all dose levels, all being Grade 1 or 2 except for 1 patient that experienced Grade 3 nausea. Now despite this, no patient discontinued tuspetinib as a consequence of an adverse event that was felt to be drug-related. Importantly, if we look at the more serious adverse events that could be related to drug, there was only two non-hematologic toxicities there. One is that Grade 3 nausea patient that I just described, and then two patients experienced muscle weakness. Importantly, there were no drug-related severe adverse events, no drug-related deaths, no occurrences of differentiation syndrome, and as I mentioned, no drug-related discontinuations of therapy. Importantly, there were also no adverse events that were related to findings that could compromise the ability to dose the drug, either at higher doses or for long periods of time. Importantly, there were no drug-related adverse events of QT prolongation and in fact, no observation of QTc change with increasing exposure in a more careful analysis. There were no dose-limiting toxicities through 160 mg. At 200 mg, one patient with a high exposure experienced an episode of muscle weakness. Just to be clear, this was not muscle breakdown. It wasn't rhabdomyolysis, it wasn't myositis. We have seen no elevations of CPK in the 60 patients treated to date. In summary, this drug is able to avoid some of the typical toxicities that get encountered by other AML therapies, including tyrosine kinase inhibitors. We've achieved efficacy across four separate dose levels now and shows that we have a very broad therapeutic range with tuspetinib. This is very promising as it will allow combination with other agents, even other agents that may be more toxic or bring different toxicities to the table, allowing for a more effective therapy that remains safe. This again, was all done in the setting of a patient population that is very heavily pretreated with chemotherapy, FLT3 inhibitors and other targeted agents that have only become available to AML patients most, more recently. Now let's go on and talk about the activity of tuspetinib in the phase I/II study. I'll start by showing this waterfall plot of blast reductions. This shows the best percent change in blasts in the bone marrow as patients treated on the study at 80 mg, 120 mg and 160 mg. You can see that more than half of the patients experienced some degree of blast reduction. The reason that this is important is that even though not all patients achieve a formal remission, many patients show signs of biologic or activity, that the drug is actually able to reduce the blasts. You could imagine that if tuspetinib were safely combined with another active agent, that more of these patients would reach the finish line and achieve a formal response remission that would be clinically meaningful. It's also important to point out that patients that receive tuspetinib and clear their blasts, even though they don't yet have recovery of counts, these patients have achieved a meaningful response, as many of them can then be taken to transplant, as we've seen in at least 1 patient in our study. I'll show these data in a slightly different way. They're broken down by the FLT3 mutation status of the patients, showing that there perhaps is a slight greater sensitivity in the FLT3 mutant population than there is in the wild type population, even though both achieve meaningful blast reductions. Quite interesting, this is very similar to data that had been presented several years ago for patients treated with gilteritinib as part of the ADMIRAL study, and you can see similar sensitivities in the FLT3 mutant patients. I'll remind you that those patients were much less heavily pretreated as they were treated at a time when there were fewer therapies available for AML in general, including of course, fewer FLT3 inhibitors as well as other active targeted agents, including venetoclax, IDH inhibitors, and so on. In this next slide, I show the same data, looking not at% change in blast, but in absolute change. Just to show you that many of these patients had very high blast counts that went down substantially with treatment, both in the wild type and the FLT3 mutant populations. Next, let's talk about the clinical response data in the patients treated on the tuspetinib phase I/II study. This is an updated swimmer's plot of the responding patients. The key findings here that are slightly different than you might have seen previously are that we now include a new response category. When the study began a CRh, this is a complete remission with partial hematologic recovery, was not available as a response option for investigators. This has now been added, and several of the CRis, the incomplete hematologic recovery, are actually CRhs, and that's reflected in this plot here. The other take home message from this plot is that we've seen responses across four different dose levels, including patients that have been able to then be bridged to potentially life-saving transplants. We include, again, this highlight of a patient with a TP53 mutation that I'll talk about in greater detail in a little bit, just highlighting the breadth of activity of this drug and how in patients who don't go to transplant, the drug can be given continuously for long periods of time without myelosuppression. I'd like to point out that we have added one additional response here at the 40 mg dose level. The data cut for this slide is October 6th. We have attached to the very top this last patient that had a more recent clinical response. Here are those responding patients shown in a slightly different way, highlighting the mutations that they carry. You can see mutations in a broad array of genes, including several adverse genes such as TP53, which I mentioned, as well as NRAS, KRAS, PTPN11, mutations in that RAS pathway that often confer resistance to drugs like tyrosine kinase inhibitors, as well as several other adverse mutations, including MLL-PTD, ROS1, and so on. Here are the response data in the efficacy- evaluable populations shown by different mutational statuses and different dose levels. While some of these numbers are relatively small, I think it highlights the breadth of activity that we're seeing. If you see, for example, meaningful activity in RAS mutant patients, meaningful activity in FLT3 wild type patients that have achieved an almost 20% overall response rate, and that's even before counting this patient at 40 mg, and meaningful response rates in the FLT3 mutant population as well. I'd like to highlight that the FLT3 NPM1 patients had a very high response rate, four in six patients achieving a remission at the 80 mg, 120 mg, 160 mg dose level. Again, highlighting that perhaps the SYK activity which NPM1 mutant patients are believed to be more sensitive to may actually confer additional activity in patients that have both of these vulnerable mutations. Here are the response data shown at, with different response criteria, overall response rate, CRc, as well as CR/CRh I'd like to highlight one patient population, that FLT3 mutant patient population that has been treated with a FLT3 inhibitor in the past. Those patients are at greatest unmet medical need, as by definition, they're coming in at least third line of therapy. 3 out of 11 patients achieved some form of response, and 2 of those 3 patients were able to be bridged to transplant. When we look at CR/CRh rates, 1 out of 11 patients achieved a formal response, but again, some of these patients were taken to transplant. We would argue that those individuals that are able to be taken to transplant are achieving clinical benefit from treatment. Now let's go on to talk about a few case vignettes that highlight some of the key take-home messages reflecting the activity of this drug. The first is a patient with FLT3 wild type disease that also carried mutations in NRAS, as well as several other adverse mutations in E2F1 and CEBPA. The 55-year-old male with significant disease at onset was failed by induction chemotherapy and then subsequently failed by salvage chemotherapy. They came under our study, took 160 mg of a once daily oral agent, tuspetinib, and achieved a CRh after one cycle of treatment. This response then matured to an unqualified CR by Cycle 5, and the patient remains on study, experiencing no dose limiting toxicities and no severe adverse events, becoming transfusion independent, highlighting that patients without FLT3 mutations can respond to tuspetinib. Patients with adverse resistance-associated mutations like NRAS can respond to tuspetinib. Importantly, patients can continue to take tuspetinib daily while seeing their response mature without experiencing prolonged myelosuppression. Here's another example of a FLT3 wild type patient. This is the patient with TP53 mutation that I alluded to earlier. This patient had a complex karyotype, identifying them as one of the most adverse genotypes that we encounter in patients with AML. This patient had been treated with induction chemotherapy, then required salvage chemotherapy, and was ultimately able to go on to a stem cell transplant. Unfortunately, as is expected with patients with this genotype, they relapsed, were able to achieve a CRi after one cycle of treatment at 80 mg that then matured to a CRh by Cycle 5 and to a formal CR at Cycle 8. This patient remained on study for over a year, again highlighting how responses can mature over time with this non-myelosuppressive agent once the hematopoietic system has been reconstituted. The patients can continue treatment for prolonged periods of time in the absence of having to move to stem cell transplant. This third patient is a FLT3-ITD patient that had been previously treated with a FLT3 inhibitor. They also carry some very adverse mutations, such as the one in MLL-PTD and in ROS1. This 49-year-old woman with 66% blasts at diagnosis was treated with induction chemotherapy and then consolidation therapy with a regimen that contained a FLT3 inhibitor, midostaurin in this case, and then went on to stem cell transplant. Unfortunately, they relapsed, began treatment at 120 mg and achieved a CRi after one cycle of treatment and was ultimately bridged to stem cell transplant after Cycle 6. Again, highlighting that patients with prior exposure to standard of care therapy that includes a FLT3 inhibitor are capable of responding to a monotherapy with tuspetinib. The last patient I'd like to touch on is a FLT3 TKD patient who had also been previously treated with FLT3 inhibitors. Just underscoring that tuspetinib is a type one inhibitor that can inhibit both the FLT3-ITD as well as the FLT3 TKD forms of the kinase. This patient previously treated with not just midostaurin in induction, but also with gilteritinib with a subsequent line of therapy, was able to achieve a CR after one cycle of treatment at 80 mg and then was quickly bridged to transplant, in this case, a potentially life-saving therapy. Now let's talk about where we're headed with the next phase of the tuspetinib study. As I've shown you already, we've completed dose escalation and explored additional patients at the 40 mg, 80 mg, 120 mg, and 160 mg dose levels, all of which have been deemed safe for further study. With that, we begin the expansion phase of the study that we're calling the APTIVATE trial. The APTIVATE trial will include patients that are treated with tuspetinib as a monotherapy. This includes enrichment for those patients with great unmet medical need, such as the FLT3-mutated patients who have been treated with FLT3 inhibitors in the past, as well as those patients with highly adverse phenotypes like the, for example, TP53 mutant complex karyotype patient population. If we see activity in this patient population that is clinically meaningful as we would expect, that would give us the opportunity to petition the FDA to do a registrational single-arm phase II study in relapsed/refractory AML patients that meet these definitions with great unmet medical need. However, we are simultaneously excited about being able to put tuspetinib into combination with other active agents, particularly venetoclax, to have an all-oral therapy for relapsed/refractory AML patients. Any patient enrolled in the APTIVATE trial will be randomly assigned to treatment either in the monotherapy arm or in the combination arm. They all have an opportunity to perhaps receive combination therapy, and this will give us the experience that we need in order to move tuspetinib into earlier lines of therapy. That could be in earlier lines of therapy after first line, perhaps second line, for example, in patients who require treatment at that point, and in patients who both have FLT3 mutant and FLT3 wild type alleles. Finally, it also gives us the information we would need to then go into a triplet combination that would allow us to treat patients in front line with tuspetinib, perhaps identifying it as a superior combination agent given its really robust safety profile. To summarize the timelines of these events, we have already begun the APTIVATE phase I/II dose expansion trial with enrollment ongoing. In early 2023, we will then open the combination arm with tuspetinib, gain additional experience with that combination, and then be able to begin an arm that includes a triple combination sometime in the middle of 2023. As we collect data on the monotherapy arm, we'll be able to identify those patient populations of great unmet medical need, and again, petition the FDA for a single-arm registrational study. To summarize what we talked about today for tuspetinib, we have orphan drug and fast track designation. We've reported additional CRs and PRs in patients in the year that we've had control of the study and identified this highly favorable safety and broad therapeutic window that give tuspetinib the opportunity to shine not only as monotherapy, but in combination with other active agents. We've seen meaningful reductions in bone marrow blasts across several dose levels and activity in select patients with different genotypes and profiles. This includes patients that have several adverse mutations, as shown here on the slide. We've now begun the APTIVATE expansion trial, including data that will help support a single-arm phase II accelerated approval and data that will help us understand the combination with venetoclax that positions us to move for earlier lines of therapy where a confirmatory study would be appropriate. With that, I will pass it back to you, Bill, to talk about the commercial potential of tuspetinib going forward. Okay. Thank you. My phone dropped there. My apologies. Let me back up one slide, please. At the end there, the commercial potential, let me just say that, thanks, Raf, for providing all the data there. Yes, the data presented do give us confidence that tuspetinib can become the kinase inhibitor of choice for triplet combination therapy, for maintenance therapy, and to treat patients who failed prior FLT3 inhibitors. We look forward to collecting additional data over the next year in our APTIVATE expansion trial. Now let's turn our attention to Lux. Lux inhibits key lymphoid myeloid kinases, including BTK and FLT3, as shown on the left part of the slide. Lux was taken into a phase I for the treatment of AML patients, as shown on the bottom part of the slide, and this was as a single agent. The original G1 formulation of Lux delivered MRD negatives, complete remission, CR, in an AML patient, demonstrating Lux is active against AML. In parallel, Lux was taken into a phase I for the treatment of B-cell leukemias lymphomas as a single agent, as shown across the top. Multiple patients had experienced tumor reductions and complete metabolic responses, but none had achieved a formal response. Well, at least until just a few days ago. As I was traveling to ASH, I learned of a DLBCL patient who had achieved a full CR by Cycle 24 using the original G1 formulation. This was great news for us and it proves Lux is an active drug against B-cell cancers and AML. That was a great finding for us. It was unexpected, and we just learned about that just a couple of days ago. Yet we also know that the original G1 formulation of Lux had less than optimal absorption properties that hampered its full potential in the clinic. We therefore created a new generation 3 or G3 self-emulsifying formulation that demonstrated up to a 30-fold increased absorption in rats and dogs relative to that original G1 formulation. During this year, 2022, we tested the G3 formulation in patients in which they received a single dose of G3, and then the PK properties were followed over 72 hours. We did this with 4 patients at 5 different dose levels, ranging from 10 mg up to 200 mg of G3. The PK modeling from these data predicted an 18-fold improvement in absorption. We took this G3 formulation back into the AML patients with continuous dosing, beginning with a 50 mg BID dosing schedule. As of today, we have two patients receiving continuous dosing of G3. We know now that Lux is an active agent against AML and B-cell cancers. Now we expect the G3 formulation to deliver higher exposures of Lux in patients and to deliver clinical responses. Having that, now let's move into the Q&A session. I'll turn it back to Dr. Bejar so he can introduce our KOL today. Thanks, Bill. On the phone with us, we have Dr. Naval Daver, Associate Professor in Department of Leukemia at The University of Texas MD Anderson Cancer Center, and a global lead investigator for the tuspetinib phase I/II trial. With that, we welcome your questions. Thank you. We'll now be conducting a question and answer session. If you'd like to be placed in the question queue, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the questions queue. You may press star two if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing star one. Our first question today is coming from Gregory Renza from RBC Capital Markets. Your line is now live. Great. Thanks. Good morning, Bill and the Aptose team. Congrats on the data and the updates this morning, thanks for taking my questions. Bill, maybe I could just turn it over to Dr. Daver. I'm curious from your perspective, Dr. Daver, just putting the test data into context. I know earlier Dr. Bejar did just allude to that potential superiority of a FLT3 inhibitor. I'm just curious what profiles and what attributes of a drug that could be potentially superior would you be looking for? How could test potentially fit that bill? I'm also curious if you could comment on, and nicely she overlays some gilteritinib data with the test data, just to get a sense of some of the patterns there. Just curious if you could comment on that as well. Thank you so much, and congrats again, guys, on the data. This is Naval Daver. I think this is a very safe agent. I think that's the number one thing. We've used it in a number of patients. It's extremely well-tolerated. You know, the efficacy, it's always difficult to compare different populations across time because when gilteritinib was evaluated in both the CHRYSALIS and ADMIRAL studies, only 11% of the patients had a prior TKI. This was 2013 through 2018. With the approval of midostaurin in the frontline setting, the current as well as gilteritinib in the salvage setting, current trials you see 70%, 80%, almost all patients have had a prior FLT3 TKI. To see kind of similar waterfall plots and similar responses in a much more difficult population, where majority have had a prior FLT3 inhibitor, I think is a very encouraging sign for this agent. Also, I think given that it does not seem to have myelosuppression, significant LFT abnormalities or GI toxicities, which have been seen with the other FLT3 inhibitors, whether it's a gilteritinib or quizartinib, I think makes it a very good agent to move forward in combination. Overall, it looks like an active agent, definitely for FLT3, but also for wild type disease. I think combination therapy is going to be really the key clinical way to move this forward in the future. That's great. Thank you so much for the color and congrats again, Bill and Dr. Bejar on the data. Thanks. The next question is coming from Li Watsek from Cantor Fitzgerald. Your line is now live. Hi there. This is Rosemary Lee on for Li Watsek. Thank you for taking my question. Thank you for the update today. Perhaps first a question for the doctor. Can you maybe tell us your perspective how you can fit the fit tuspetinib in with approved targeted agents that are present already? Just to understand, you're saying what would be the approval pathway or how this agent would fit in the current landscape? Yeah, exactly. How it will fit in with what's already there for patients. Right. Yeah, absolutely. I mean, you know, two examples I like to give are CML, right, where we have now five and actually a 6th TKI approved and a 7th one potentially being approved. We see different profiles in these TKIs, and, it's quite possible as safer and better ones come over time, they will actually get approved and replace the previous ones. Similar with the JAK inhibitors, we now have a 4th JAK inhibitor that will be approved, in the same disease setting for the same population. I think if the drug continues to show very good safety, good activity, and especially in combination, if it delivers synergistic responses, which we can get with combination venetoclax gilteritinib, but without the myelosuppression that we see with venetoclax gilteritinib, I think that could be a potential game changer to move this drug actually as a preferred FLT3 inhibitor, for example, in the first relapse patients who have failed frontline therapy, induction midostaurin induction, quizartinib potentially in the near future. Once quizartinib is approved, you could give venetoclax with tuspetinib as a first salvage option with less myelosuppression, good activity. Of course, we have to show that. That could be a path. The other path could be in the post-gilteritinib setting, and this is again from CML, where we use imatinib or nilotinib, dasatinib up front, but then if they fail, we use ponatinib, and then if they fail, we're using asciminib. We still have a big population that fails gilteritinib at some point, either a fracture or relapse. There, even if we see 20%, 15%-20% response, it's better than 0%, which is currently what we have. 'Cause no drugs work in that setting. That could be a second potential registration path. Okay. Thank you. Perhaps one other question for the team. Do you know if co-mutations impact the response to tuspetinib? If, you know, maybe there are certain co-mutations or even prior treatments that make certain patients more sensitive or less sensitive to tuspetinib? I can take that question. Okay. Thank you. Go ahead. That is an excellent question. We have looked to see if there are factors that may predict response or failure of response. Looking broadly, we haven't yet found any features that totally preclude the ability for patients to respond. We will do a more formal central genetic analysis, but with the data that we've shown you, there are a wide variety of mutations that we see that are associated with resistance to other agents really don't seem to prevent patients from having a response at some point. Thank you very much. Thank you. Next question today is coming from Soumit Roy from JonesTrading. Your line is now live. Hello everyone, and congratulations on the continuing a robust data. One question on the baseline blast count, if you can provide us any color where the baseline was, especially for the ITD mutant patients who seems to be more partial responding even at high dose of high 20, high 60. Were they any reason for them being more refractory than the other patients? Yeah, that's a good question as well. Obviously when patients relapse, sometimes they have a tremendous blast burden, and sometimes they have a blast burden that is slightly close to where they were when they were in remission because we're keeping a close eye on these individuals. We've really seen both types in this study, and it wasn't necessarily the case that the FLT3 mutant patients had the greatest blast count, although that tends to be true at the first diagnosis. We've seen a breadth of that, some patients with high blast burden, some patients with low blast burden, and both of which have seen meaningful decreases in responses. Got it. I know you are trying to combine with HMA and try to move up the line, but would you, given the safety profile and pretty broad response in all genotypes, would you even consider going head to head with gilteritinib or any other approved drugs, to show it is active as a monotherapy and can go ahead? My first impression is that I think we have a lot of spaces to explore in combinations that perhaps some of these agents haven't yet gone or aren't able to go. For example, the one key differentiating factor there is the activity that we've seen in the wild type population being almost equal to the activity we've seen in the FLT3 mutant population. When we go into combinations, if we see that activity continue and expand in the wild type population, there would be no need to compete against other agents in that context. The other thing is that many of these other active agents that are in development now aren't necessarily competitors to this drug. They're really opportunities to go into combination. For example, yesterday we saw data presented on the menin inhibitors, drugs that are targeting a subset of patients with AML, particularly with NPM1 mutations for example. No reason to think that we wouldn't be able to combine with a drug like that and for example, bolster the response rates that we see in that patient population and perhaps even move into earlier lines of therapy. Bill, do you have anything additional you would like to add? No, I think you covered it well. I mean, the main point there is having the free space to explore triple combinations moving forward as meant Dr. Daver mentioned, the wild type populations, maintenance. Perhaps Dr. Daver wanted to add to that. Yeah, I think, you know, that's one area I didn't talk about, but yeah, the future as I see it and MD Anderson and many centers now are moving that way is upfront combinations of effective non-cytotoxic chemo agents, very similar to what's being done in multiple myeloma and acute lymphoblastic leukemia successfully. HMA then we think now has established a very good backbone for this to become a reality in the future. The next major step is what agents can be safely added to it to synergize and improve activity. At this year's ASH, you'll see a lot of that data, a lot of which is being presented out of Anderson, leading these efforts, adding antibody-based therapies, targeted agents, immunotherapies. I think that the big issue we face there is myelosuppression with some of those agents. What we're really looking for is an agent that does not have inherent myelosuppression, is well tolerated and has activity both in FLT3 targeting, but also in the wild type. I think that frontline triplet space could be very attractive one to evaluate with the tuspetinib. We're looking forward to that. Thank you again for all the color and congratulations again. Thanks. Thank you. Next question is coming from Matt Biegler from Oppenheimer. Your line is now live. Hey guys, congrats on this update. Super encouraging. I'm curious, the FLT3 inhibitor refractory patients, the responses you're getting seem pretty impressive. Just curious, Dr. Daver's thoughts on like what the efficacy bar would be as a monotherapy or potentially in combination with them, there. That's the first part of my question. Then Bill and Raf, just on the safety profile, you know, you're hitting JAK, SYK, c-KIT, and some of these are kind of bad actors, right? You're not seeing myelosuppression. How do you explain that? Is how is the drug seemingly threading that needle, you know, between safety and efficacy? Thanks and congrats again. Why don't I address the safety one in terms of the targets first. One of the best parts about this drug is that, and one of the PIA assay, Dr. Bejar highlighted the fact that we didn't have to get complete suppression of phospho-FLT3 or phospho-JAK to get responses. What it shows is the drug is hitting multiple targets. Each of those is contributing to the activity, and you're not just quote, dependent entirely on knocking out JAK1 or JAK2 to have the activity. That may be part of it. Also part of it may be in terms of many of the other JAK inhibitors that you mentioned that had toxicities associated with them. It's not just the fact that they rely on knocking out the vast majority of JAK. It's also potential other targets that they're hitting, that certain other JAK inhibitors, will hit other targets that cause safety concerns. Perhaps Dr. Bejar and Dr. Daver wanted to add to that and then talk about the sensitivity of the FLT3 patients who have failed FLT3 inhibitors. I think, Bill, I think you hit the high points. I think that whenever you have a tyrosine kinase inhibitor, it's the targets that you hit that really determine the phenotype the patients will experience. While we're hitting targets like FLT3, JAK1, and SYK. When you look at other agents that target those more narrowly, they tend to be fairly well-tolerated. We have a SYK inhibitor in the market, for example, for ITP. It seems very well-tolerated, doesn't seem to cause significant immunosuppression. No reason to think that SYK inhibition in this context would be any different. I think we just are fortunate in that TUS happens to hit several active and important oncogenic kinases with few perhaps off-target activity that could contribute to additional toxicity. Maybe, yeah. Oh, yeah. My message. Yeah, about the FLT3 inhibitor. Yeah, I think the other question was, you know, in the post-FLT3 inhibitor setting, what the bar would be to consider it effective or for approval. I think the bar would be extremely low. In these patients, we, you know, let's say somebody got front line induction chemo with midostaurin, which is the current standard today, and then failed and then got gilteritinib or gilteritinib and venetoclax and then relapsed. The majority of these patients, about 70%-80%, are actually sent to hospice. Very few of them respond to subsequent therapy. About 15%-20% response rate. We actually looked at this along with the Sloan Kettering group a couple of years ago, post for at ASH. I think a 20% or so CR/CRh rate actually would be a reasonable entry point to even start discussions with the FDA in a ultra unmet need population with kind of no established or approved agents. This is something that the FDA would even, I think, consider as a kind of a single-arm population for severe unmet need. Got it. Good day for patients. Thanks, guys. Congrats. Thank you. Next question is coming from Ted Tenthoff from Piper Sandler. Your line is now live. Great. Thanks. Good morning, everyone. I think most of the questions on tuspetinib were asked, so I'll just ask about Lux. You know, encouraged to see that result. You know, is the goal here to generate additional data with the reformulation and then potentially seek a partner? Does it make sense to evaluate this in both AML and DLBCL? Because of tuspetinib's activity, maybe does Lux make more sense in more for the for B-cell malignancies? Thanks. Hi, Ted. Thanks for the question. I'll take that one. Yeah, Lux. Well, first of all, it was great news that now that we've seen complete remissions in both the B-cell malignancies as well as the AML. We knew it was active there, but we really wanted to get a better formulation, a more improved formulation, and now we have one. At this point in time, we're AML patients are the only patients receiving it in a continuum dosing of G3. We then want to be certain that we're getting increased exposure, which we expect, and that will hopefully deliver additional responses in these patients and tell us that, yes, it continues to be active, it continues to be safe, but now we're getting the exposure levels that we want. After that, it brings on a much better partnering opportunity for us. We can look at regional deals, we can look at deals by indication. We believe it could be moved forward not only for AML and B-cell malignancies, but also for inflammation and certain other diseases because of the targets that it hits. A point that Dr. Daver made earlier, he mentioned that in CML there are seven TKIs. I would mention all kinases are different. Lux is very different than tuspetinib. Even though they both may hit FLT3, and they may be targeting AML, they will have different activities and likely different response rates in patients and potentially different populations in AML. I can tell you in vitro we've done studies, and they were not antagonistic with each other, when we combined them in vitro. Let's see the activity as it goes forward. We hope we see better exposures, more responses, that opens up the possibilities for us. It's a really good question. Yeah. Well, thank you. That's a thorough answer. Dr. Daver, I really appreciate your perspective on tuspetinib. That was super helpful through the earlier questions. Thank you. Next question is coming from John Newman from Canaccord. Your line is now live. Yeah, thanks for taking my question and congrats on a nice data update. Question is for, I guess, both Dr. Daver and the Aptose team. What do you think is the most important subset to really focus on going forward here? What is the subset of patients where there's either the highest unmet need, or in your view, the data that we've seen to date suggests maybe a really differentiated profile there? Thanks. Dr. Daver. Dr. Daver had to disconnect. His line disconnected. Sorry. Perhaps Dr. Bejar would take that one. Yes, my line dropped earlier. I apologize. Hopefully we can get him back. I can stop in. I can start in. If he comes back on, I'll pass it over to him. Okay. You know, our impression is, first of all, that any patient with relapsed AML is in dire straits, that the entire patient population that relapses really is in trouble and needs further active agents. Right now, short of a transplant. Anything we give is going to, at best, control the disease for a short period of time and won't be curative. There is a important need to have therapies that patients can tolerate for long periods of time that can be given to patients who have perhaps comorbidities, advanced age, or have suffered consequences of their frontline therapy that can make them more vulnerable. Having a safe agent that can do this, I think, is really important. In terms of subsets of AML patients with great unmet medical need, I think we mentioned one, we've mentioned the patient population that really has been failed by all conventional and targeted therapies as being the greatest unmet medical need. There are patients with specific subtypes of disease that we know are not gonna do well with anything that we have available, even in early lines of therapy. For example, the TP53 mutant population comprise 15%-20% of AML, especially in the relapse setting. Those patients with complex karyotype and so on. Finally, patients that have certain other adverse mutations like MLL, NPM1, RUNX1, and so on, are even in a worse position than patients with relapsed AML more generally. If we were able to recover Dr. Daver, I would have him follow up with that. Otherwise, we can address any additional questions you have. Now, another population that you mentioned earlier was the RAS mutated population. Right. Okay. One additional question. Yeah, one additional question. Going forward in the expansion study here, will the criteria be the same in terms of transplant if physicians feel that, you know, a patient has a complete response, and they would be a good candidate, will the patients continue to go to transplant as they have in some of the earlier work? That's excellent question. There is no change in terms of guidance for investigators. That still remains an option that we would be very happy if patients are able to achieve a potentially life-saving therapy like that. Now that we have a better understanding of how tuspetinib is tolerated, particularly in patients taking it for longer periods of time, we will petition the FDA for the opportunity to put the drug into a maintenance after transplant setting for the patients that were able to achieve a remission go to transplant on our study. While we haven't done it to date, we will include in the future the ability of patients to continue to take the drug after transplant to help maintain the remission. Yeah, let me just add to that because, John, I actually saw you yesterday in the session, the AML session, and one of the points that physicians were making is that patients who not even have a full CR, maybe have a CRi, CRh, CRp, they're taking many of these patients onto transplants as quickly as they can. We all will be petitioning the FDA to make sure we get credit for that, not just a CRh or a full CR, that some of these patients that they wanna get them into a transplant as quickly as possible to potentially save their life. Even though it may just be a CRi, we expect that would count toward the approval. Okay. Thank you. We've reached the end of our question and answer session. I'd like to turn the floor back over to Dr. Rice for any further or closing comments. All right. Well, let me thank everyone. First of all, I wanna thank the patients who participated in our trials and their families, the clinical investigators and their staff at the clinical sites, and all of our investors who have stuck with us. Lastly, I do wanna have a shout-out to all of our employees and consultants at Aptose. This is, everyone's working tirelessly to bring our medicines to patients and then ultimately to the target. I guess now we'll get back to the ASH conference. Everyone, have a great day and please follow up with us for additional questions because we're always getting questions about dose responsiveness of targeted agents. Dr. Daver could answer some of those. We're happy to answer any of your questions. Maybe we'll see you at the posters a little bit later today. Thank you, everyone, and we'll bring it to a close now. Thank you. That does conclude- Thank you. -today's teleconference and webcast. You may disconnect your line at this time and have a wonderful day. We thank you for your participation today.