Aptose Biosciences Inc. (APS) Earnings Call Transcript & Summary

Hello, and welcome to the Aptose Biosciences Clinical Update and Data Review Conference Call and Webcast. [Operator Instructions] 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, and 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 and Chief Medical Officer. Further, Dr. Naval Daver of MD Anderson Cancer Center, Global Lead Investigator for tuspetinib Phase I/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 is 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 and 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, and 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, and 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, so we will be respectful of your time. On our agenda today, I'll first will introduce our clinical stage molecules, tuspetinib, also known as HM43239 and luxeptinib, also known as CG-806 or just lux. I'll then provide our view of the future medical and commercial applications of tuspetinib; then 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. Then 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 will 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. So be certain to take advantage of the access to Dr. Daver and prepare your questions with regards to combination therapies, response rates, safety profiles and dose 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. AML reported new CR from our B-cell trial with lux. And then we'll underscore our ongoing studies with our new oral G3 formulation of lux. But 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. We'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, and 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. But first, I'm going to 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 $1 billion-plus commercial success. The first need is to identify a safe and highly active drug to add to venetoclax and hypomethylating agents as a triple combination that can place frontline patients in an MDR-negative (sic) [ 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 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 it's more than just a FLT3 inhibitor and connect 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. And 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, and I'll start with focusing on emerging clinical PK and safety data and why this could be a potentially superior AML therapy. So let's begin by talking about the status of the trial as it stands on October 6, where we have completed what we're calling Part A or dose escalation on the left, taking patients from 20 milligrams all the way up through 200 milligrams once daily. Now the study is designed in such a way that we can then explore additional patients at those dose levels and show signs of activity, and we began to add additional patients not only at 80 milligrams but also at 120 and 160 milligrams. We've now gone back and added additional patients at the 40-milligram 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 4 of these dose levels and none of these patients at the 40 to 160-milligram 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-milligram 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. And as you can see on the next slide, we break down the number of patients treated at each dose level, identified by whether 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-milligram dose level shown there in light blue, achieved a slightly higher exposure than the average exposure of patients in the 80-milligram dose level shown in green. For this reason, we have selected the 120-milligram dose level as our go-forward monotherapy dose since it puts more patients above the minimum threshold that we think is required for response, even though we've seen substantial activity even at the 80-milligram dose level. Now 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, that this is really much more than just a FLT3 inhibitor. While it does inhibit FLT3 and 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 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 and inhibition of just one or a couple of these may not be sufficient to provide long-term control of disease. Now I'd like to highlight 2 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, and that's shown here on this next slide. These are plasma inhibition activity assays both for Phospo-FLT3 on the left and Phospo-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, and in blue are shown the range of exposures that were achieved at steady state in those individuals that had a response. So 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. Now 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, and 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. And the types of therapies that patients received are quite varied. They have more than 70% of patients that received prior cytotoxic chemotherapy, 60% of patients have received a prior hypomethylating agent and 50% of patients have received prior venetoclax before coming on to our study. More than 1/4 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 is great unmet medical need. This slide summarizes our safety in the Phase I/II study to date, shows that tuspetinib is very well tolerated. While patients with acute leukemia often have adverse events, only 28.3% of patients experienced a drug-related adverse events, 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 one patient that experienced grade 3 nausea. And 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 2 non-hematologic toxicities there. One is that grade 3 nausea patient that I just described and then 2 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 milligrams. At 200 milligrams, 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. And 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 encountered by other AML therapies, including tyrosine kinase inhibitors. We've achieved efficacy across 4 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 [ synergy ] that remains safe. And 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 only become available to AML patients more recently. So 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 blast in the bone marrow of patients treated on the study at 80, 120 and 160 milligrams. And 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 biological activity that the drug is actually able to reduce the blast. And 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 in 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 one patient in our study. Now I 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 achieved meaningful blast reductions. Quite interesting, this is very similar to data that have 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, but 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. Now on this next slide, I show the same data, looking not at percent change in blast but an absolute change just to show you that many of these patients have very high blast counts. They went down substantially with treatment, both in the wild-type and the FLT3 mutant populations. So 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 plot on 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, CRh, this is a complete remission with partial hematologic recovery, was not available as a response option for investigators. This has now been added in 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 4 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. Finally, I'd like to point out that we have added one additional response here with the 40-milligram dose level. The date of clinical response is October 6. However, we have attached to the very top, this last patient then had a more recent clinical response. Here are those responding patients shown in a slightly different way, highlighting the mutations that they carry. And 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, RUNX1 and so on. Here are the response data in the efficacy evaluable populations shown by different mutational statuses and different dose levels. There -- while some of these numbers are relatively small, I think it highlights the breadth of activity that we're seeing. As 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 milligrams, 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, 4 out of 6 patients achieving a remission at the 80, 120, 160-milligram 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, the response data shown with different response criteria, overall response rate, CRc as well as CR/CRh. And I'd like to highlight one patient population, that FLT3 mutant patient population and has been treated with the FLT3 inhibitor in the past. Those patients are at greatest unmet medical need is by definition are 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, there 1 out of 11 patients achieved a formal response. But again, some of these patients will take it to transplant. And we would argue that those individuals that are able to be taken to transplant are achieving clinical benefit from treatment. So now let's go on to talk about a few case vignettes that highlights some of the key take-home messages, reflecting the activity of this drug. So the first is a patient with FLT3 wild-type disease that also carried mutations in NRAS as well as several other adverse mutations in U2AF-1 and SETBP1, a 55-year-old male with significant disease at onset was failed by induction chemotherapy and then subsequently failed by salvage chemotherapy. They came on to our study, took 160 milligrams of a once-daily oral agent tuspetinib and achieved a CRh after 1 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 and 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. And 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 him as one of the most adverse genotypes that we encountered in patients with AML. This patient had been treated with induction chemotherapy and required salvage chemotherapy and was ultimately able to go into a stem cell transplant. Unfortunately, as is expected with patients with this genotype, they relapsed, but we're able to achieve a CRi after 1 cycle of treatment at 80 milligrams that then matured to a CRh by cycle 5 into 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, and that patients can continue to treatment for prolonged periods of time in the absence of having to move to stem cell transplant. The third patient is a FLT3-ITD patient that had been previously treated with a FLT3 inhibitor. He also carries some very adverse mutations such as MLL-PTD and RUNX1. This 49-year-old woman with 66% blast at diagnosis was treated with induction chemotherapy and then consolidation therapy with a regimen that contains a FLT3 inhibitor, midostaurin in this case, and then went on to stem cell transplant. Unfortunately, they relapsed, began treatment at 120 milligrams and achieved a CRi after 1 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 include the FLT3 inhibitor are capable of responding to a monotherapy with tuspetinib. And 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 1 inhibitor that can inhibit both the FLT3-ITD as well as the FLT3-TKD forms of the kinase. And 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 1 cycle of treatment at 80 milligrams and then was quickly bridged to transplant, in this case, a potentially life-saving therapy. So now let's talk about where we're headed with the next phase of the tuspetinib study. As I've shown you already, we completed dose escalation and explored additional patients at the 40, 80, 120 and 160-milligram dose levels, all of which have been deemed safe for further study. With that, we began 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 quite 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 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. It 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 frontline with tuspetinib, perhaps identifying it as a superior combination agent given its really robust safety profile. So to summarize the timeline for 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. So 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 gives tuspetinib the opportunity to shine not only as monotherapy but in combination with other active agents. We see 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 the 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. So 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 drop there, my apologies. All right. So let me back up 1 slide, please. All right, so at the end there, the commercial potentials. Let me just say that thanks, Raf, for providing all the data there. And yes, the data presented do give us confidence that tuspetinib can become the kinase inhibitor of choice for triple combination therapy, for maintenance therapy and to treat patients who fail the prior FLT3 inhibitors, and we look forward to collecting additional data over the next year in our APTIVATE expansion trial. But 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 is as a single agent and the original G1 formulation of lux delivered MRD-negative 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 that 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 as an active drug against B-cell cancers and AML. So 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 milligrams up to 200 milligrams of G3. The PK modeling from these data predicted an 18-fold improvement in absorption. We then took this G3 formulation back into the AML patients with continuous dosing, beginning with a 50-milligram BID dosing schedule. As of today, we have 2 patients receiving continuous dosing of G3. We know now that lux is an active agent against AML and B-cell cancers, and now we expect the G3 formulation to deliver higher exposures of lux in patients and to deliver clinical responses. So having that, now let's move into the Q&A session, and I'll turn it back to Dr. Bejar so he can introduce our KOL today.

Thanks, Bill. So 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. So with that, we welcome your questions.

[Operator Instructions] Our first question today is coming from Gregory Renza from RBC Capital Markets.

Congrats on the data and the update this morning. Bill, maybe I could just turn it over to Dr. Daver. I'm just curious from your perspective doctor, we're just putting the test data into context. And earlier, Dr. Bejar did just alluded to that potential superiority of a FLT3 inhibitor. I'm just curious what profiles and what attributes of the drug that could be potentially superior would you be looking for. How could test potentially fit that bill? And I'm also curious if you could comment on overlay some gilteritinib data with the touch data just to get a sense of some of the patterns. I'm just curious if you could comment on that as well. Congrats again guys on the data.

Yes, sure. Yes, this is Naval Daver. I think this is a very safe agent. And I think that's the number one thing. We've used it in a number of patients. It's extremely well tolerated. And the efficacy is always difficult to compare different populations across time because when gilteritinib was evaluated in both the CHRYSALIS and ADMIRAL studies, only 11% of patients had a prior TKI. This was 2013 through 2018. But with the approval of midostaurin in the frontline setting, the current -- as well as gilteritinib in the salvage setting, in current trials you see 70%, 80%, almost all patients have had a prior FLT3 TKI. And so to see kind of similar waterfall block and similar responses in a much more difficult population where majority had a prior FLT3 inhibitor, I think is a very encouraging sign for this agent. And 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. So overall, it looks like an active agent, definitely for FLT3, but also for wild-type disease. And I think combination therapy is going to be really the key clinical way to move this forward in the future.

The next question is coming from Li Watsek from Cantor Fitzgerald.

This is Rosemary Lee on for Li Watsek. Perhaps, first the question for the doctor. Can you maybe tell us your perspective, how you can fit the tuspetinib in with approved targeted agents that are present already?

So just to understand, you're saying what would be the approval pathway or how this agent will fit in the current landscape?

Yes, exactly, how will it fit in with what's already there for patients?

Right. Absolutely. So I mean, 2 examples I'd like to give are CML, right, where we have now 5 and actually a 6 TKI approved and the seventh one potentially being approved. So 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. And similar with the JAK inhibitors. We now have a 4-JAK inhibitor that will be approved in the same disease setting for the same population. So 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 of venetoclax and gilteritinib but without the myelosuppression that we see with venetoclax and gilteritinib. I think that could be a potential game changer to move this drug actually as the 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, then you could give venetoclax with tuspetinib as the first salvage option with less myelosuppression, good activity. Of course, we have to show that, and that could be a path. And then the other path would be in the post gilteritinib setting, and this is again from CML where we use imatinib or nilotinib, dasatinib upfront, but then if they fail, we use ponatinib and then if they fail, we're using asciminib. So we still have a big population that fails gilteritinib at some point, either refractory or relapse. And there, even if we see 20% -- 15%, 20% response, it's better than 0, which is currently what we have because no drugs working that setting. So that could be a second potential registration path.

Okay. And perhaps one other question for the team. Do you know if co-mutations impact the response to tuspetinib? And if 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.

Well, this is -- okay. Go ahead.

That is an excellent question. We have looked to see if there are factors that may predict response or failure response. And 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 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.

Next question today is coming from Soumit Roy from Jones Research.

Congratulations on the continuing 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 given at high dose of high 20, high 60, were there any reason for them being more refractory than the other patients?

Yes, that's a good question as well. So 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 the study. And it wasn't necessarily the case that the FLT3 mutant patients have the greatest blast counts, although that tends to be true at first diagnosis. So 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. And 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 by 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. So 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 kind of activity we've seen in the FLT3 population. So when we go into combination, if we see that activity continue to 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. There are really opportunities to go into combination. So 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 to move into earlier lines of therapy. Bill, do you have anything addition 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 Dr. Daver mentioned, the wild-type populations, maintenance. So perhaps, Dr. Daver wanted to add on that.

Yes. I think that's one area I didn't talk about. But yes, the future, as I see at MD Anderson and many centers now are moving that ways upfront combinations of effective non-cytotoxic chemo agents, very similar to what's being done in multiple myeloma and acute lymphoblastic leukemia successfully. So HMA, when we think now has established a very good backbone for this to become a reality in the future. And the next major step is what agents can be safely added to synergize and improve activity. And 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. And I think that the big issue we face there is myelosuppression with some of those agents. So 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. And I think that frontline triplet space could be a very attractive one to evaluate with tuspetinib. So we're looking forward to that.

Next question is coming from Matt Biegler from Oppenheimer.

Congrats on the update, super encouraging. I'm curious, the FLT3 inhibitor refractory patients, the responses you're getting seem pretty impressive. So 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. And then Bill and Raf, just on the safety profile, you're hitting JAK6 kit. Some of these are kind of bad actors, right? But you're not seeing myelosuppression. So how do you explain that? Is -- how is the drug seemingly threading that needle between safety and efficacy? Congrats, again.

So why don't I address the safety one in terms of the targets first. One of the better 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. So what it shows is the drug is hitting multiple targets, each of those is contributing to the activity, and you're not just "dependent entirely" on knocking out JAK1 or JAK2 to have the activity. So that may be part of it. But also part of it maybe in terms of many of the other JAK inhibitors that you mentioned that had toxicities associated with. 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 to cause safety concerns. But 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. So I think that whenever you have a tyrosine kinase inhibitor, the targets that you hit to really determine the [feelings] that the patients will experience. And 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. So we have a SYK inhibitor in the market, for example, for IDP. It seems very well tolerated. It doesn't seem to cause significant immunosuppression. No reason to think that SYK inhibition in this context would be any different. So I think we just are fortunate in that test happens to have several active and important oncogenic kinases with few, perhaps, off-target activities that could contribute to additional toxicity.

Yes, I think the other question was in the post FLT3 inhibitor setting, what the bar would be to consider it effective for approval? I think the bar would be extremely low. In these patients, we -- let's say, somebody got frontline induction chemo with midostaurin, which is the current standard today and then paid and then got gilteritinib or gilteritinib-venetoclax, and then relapsed. A majority of these patients, about 70%, 80% are actually sent to hospice and a 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 read at ASH. So I think a 20% or so CR/CRh rate actually would be a reasonable entry point to even start discussions with the FDA in an ultra-unmet need population with kind of no established or approved agents. And this is something that FDA would even, I think, consider as a kind of a single-arm population for severe unmet need.

Your next question is coming from Ted Tenthoff from Piper San.

So I think much of the questions on tuspetinib were asked, so I'll just ask about lux. Encouraged to see that result. Is the goal here to generate additional data with the reformulation and then potentially seek a partner? And does it make sense to evaluate this in both AML and DLBCL? Or because of tuspetinib's activity, maybe does lux make more sense in more for the -- for B-cell malignancy?

Ted, thanks for the question. I'll take that one. Yes, lux, the path forward, 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, more improved formulation and now we have one. So at this point in time, where AML patients are the only patients receiving it in a continuous 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. But 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. But a point that Dr. Daver made earlier, he mentioned that in CML, there are 7 TKIs. I would mention all kinases are different. So lux is very different than tuspetinib. And even though they both make it 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. And I can tell you, in vitro, we've done studies, and they were not antagonistic with each other when we combine them in vitro. So that gives us -- let's see the activity as it goes forward. We hope we see better exposures, more responses and then that opens up the possibilities for us. But it's a really good question.

Our next question is coming from John Newman from Canaccord.

Congrats on 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? Where -- 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?

Dr. Daver?

Dr. Daver had disconnect.

Oh, his line disconnected, sorry, then perhaps Dr. Bejar would take that one. Yes, my line dropped earlier, so I apologize. Hopefully, we can get him back.

I can stop and if he -- I can start and if he comes back on, I'll pass it over to him. Our impression is, first of all, that any patient with relapsed AML has -- is in dire straits. 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. So there is an 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 stage, or have suffered consequences of their front-line therapy that make them more vulnerable. So having a safe agent that can do this, I think, is really important. But in terms of subsets of AML patients with great unmet medical need, I think we mentioned one, we mentioned the patient population and really has been failed by all conventional and targeted therapies as being the greatest unmet medical need. But then there are patients with specific subtypes of disease that we know are not going to do well with anything that we have available even in earlier lines of therapy. For example, the TP53 mutant population comprised 15% to 20% of AML, especially in the relapse setting, most patients with complex karyotype and so on. And finally, patients that have certain other adverse mutations like MLL-PTD, RUNX1 and so on are even in a worse position than patients with relapsed AMLs more generally. So 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.

Another population that you mentioned earlier was the RAS mutated population.

Yes. One additional question going forward in the expansion study here. Will the criteria be the same in terms of transplant if physicians feel that 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?

Yes. That's excellent question. So there is no change in terms of guidance for investigators, that still remains an option, but we would be very happy if patients are able to achieve a potentially life-saving therapy like that. But 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 remission go to transplant on our study. So that 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.

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 we're 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 transplant as quickly as they can. And so 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 want to get them into the transplant as quickly as possible to potentially save their life. So even though it may just be a CRi, we expect that would count toward the approval. Okay.

We 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 want to 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. And then lastly, I do want to have a shout out to all of our employees and consultants at Aptose. Everyone is working tirelessly to bring our medicines to patients and then ultimately to the target. And I guess now we'll get back to the ASH conference. But 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. And so we're happy to answer any of your questions, and maybe we'll see you at the posters a little bit later today. But thank you, everyone, and we'll bring it to a close now.

That does conclude 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.