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

Good afternoon, and welcome to the Aptose Biosciences KOL data call. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Aptose website following the conclusion of the event. I'd now like to turn the call over to Dr. William Rice, President and Chief Executive Officer of Aptose Biosciences. Please go ahead, William.

Thank you, Tera. Good day all, and thank you for joining us. I am Dr. William Rice, Chairman, President and CEO of Aptose Biosciences. Aptose is a clinical stage biotech company, developing oral kinase inhibitors for the treatment of patients with hematologic malignancies. And today, we'll hold an AML-focused KOL event and a high-level update on our clinical programs. And as a reminder, we will make certain forward-looking statements today. At Aptose, we're developing 2 distinct clinical-stage oral kinase inhibitors. Our most advanced molecule, HM43239 or just 239 as we call it, is a clinically validated myeloid kinome inhibitor that potently suppresses high-value targets, including FLT3, SYK, JAK kinases and the mutant forms of c-KIT, all operative in acute myeloid leukemias or AML. Oral 239, as a single agent, already has delivered multiple complete remission in a diverse group of patients with relapsed or refractory AML, an ongoing international Phase I/II trial. This includes highly refractory patients with wild-type FLT3 or in patients harboring the ITD or the tyrosine kinase domain mutant forms of FLT3, including patients with prior failure by other approved FLT3 inhibitors, such as gilteritinib and midostaurin. It also includes a patient with complex karyotype and a TP53 mutation and patients with mutations in the NPM1, RAS, RUNX1 MLL and IDH genes. 239 has received orphan drug designation from the U.S. FDA and recently received Fast Track designation for the treatment of relapsed or refractory AML patients with mutated FLIT3. It's noteworthy that the ongoing trial now has delivered safety and efficacy data that allowed us to select our doses as well as our genetically defined patient populations to explore in the next stage of clinical development, which includes expansion trials planned to begin in the second half of this year with an eye toward transitioning these expansion trials when ready into registrational studies. Our second molecule, luxeptinib, also known as Lux or CG-806 also is an oral kinase inhibitor. And this molecule lux inhibits BTK, FLT3 and other important kinases. Lux is in 2 separate Phase I dose escalation trials for the treatment of patients with B-cell leukemias and lymphomas and for patients with AML. And antitumor activity already has been demonstrated in heavily pretreated cancer patients. Now we are exploring an improved formulation, and we have encouraging data that our new G3 formulation may deliver higher plasma exposures with reduced dosages. With this background information on our clinical pipeline, let's now introduce our key opinion leaders. It's truly a pleasure to have with us today 3 well-known KOLs to discuss the historical role of kinase inhibitors in cancer, including AML, and in particular, the potential application of Aptose's 239 molecule to the treatment of AML. Dr. Brian Druker is best known for his role in the development of imatinib, also known as Gleevec used for the treatment of chronic myelogenous leukemia, and this was the first kinase inhibitor ever approved. I recall when I was the Head of the Drug Mechanism Lab with National Cancer Institute during the 1990s, and I heard about a physician scientist developing a small molecule to target kinases. Many scientists at that time said it could not be done because it would not be possible to create a small molecule to selectively bind to the ATP binding pocket of 1 particular kinase because that ATP binding pocket is found in every kinase. Well, now we all understand that ATP binding pockets differ among kinases, and a drug selectivity can be achieved. And Dr. Druker's insights ushered a revolution in cancer treatment that now has yielded many targeted kinase inhibitors for many indications, but I'll let him describe how the field has evolved. For all of Dr. Druker's contributions to medical science, he was named a Howard Hughes Investigator and a member of the National Academy of Sciences. And I'll underscore that he has received numerous awards for his achievements, including the Lasker-DeBakey Award, The Japan Award, the Lifetime Achievement Award from the Leukemia Lymphoma Society and the Medal of Honor from the American Cancer Society. Remarkably, he's also a true gentleman, and it's been a pleasure to work with him over the past 2 decades, and you'll hear from him in a few minutes. In addition to Dr. Druker, we're thrilled to have with us today 2 KOLs that actually are treating AML patients with our drug 239. Dr. Naval Daver is a professor and hematology-oncology clinical investigator at the MD Anderson Cancer Center, who has made a name for his health as an extraordinarily knowledgeable principal investigator on many institutional, national and international clinical trials. For [ NE ] studies, a breadth of single-agent drug combination therapies that evaluate small molecules, immunotherapies and cytotoxins and is driving motivation is to deliver to hematologic cancer patients, new therapies that are better tolerated and more effective and that can overcome mechanisms of resistance. Dr. Daver is the global PI for our ongoing clinical trial with 239, and you'll hear from him in a few minutes, too. And we have with us Dr. Brian Jonas, a professor and physician scientist from the Division of Hematology and Oncology at the University of California, Davis Comprehensive Cancer Center, where he leads the translational research program in AML, MDS and ALL, serves as the PI on multiple clinical trials and chairs the hematologic malignancies working group and the Data and Safety Monitoring Committee. In a spare time, he serves on the National Cancer Network panels for various hematologic cancers, and he too is treating AML patients with 239. His insights with the responsible AML patients to 239 will be very telling, and we're excited to have him here today to discuss his thoughts. In fact, I want to thank all of our KOLs in advance for the willingness to participate and share their wisdom. While I'm certain you're eager to hear from our KOLs, you'll first need to bear with us as Dr. Rafael Bejar, our Chief Medical Officer here at Aptose and I, will provide clinical highlights of our 239 and lux programs. And this truly will represent the highlights as the bulk of the clinical data will be presented separately from this KOL event. Following our clinical update, Dr. Druker will discuss the impact of kinase inhibitors on cancer treatment and the future needs of AML patients. And then Dr. Druker will ask questions of Dr. Daver and Dr. Jonas, particularly regarding AML disease and their experience in treating patients with AML and their views of 239. Let's begin with the update on lux and the emerging data with the new G3 formulation. As you recall, luxeptinib inhibits validated lymphoma and leukemia targets and is the only molecule reported to potently inhibit the wild-type and mutant forms of both BTK and FLT3, yet it divulges many of the kinases that negatively impact safety. While lux is in 2 ongoing clinical trials, what is critical for lux program is to transition to a new and improved formulation that we refer to as Generation 3, or G3, which is being tested in patients as a single dose. And to date, we have dosed patients with 50 milligrams, 100 milligrams and 200 milligrams of G3. In these studies, after a patient receives a single dose of G3, we followed the plasma exposure levels over 72 hours and then have the patients migrate to the original G1 formulation with continuous dosing so that we may follow their pharmacokinetics and all of them over longer periods of time for efficacy signals. Today, we first present the mean and standard deviation PK curve from the 4 patients administered a single dose of 50 milligram and the 3 patients administered 100 milligrams of G3. 72 hours following the single dose of G3, patients have received either 750 milligrams or 900 milligrams of the original G1 formulation, depending on the site in the trial from which the patients were recruited. Therefore, in this plot, we are only illustrating the G3 PK profile and do not include the G1 PK profile. And I'll remind you that these data represent a single dose of G3 that would not be expected to achieve the micromolar steady-state levels yet. As you can see, weather delivered as 50 milligrams in the red curve or 100 milligrams in the purple curve, lux from the G3 formulation was absorbed rapidly over the first 2 hours and maintained exposures through 72 hours. Indeed, we had never seen such rapid absorption with the original G1 formulation, and this was very encouraging. But these mean and standard deviation curves with G3 do not give you the big picture. So I'll also present PK data from a single patient so that we can compare the PK properties of G3 directly with those of the original G1 formulation. Here, I'm showing the PK findings from the very first patient ever administered G3. At time 0, a single 50-milligram dose of G3 was administered. Lux was absorbed rapidly, as I said, over the first 2 hours and then maintain exposure through 72 hours, after which a single dose of 900 milligrams of the original G1 formulation was administered. G3 exposures can be identified with the red and white markers while the original G1 formulation exposures are identified with green markers. And I will take the first 24 hours of PK data from each formulation shown in here in the purple boxes and overlay them on the right side of the slide. This graph now compares the exposures from G3, the red and white markers to the original G1 formulation, green markers during the first 24 hours following our respective administration. And I'll remind you that lux from the G3 dose remained in the plasma at 72 hours. So the G1 actually began at a higher threshold. Overall, the exposure looks roughly equivalent among the 2 formulations, although 18x more G1 was administered than G3. To provide additional perspective, we also have data from a dose of 150 milligrams of the original G1 formulation that had been administered to a separate patient some time ago. And those exposures are shown here with the blue markers. On a per milligram basis at the 2-hour time point, 50 milligrams of G3 delivered approximately 200x the exposure relative to 150-milligram dose of G1. So yes, we find the G3 now to be very encouraging. So where are we going with lux? Well, I'll draw your attention to the right panel to highlight our plans. During the third quarter of this year, we plan to perform PK modeling with data derived from the G3 single-dose studies. The modeling can predict the PK properties of continuous dosing with G3 are modeling different dosage levels and different schedules of dosing, such as once daily versus twice daily dosing. If the modeling data are compelling, we plan to submit the data and our new dosing plan to the FDA likely later in this year. With a plan to transition our clinical trials away from the G1 formulation toward continuous dosing and dose escalation of the G1 formulation. This represents a significant action because transition to the G3 formulation may allow us to deliver higher plasma exposure levels at reduced doses to patients with hematologic malignancies. Our team remains steadfast in their belief of lux. Preclinically, it remains one of the most impressive molecules we've ever seen, and the team is working hard every day to execute on these important studies. So stay tuned for lux. Now let's turn to HM43239 or just 239. Shown here is the kinase inhibitory profile of 239, illustrating that 239 potently suppresses kinases, central to the proliferation and resistance conferring pathways of AML. This includes potency on the wild type as well as the ITD, tyrosine kinase domain and gatekeeper mutant forms of FLT3, and the SYK signal transduction kinase. JAK kinases, 1 and 2 and mutant forms of c-KIT. Illustrating that 239 has the potential to serve as a multidrug therapy in a single tablet by concurrently suppressing multiple plifheration and resistance confirming pathways in AML. And to support the concept that 239 has the potential to suppress mutations that confer resistance to other drugs, here we illustrate that in subcutaneous models shown across the top, and systemic animal models of AML shown across the bottom, 239 consistently demonstrates superior antitumor activity relative to gilteritinib, a FLT3 inhibitor currently used to treat AML patients with FLT3 mutations. With that, let me pass the microphone to Dr. Bejar so he can describe our clinical findings with 239. Dr. Bejar?

Thank you, and it's a pleasure to have you all here for the call. We are extremely proud of the progress we've been able to make with 239 since we picked up the study in January. And just to summarize some of the key points that were just mentioned. We believe that is really positioned well and potentially superior to other FLT3 inhibitors as it does inhibit all mutant forms of FLT3, kills AML cells that are resistant to other FLT3 inhibitors in the clinic, and hopefully, in the lab and hopefully in the clinic as well. And by targeting multiple different important kinases, we get that combination therapy in 1 molecule phenotype, which is described. So we are now going to bring you up to date with where we are with the clinical program. We are exploring molecular subgroups that make sensitive potentially resistant in relapsed/refractory AML patients, particularly those with adverse mutations in order to help us understand the full scope of their activity. So this is a diagram that shows you where we are with the clinical study. This is a Phase I/II international study that includes a dose escalation portion on the left, and we've completed 6 different dose levels there, starting with 20 milligrams and having cleared the 160-milligram dose level. We're currently in the 200-milligram dose escalation cohort. But as we do dose escalation, we have the ability to perform dose exploration in a larger number of patients at dose levels that show signs of activity. So to that extent, we've expanded the 80-milligram dose level to 20 treated patients, the 120-milligram dose level to 12 treated patients and the 160-milligram dose level to 9 treated patients. And these additional patients at each of these dose levels gives us a better understanding not only of the safety and tolerability of the drug but also on the pharmacokinetic properties of the agent and the efficacy that it can have in these different dose levels. So down below, you see a swimmers' plot showing the duration of treatment, very different patients in the study. And I'll go over some of the responders and what the eventual outcome is in the next slide. And you can also see in these PK plots that show the pharmacokinetic exposure over the first 48 hours on the middle and over a longer period over on the right at steady state. How we are getting incremental increases in dose exposure up to 120 milligrams? At 160 milligrams where we have the fewest patients treated to date, it looks like we don't quite have a greater increase in efficacy there, suggesting that 160 milligrams may be the optimal dose, which we're getting maximum absorption at the moment. Now I want to highlight the responses that we've had on the study to date. As I mentioned, we're able to expand dose levels where we see signs of activity and that began at the 80-milligram dose level. We've now seen activity at 120-milligram dose level and at the 160-milligram dose level, as I will mention in a moment. This slide was actually prepared more than a week ago before we had that information of 160 milligrams. But what I want to highlight about the responding patients is the diversity of patients that we've had in the study with complete responses. They do include patients that have FLT3 mutations, including the FLT3 ITD shown there in red on the left. It also includes a patient with a FLT3-TKD mutation, that D835 mutation. It includes patients that have been previously treated with other tyrosine kinase inhibitors that target FLT3, including midostaurin and gilteritinib. But importantly, we've seen complete remissions in patients that have very adverse mutations. And in the FLT3 mutated group, these include mutations such as mutations in NRAS, mutations in RUNX1 and mutations in MLL-PTD as well as KRAS and PTPN11. Some of these mutations are typically associated with resistance to tyrosine kinase inhibitor exposure. Importantly, we've also seen activity in patients who do not carry a FLT3 mutation. These FLT3 wild-type patients, as we describe them on the right. And in particular, 1 patient that had a very adverse genotype, a TP53 mutation along with highly complex cytogenetics, had a very prolonged remission. In fact, they stayed on study for over 14 cycles. Now you'll see that many of the other patients didn't stay on study quite as long, and that's because 5 out of 6 of those patients went on to undergo hematopoietic stem cell transplant. That is an excellent clinical endpoint that you're able to get your patients to, if you can, because it represents a potentially curative therapy. And for patients with relapsed/refractory disease, it can often be difficult to put them into a deep enough remission such that a stem cell transplant makes sense. And our most recent responding patients shown there in the middle of 120 milligrams that are achieved to CRI, actually just now has come off study in order to begin a stem cell transplant. Now this is a swimmer plot of those responding patients that I just showed you, highlighting the depth of the response. And you see that many patients actually had maturation of response, leading them to a CR and suggesting that despite daily dosing of 239, they don't see additional myelosuppression that true CRs of that qualification are definitely possible. And as I mentioned over the last couple of days, we've learned that we have another patient that had a response to a patient that had a newly reported CRI at 160 milligrams, also with many adverse mutations, including mutations NRAS, U2AF1 and SVEP1, and this patient does not have a FLT3 mutation. This is another, what we call wild-type AML patient. Interestingly, they had AML with myelodysplastic-related changes which are patients that often have these kind of more difficult to target mutations or more difficult to treat disease. So we're hopeful that, that patient will progress the depth of the response as time goes on. Now let's talk briefly about the safety of 239 in our experience to date. We have not had any drug-related severe adverse events. We've not had any drug-related deaths. And we have not had any of the common side effects or dose-limiting effects that have affected other tyrosine kinase inhibitors. In particular, we have not seen adverse events related to elevated creatinine kinase. We have not seen adverse events related to QT prolongation, and we have seen no observed relationship between the change in QTC and dose. And importantly, we have not had any dose-limiting toxicities up and through the 160-milligram dose level, although we do have 1 dose-limiting toxicity of muscle weakness that was not a muscle breakdown or rhabdomyolysis, and this occurred in the 200-milligram dose level. So we believe we've identified a safe therapeutic range where they brought therapeutic window, spanning the dose levels of 80, 120 and 160 milligrams in which there were no dose-limiting toxicities encountered despite now having treated tens of patients at these dose levels. And we're continuing to explore the safety process cohorts as we expand them further in order to optimize the dose that we will carry forward into our subsequent studies, which I'll tell you about shortly. So where we are today is that we have had a successful dose escalation and dose exploration phase of the Phase I study, where we demonstrated CRs in FLT3 mutant AML, and we received Fast Track designation for treating FLT3 mutant patients. We've also selected 3 expansion doses that we'll take forward, as I will described shortly, and we continue to explore molecular subgroups, particularly with adverse mutations to identify other potential groups that might carry forward for Fast Track and share with you with ongoing news flow. So our plan will be to select 120 milligrams as our primary single-agent expansion dose with 80 milligrams and 160 milligrams bracketing doses that we can adjust to in order to refine our dose selection. And we plan to explore this both in FLT3 mutant patients as supported by Fast Track designation, but also in FLT3 unmutated patients with adverse mutations like the ones we just described. The single-agent studies, we expect to begin in the second half of 2022 in combination studies of 239 plus venetoclax in FLT3 mutated and unmutated patients to begin in the first half of 2023. So what does that look like in diagram form? Patients who are enrolled after this expansion phase goes live later this year will be stratified first by their mutation status, whether they have a FLT3 mutation or whether they do not. And then they will be assigned to either the single-agent treatment group or the combination treatment group with venetoclax once that study becomes available. Finally, we do plan to include a triplet group of HM43239 plus venetoclax and the hypomethylating agent later on that will enable us to then explore moving to earlier lines of therapy. And the key objectives for the study will be as you see there on the right, primarily focused on safety and tolerability, but also helping us ensure that we have the right doses for our studies going forward, including potential registrational studies that would follow these important expansion studies that we're doing as part of our Phase I. So to summarize the major objectives in AML target populations that 239 could explore, the first and most important is relapsed/refractory AML patients with FLT3 mutations who have been failed by a prior FLT3 inhibitor. These patients have great unmet medical need and really know available off-the-shelf options. So therefore, the ability to rescue these patients and perhaps in the new transplants, we now have with several patients in our study would allow us a quicker path to registration and that is in line with the accelerated approval that we have. Then we would explore relapsed/refractory AML patients with FLT3 mutations that have other adverse mutations such as TP53 mutations and others we've seen and primarily explore them both as a single agent, but also in combination. And this also could lead to other options for accelerated approval. Then we'll look at relapsed/refractory AML patients in combination studies, primarily venetoclax to begin with, perhaps a triplet regimen if that allows us to go into earlier lines of therapy. And that would include focusing on patients who are unfit for chemotherapy. It would be relegated to a hypomethylating agent, perhaps in combination with venetoclax as well as potentially fit patients who would be treated with high-dose chemotherapy, again, to see if they would benefit from additional FLT3 inhibition at the time of the first treatment. So I'll summarize our experience with 239 thus far. We inhibit a variety of important kinases that essentially give us the opportunity to treat multiple targets with 1 medication, so multi-target treatment and 1 medication, including some of the mechanisms of resistance that often arise to other FLT3 inhibitors. And our clinical experience to date suggests that we have an excellent safety profile associated with an excellent activity profile that would allow us to explore this further, not only in a single agent, but also in combination in varieties of different populations, including those with highly adverse mutations, whether or not they have FLT3 mutations. And supporting that is our FLT3, our Fast -- FLT3 AML Fast Track approval that we received earlier this year. So our goals going forward would be to explore additional adverse genotypes to see which ones are sensitive, so go on and share this news with you in a rolling manner throughout 2022 and to plan those expansion trials that I mentioned in the second half of this year and then in the early part of 2023 that will allow us to move on to registrational studies. So enough from us. What I'd like to do now is pass it to Dr. Brian Druker, Head of our Scientific Advisory Board and obviously an expert in this area, to share his opinions about how kinase inhibitors have shaped treatment landscape for cancer in general, but AML in specific. And then I'll ask him to share some of the questions that others have about 239 AML with some of our other KOLs on the call today. So Dr. Druker, I will pass it to you.

Thank you very much, Dr. Bejar. It's really nice to be here and to be able to share some perspectives with you. And as Dr. Rice noted, I've been involved in the development of kinase inhibitors for well over 20 years. And in fact, I was in clinic this morning and had a patient on imatinib, who's been with me for 20 years. His youngest daughter is now a 10th grader, and he's just gotten to do amazing things over the last 20 years that you never thought he'd get to do. But the reality is, is that CML or chronic myeloid leukemia now has 6 different kinase inhibitors FDA approved, and it gives us a whole suite of drugs to choose from. You really get other kinase inhibitors and targets that have come along. You have EGF receptor inhibitors in which they are 4. And interesting that there are actually 2 FDA-approved inhibitors for FLT3, midostaurin and gilteritinib. And midostaurin is a much more difficult kinase inhibitor. And I think there's lots and lots of room for improvement. Now about a decade ago, one of my colleagues who is the President of ASCO said, well, CML and what Brian worked on was a pretty easy cancer. Why don't you work on something a little bit more difficult? So for the last decade, I've transferred most of my laboratory work into AML, which I view as one of the most difficult-to-treat cancers or leukemias. If you look at the number of new cases over 20,000 and that 50% of those are going to die with -- even within that first year or 2. So this is the most common adult leukemia. The 5-year survival rate has been stuck at about 30% for as long as I can remember. In patients who relapse, their median life expectancy is less than 6 months. And despite that, we know an awful lot about the molecular drivers of AML, and FLT3 is clearly one of the top targets that have been identified over the past several decades. And it's absolutely clear that we need new and better targeted agents to treat newly diagnosed as well as relapsed/refractory patients with AML. But in addition, what's absolutely clear for AML is that to achieve durable and long-lasting remissions and higher remission rates, we have to get to combinations of therapy. And to do that, we need well-tolerated agents that can be combined. And I pretty much just summarize where we are. Clearly, for patients with refractory AML, we need something right now. And I've certainly been impressed already with 5, 6 complete responses to single-agent therapy with 239. But more importantly, if we're going to really make an impact on this disease, we have to be able to move these therapies up, and we have to combine them to get durable responses. But if we're going to combine these drugs, we have to have safe drugs that are well tolerated so they can be effectively combined and then moved up into newly diagnosed and even into patients who might be otherwise candidates for the combination chemotherapy that we currently give to our patients. So I see there is a huge unmet medical need in the field of AML. And I'm certainly hopeful that 239, as Dr. Bejar noted, can fill some of these gaps, both relapsed/refractory, but then in combination and then ultimately in the upfront setting. So rather than listening to me, I actually want to bring on our other key opinion leaders, and that will be Dr. Brian Jonas and Dr. Naval Daver, who are currently investigators on the 239 study. And I really want to get their views on both relapsed/refractory AML and the results they're seeing with 239. So Dr. Daver or Dr. Jonas, if you could just start and let people on the call know a little bit about what a typical relapsed/refractory AML patient is like? What kind of condition are they in? What kind of treatment options they have? And how many treatments are they typically gone through when they come to see you in your clinics?

So sure, I'll start and then I'll turn it over to Dr. Jonas. So I totally agree with Dr. Druker that AML is probably the most difficult of all malignancies. These patients hugely present acutely ill, especially in the relapse setting and especially FLT3 mutated often come with elevated white count, because FLT3 is a proliferative mutation, and these patients will often have 4 to 5x higher than normal white count, and that usually leads to liver dysfunction, kidney dysfunction, pulmonary issues. 30% to 40% will present with an active infection because even though their white count is high, they are not functional white cells, and they have immune dysfunction. And the other common thing that we can sometimes see is that these patients who have had prior allogeneic stem cell transplant may also be having some degree of graft versus host disease or be on other medications that are being used to control the post-transplant immune flares. So it's a very complicated situation compared to, let's say, a newly diagnosed lymphoma or lung cancer. These patients already are kind of starting at a more difficult position. So I completely agree, there's a huge need for drugs that are not only effective but are also safe. And I completely echo Dr. Druker's comments that combination therapy that can be delivered safely will be very, very critical. Dr. Jonas.

Yes, thanks, Naval, and thanks, Dr. Druker. I think the -- I would echo everything that's been said, the patient population is very diverse, but the FLT3 mutated patients, in particular, as Naval said, often present with high white count hyperleukocytosis and other challenging clinical scenarios and can be very sick and get very sick very quickly. A lot of times, when they get to me at the academic center, they've already been through a few lines of therapy, sometimes some of the standard therapies, and they can be relatively beat ups for, lack of a better expression, from the impact of all their therapies and highly susceptible to infections, maybe the performance status has suffered as a result of long-standing disease or potentially being relapsed and not back in remission for some long period of time. And so I think to really drive on the point that was mentioned already twice now, effective therapies that are tolerable are so important for these patient populations and to give them the opportunity to actually take therapy and get enough therapy in them to have a response and then maybe they can get well enough to get something like a transplant that might be required for them to have any sort of chance of the long-term survival.

So you've both been involved in any number of drug development in AML. How difficult is it to get to a complete remission with a single agent in this patient relapsed/refractory population? How do you see that with a single agent?

Brian, do you want to...

Yes. I mean it's not a common event. I mean the response rates in the teens and 20s are sometimes -- that's -- we get all excited when we see numbers like that and often, they're much lower than that. It's very challenging.

Yes. I mean even to look at drug that's approved, right, which is currently the gold standard gilteritinib in FLT3, if you look at the complete remission rate in relapse, a single agent is about 14%, 15%. If you add CRIs and CRHs, then yes, it probably gets around 25% to 30%. But I think there's definitely room to try and improve that.

So when you look at 239, 5, 6 patients who've gone, have received -- achieved a CR, several have gone to transplant, is this typical, unusual? And what's your view on this? And what you're seeing in the clinic?

I'd say this is very encouraging. I think a couple of things me and Brian both use this in clinic in a number of patients is, it's been very safe. This is something we started noticing early on even before, I think the responses. We have not seen liver toxicity. We have not seen GI toxicity, cardiac issues. And I mentioned these because these are the common ones that have been seen with other agents in the FLT3 space, gilteritinib, crizotinib, sorafenib. So that's been quite positive. And then seeing responses even at the early doses 80 and 120 and a number of responses, if we see one response, we always kind of joke in the academic community, right, that happens a lot with the first patient usually. But when you have 7, 8 and it's happening consistently, I think this is a real effect. And Dr. Bejar mentioned, I'd highlight that some of these patients had received prior PKIs that target FLT3 like midostaurin and gilteritinib. So to have a response after that is really, really positive.

Yes. I guess the 2 that I wanted to focus on, Dr. Jonas, I know you had the 1 patient who had got midostaurin and gilteritinib. And I'd love for you to hear about your experience there, but I was impressed with the TP53 mutant patient who got to a CR. I can't remember ever seeing a patient get to CR with a single agent with the TP53 mutation.

Yes. I mean that's -- those patients have a terrible prognosis. And that's -- it's even a pretty terrible prognosis even in the first line, let alone somebody who's had extensive pretreatment. And so I think, I agree with you, this is -- I think that's another thing that strikes me about the data that we've seen so far is the diversity of responses, which is, I think, very impressive.

And Dr. Daver, you mentioned a little bit about the tolerability. Perhaps you can tell us -- both of you tell us a little bit more about what you're seeing as far as a safety and tolerability? Because again, in my view, and every -- all of you have timed in that combinations are essential. So what have you seen in terms of your patients who are really pretty sick, how have they done on this medication?

Right. Yes. I think that's a great question, Dr. Druker. And I think that's what we have highlighted. These patients, the median is about third salvage, second-third salvage. So these are actually sicker patients and more advanced patients that were evaluated in the previous studies, many of which we were involved with and lead, for example, with quizartinib and gilteritinib because those were kind of the first major FLT3 inhibitor. So we use them in the first salvage setting 7, 8 years ago when those trials were being done. And now we have those drugs. So the people who are going on 239 are more advanced salvation. So I was nervous that we would see more toxicities and difficulties and tolerability because we know that the more prior therapies the patient has had the more prior transplants, the more infections. The weaker they are, the higher risk. So it's been very pleasant to see that it's overall been well tolerated. I think the only things we have seen are minor GI issues, some degree of diarrhea cramping. We have not seen any significant GI, hepatic, cardiac, renal toxicity. We have seen some muscular ages and inflammation, and that's something we kind of have seen with other TKIs, even in CML. So we're measuring that. But all in all, I think as a single agent, we will see how the responses pan out. This is definitely encouraging, but I think it really opens the door to move quickly into combination with this drug given its good safety profile.

Yes. I'll echo that. And my own personal experience on the trial, the drug has been very well tolerated. And my patient who responded, for example, felt better on the treatment -- on the 239 treatment than they did on the previous treatments that they had before. So not only do they -- they not have significant toxicity, but they're their overall well-being, I mean, maybe that correlated with the CR, but nevertheless, they felt better on the medication. So I thought that was kind of impressive.

I know in the past, a lot of people have debated about whether the endpoint of eligibility of moving transplant is a fair endpoint. What are your views on that one and getting a number of these patients into remission and on to transplant?

I mean, I think that's the goal of treating people with relapsed/refractory AML, if possible, to get them to transplant, at least that's my opinion. That's the only real effective treatment for producing a durable long-term remission at least in our current armamentarium. So yes, that's outstanding to see patients going to transplant on the single agent.

And just to echo, Brian, that's something that historically, the FDA regulatory-wise, did not consider a valid endpoint 10 years ago. But now actually, recently, and this is reflected in the gilteritinib approval as well, they actually did allow both duration of response and overall survival as well as best response capture post-transplant in patients who are on the ADMIRAL study. So I think that there has -- and we've seen this in other studies as well, so there's a shift to accepting there a drug that can safely get patients to stem cell transplant actually is a benefit to the patient and should be considered favor of the drug. So it's a good sign.

Great. And do you have any final thoughts about 239 and where you think this will land?

Yes, I can -- I mean, I think that we have to be cognizant of the fact that this is still a competitive space. There are other effective FLT3 inhibitors that have been around for 8, 10 years, gilteritinib and crizotinib were probably the most effective single agents and in combinations with venetoclax, [indiscernible] activity. I think the paths here are: one, to see how we can continue to hopefully generate responses after prior TKIs, as we saw with Dr. Jonas' population because that's still a big area of unmet need. We get a lot of referrals at MD Anderson for patients who have gotten midostaurin induction, then got gilteritinib, single agent or combo and then failed and they have no option. So there, any activity, even 20%, 30% would be better than 0, which is what we have currently. And then the other would be, as Dr. Bejar showed, to move the combinations because we do have combination data with gilteritinib/venetoclax, with crizotinib/venetoclax, but it is quite myelosuppressive. And that may be a class effect that may be seen when we combine other drugs with venetoclax. But if it's not, then that could really open up a path to move 239 ahead quickly, Brian?

Yes, I agree. I don't have a lot to add to that, but I think the combination therapy, especially with the venetoclax combinations, as you point out, are not necessarily easy to give and especially in a relapsed/refractory patient, for example, but even in the front-line unfit patients. So I think if the drug ends up being as well tolerated as we're seeing so far in combination therapies, that would be also very exciting. And I think something that would be maybe able to distinguish it more from some of the other drugs that are out there.

Wonderful. Thank you both for sharing your perspectives on this exciting advance in the treatment of AML. And Dr. Bejar, I'll turn it back to you.

All right. Thank you. And thank you all for the great discussion and participation there. I think it's wonderful to hear your personal experiences and your thoughts about the drug going forward. So just to recap our future plans here before we get to questions that HM43239 has already shown itself to be a drug. It's clinically validated in having treated both FLT3 mutated FLT3 unmutated patients and having achieved CRs. We plan to continue our current phase of the study where we explore different dose levels to get a better sense of their activity and exposure in patients and use that to refine or subsequent studies that are going to come later this year. And that includes that single-agent trial that I mentioned, both mutant and unmutated for 3 patients with adverse mutations with a single agent and then in combination with venetoclax, something that we highly anticipate being able to do and move the drug forward with. Our plan is to start with 120 milligrams as a single agent dose, and then bracket that with 80 and 160 milligrams is tolerated, perhaps even allowing patients to dose escalate should they need to after an initial cycle of therapy at a lower dose. So data permitting, we will then request allowance to move additional genotypes into this high-need category and for potential accelerated approvals and ultimately plan what our registrational studies will be based on this experience that will come with the subsequent expansions. Ultimately, we're looking beyond that and looking to see what our plans for commercialization might be, and that is to include as many patients with AML as possible as long as we learn about, which are likely to respond. So that includes FLT3 mutant, but also could include FLT3 unmutated patients having seen the activity that we've noted thus far. And as we move into earlier lines of therapy, that also could include treating patients who are fit or unfit as well as relapsed/refractory patients, not just in first line, but also in second line and beyond. And then with luxeptinib, we're very excited by this early data that we've gotten with G3. I think it really does hold further promise for this drug and our ability to move forward and will continue to explore G3 and then hopefully move to continuous dosing as soon as we have a better understanding of the ideal dose with which to do that, leading us to getting higher exposures with less drug, less pill burden and less drug to manufacture. So at this point, I will, again, thank our key opinion leaders: Dr. Druker, Dr. Jonas, Dr. Daver. I think it's really illuminating discussion. Very much appreciate you having you on the call with us today. And we will move on and open it up to questions.

[Operator Instructions] So our first question comes from Gregory Renza from RBC.

Thanks to Bill, the Aptose team and the physician experts for joining us today, very helpful presentation and dialogue. Maybe to kick off and maybe pitch it to the panel, if I may. You covered a great deal of attributes about 239, both on the efficacy potential as well as the safety set. I'm just curious if you could help boil down some of the -- maybe just the top area of the profile that you are excited about, certainly helpful to hear about the safety and, of course, the combination potential, the diversity. But maybe just helping us understand that area that is most exciting to you? And then on the flip side, maybe some commentary on some of the greatest risks to the profile that you think are worth considering.

Yes, I can start. I mean I think that the greatest risks are obviously in this very high-risk population is the efficacy parameter. I mean that's something that is going to be compared. And I think one of the things you have to be very careful of is when we look at the profile of these patients, we really have to match apples-to-apples. So we're going to see that a lot of these patients have had prior TKI. And I think we have to compare that. And there is data now being published from our group and from others of outcomes in prior TKI exposed patients with drugs like gilteritinib and crizotinib. So I think looking at it in that apples-to-apples comparison will give us a fair view because the 239 is going to get much heavier treated exposed population. I think the greatest opportunity, as both Dr. Jonas and me mentioned is really if the safety continues to be this encouraging to move quickly with combinations initially in salvage with venetoclax and then really upfront with the established FDA-approved backbone of HMA venetoclax in both FLT3 and maybe even in non-FLT3 mutated populations.

That's really helpful. And perhaps Dr. Daver, if I could just follow up, you mentioned on the muscle weakness finding. And I believe Dr. Bejar talked about a DLT at the 200. Perhaps you could just expand a little bit about the quality of that. And Dr. Bejar, any additional information you have on that finding in addition to [indiscernible] present, that would be very helpful.

I can...

Go ahead. Yes.

I can take that. Yes. So we did have a dose escalation cohort of 200 milligrams in 1 patient that developed muscle weakness during that first cycle of treatment. And one of the things that we worry about when you see muscle weakness all sorts of different potential causes. So was it due to muscle damage or muscle breakdowns? We explore that extensively and did not find any evidence of that. If anything, it had more of a myasthenia gravis type quality and ultimately, the patient did come off study and did have some improvement after they came off study and then moved on to the next therapy. So unfortunately, we lost a follow-up. So I would point out that this patient actually had one of the highest exposures that we've seen on the study today. I think it was the second highest exposure of any other patient treated at the 200-milligram dose level. And in part, influenced our decision having seen activity at 2.5x lower dose, to focus on our expansion studies at 80, 120 and 160. So that -- were this to be something that might crop up again, would be less likely to see it at these dose levels. We had a couple of other cases of unrelated muscle weakness. But as Mr. Daver mentioned, these patients are come to us with a lot of comorbidities, and it's not unusual to see this even in patients who are treated with other agents.

Congrats on all the progress.

Our next question comes from Li Watsek from Cantor Fitzgerald.

I guess for the doctors, I mean can you talk a little bit about the [ Clinical-VaR ] for 239 perhaps in relapsed and refractory AML patients that failed FLT3 inhibitors. And the second question is, I know it's small numbers, but how are you thinking about the dose response here? And I guess in the expansion cohorts, I guess, what do you need to see there to select, I guess, the going-forward dose? And you sort of select 120 mg as a primary dose. I just want to understand what's the reason behind that?

I can take the last part of that question first. I think the -- one of the advantages we have with the trial design that we're working with is that we could explore multiple patients at different dose levels, not just the 3 plus 3 that you get in dose escalation, and it gives us a better understanding of not only the safety, but also the PK and the efficacy. And noting that we are not getting substantially greater exposures at above 120 mg. we selected the 120 mg would be the go-forward dose with the caveat that we might be able to adjust that for certain patients who aren't achieving the desired exposure. I think that is a good balance between the safety that we've observed at these dose levels, the efficacy that we observed as low as 80 milligrams and the likelihood that we'd be able to treat a greater number of patients successfully by going slightly above it at minimally effective dose. So that's our thought. Now the beauty of the expansion studies is that they have some flexibility built into them, so that if 120 mg after treating additional patients doesn't seem like ideal to us, we'll have the ability to adjust that. As you may know, the FDA now is very interested in ensuring that companies have done a good job of dose exploration in early phase studies before they're treating a large number of patients and struggling on what may be a too toxic dose of their drug for eventual regulatory approval study. So we're hopeful that this exploration we're doing now will pay off in the long run. It might take us a little bit longer to get through it. I'll get some better understanding and a more solid rounding when we select our final dose.

And I think to the first question, it was really teasing out the importance of responses in prior TKI exposed patients. I mean, I think we need more numbers. I mean just to see activity in priority TKI exposed off the bet is already encouraging. Now we have to kind of look at it with more patients and see if this is 20% or is this 40%, where those response numbers will fall. So I think that's what's going to happen in the next stage of development, where we're probably going to want to have a dedicated number of cohort of patients who've had prior gilteritinib, for example, and try to get an actual percent response to see if that could be a path for early registration potentially if we do see activity.

So Just to echo that point, we are enriching our FLT3 mutant cohort, 4 patients with prior treatment, at least 50% of them have had a prior FLT3 inhibitor in that cohort. So we do want to make sure we have enough numbers there to explore that adequately.

Our next question comes from John Newman from Canaccord.

And I just had a few questions. The first one, I don't know if there would ever be a reason to continue dosing 239 during stem cell transplant, given the safety profile. I'm assuming that most TKIs are stopped or really any drug treatment is stopped before transplant because you have to blade the patients. Just curious if that's something that has really ever been tried. I'd be curious to hear a response from the physicians on the call. And a quick second question is just, have you identified any agents besides venetoclax that could be an interesting combination next year?

I'll let the AML experts weigh in, but I don't know that drugs have been used during conditioning for transplant but there's a huge opportunity to use a well-tolerated agent after transplant as a maintenance therapy to prevent a relapse. So perhaps on one of the 2 experts or both would weigh in on that.

Yes. I think Dr. Druker's point is a good one. There's a huge -- well, there's emerging data already showing that sorafenib, which is what we call a first generation and is a good drug but has a lot of issues with tolerability. But even with that agent post-transplant, now 2 randomized Phase II studies, one from China, one from Germany, have shown event for an overall survival benefit. And we think we can do much better if we have a drug that's actually more specific, more potent to FLT3 and better tolerated. And I think that's where, of course, gilteritinib is being evaluated, but could also be a path for 239. Now there is some data, actually our center has been looking at sorafenib for many years, an ongoing study with conditioning. And some of the preliminary data that Dr. [indiscernible], who was the Vice Chair of our transplant group, has presented, looks encouraging. So again, if it's a very safe drug, maybe it could definitely go into maintenance post-transplant, but there may even be a role to add it to the conditioning regimen. So it's a much harder regulatory path. Sorafenib, for many years, an ongoing study with conditioning and some of the preliminary data that Dr. [indiscernible] who was the Vice Chair of our transplant group has presented looks encouraging. So again, if it's a very safe drug maybe it could definitely go into maintenance post-transplant, but there may even be a role to add it to the conditioning regimen. So it's a much harder regulatory path. I think that's something that could be done as an extension after you have FDA approval, but it is an interesting thought.

Yes. I'll echo what Naval said on the aspect of adding additional drugs to conditioning. I mean that's -- that is an area of investigation, not just with small molecule inhibitors, but they're kind of immunotherapies and things like that. And so obviously, done on the clinical trial and really in the setting. And then I think the role of maintenance after transplant is very important. And clearly, there is data showing improved outcomes such as the [ Soma ] trial, as was mentioned. But clinically in practice, these drugs are not easy to administer. And I think that's -- and obviously, if you can't administer a drug that just can turn a benefit, then the patients are going to not get that benefit. And I think that's really a big issue. And the quality of life aspect I think as well. So I think, yes, maintenance after transplant is another really great opportunity.

Our next question comes from Matt Cross from AGP.

Just one question on each program here. So starting with 239. I just wanted to kind of go over the response levels that you're seeing very preliminary at this stage, I know, but across dose levels. Just was curious, I know Dr. Bejar, you commented that you're not really seeing substantially greater exposure at doses above 120 mg, looking at the 160 mg and the 200 mg. So I guess, is there anything else you can flesh out there about the [ therapy ] exposure trends you're seeing? And maybe as we look in and kind of project what we think may happen as you expand those cohorts at 160 mg, 120 mg and possibly 200 mg? Is there anything you can say about the mutation profile of -- and that element of patients at 120 mg or 160 mg that have not responded? We kind of emphasized who is responding, but whether how much that plays into the equation and who's not and whether what could be addressed by expanding the number of patients you're looking at?

No, thanks, Matt. That's a great question. I think that is one of the things you can learn about the drug in the clinical study beyond the safety and efficacy is you can learn a lot about the target patient population that's best served by it, and that involves looking at those patients that maybe don't respond. I think to Dr. Daver's point earlier, the patients on the study are very heavily pretreated, not just with BRAF 3 inhibitors, but all sorts of varieties of other agents, including some experimental agents. It becomes difficult to tease out whether or not their resistance is due to a previous mutation or prior or selection for resistance in a more general way, but we are taking a look at this. I think what really surprises me is that some of these mutations that I would expect to be more consistent resistance mutations like the RAS pathway mutations and TP53 mutations haven't necessarily been absolute barriers to response. And that gives us hope that we'll be able to treat some of these more challenging patients to treat. And as we get into earlier lines of therapy, see even greater activity than we're seeing now in those less heavily pretreated patients. So we are exploring that further. And to your question about the PK, the reason that we're taking the time to do this additional expansion is to really understand that better. Like most drugs with a lot of variability between individual patients and you don't really get a full picture of that after just treating a handful. I mentioned that we don't see what looks like greater exposure of 200 milligrams, yet one of those patients had one of the highest exposures we've seen on study today, suggesting that there's a lot of variability at that dose level, some patients actually have lower exposure to patients at even lower dose levels. So we'll need more numbers in order to make more firm statements about dose response relationships or even dose toxicity relationships. And we're taking the time to get that information so that we'll finally get to the point wanting to move to the next regulatory step. We'll have that data to back us up and won't be asked to go back and have to repeat it.

I want to kind of piggyback on that as well. We didn't talk about it, but the mutations that Dr. Bejar is mentioning are typically ones that are known to be resistant to gilteritinib. So both Catherine Smith and our group have published now papers in cancer discovery and blood cancer discovery showing that people who have treated with gilteritinib at the time of relapse, about 35% of them have emergent RAS-MAP kinase mutations, which, in fact, drive resistance. And even if you look at them pretreatment, patients who have a higher allelic burdens of RAS, don't respond. So there were 2 patients at least who had a RAS or a RAS-MAP kinase mutation like PTPN11 who responded to the 239. And then there was one who had an MLL, which also is historically associated with the resistance to FLT3 inhibitor single agent or short duration of response, if not resistant. So that is, again, small numbers. But biologically, is very interesting and could start differentiating 239 from gilteritinib and quizartinib if we continue to see that.

Perfect. That's exactly what I needed. And then just briefly on lux. I wanted to address similarly on kind of a PK angle. Very helpful to see some of the comparison in this single-dose setting between the G3 and the G1 exposure levels, it looked like, I guess, across patients, the 50 milligram and the 100 milligram G3, were sort of in the same ballpark. I know you're expanding to look at 200 milligram as well. So I just wanted to review the rationale given that it looks like the 50 milligram and 100 milligram doses, you're getting exposure levels that are, again, in the same ballpark as the 750 milligram or 900 milligram. So dose change here is great from like a pill burden perspective. But is there kind of a ceiling there that you think you can push past with looking at 200 milligram? Or what -- any additional context on that, those takeaways at this stage would be super helpful.

Yes. I think one of the reasons for exploring different dose levels of G3 is really to get more information about how to model it in continuous dosing because that's going to be the next step. After we get this data, we'll look at the PK parameters associated with G3 and then try to predict what it will look like when we give it continuously. So even though small differences after a single dose can really add up. As you saw, there were still a drug left over after 72 hours, and the small initial differences with those could lead to very different -- steady-state differences in concentration. And our goal is to get to higher exposures through this dose escalation mechanism so we can truly test the efficacy and the drug at exposures we haven't been able to reach with G1. I think if you look at the PK curves at G1 that we published previously, there is a ceiling there that as we went from 750 milligram to 900 milligram, for example, we didn't necessarily see more drug get in. So on a per milligram basis, G3 is definitely doing better. And the small differences that you see in the single dose may actually translate to more meaningful differences to steady state down the road. So that's the reason for exploring it. I think we just did a single dose and said, well, that's roughly equivalent, let's go. We wouldn't necessarily have that understanding that we need in order to do more accurate modeling. So we'll take the time to get a few additional patients to 200 milligram, get that data together, do the modeling and then push the continuous dosing.

So our next question comes from Joe Pantginis at H.C. Wainwright.

So first, I just wanted to ask the company if you could provide any comments around the ease of manufacturing of G3 of blocks. And are there any rate-limiting steps that we need to be aware of to be able to have all the ample drug supply that you need for your plans and beyond? And then second, and more importantly, obviously, as everyone is talking about the profile of 239, Aptose has always been very good with the visibility around and especially the slides where their particular drugs FLT3 kinome, kinome trees and which dots are more red than others and how big the dots are, et cetera. So I mean, I know the slide is not up right now, but obviously, you're hitting a lot more of the kinases that talked about maybe for the physicians on the line, when you consider the broader hits that 239 is having. So far, the safety profile has been discussed already, but do any of those particular kinases give you pause or potential concern with longer-term exposure?

Well perhaps I can -- can you hear me Joe?

Yes.

All right. So perhaps I can start with the G3, the manufacturing. We have an ample supply of the drug substance because you'll remember when we were manufacturing the G1, G2, we were having to manufacture the drug substance so frequently, very expensive and then making the capsules also for the G1, G2. It looks like we've been able to -- are going to be able to deliver much less API drug substance in the G3 to be able to support these exposures that we want to achieve. And so that's greatly reduced our need for the amount of drug substance that we produce. You also asked about the manufacturing of the drug product. It's that G3 capsule. So it's a relatively simple procedure. Once we identified the excipients that were included in there, it's a self-emulsifying process. It's relatively simple to manufacture. We've been able to manufacture at least 2 manufacturing runs of the GMP material now. It appears to be stable over time. So we don't see that as a problem right now. We will have to continue to manufacture over time as we expand -- hopefully expand out in these continuous dosing studies as we get to the latter part of this year and already next year. But at this point, I don't see that as being a showstopper by any means, whereas it would have been with the G1, G2. And then I'll let somebody else talk about the 239 and the kinases. Dr. Bejar, do you want to talk about that one?

Yes. And I'll let Dr. Daver and Dr. Jonas jump in. I think that agents that are very, very highly selected that target really only 1 kinase may show a lot of activity potentially in untreated patients because that target is active in that disease. However, these cells can quickly evolve other mechanisms to get around that. And you heard the discussion about NRAS MAPK pathway mutations that can do just that, they can bypass for 3 signaling. But if there are other mechanisms that are in play that cells are using in order to do that kind of bypassing, having a little bit broader activity can be helpful. If it's too broad, then -- as you mentioned in your question, then you can hit kinases that are important for toxicity and targets, you don't necessarily need in order to kill the cell but that might lead to toxicity of targets like eGFR inhibitor inhibition can be skin problem, HER2 Inhibition competed cardiac issues and so on. So I think having kind of a sweet spot where you have a good breadth of activity against important kinases not hitting those that are more relevant for toxicity is the spot to be. And we've shared that kinome tree, I think we'll have to take a closer look at it to see if there's anything there that might be concerning in long-term study so far, but we certainly haven't seen that to date in multiple patients running like that in the study.

Just a quick addition to that. When we were looking around at molecules, we were looking for a molecule, of course, that couldn't hit with the FLT3 through because it's one of the major drivers of AML. And we all wanted FLT3 inhibitor. But we also wanted one that inhibits all different forms of FLT3 that have been tested thus hard so that, that could minimize the resistance. But no one wanted just another FLT3 inhibitor because it's insufficient. So we wanted a molecule that also could suppress some of the downstream pathways, the JAK-STAT pathway, the Ras-MAP -- ERK-MAP kinase pathways as well as some of the AKT pathway without having to directly target PI3K or AKT. So that's what we were looking for. And so we actually saw this molecule a number of years ago before we ever licensed it in. And we thought that's going to be an impressive molecule, if it's safe because of the kinases that it hit and the pathway it affected. And so that was the reason we brought the molecule in. It did hit those pathways. It suppresses the right pathways. But thus far, it's been very safe. And then I'll pass it over to the other physicians if they have any other comment.

I want to just say real quick, we know from lots of lines of evidence at this point that AML is an oligoclonal disease, often in presentation. And so having broader activity is in theoretical -- theoretically is advantageous, -- and so I think that's one distinct advantage that allows maybe targeting some of the minor clones at the same time.

Great point. And many of the patients with FLT3 mutations relapse without that FLT3 mutation in part because they selected for those clones that don't have it. So if you can have some broader activity against both mutant and non-mutant cells, it might help suppress some of those potentially emerging clones.

So our next question comes from Matt Biegler from Oppenheimer.

One for the docs. Are you guys seeing any anemia-related side effects? That's obviously an issue with a lot of targeted agents in AML. And if you are kind of what's your confidence as you start thinking about venetoclax combination, considering you're probably going to be dealing with pretty frail patients? So that's the first question. And then I had a follow-up for management on maybe just qualitatively -- can you talk about the types of patients you enrolled into the 120 mg and 160 mg cohorts. Did you enroll less FLT3 mutant patients in those cohorts and might that explain maybe the top line differences in what we're seeing in response rate granted? We are dealing with very small numbers, obviously, but just any way you could speak to that would be great.

Yes. I can start with the anemia question. So no, we have not seen any significant signal at least to my knowledge, FLT3 in anemia per se. And actually, with most FLT3 inhibitors, gilteritinib and quizartinib, we haven't seen anemia as much. We do see more neutropenia with for example, quizartinib, which also hits KIT which is an important pathway for normal neutrophil and platelet development. Now in combination with [indiscernible], we're doing a lot of study Manderson, in the U.S., combining different drugs with venetoclax in, there is definitely cumulative myelosuppression, and it depends on the drug with FLT3 inhibitors, gilteritinib and quizartinib, we do see more significant cumulative myelosuppression. With IDH inhibitors, for example, [indiscernible] ivosidenib, we do not see that much cumulative myelosuppression. So I think that it just depends on the properties of the drug, and it will be very -- it's hugely obvious very quickly within 8 or 10 patients that this is going to lead to significant cumulative myelosuppression, we're going to have to do a lot of things to adjust it. It may still be effective, but it won't be straightforward and easy or it could actually not have significant myelosuppression. So I'm hoping that with 239, we see kind of what we're seeing with IDH, where we don't see much myelosuppression beyond what we see, for example, with HMA venetoclax standard therapy.

To follow on with that, once patients achieved remission and you follow them, the leukemia is kind of out of the picture before then, it's very hard to determine whether the cytopenias are due to active disease or the drug that you're giving. But we have had patients that have been able to continue to take the drug daily for weeks on end, including 1 patient over a year where they didn't see any additional myelosuppression. We've had no Grade 3 adverse events of anemia and certainly not in patients who have achieved response. So I think from that standpoint, it's not particularly myelosuppressive outside of the context where the patient's bone marrow is already challenged by either existing disease or perhaps another agent. And then, the management, could I just repeat that real quick? Yes, makeup of the different cohorts and might that explain the difference in response rate. No, I think the way the study is designed, we want to make sure that in those kind of expansion cohorts that we have at least 50% of the patients with a FLT3 mutation so that we don't bias at all one way or the other. I have to look back to get the exact makeup of each of those different cohorts. But I don't think it's necessarily that. One thing that we have seen over time is that gilteritinib has made greater penetrants into the patients that we've seen. So we're seeing more patients with prior pretreatment in particular, in Korea, where some of our study -- where some of our sites are and where some of our patients have been treated. Like gilteritinib, it was not widely available when the study opened in 2019. However, as of March of this year, gilteritinib is now reimbursed by the National Health System becoming more prevalent in the patients treated there. So I think we're going to see more of these heavily pretreated patients with that greater unmet medical need and perhaps the response rate overall will be a little bit lower. But interestingly, if you look at the response rate of the FLT3 treated patients in our FLT3 population, small numbers, but it's 50%. So that's really impressive. And overall, in the 80 milligram cohort the response rate, including the wild-type patients, was about 25%. So perhaps there is a difference over time in the patient population that we're treating. But I think as we get to larger numbers, we'll get a better sense of what that efficacy is.

Our next question and final question comes from Soumit Roy from Jones Trading.

Congratulations, panel for the comprehensive presentation. One, Dr. Bejar, if you can just reiterate, how many were the evaluable patients in the 120 milligram, 160 milligram and 80 milligram cohorts? And was there anything other than the blast count difference? How do a gilteritinib pretreatment in blast count difference or age or anything else that stood out accounting for the difference in the response rate?

Yes. A good question. No, we haven't formally looked at those measures as to whether they might account for a difference in response rate, I think it is just the classic variation at this point given the small numbers of patients that we've had. The -- remind me the very first part of your question.

The number of evaluable patients in the 80 milligram, 120 milligram and 160 milligram.

We haven't reported it as the number of evaluable patients we've really kind of treated as an intention to treat, so to speak, and we've told you the number of patients who received drug. Now it is true that some of these patients didn't necessarily make it to the a variable for safety, meaning they had a complication or something else that perhaps their disease progression where they didn't necessarily finish that first cycle. So technically speaking, they wouldn't have been evaluable for that first response, but we've just shown the numbers of treated patients. I think later on, we can consider doing a more nuanced example, but I think it's a fair less cherry-picking way of presenting the data, and that's what we show.

Okay. One last question is, given the visibly conservative nature of FDA taking recently, do you think a later line patient would have to move into a randomized Phase III to be the registration trial with median OS as the primary endpoint? Or...

I think it's a great question. I don't think the FDA was saying that you have to do that. I think the FDA was saying, you have to be very careful about what your dose is in that patient population and what your confirmatory study is going to look like, that you really have to do your homework before you propose to do a single-arm registrational study. However, if the patient population has great unmet medical need as these patients certainly do, then I still think that, that fast pass approval is going to be the most appropriate thing both for patients and for the FDA as long as you have a good plan for falling that up and getting to full approval that you thought about ahead of time, even before beginning the single-agent study. So I think that what the FDA was telling us is that there is a way to do it and you have to do your homework and you have to lay the groundwork for that, but that it's still an important pathway.

Yes. I want to echo that as well with -- sorry, Bill. Just with the FDA, I actually don't necessarily think in leukemia as they have become more conservative. Actually, if anything, I think they are now kind of seeing the benefit of targeted immunotherapies and trying to get these drugs approved very quickly. I mean, as you all know, 9 drugs have been approved in AML in the last 4.5 years, right? And many of them were actually single arm studies when they were approved with eventual confirmation, venetoclax, IDH inhibitors now, gilteritinib even right before the full Phase III survival. So I think in a major area of unmet need post [ mito ] gilteritinib, any drug that shows any efficacy with a good safety, I think safety is going to be what they really focus on there. They were not doing any harm, and we're having some benefit. I think that would open the path for early approval with then a larger study, probably in an earlier line as single agent or combo to confirm that. So yes, I think major unmet need in a rare population of AML will be treated very different from breast cancer or lung cancer, where absolutely they want full phase to randomize data upfront.

Congratulations again.

Thank you for the questions, Soumit. This concludes our Q&A session. I'll now turn it back to Dr. Bejar for closing remarks.

Thank you, Tara, I thank you all for your participation on the call. The discussion has been outstanding. I really appreciate the insight from Dr. Daver, Dr. Jonas and Dr. Druker, and the questions were excellent questions so either way some excellent points so we didn't have a chance to cover in detail. We'll have more information for everyone down the road as we collect the more nitty-gritty fine-tuned clinical data. So apologies to those who submitted questions we weren't able to get to in the question-and-answer session. We hope that those were answered in that subsequent presentation. So once again, thank you all.