All right, it seems that we've reached the noon time point. So good afternoon, everyone. According to the name badge, I'm Dr. William Rice. I'm the Chairman and CEO of Aptose Biosciences, and I wanna welcome you here this afternoon, and also thank you for joining us for this KOL event. Both all of you who are present today, as well as those who are listening remotely. I also want to, before we get into the activities, introduce everybody to the members of the management team that are here today. You see Mr. Greg Chow over by the door, Chief Financial Officer. Dr. Jotin Marango, Chief Business Officer, also over by the door. And here we have Dr. Rafael Bejar, our Chief Medical Officer.
So hopefully, you'll have the opportunity to engage all these individuals, okay? So finally, let's talk about or remind you of why we're here today. So I, I would—I suspect on many occasions you've heard me talk about our, our small molecule kinase inhibitor known as CG-806. We've also, we refer to it as eight oh six. This molecule has a highly unique kinase inhibitory profile, and that unique profile then positions it for development across a, a broad span of hematologic malignancies, including lymphoid malignancies as well as myeloid malignancies. So eight oh six has garnered a, a bit of notoriety recently because of its role as a, as a non-covalent or reversible BTK inhibitor being developed for the B-cell malignancies. Okay.
In fact, CG-806 is in a clinical trial currently for patients being treated with CLL as well as non-Hodgkin's lymphomas. And we're continuing to dose escalate the patients on that trial. We're thrilled about that trial and the fact that CG-806 is a reversible BTK inhibitor. But it's also very important to remind you that CG-806 is far more than just a reversible BTK inhibitor. And so what we want to do today is to bring awareness, shine a spotlight on the fact that CG-806 is also going to be developed for the myeloid malignancies. In particular, when we talk about myeloid malignancies, we're talking about acute myeloid leukemia or AML. So today what we've done is we've assembled a stellar group of key opinion leaders.
That's what they're gonna do is give you a quick overview on AML, the disease itself, the current therapies, the needs of the patients going forward, as well as how 806 might address the needs of those patients. Rather than stealing all the thunder, what I'm gonna do is I'm going to ask our Chief Medical Officer, Dr. Rafael Bejar, to serve as the moderator today, and he'll introduce our KOLs. Thank you so much. Thank you for being here.
Thanks, Bill, and it's great to have you all here in the room, and to those of you who are on the webcast, welcome. I'm glad you could spend your lunch hour with us learning a little bit more about AML and how CG-806 might fit in that landscape. We have a great series of speakers today that are gonna do most of the talking. The first is Dr. Eytan Stein from Memorial Sloan Kettering. He is a hematologist oncologist, treats patients with AML, and has played pivotal roles in developing targeted therapies in AML, including taking drugs all the way through to approval. He'll tell us a little bit about AML in the age of targeted therapies. How has treatment for this disease changed in the last few years, where we've seen a lot of drug approvals and a lot of changes to our therapeutic approach?
The second speaker will be Dr. Aaron Goldberg, also of Memorial Sloan Kettering, another expert in leukemias, and he'll be speaking more in the area of FLT3 inhibitors specifically. How has that landscape changed, and what are the emerging challenges that we see now that we have used those drugs in the clinic? And finally, we'll have Dr. Druker, who has kindly come all the way over from the West Coast to speak with us a little bit about his impressions. So I'm sure you all know who Dr. Druker is, but he has been the pioneer in establishing tyrosine kinase inhibition in cancer, not just in hematology, but in cancer in general. And I look forward to hearing his perspective on how CG-806 compares to other molecules he's worked with and what he sees as a potential use for this drug in the future.
Without further ado, since we have a lot of slides to get through, I'm gonna start with inviting Dr. Eytan Stein to come up and tell us about AML in the age of targeted therapies.
Okay, thank you very much. Thanks, Dr. Bejar. So we're gonna be talking a little bit about treatment of acute myeloid leukemia in the age of targeted therapies. These are my disclosures. So all of you know that what we have discovered over the past 10-15 years is that acute myeloid leukemia, while it has the same phenotype of having a block in myeloid differentiation at the myeloblast stage of development, it's really driven by many, many different molecular and cytogenetic alterations that are depicted here in this slide, put together by Hartmut Döhner in the European LeukemiaNet criteria for the diagnosis of acute myeloid leukemia.
It's becoming clear that in order to target this disease, you really have to pick off the individual genetic events that are happening, such as FLT3 inhibitors, IDH inhibitors, which we're gonna talk about in a second, to make any real progress in the treatment of this malignancy. So my colleague, Dr. Goldberg, is gonna talk much more extensively about FLT3 inhibitors. I'm just gonna say very briefly that FLT3 ITDs are very, very common, and FLT3 tyrosine kinase domain mutations. Together, they occur in about 30% of patients with acute myeloid leukemia.
There have been multiple attempts to target FLT3, and having a FLT3 mutation, an ITD or a TKD, despite what the European LeukemiaNet says, that maybe some of these patients might be favorable risk disease, I would still consider them all unfavorable risk disease, who are at very, very, very high risk of relapse and then death. You all know about the Phase III RATIFY trial, which was a randomized controlled trial comparing the combination of a moderate FLT3 inhibitor called midostaurin in combination with chemotherapy.
... to placebo with chemotherapy, with the key outcome of this trial being overall survival. At five years, there was a 7% overall survival benefit with the multi-kinase inhibitor that also targets FLT3 mutation compared to placebo. The second thing that Dr. Goldberg is going to talk about, but I want to mention very quickly, is the use of targeted FLT3 inhibition in relapsed and refractory acute myeloid leukemia. This was a randomized controlled trial published a few months ago in the New England Journal of Medicine by my friend and colleague, Dr. Alexander Sasha Perl, randomizing patients with relapsed and refractory FLT3-positive acute myeloid leukemia to salvage chemotherapy, which you can see on the bottom after the 2-to-1, or the targeted FLT3 inhibitor, gilteritinib.
The results of that trial show that there is an overall survival benefit, with a median overall survival with gilteritinib of 9.3 months versus 5.6 months with salvage chemotherapy, making gilteritinib really, I think, the standard of care right now in patients with relapsed and refractory AML. So what about other targeted therapies that we can use? So I've worked a lot, like Dr. Bejar said, on targeted inhibition of IDH1 and IDH2. I find this very interesting because IDH1 and IDH2 inhibitors function as differentiation agents. So what does that mean? So what that means is that when you have a mutation in IDH2, which is found in the mitochondria, or IDH1 in the red, which is found in the cytoplasm, the end product of the normal reaction, which is alpha-ketoglutarate, gets converted to what we call an oncometabolite, beta-hydroxyglutarate.
Increased levels of beta-hydroxyglutarate lead to a freezing of the cell in the undifferentiated state, in the myeloblast stage of development. Then if you target mutant IDH, you lower intracellular levels of beta-hydroxyglutarate, allowing the cell to then differentiate and then getting rid of the disease. This acts as a differentiation agent rather than acting as a cytotoxic. Interestingly, gilteritinib, the FLT3 inhibitor, can also act as a differentiation agent rather than than acting as a cytotoxic. There are a couple of different IDH inhibitors.
One of them that has been approved by the FDA is the IDH2 inhibitor, enasidenib, in relapsed and refractory AML, based on this clinical study over here, showing that an overall response rate of 40% in patients with relapsed and refractory AML, who got 100 mg of enasidenib once a day, and a complete remission rate of about 20%. And then when you look at this single-arm trial, the median overall survival, the median overall survival in all patients who are treated was 8.8 months. Obviously, the patients who would achieve a complete remission do much better. Those patients have an overall survival, median overall survival of 23 months. Now, what happens if you take IDH2 inhibitors and you combine them with standard of care, enasidenib, for newly diagnosed patients who are unfit for intensive chemotherapy?
So this was a randomized trial presented at ASH this year by Courtney DiNardo, and forget this part over here. This is the part that's important over here, where patients with newly diagnosed IDH2 mutant AML were randomized to receive azacitidine alone or azacitidine with the IDH2 inhibitor, enasidenib. Interestingly, the overall response rate is dramatically higher, 71% versus 42%, in patients who received the combination. Similarly, the CR rate is much higher, 53% versus 12%. However, the overall survival is equivalent, okay? So that might be, if you look at the event-free survival curves here, the combination appears to be numerically better than giving azacitidine alone.
And what we know is that some of these patients who received azacitidine alone, specifically seven patients, they actually, when they did not respond to azacitidine monotherapy, they crossed over and were able to receive enasidenib sequentially, and that might be what led to the equivalent overall survival. But I think it does raise the question, when you're thinking about targeted combined therapy with IDH inhibitors or any targeted therapy with azacitidine, it raises the question: Should you be giving these drugs together, or can you be giving them sequentially and get the same or perhaps even a better effect? What about the IDH1 inhibitor, ivosidenib? So similarly, in a clinical trial of patients with relapsed and refractory acute myeloid leukemia with an IDH1 mutation, the overall response rate was quite high at 41.6%.
The rate of CR was 21.6%, and then this new category we have, called CR with partial hematologic recovery and combination with CR, was 30.4%. Similar to the IDH2 inhibitor, the median overall survival that's depicted in black was 9 months, 8.8 months for the IDH2 inhibitor, and patients who achieved a CR or a CRh, depicted in blue at the top, had a median overall survival of 18.8 months. Okay, so moving on to different targets, targets that might be available in all patients with acute myeloid leukemia, not just a genetically mutated target. There's been a lot of activity about inhibiting BCL-2, not only in CLL, but also in AML. So you all know that BCL-2 is an anti-apoptotic protein.
So you get overexpression of BCL-2, cells live, you inhibit BCL-2, the malignant cells are supposed to die. And when you combine hypomethylating agents with venetoclax in newly diagnosed patients unfit for intensive chemotherapy, you get these really dramatic rates of CR and CRi of about 70%, and those rates of remission really persist whether you have intermediate risk disease or unfavorable risk disease, poor risk disease. So here you're getting 60% remission rates in patients with poor risk cytogenetics. And what that translates into is median overall survival in all patients treated of 17.5 months, and this is regardless of what dose of venetoclax these patients got. I think what's important to note when you look at these slides, which are shown everywhere, is that just because the rates of complete remission are high, the rules still stand.
Meaning unfavorable risk patients continue to do poorly, and why is that? They all go into remission, but the unfavorable risk patients relapse very, very quickly. So if you have a p53 mutation, we're getting these p53 mutant patients into remission now, but they're relapsing 2 months after going into remission, while the NPM1 mutant patients, which would be favorable risk, those patients may have very, very prolonged duration of response. And if you look at the sort of the survival curves, the poorest disease continues to do bad, the good risk disease continues to do well. So BCL-2 inhibition doesn't alter the underlying biology of how you think a patient would do. It doesn't turn bad risk disease into good risk disease. It's still bad risk disease. Okay, finally, I want to talk about this trial here, because I do think that this is potentially practice-changing.
Let us go back over here. This is the first randomized controlled trial to show an overall survival benefit with maintenance therapy in acute myeloid leukemia. There was actually a randomized controlled trial with a histamine agonist called Ceplene that showed a progression-free survival benefit. But this is a trial taking patients in complete remission, older than the age of 55, who had a performance status of 0-3, intermediate or poor cytogenetics, who did not have an allogeneic bone marrow transplant, and then randomized those patients to receive CC-486, which is an oral formulation of azacitidine, or randomized them to receive placebo.
Patients who had a CR continued CC-486, patient who had sort of an early relapse were able to increase the dose of CC-486, and patients who had a real relapse had to stop treatment, no matter if they were getting placebo or CC-486. This is really, really interesting. You can see that there is a overall survival benefit for those patients who receive CC-486, 25 months versus 15 months in these patients. I do think for patients who don't have an allogeneic bone marrow transplant, I think maintenance therapy is really going to be a real thing, either with CC-486 or in the context of patients who have FLT3 mutations, getting a FLT3 inhibitor, either if they don't have a transplant, without a transplant, or post-transplant for those patients who have had an allogeneic bone marrow transplant.
With that, I'm going to move it on to Dr. Goldberg. Thank you very much.
All right. Thanks so much, Eytan, and thanks to Raf and the organizers for this opportunity. So I'm gonna talk more specifically about FLT3 inhibition in the context of acute myeloid leukemia, recent advances and also emerging challenges that, you know, Eytan and I see in the clinic all the time. These are my disclosures. So I think just backing up, it's important to remember that even now, in this era of novel and targeted therapy, AML is a deadly disease. Unfortunately, the vast majority of patients that Eytan and I see in the clinic will die of this blood cancer. It can be diagnosed at any age, but the median age at diagnosis is 68 years old. It can progress rapidly. It can be very difficult to treat.
It's actually the second most commonly diagnosed leukemia, just after CLL, with 21,000 people diagnosed with AML this year, but it's not so prevalent, and the reason for that is because so many people die of the disease. So with 10,920 deaths approximately from AML occurring this year and a five-year survival rate even now of about 28.3%. We see that AML is a deadly disease, even in so-called favorable risk subtypes. This data is a little bit older, but the curves don't look, unfortunately, all that different even now.
Favorable risk patients, a 55% chance of overall survival doesn't sound so very favorable when you're, when you're a patient, and it's obviously much worse if you're intermediate or unfavorable risk, and that's of course, based upon the cytogenetics and molecular abnormalities at diagnosis. And this is particularly true when you look at older adults, and again, we talked about the median age of diagnosis is 68 years old. Many of the benefits that we've seen, at least until recently in acute myeloid leukemia, have gone to younger patients.
This is just looking at survival curves in MRC trials in England from the 1970s up to the 2000s, and you can see that over time, younger patients seem to have done better, not so much with older patients, and a lot of that may just be due to advances in supportive care, antifungal medications, ICUs, patients who were able to survive therapy, you know, more better, but they weren't actually getting biologically directed treatment. FLT3 activation is actually the most common abnormality in AML. Backing up to what Eytan showed you, that slide, in the modern era, what we would like to do ideally is target the underlying biology of the disease. So this is actually looking at genomic sequencing of over 1,500 patients.
This is from Elli Papaemmanuil at Sloan Kettering, and what she found is that there are a variety of, you know, heterogeneity of mutations in AML. One really stands out, and that's FLT3, which is a tyrosine kinase that's found mutated in 25%-37% of patients, so really about a third. FLT3 is a tyrosine, or receptor tyrosine kinase. There are two, in general, types of mutations in FLT3 in AML patients. There's these ITD, internal tandem duplications, in the juxtamembrane domain. That's in about 25%-30% of patients. This really confers a high relapse risk and unfortunately, makes patients really less sensitive to intensive chemotherapy, and is clearly a poor prognostic marker. FLT3-TKD, tyrosine kinase domain mutations, about 5%-10% of patients.
The prognostic significance, I would say, is still controversial in the context of chemotherapy, but they certainly can be a mechanism of resistance to FLT3 inhibitors. In particular, TKD mutations confer resistance, for example, to quizartinib, which we'll talk about. Here's the data showing that FLT3 ITD mutations, in particular, are poor prognostic markers in AML. You know, back in 2002, in these patients who received intensive chemotherapy, the ITD mutation patients obviously did the worst, and then DNMT3A perhaps really think worse than FLT3 mutation, non-FLT3 mutated patients. The worst outcomes were actually seen in patients who were triple mutated for NPM1, DNMT3A, and FLT3 ITD, which is actually the most common triplet occurring mutation in all of the AML.
So in terms of the landscape of currently available FLT3 inhibitors, that's summarized here on this slide, there are three FLT3 inhibitors already approved worldwide, only two in the United States. So midostaurin, so, you know, I'd really think of this as a dirty drug, right? It's a multi-targeted, but really dirty tyrosine kinase inhibitor. It's given orally, all these drugs are oral, twice daily. FDA approved in 2017. It's approved only in the context of newly diagnosed patients and only in combination with chemotherapy. It has been tested, of course, as monotherapy in relapsed refractory AML and has very poor response rates, but does seem to provide some overall survival benefit, which we'll talk about. It targets both FLT3-ITD and TKD mutations, and there are some adverse effects, particularly GI toxicity.
Gilteritinib is the only FDA-approved FLT3 inhibitor in the context of relapsed and refractory AML with FLT3 mutations, more recently approved. It's approved as monotherapy, so as a pill alone, targets both ITD and TKD, and also has its own set of side effects, although I'd say overall, well-tolerated, though we certainly can see LFT abnormalities, CK elevation, and other rare toxicities, including myopericarditis, which I've seen. Quizartinib, so this is an interesting story. So quizartinib is approved in Japan on the basis of data which I'll talk about, but not FDA-approved in the United States. Also tested in relapsed refractory AML, approved in Japan as monotherapy, and really only targets FLT3-ITD, does not target the FLT3-TKD mutations, which really serve as a key mechanism of resistance, and adverse effects really are QT prolongation in particular.
So Ethan already showed you the RATIFY study, which led to the FDA approval of midostaurin. These are fit patients, you know, up to the age of 59. And remember, you know, the median age of diagnosis of AML is 68. So these are, you know, younger patients, right, than even the median age of diagnosis. Younger patients with FLT3-ITD or FLT3-TKD mutated AML, with a greater than 5% FLT3 allele frequency, were randomized to receive intensive chemotherapy, plus midostaurin or intensive chemotherapy plus a placebo. If they achieved a complete remission, they could go on to get maintenance, and they could actually also go and just receive allogeneic stem cell transplants. So I'll use the pointer now. The remission rates on this study were superior in the midostaurin group, but overall, relatively similar, 59% versus 54%.
When you look at the median overall survival, this looks like an enormous difference, 74 months versus 25 months, but it's really because that's where the curves separate. When you look at the actual landmark of four years, the difference in overall survival is about 7%. So we agree that this is the new standard of care for patients who are fit for intensive chemotherapy with newly diagnosed AML with FLT3 mutation. And of course, as we say in the clinic, you know, you'd rather be on the blue curve, right? But at the same time, this is not, I would say, a dramatic advance as we would like, and there's certainly room for more effective FLT3 inhibition in the upfront setting.
So in terms of limitations, as I spoke about, this was a younger group of patients, the mean age of diagnosis, 68, a marginal benefit with the four-year overall survival of 51%, and still half the patients dying of their disease. Midostaurin is a dirty TKI and among the least potent FLT3 inhibitors, and there are more potent FLT3 inhibitors, including crenolanib and gilteritinib, that are being combined with chemotherapy and that are very promising in phase II studies, with phase III randomized studies that are ongoing. So turning our attention really to, I think, one of the most interesting topics, which is relapsed and refractory AML, and particularly the stories of quizartinib and gilteritinib. So backing up, relapsed and refractory AML patients, this is a different patient population than what we just saw in RATIFY.
These are patients who've already received prior therapy, so they've, for example, gone into remission, then relapsed, or they were just refractory to upfront therapy and never even went into remission. And of course, they have a very poor prognosis, particularly, just really across the board, but particularly for the FLT3 mutation. So this is looking at patients with a FLT3 mutation who were either relapsed or refractory and relapsed within 6 months in the Cephalon 204 trial, and this is a Johns Hopkins cohort, a similar group of patients. And we're looking at median overall survivals of 3-6 months.
This is a terrible, you know, obviously, survival rate, and it's gonna be devastating, of course, as a patient, if your leukemia comes back, and there really, up until recently, particularly with the FLT3 mutation, there really wasn't much to offer these patients. With intensive chemotherapy, CR rates of about 12%. So this brings us to the story of quizartinib. So quizartinib is a FLT3 inhibitor that specifically targets FLT3-ITD, does not target FLT3-TKD mutations. And this was developed by Daiichi Sankyo and was tested in this case in a randomized phase III study, now most recently, in 367 patients with FLT3-ITD positive AML, who were relapsed or within six months or refractory to intensive chemotherapy.
They were randomized 2 to 1 to receive either quizartinib, which again, this is a pill, a pill alone, versus a variety of chemotherapy backbones, a non-intensive low-dose cytarabine regimen, or intensive salvage chemotherapy. If they responded, they could go on to receive an allogeneic stem cell transplant and could continue maintenance quizartinib. They were randomized 2 to 1, 245 patients received quizartinib, 120 received salvage chemotherapy. 32% of patients in the quizartinib arm did receive hematopoietic stem cell transplants after treatment, only 11.5% in the salvage chemotherapy. Then this is one thing that caught the FDA's attention. For those patients who were randomized to salvage chemotherapy, 23% did not receive treatment, but 1.6% received treatment with quizartinib. Why is that?
So, but as a clinician, that's not totally surprising to me. Eytan and I were talking about this after the ODAC meeting. If my patient's randomized to receive salvage chemotherapy, and they're really not fit for that, what do you... I mean, how are they gonna even go onto that, onto that study? Or maybe they might say, "You know what? There's another study of a FLT3 inhibitor down the road. I'm gonna go do that. This doesn't seem like a good idea." So it's not, at some level, surprising, but it is a profound imbalance, obviously, in the arms, which caught the attention of the FDA. So looking at, the...
The response rates, the response rates were superior for sure, in quizartinib, you know, with an overall response rate of 69%, even looking at a complete composite, complete, remission rate of 48% versus 27%. There was a modest but statistically significant benefit in terms of overall survival, with a mean overall survival of 6.2 months versus 4.7 months. Again, this is modest and really because of the very modest nature of this benefit and because of also the adverse effects that we're seeing in terms of QT prolongation and because of the imbalance in the arms and concerns about the quality of the data, the FDA actually recommended in their ODAC meeting not to approve quizartinib in the United States. Based upon the same data, it is approved in Japan.
One of the reasons also that we see the response rates are probably so modest is, again, quizartinib only hit FLT3-ITD and not TKD mutations. And this is, I think, really beautiful work by Cathy Smith and colleagues that was published in Nature, looking at specific mechanisms of resistance. And a lot of them really converge upon emerging mutations in FLT3-TKD, tyrosine kinase domain mutations, that came up in the setting of FLT3 inhibition. So FLT3 inhibition is important and was a clear driver, but when you gave a targeted therapy that only hit one specific target on FLT3, there were clonal evolution and emergence of mutations that conferred resistance. So it validates FLT3 inhibition, but there were, in particular, multiple mechanisms of resistance, but in particular, D835 TKD mutations.
There are FLT3 inhibitors that are currently undergoing development that are active against FLT3 TKD mutations, and in particular, gilteritinib. So Eytan mentioned this is the phase III ADMIRAL study. This is a study that, again, similar to quizartinib, randomized patients with relapsed and refractory AML to receive either oral targeted therapy with gilteritinib versus salvage chemotherapy. They were randomized 2:1. And the primary endpoints really were overall survival, as well as CR and CRh rate, with other secondary endpoints, including event-free survival. And in terms of the salvage options, again, also low-dose cytarabine, azacitidine, or MEC or FLAG-IDA. These are intensive salvage regimens.
Based upon the data from this study, gilteritinib is now approved both in Japan and in the United States, and is really, of course, the only FLT3 inhibitor approved in the United States in the context of relapsed refractory AML and as monotherapy. So I think what's so striking about this already is that if you do target the biology of the disease, you can actually provide benefit even over multi-chemotherapy drugs, right? Multi-agent chemotherapy. So that's striking. In terms of the remission rates, 54% versus 22% in terms of a composite complete remission rate. 26% of patients being able to be bridged to allogeneic stem cell transplantation, and the survival curves are different. You know, a mean overall survival of 9.3 months versus 5.6 months.
If you look at a landmark of 12 months overall survival, 37% of patients still being alive on the gilteritinib arm. Again, an oral targeted therapy alone versus salvage chemotherapy, only 17% of patients. This survival benefit is really what led to the FDA approval of gilteritinib. If you look at the patients who do the best, it's really those patients who are able to be bridged to allogeneic stem cell transplant. What I think is really clear is that gilteritinib alone is not a cure. I don't sell this to my patients as a cure. I don't say, "We're gonna give you this pill, and we're gonna cure you of your leukemia." You know, I'm hoping this will provide some benefit to you and prolong your life and give you a good quality of life.
Maybe, you know, not have you had to have transfusions, for example, for a time. If they're candidates for allogeneic stem cell transplantation, then yes, I'm trying to actually bridge them to allogeneic stem cell transplant, which could be a potential cure. But even in the context of stem cell transplantation, you still see that many, and really most of these patients, eventually are progressing and dying, from either complications of the transplant or of relapse of their disease. Outcomes do seem to be better, again, validating the concept of FLT3 inhibition in those patients who resume gilteritinib. But of course, there are confounders, which is those patients who resumed gilteritinib obviously were healthy enough to do so, for example.
But going back to the overall survival curves, although I think gilteritinib is an incredibly important advance, this is not curative therapy, and eventually, everyone in this therapy appears to be progressing, basically. Over time, if you don't bridge the patient to allogeneic stem cell transplantation, you're not going to be curing the patients of their, of their AML. And I see these patients all the time in the clinic, and we'll talk about the mechanisms of resistance, but this, in my mind, represents an urgent clinical need for these patients. There is a really important tool out there, but it's, it's not enough. So when you look at the mechanisms of gilteritinib resistance, and this is, I think, a really interesting paper in Cancer Discovery by McMahon and colleagues. So these are oncoprints.
So we're looking at here, these are just different patients, 41 patients that were enrolled in the study. And so those are the different columns, different patients. The rows are different, types of mutations. So you can see in blue, all the patients had different FLT3 mutations. They either had FLT3-ITD mutations at the top or FLT3-TKD D835 mutations here in the second row, and other mutations are indicated below. If you look at the time of progression on gilteritinib, the landscape, the genomic landscape in this case, looks different, at least in many patients. We see this all the time in the clinic. AML is a polyclonal disease in many patients, in most patients really, at diagnosis, particularly in response to therapy.
And so in some cases, you simply see that the gilteritinib is effectively treating the FLT3-mutated clone, but then other clones of AML just grow out, and so you see a loss of FLT3. In many cases, you see that those other clones actually grow out with NRAS or RAS mutations. RAS mutations in general, it was the story of this paper, these are mutations that really confer a proliferative capacity to the AML, and this seems to be a primary mechanism of resistance to a targeted therapy with gilteritinib, and seems to grow out in a large number of these patients and confer resistance, unfortunately, to the therapy.... 'cause it's not targeted by gilteritinib. There's also this gatekeeper mutation, FLT3 F691L, which wasn't present at diagnosis, but then emerged basically on treatment with gilteritinib, that seems to not be hit by gilteritinib.
There's also cytogenetic evolution, the karyotype and the chromosomal complexity increases over time. Then there are other mechanisms. If we, you know, made a whole genome-wide oncoprint, I'm sure there would be other mutations that we would see that are simply not captured, you know, on these next-gen sequencing panels that were used. But there are other mechanisms of resistance. But what you can see, interestingly, most of these patients still have the target FLT3-ITD and TKD, but yet they are resistant to gilteritinib. And what about venetoclax? I think, you know, venetoclax is certainly one of the most exciting advances in AML treatment, not as a monotherapy, but really given in combination with either hypomethylating agents or low-dose cytarabine, approved in the context of newly diagnosed AML patients.
At least up front, the response rates with FLT3 mutations seem to be close, basically, to non-FLT3-mutated patients. But over time, again, FLT3-ITD mutations seem to serve as a mechanism of relapse. This is a paper from Courtney DiNardo that just published in Blood, looking at mechanisms of clonal evolution in response to patients who were treated up front with venetoclax combinations. And you can see that patients with FLT3-ITD at diagnosis, maybe a lower varying allele frequency, over the time, can go up. In this patient, actually, when they achieved remission, all of a sudden, everything's undetectable, and that's great. But then at the time of relapse, it appears to be FLT3-ITD that's a driver of this particular clone at relapse.
Similarly here, and down here, even though you didn't have any detectable FLT3-ITD at diagnosis, over time, at relapse, it became a strong driver of the clone. So I think the story here with FLT3 is that outcomes have improved with our better understanding of the biology of the disease. But most patients with AML, particularly FLT3-mutated AML, still die of their disease. FDA-approved combinations include midostaurin, which is given really and approved only in the context of newly diagnosed AML, for patients who are fit to receive intensive chemotherapy in combination with chemotherapy. Gilteritinib is the only FDA-approved FLT3 inhibitor, which is approved as monotherapy in the context of relapse and refractory AML. Quizartinib, a similar patient population, is not approved in the United States, but approved in Japan, and again, only hits FLT3-ITD and not TKD. Current FLT3 inhibitors, however, are not curative.
As we saw, there are multiple mechanisms of resistance, and I see this, we see this in the clinic all the time. Even responding patients will eventually progress. The mean overall survival is still only 9.3 months. And I think the development of FLT3 inhibitors for FLT3-mutated AML patients, particularly who fail gilteritinib, represents an urgent clinical need. I see these patients all the time. And what I would... If I could make a list sort of, of characteristics of a drug for, that would be an ideal drug for gilteritinib failures, I would want a, a drug that's a potent FLT3 inhibitor, highly potent. It should target both FLT3 ITD and TKD. It should also target multiple mechanisms of FLT3 resistance.
I want it to be active also in the context of RAS mutations, because that's a clear mechanism of resistance to gilteritinib, and ideally, it would synergize with venetoclax. That's, of course, the reason that we are here, is that I think that CG-806 is that drug. That's why Eytan and I are so excited to participate, you know, in this upcoming study. So with that, I would like to thank you for your attention.
That's great. I wanna thank Dr. Stein and Goldberg for their presentation. I think that they've done a lot of the heavy lifting today. My role here is now to just tell you a little bit about what we know about CG-806 and why we are excited about putting it in the clinic for AML. I don't know if you guys know, but I joined Aptose about a month ago. Prior to that, I was working as a physician scientist at UCSD, where I have a lab that focuses on myeloid malignancies, MDS in particular, and a clinic where I see patients with the same disease. So my understanding of the myeloid disorders and the need in this space was...
One of the things that actually drew me to join the company in the first place, was that I saw that this was an incredibly promising agent. It really is very different than some of the other things that are out there. As you know, it is not just an oral FLT3 inhibitor, it also has activity as a reversible BTK inhibitor, and that makes it very unique. It's really a first in class in that, in that way. Not only does it inhibit these enzymes, but it also inhibits the wild-type and mutant forms of both BTK and FLT3 that gives us broader applicability in patients that either have or don't have the mutations, might still be candidates for treatment.
And as I'll show you, it targets more than just these two kinases, that it really does target other very important kinases that confer additional signaling to the cells that they might be able to use as a mechanism of resistance. And fortunately, at least as far as we can tell, with all the preclinical data that we've been able to gather, that it appears to be very safe. It spares those kinases that we believe are associated with more toxicity and have given other drugs in this class difficulty in clinical studies. I'll give you a quick update on CLL, where we are with CLL and non-Hodgkin's lymphoma, because we're in the clinic with CG-806 in those patients, and I'll tell you how that is gonna inform our ability to open the AML trial. So no talk about a kinase inhibitor is complete without the kinome map.
I'm sure you've seen this thousands of times. But what I wanna point out is that this is not like midostaurin. This is not a drug that hits kinases all throughout the map. It really hits kinases in restricted clusters. So we refer to this as a cluster selective kinase inhibitor. You can see it has activity in this cluster labeled BTK. This is the TEC cluster. Interestingly, it doesn't actually inhibit TEC itself, which is one of the toxicity-associated kinases. It has activity against TRK, and it has activity in the FLT3 kinase domains, including neighboring kinases that I think are very important for AML in particular, like CSF1R and PDGFR alpha. So why is it important to hit more than one kinase when you're going after a target? As Dr.
Goldberg showed you, there are multiple mechanisms of escape that cells can use, either by mutating the target itself or by mutating neighboring pathways or upregulating neighboring pathways that allow the cell to bypass that targeted protein. So in AML, we think of FLT3 as being the target. In CLL and non-Hodgkin's lymphomas, we think of BTK as being the target. But the reality is that all of these often coexist in the same cell, whether it's AML or CLL that we're talking about. And in particular, if you inhibit FLT3, you can see that all the other pathways that are available to the cell can crosstalk and activate those downstream signaling genes, essentially bypassing the target that you've hit with a very selective inhibitor.
So CG-806 has the good fortune of actually targeting multiple of these receptors, starting with surface receptor tyrosine kinases, as well as intracellular receptors, intracellular kinases that can activate downstream pathways. So these are where CG-806 directly inhibits these enzymes. But as a consequence, it also downregulates the activity of all of these downstream signaling molecules, as I'll show you in the next slide, and ultimately downregulates the important survival signals that get transcribed and get upregulated in the setting of cancer. So my thesis advisor once said that if you show more than one Western blot on a slide, you have to apologize. So a thousand apologies, but I think that this actually is useful.
What I'm trying to show here is that there are multiple different AML cell lines that we've looked at, where we've treated them with nanomolar concentrations of CG-806 and looked at what happens not only to the enzymes that we target directly, like FLT3 and BTK, but also those other downstream signaling molecules that get phosphorylated when that signaling pathway is in its active state. And you can see that even with these low doses in these in vitro studies, you get loss of those phosphoprotein signals, like loss of phospho-AKT, loss of phospho-STAT5, loss of phospho-SYK, loss of pS6K, and ultimately downregulation of some of these very important signaling transcriptional profiles like those driven by c-MYC.
These are AML cell lines, yet you can still see that BTK has activity in the untreated state, and then when you treat them, that activity goes away. So where are we with the development of this drug? As I mentioned, we are in phase I clinical trials for CLL and non-Hodgkin's lymphoma. We again, have the good fortune of having a fairly clean preclinical, safety signal, and we're allowed to do rapid dose escalation, where we could put it in single patients at the lowest doses and eventually get to a cohort where we need to put three, patients on at a time. And so far, we have completed dose level one, we have completed dose level two, and we have fully enrolled dose level three.
This is important because this is going to inform how we carry out and when we carry out our AML study. Essentially, we didn't feel like it was appropriate to treat AML patients who have very short expected overall survivals in the absence of therapy with drugs that we knew were gonna be subtherapeutic. We really wanted to do our dose escalation in a population that was gonna be more tolerant of taking subtherapeutic doses, and then be able to translate what we think is going to be an effective dose into the clinic with AML at the start. So what have we learned from the B-cell study so far? So far, we have evidence of safety, that the drug does not seem to cause myelosuppression in these patients that we treated, including some that have very compromised bone marrow function to begin with.
We haven't seen any SAEs or any dose-limiting toxicities, and we have seen evidence of engagement with the target. I would call this pharmacologic activity, where we see downregulation of phospho-BTK, both in the cells from treated patients themselves and in cells that are exposed to the plasma from treated patients, where the drug is actually in circulation. We have a hint of clinical activity as well, but as I'll show you, we don't necessarily equate phospho-BTK inhibition with therapeutic response. That those two things need to be, need, need to occur, but the dose is gonna be very important. And fortunately, we have well-behaved, steady-state oral pharmacokinetics, which I'll dive into here. So these are the PK curves from our first and second patient. We presented this before. You can see that with our first patient, we achieve a steady dose level with twice-a-day dosing.
Our second patient at 300 milligrams twice a day actually achieved quite high levels. They're about 0.6-1 micromolar. These are levels that we think are just below where we would expect to see some therapeutic responses. As I told you already, we do see some inhibition of the target pathways, even at that dose level. What we hope to do is get up into the 1 to 2, 3, 4 micromolar range. This is where, based on our preclinical data and our experience with other drugs, we expect that we are gonna see on-target inhibition and the potential for efficacy. This is where we want to get to.
We're hopeful that that third dose cohort that we fully enrolled will bring us there, that we'll see the PK data from those patients and make us feel comfortable that when we go into AML, we'll have a potentially therapeutic dose. But if that isn't the case, we'll have the opportunity to dose escalate in the next cohort and learn whether that's the appropriate dose. Regardless, when we do get to AML, we are gonna be wanting to dose escalate in those patients as well, to make sure that we're treating them as effectively as we can. Skip this slide real quick. Now, I wanna share some of the preclinical data that really drove us to consider AML as a primary indication for CG-806. The first is obvious, is that it inhibits FLT3-ITD extraordinarily well. With 800 picomolar, we reach an IC50 for this drug.
That compares favorably or even better than many of the other drugs that are in development that you've heard about today. But in particular, we have activity against the tyrosine kinase domain mutation that Dr. Goldberg referred to. Sometimes this occurs in de novo patients, but often it occurs in emerging resistance in patients that are treated with drugs that don't adequately cover these mutations. And if you take cell lines that are driven by this mutation, you can see that CG-806 is extraordinarily effective at killing those cell lines. Almost 1,000-fold better than drugs like quizartinib at killing these TKD mutation-driven cells. Giving us hope that at least for this mechanism of resistance, that we're shutting that door for patients that have FLT3-ITD. Now, that is obviously in a Petri dish where we're exposing cell lines to drug.
What happens when you actually go into animal models? This is a very typical AML model where they get MV4-11 cells injected under the skin and allowed to grow over time. This is a cell line that's driven by FLT3-ITD. And you can see that the vehicle-treated mice die within short order. And as we go to increasing doses of CG-806, the mice live longer and longer, and at the two highest dose levels, the mice are essentially cured of this disease. We didn't, you know, at the time that we had to eventually sac the mice, they were still alive and healthy. And importantly, we didn't see anything that would be concerning for a signal of toxicity in these animals. There wasn't a preferential loss of weight.
If anything, the animals that were treated, looked healthier, obviously, than the ones that, were treated with vehicle. But I wanna do a, a slightly deeper dive on these last two dose levels because I think it's also instructive and informs how we're gonna do our clinical study. So this is the same data shown in a slightly different way. The black shows animals that were treated with vehicle, and it shows that the tumor growth occurs very, fairly quickly. This is during the 28-day dosing period, where mice were given CG-806 twice a day. And you can see for the animals in the 2 highest dose levels, that completely suppressed tumor growth. These animals didn't show any tumor progression. You stop dosing after 28 days, you let the animals roam and see what happens. And for some of the animals, they were outright cured.
5 of the 11 in this middle dose range and 10 of the 11 in the highest dose range didn't show any recurrence of disease. However, six of these did, and one of these did. We let those tumors grow out again and then retreated these mice, this time with the highest dose level, and we were able to cure all of the mice that had recurrent disease. Essentially, we didn't kill them all in that first round. So with two cycles, one or two cycles of therapy, we eliminated the tumor from 22 mice without any sign of effective toxicity. And I think that that gives us a lot of promise about what we're gonna be able to do in a more complicated in vivo system.
Now, of course, that is with a cell line model, and we're fully aware of all the limitations that those can have and how good they can look in practice, and then maybe how they don't necessarily bear out in theory. So I want to tell you about one other animal study that we were able to do in collaboration with folks at MD Anderson. This is where we take patient cells. This comes from a patient who had AML with FLT3-ITD, who was treated with sorafenib, a drug that's active against the FLT3-ITD, plus azacitidine, and actually went into a CR after 1 cycle of therapy. When that patient relapsed after 3 cycles, they had acquired a D835 mutation and now had a double mutant kinase.
These cells were extracted from the patient and put in the Petri dish, exposed to CG-806, where we saw dose-dependent killing of these cells. However, we did not see that with quizartinib, as expected, since again, quizartinib doesn't target that 835 mutation. When we look at these cells in a mouse model, where we do a PDX xenograft model, we allow the tumors to grow, and then we treat the animals, and this time with once a day, weekday-only dosing, due to some limitations of the lab doing the studies. But you can see that the tumor grows pretty rapidly in those mice that are untreated, but in those treated mice, the tumor growth is almost completely suppressed.
We have substantial reduction in leukemia cell burden in these CG-806-treated animals that have been engrafted with not just an AML mutant cell line, but with a patient FLT3-ITD mutant cell that has been resistant to prior therapy with a FLT3 inhibitor. So I'm gonna end there and allow our last speaker, Dr. Druker, to come up and tell us more about his experience, not just in one scenario, but looking at a multitude of patient-derived cells in the clinics. As he said, the opportunity to work with us quite extensively, and I look forward to hearing his perspective. Thanks.
Oh, thank you. Thank you, Raf, and thank you all for being here. I'm just gonna walk you through some of the data that we've been generating over the last several years on CG-806. But, as Bill reminds me, we're the old-timers here, and I've been involved in the development of kinase inhibitors for quite some time. As you've heard, there are over 500 kinases in the kinome, and mutated kinases can lead to cancer. There are now 50 kinase inhibitors approved for use in the U.S. And again, I'm old enough to remember when kinases were not a druggable target, and despite that, we were able to develop the first kinase inhibitor, imatinib or Gleevec, for chronic myeloid leukemia, and it's been on the market since 2001.
What's been interesting about the evolution of kinase inhibitors over the last several decades is that imatinib was actually relatively selective. It inhibited three, maybe four kinases in the kinome. When the second generation came along, it was sort of the midostaurins and sorafenibs and sunitinibs, which inhibited pretty much everything in the kinome. The view was, let's inhibit kinases and get into the clinic, and we saw lots and lots of toxicity with those drugs and have been unable to effectively combine them. So then the industry went to, "Let's make them really specific, single targets." What happened with those is we rapidly saw resistance, as you saw with the FLT3.
Now we're coming along with the notion, as you've seen with CG-806, is that what if we start to target clusters of kinases, try to understand which kinase in kinases to avoid, which cause toxicity, try to shut down some ancillary-resistant pathways, and that's really where we are in the current era and generation with CG-806. I don't expect you to read anything on this slide. This is just a slide that Bill and I put together to show you that this is data from my laboratory. We've been working with CG-806 for quite some time. We presented at numerous conferences over the past several years and are working on a publication of this data to summarize. I just want to zoom in on one of the most recent bits of data we published, which is looking at patient-derived cells.
So over the last decade, my laboratory has been collecting patient samples from patients with leukemia and incubating those cells in vitro with a variety of drugs, from kinase inhibitors to the favorite flavor of the day in terms of of the drugs that are available. I put on this slide a variety of the different kinase, FLT3 kinase inhibitors. In red, you see sensitivity. And what's remarkable about CG-806 is you see that virtually every single one of our patient samples, whether they're FLT3-ITD mutation positive or have the ITD or FLT3 negative, but they express FLT3, all are sensitive. And along here, you can see that other drugs like crenolanib, midostaurin, they have holes in their coverage, not every single patient sample sensitive. So there's probably two questions you're gonna ask. First is: what does this do against normal cells? Is this just nonspecific toxicity?
The answer is, when we incubate 806 with normal cells, we see no toxicity, so this is specific for leukemia cells. The second thing you're gonna ask is: Well, how does this predict how these drugs will perform in a patient? And I can tell you that we can't always tell that. That's what clinical trials are for. But the real point of this slide is I'm using this as a comparator. It's the best FLT3 inhibitor we've seen compared to any other FLT3 inhibitor that's already out there. So that gives us some confidence that when we go to clinic, that if these other drugs work against FLT3, that this will work, but it also should work against some of the FLT3 mutation negative patients.
So then you're gonna ask, as you heard from Aaron and Eytan, who gave fabulous setups for what I want to talk about next, which is: how does it work when patients have other mutations? Because everybody's gonna have FLT3 with something else, whether it be a TP53, IDH, NPM1. I'm just gonna walk you through a few examples. When we look at either NPM1 or the FLT3 allelic ratio, we see that as you sort of track to the right here, with high FLT3-ITD, these patients are extremely sensitive, and that's regardless of whether they have NPM1 mutations or not. If you then look at IDH, if you have IDH mutations, you're actually extraordinarily sensitive. Particularly, IDH1 mutant patients are extremely sensitive to 806.
But more importantly, p53, which is the worst prognostic factor for any patient with AML, again, wild-type, mutant, similar sensitivity in terms of ability of CG-806 to kill these patient samples. But as you heard from Aaron, one of the other things we're, we look at is RAS, and whether you're RAS wild type or RAS mutated, you're equivalently sensitive to CG-806. So the view would be that if we combined or we use this drug in patients with RAS mutations, we might be able to avoid some of the resistance that's seen with other FLT3 mutations. In addition, you heard from Aaron, what about venetoclax? And it combines extremely well. You can see here's the average sensitivity to venetoclax, average sensitivity to CG-806, and significantly synergy with a combination of CG-806 and venetoclax.
Now, what's interesting as well is when we've looked at venetoclax resistance, oftentimes patients with p53 mutations are resistant to venetoclax, and one of the reasons they're resistant is they upregulate TRK kinase. And you heard from the profiling that 806 inhibits TRK, TRK activity. So our view is there actually may be some mechanistic reasons for why we, this combination might be extremely effective. And as you also heard, we know that single agents aren't gonna get us to the goal of curing more patients. We need to get to these combinations, and we think this would be an ideal combination to strive for relatively quickly. So just to summarize, this has an extremely favorable preclinical profile, strong efficacy and safety, and we think it might be able to avoid some of the resistant, emergence of resistance.
It's hitting a lot of the operative pathways, but doesn't hit some of the ones that we think would compromise safety. My view is that this is one of the best kinase inhibitors we've seen in my lab in quite some time, at least preclinically. Of course, we've got to get to the clinical studies, but as I said in the comparative analysis, it looks extremely promising. So our view is, highly promising drug, more than just a FLT3 inhibitor. We're eagerly awaiting more of the data from the CLL studies. It inhibits some of the really critical signaling pathways that might lead to resistance, and as you heard, it's safe and well-tolerated to date. So again, I want to thank you for your attention, and I'll turn this now back to Rafael. Thank you.
Thank you, Dr. Druker. Before we get to the question-and-answer session, and we'll have plenty of time for that, I just wanna take some elements from the talks that we heard earlier and put them together to just make some take-home points. So this is actually another way to look at the data from the Beat AML program that was actually run out of OHSU in Brian Druker's lab with collaboration with Jeff Tyner. What we were able to do with this data is you're able to look at certain types of AMLs, for example, in this case, I'm showing NRAS mutant AMLs, and ask: Are there drugs that have particular differences in sensitivity to this agent?
So for example, drugs on this side of the curve are drugs that are gonna take higher doses to kill NRAS cells than they do to kill non-NRAS mutant cells. And here are drugs that are maybe a little bit more potent, and they're able to kill NRAS mutant cells better than they kill NRAS wild-type cells. And you can see there's a lot of drugs on this right-hand side, and all of the common FLT3 inhibitors are here. So sorafenib, Sutent, quizartinib, midostaurin, gilteritinib. This suggests that these drugs have less activity against NRAS mutant disease. If we look at the drugs themselves, we can then ask what mutations are likely to require higher doses of these drugs to kill in this in vitro study, and you can see for quizartinib, not surprisingly, it is NRAS, KRAS, and TP53. For gilteritinib, it is NRAS as well.
Now, they are also very highly specific for FLT3-ITD mutants, which is not surprising. That's what they target. And I wanna frame this in two ways. One is that obviously these are important. We've hammered on this a couple of times in the talk today, that NRAS is an important resistant mechanism that we hope we have activity against, but these drugs really are FLT3 inhibitors. And then, at least for gilteritinib, the indication is for FLT3 mutant patients.
However, if we look more broadly, and we look at activity both in FLT3 mutant or in NRAS mutant or NRAS wild type, what I can show you is that for NRAS wild type AML cells shown here in red, when we do this assay side by side with these other agents, we see that CG-806 has a fairly low mean IC50 for killing these cells. That a large number of these cells are readily killed at concentrations that we think we can actually achieve in vivo. When you look at the NRAS mutant cells, that there is a slight difference in the amount of CG-806 required to kill those cells, but that difference is not significant. In contrast, for gilteritinib and for quizartinib, the difference between killing all the cells and killing the NRAS mutant cells, there is a significant difference.
It takes substantially more drug to kill the NRAS mutant cells than it does to kill the NRAS wild-type cells. For midostaurin, which as you heard, is not as potent of a FLT3 inhibitor, actually has difficulty with both. But if this is the range of concentrations that we're looking for in patients that we think is likely to be effective, those ranges can be readily achieved for killing NRAS wild-type cells. They can be readily achieved for killing the vast majority of NRAS mutant cells for CG-806. That is not the case for gilteritinib, quizartinib, and midostaurin, where many of these patients' samples lie well above those concentrations that we're likely to achieve in patients. So again, giving us hope that we're at least shutting down maybe even another pathway of resistance that could emerge after treatment with this drug.
Here's just highlighted a little bit differently, where we're showing them broken out by group. The NRAS mutant cells for CG-806 have a mean IC50 of about 1 micromolar. That's substantially higher for the other three tyrosine kinase inhibitors that were tested in parallel. So to summarize all the talks that we heard today, there clearly is a medical need to control relapsed/refractory AML, and even an opportunity, I think, to go up front with some of these agents, that they'd be more powerful and more effective than midostaurin. So the fact that we have multiple agents now online for AML hasn't really removed the need to treat these patients, as most of these therapies are not curative, and we need therapies that are able to treat particularly those unfit patients that may not benefit or may not be able to tolerate high-dose chemotherapy. CG-806 has an appropriate profile.
It targets all forms of FLT3, including the resistance mutations and even the wild type form as well. We are close to achieving PK doses that we think are gonna be therapeutic in AML patients, and we're planning to submit that IND quickly, so we can get that clinical trial up and running. It's very attractive from a clinical standpoint, but it's also attractive from a commercial standpoint in that it has activity against a validated target. FLT3 is a validated target for which there are other approved drugs on the market. Our safety profile really gives us a lot of combinatorial optionality.
That if you are bringing a toxic drug to combination, you may not tolerate that combination well, but if you take a drug that is very safe and effective, and you combine it with another drug, then you are gonna be less concerned about combinatorial toxicity. In fact, we could imagine this as a potential cornerstone of therapy. This is an oral agent. There are other oral agents that it might pair with very nicely. We already discussed venetoclax. I could even imagine some of the oral hypomethylating agents, like the ones that Dr. Stein mentioned, as potential partners for this drug in the future.
Ultimately, the fact that we're not limited to the FLT3 mutant patients and that we're not designing our initial AML study to be limited by genotype, may mean that we're unlikely to require a genomic biomarker when we eventually get to market. The take-home point I want to talk about also is: What is the low-hanging fruit? We are gonna want to put this drug into a broad category of AML patients. We're not gonna want to restrict it based on genotype or other factors, but there are some patients who I think have the greatest need, as Dr. Goldberg mentioned. Those are those patients that are failures after the effective FDA-approved therapies that we have today, and CG-806 checks all those boxes that Dr. Goldberg mentioned in the last point of his slide.
It's a potent inhibitor that inhibits all mutant forms of the kinase, targets multiple mechanisms of potential resistance, including those RAS mutations, and it has the ability to synergize with venetoclax and potentially other drugs. So we're gonna stop now for questions and answers. I'm happy to hear your thoughts. We can always answer your questions here at Aptose, but I would encourage you to take advantage of our experts that are here with us today. Okay.
What, sorry? I thank the speakers.
So while you're thinking of your questions, I wanna thank Dr. Stein, Dr. Goldberg, and Dr. Druker for coming out here today and spending time with us, and sharing their thoughts and insights on, on this drug. After hearing their talks, I am even more enthusiastic than I was beforehand, and I'll admit, having heard these kinds of talks very often, I learn something new every time. So I appreciate you guys coming out and doing that.
Thanks. That was a great presentation. Tyler Van Buren from Piper Sandler. I guess the first question I had is, in the animal models, you noted that CG-806 was very well tolerated, even at the higher doses, and there was no weight loss. Can you speak to perhaps the gilteritinib experience and if there was any weight loss or kind of toxicities observed in early animal models? And just maybe as a follow-up to that, with gilteritinib, do you expect... Since it's better tolerated than midostaurin, for the physicians on the panel, do you expect to use it front line over time in combination with chemo?
Do you guys want to take the latter question?
... Yeah, I think we can take the clinical question for sure. I would say that overall, it is a well-tolerated drug as monotherapy. I mean, some patients, I would say, do experience fatigue on the drug, and it's hard to say if that's really, you know, an adverse effect or not. We do see LFT abnormalities. We see sometimes CK elevations. We have to check the CK over time to make sure that's not going up. But it doesn't significantly really have QT prolongation. It's overall, I think, a well-tolerated drug. I think that the challenge really is that over time, patients develop resistance, of course, you know, to it. So that's why there's such an urgent clinical need.
I can't speak to the mouse data, unfortunately, in terms of how it was tolerated. Yeah.
So I'll speak to it briefly. So if you look at some of the other FLT3 inhibitors, in particular, quizartinib, gilteritinib, it turns out what was observed in mice and dogs was equivalent to what was found in humans. For instance, the quizartinib, the QTc prolongation, the cardiotoxicity there, it was seen in mice early on, and it was hoped that in humans, it would not manifest itself at such low concentrations, but it turned out to be dose-limiting. I think the same is true, well, not QTc prolongation, but gilteritinib also, it definitely manifested certain toxicities at higher dose levels in mice, but they clearly are able to achieve doses in humans now that are effective.
But you can't continue to dose escalate further because if you could, you might be able to avoid some of the drug resistance. But as was shown here, like for the NRAS mutation, they just can't go high enough in order to achieve those levels, and it's driven by avoidance of toxicity. So typically, with these kinase inhibitors, what you see in animal models correlates very well with what you see in humans, generally speaking.
I think what I would say also as a follow-up to that is in terms of gilteritinib, the half-life of the drug is very long. You know, we're talking, you know, like 5-7 days, basically. So when we do, for example, a washout of gilteritinib prior to, you know, enrolling someone in five half-lives, that's a long time. So your, the washout period here in your trial is shorter. But it's
Yeah.
Yeah, exactly. So that can be a problem if we do observe any toxicity because the drug sticks around for a long time. Yeah.
The second question was just related to the dose for AML. The IC50 data at the end in resistant clones was pretty interesting, showing the 1-5 in a predicted micromolar doses. So for cohort 3, if you see, I guess, a plasma concentration within that range to have the confidence to go to the FDA to start AML, or do you want to see, you know, secondary measures of activity in those patients as opposed to going to cohort 4 and waiting to see that data?
No, that's a great question. I think we wanna see doses in patients that we think are gonna be effective in AML. We don't necessarily need to see, wait for responses to occur in patients in that cohort. Those patients are in the B-cell study. They often take much longer to show responses than an AML patient might, where you expect responses relatively quickly after starting therapy. So we are gonna hope that we achieve those levels in this third dose cohort, but are obviously going to continue to dose escalate in this population until we find the right dose for the AML patients.
Yes, let me add just a bit to that. So, Dr. Druker mentioned we're the old guys in the room. We'll, we'll call it elder, elder statesman, if that's okay with you. So something he told me, I think it was about two decades ago, is, "You have to have the right drug for the right patient at the right dose." And it sounds so simple, but it's true. So we need to make sure that if dose level three here and in these B-cell malignancy patients, we think we have the right drug for the right patients to go into AML, but we need to make sure we have the right dose.
If, if, dose level three, if we feel confident we're, we're in that micromolar range, steady state, and we can affect the patients with AML, then we'll try to go there as long as we have a good safety profile. But we don't wanna make an error, an unforced error. If it, if it turns out that we believe we should go to dose level four, we will. So in effect, what we're doing is our dose escalation for AML, but in these B-cell cancer patients. So don't be frustrated if we say we're gonna go to dose level four before we go into AML. Just know that we're gonna be taking a higher dose and a higher exposure into that. So that's, that's the way we... We're very data-driven, so that's the way I look at it. So.
Hi there, John Newman from Canaccord. Thanks to all the physicians, and to the company for holding the talk today. My question is, regarding the experience that the physicians have had in terms of selecting patients for AML studies in general. One of the points that Dr. Stein made was different patients with different types of mutations have different prognoses, and sometimes those poor prognoses patients progress very, very quickly. So it's a question for, the physicians and the company. When you think about selecting patients for these relapsed refractory studies, what are the things that, give you the signal, this would be a good patient to put into the study, versus other things that say to you, "You know, this patient's progressing too fast," or "There are just other things here, this patient really shouldn't go into this trial?" Thanks.
So I don't think it's much beyond what you might think, which is that patients who have a relatively good performance status of 0-2, patients who aren't clearly having, you know, rapid doubling of their white count quickly over time. I think the benefit of targeted FLT3 inhibition, though, at least in a FLT3 mutant patient, is that those patients often have rapid leukocytosis, and you might not want to put them on some trials. But when you're giving them a targeted FLT3 inhibitor, what that does is that shuts off the leukocytosis when it works very, very quickly.
So I think in some measures, drugs that specifically target FLT3 and target RAS are able to, you actually have more patients you could potentially put on those studies because you're shutting off the pathway that leads to a proliferative advantage of those cells.
Yeah, I would just mention, when the trial expands to AML, it won't gate necessarily on FLT3-ITD or TKD, or mutation only, because it may have activity broadly in AML. So it's a bit of an advantage in that, as you heard from Eytan, that sometimes the FLT3-ITD patients do have a very rapid doubling, whereas some of the other patients without FLT3-ITDs will be a little bit less rapidly progressive. But we think this compound might have activity broadly in AML. That's part of what the clinical trials will tease out. And part of the problem in any of these AML studies, you heard this is an incredibly heterogeneous disease, but the hope is that this could have broad activity regardless of mutation status. But that has to be tested.
Yeah, I, I agree completely. I think the other opportunity, potentially for, for this drug, which we see in the clinic, is in the setting of venetoclax failures. So, venetoclax, I think it's fair to say, has revolutionized really the frontline treatment of, of AML, particularly 'cause it can be given in combination with hypomethylating or low-dose cytarabine to patients who are not fit to receive intensive chemotherapy, who are older, for example, or have comorbidities. And the response rates to that combination are, are quite good, up front, right? So, like 70% complete remissions, complete remission, the complete blood count recovery.
But over time, patients do tend to progress, and when we look at the outcomes, this was just presented by MD Anderson, actually at ASH, for patients who were on venetoclax, for example, who are either primary refractory to it or who, who failed, you have an overall survival of about two or three months. So it's, it's really a devas-- it's devastating at that point. And as you saw in one of the last slides that I presented, FLT3-ITD mutations do appear to be one of the mechanisms that can-
NRAS.
Yeah, and NRAS, of course, as well. Both are key mechanisms of resistance to venetoclax, and both of those pathways are targetable, it seems, preclinically, by CG-806. Which is why I think we're really excited. We see. We were just talking actually before about what are we gonna do for some of these patients right now? This trial is not yet open. You know, I wish it were, because then I'd put them on this trial tomorrow.
So I have a couple of questions. First of all, obviously, in this disease, I mean, the progression is very, very rapid. So if you have an effective drug, it would be interesting to me to sort of hear literally within, from what I understand, within a week, two weeks, three weeks, you would already see quite different things happening between the two groups of patients. So if you could just talk a little bit about if this were effective, what you would be seeing almost in real time between, you know, this 806 group and the placebo, the other group. And my other question is, in terms of dosing, I mean, where is the... You know, I have no idea why 450, 600, 750.
I mean, can you talk a little bit about why you would want to necessarily limit the dose, or how you would identify the optimal dose, in terms of a trial?
I mean, I guess I can speak to what one might expect sort of clinically, and I'll let other people handle some of the dosing questions. But so, clinically, first of all, there won't be a placebo on this phase one, because, you know, the technical intention, of course, of a phase one study is really to test safety. Although, we—the reason we're giving it to our patients is because we hope it's going to be effective. So it's, there won't be a placebo-controlled arm in the phase one. But what I would say is, what I would expect to see is what we've seen when you have an effective, so a FLT3 inhibitor.
If you have a patient with a very high white count, hyperleukocytosis, with a lot, large percentage of blasts in the peripheral blood, for example, if you have an effective drug, you'll see that count drop even within the first several weeks, even sometimes in the first several days. You can see that peripheral blast percentage drop. It can take time, though. I mean, the median time to, you know, response is still several, best response is several months, you know, on gilteritinib, for example. So it will take time, if you look in the bone marrow, to achieve a full, for example, complete remission, which would be defined by less than 5% blasts in the bone marrow, and also an improvement in the other peripheral blood cell counts, like platelets above 100, neutrophils above one.
So what we're really trying to achieve is an improvement in hematologic parameters, a reduction in the white blood cell, the bad white blood cell count, the blast percentage, you know, and restoration of normal hematologic parameters. You could do it pretty rapidly.
In patients with a very poor prognosis-
Uh-huh.
Would you expect to see very much more rapid changes relative to what you'd expect in their baseline from that perspective?
I think you would hope to see changes relatively quickly if the drug is effective within the first several weeks to a month, at least some changes.
Yeah. It's very different from B-cell malignancies.
Correct, yeah. And it's different from-
... drug to drug, it's different from B-cell malignancies. It's true, it's fair to say. And I think, you know, Eytan can speak to this more, though. Depending upon the agent, sometimes it can take time for best responses. You know, IDH inhibitors, for example, can take really many months to see excellent responses.
Yeah, just speaking from the experience of IDH inhibitors, whether if I'm understanding your question correctly, whether you had an IDH mutant patient who had unfavorable cytogenetics or whether they had favorable cytogenetics, 'cause both, both occur, those patients responded at the same rate.
Right.
So, there was no real difference. If you were unfavorable, if the drug was working, the drug was working-
Correct.
as quickly as it worked in a favorable risk patient.
Yeah.
Yeah, but I guess for Aaron and Eytan, one of the advantages of AML is that patients will, some patients will have a pretty high peripheral blast count.
Correct.
And my impression has been that in patients with a high peripheral blast count, the FLT3 inhibitors can lower that pretty quickly.
Correct.
and oftentimes within a week or less.
Correct.
Just wanted to clarify that,
Yeah.
My limited exposure to the clinic is correct.
That's correct. Yeah. Yeah, yeah. So even if you, if you did a bone marrow and the biopsy on that patient, you probably wouldn't see, of course, a complete remission, but in the peripheral blood, I completely agree. Yeah, you can already see responses.
So I was gonna dive into the dose question, which is a really interesting question that we've faced for a long time in targeted therapies, which is: Should you identify a maximally tolerated dose or not? And I'm gonna come down on the side of, yes, I think you should, because think back to the slides about the FLT3 inhibitors and the doses required to inhibit RAS. If one of the FLT3 inhibitors was able to be tolerated at those 2-5 micromolar, they'd be working, and you wouldn't see resistance. But they're not tolerable at those doses, so you can't use them. With 806, there may be some resistance that's dose-dependent, and if you could escalate to it safely and capture some of those patients that might be resistant, I would suggest that, that you'd want to do that. Of course, you wouldn't...
If you get to 10 micromolar and you're giving 500 pills a day, you might come to a sort of impractical dose. But in general, my view is that you'd want to try to see what the maximally tolerated dose would be because there may be other indications where that drug might then be effective. But at the same time, once you're achieving sort of the 1-3 micromolar, you know that's where your effective dose range is gonna be. You need to expand your cohorts pretty quickly to see how effective your drug's gonna be in sort of a phase I-b, phase II setting.
To be clear, we will continue to dose escalate in the AML cohort, even though we're starting at a dose that we think is gonna be effective, exactly to that point that Dr. Druker made.
Hey, guys. Matt Biegler, Oppenheimer. Thanks for... Again, thanks for the presentation. Dr. Bejar, I think you mentioned it, I just had a quick clarification. So eligibility for the AML trial, you will be enrolling both FLT3 mutant as well as wild-type patients?
That's exactly right.
Okay. What about MDS patients?
So we're gonna start with AML patients in particular. This is where we have most of the preclinical data. I think ultimately, we will want to expand to see if higher-risk MDS patients, patients that are close to being at that threshold for acute leukemia, might have activity. But this is something that is for consideration down the road. Our plans are to open it in AML.
Got it. That does kind of tie into the second question, 'cause we've obviously, you know, the topic today has been AML, but what is the drug's kind of activity in MDS? Do you see kind of the same level of potency against primary MDS samples if you have tested them as versus AML, and is there a market opportunity for a safe drug in MDS?
So, you know, as I mentioned earlier, my background is primarily in MDS. I think one of the challenges we have in the MDS field is that it is very hard to grow cells from patients who have a disease where the cells don't grow well in them in the first place. So we don't have a lot of great models like the similar models that we have for AML, where we can take those cells, put them in the Petri dish, expose them to drugs, and really extrapolate what that means for patients. So that has been challenging for MDS.
There's also not the kind of experience in AML, in MDS, using kinase inhibitors, that this is a disease that's been primarily treated by what we consider to be epigenetic therapy, hypomethylating agents for the most part, or now some targeted therapies where patients have very specific mutations like IDH1 and IDH2. Venetoclax is really revolutionary in what we do in MDS as well, but again, there, that was borne out in the clinic. That wasn't borne out by doing preclinical testing of the kind that you saw here.
Just a quick addition to that. So as Raf said, we don't have cell lines that really represent properly MDS patients. However, the drug CG-806 has been tested against a number of patient-derived MDS samples, and Dr. Druker's lab also did those patient studies. And that was done single agent with venetoclax, single agent, our drug and drug combination. So we do have those data, and we've shown that it's active, and it's... And we showed that it works well in combination with venetoclax in the patient-derived samples from MDS patients. But again, first in AML, then MDS. It's a more complex situation. We hope we get there, but no guarantees.
Hi, Akash, Wolfe Research. So, just stepping back, I think ArQule showed its first response kind of at the 1 nanomolar range. And you talk about your therapeutic threshold somewhere between 1-4. So can you dive into what's really what makes you confident that from your animal data, that your threshold is a bit higher than maybe some of the other reversible BTKs? And then how do you kind of take that therapeutic threshold window and apply it to AML? And then maybe also just dig into-
... kind of the importance of constantly suppressing the target. So maybe why go to a BID dosing?
Regarding the 531 compound, the ARQ 531 compound, you had said 1 nanomolar. It's actually 1 micromolar.
Exactly.
So, yeah. So they had spoken about this overtly. They were saying they were trying to target the 1-4 micromolar range, that they felt that was the range that they needed to hit to truly drive activity. Yes, they did start seeing some activity at the 1 micromolar range, but again, that's the range that we're talking about, too. We're talking about 1-3, 1-4 micromolar. We're trying to hit that same range. There's also another. Since you're talking about the reversible BTK inhibitors, the 305 molecule. And so they are also trying to hit the 1-3, 1-5 micromolar range, too. So it's in the same range of potency in terms of the exposure level.
Now, all of them may have a different dose because they all have different rates of absorption, percent, fraction of absorption, oral bioavailability, but we're all trying to hit about the same area. And we hope we hit that range, that dose range safely in the 1-3 micromolar. We may be able to dose escalate above that, and that'll be great. So that addresses that concern. And what was the other one in terms of BID dosing? Many of the animal models that we had performed with CG-806 were done once-a-day dosing. But we knew that as we got into our GLP tox, that we would need to present to the FDA. The FDA wants to see toxicity. They wanna know what is your target organ for toxicity.
So when we went into our GLP tox, we decided we're gonna dose twice a day because that certainly would get enough drug in to drive toxicity. So we did all our GLP tox studies, twice-a-day dosing, 28 days, and at the maximum feasible dose in animals, and we still got no toxicities. And those were the data. And we were clearly achieving well into the micromolar range, and it was well tolerated, but we did not see any adverse events in animals. So we decided to carry that on into the clinic for twice-a-day dosing, and that's the reason. Because in cancer, as what was said earlier, you wanna hit those cells as hard as you can, maintain the pressure.
At some point in the future, we may go back to once-a-day dosing, but right now we want to hit them as hard as we can, as long as we're still safe.
Hi, Pasquale Sansone, H.C. Wainwright. Maybe a question for Dr. Druker. In the preclinical model, you saw very low resistance to 806, differently from other FLT3 inhibitors. I was wondering, have you any clues on what kind of mechanism or genetic driver can lead to that resistance?
Yeah. We have quite a bit of data analytics that looks exactly at those questions, and we have not identified any consistent theme in terms of what drives resistance to each of the individual FLT3 inhibitors. Part of it is that even with 1,000 samples, there's so much genetic heterogeneity that it's really hard to get to statistical significance when we start to do the bioinformatics, because the numbers of the combination, the mutations are quite large. So I don't have a clear view of what the resistance mechanisms are. And Raf showed some of what we're calling these volcano plots, which look at sensitive versus resistance, and there's actually very few genes that reach statistical significance with some of these drugs.
Thank you.
So just to add to that, the possibility is not only—So with a drug like this, you would expect to have to see multiple mutations occur simultaneous because we're hitting multiple pathways. But there are also mechanisms that cells have that they can pump a drug out of the cell. And so that's one way you could possibly get drug resistance. We tested for that. It's not a substrate for P-glycoprotein, but the cell can upregulate certain types of pumps that can pump these out. So that's one potential mechanism, but we haven't seen it yet.
Hey, guys. Excuse me. Matt Cross from JonesTrading. Thanks to everybody for the presentations today.
Thank you.
Just had two quick ones. One was, you know, you've discussed CG-806 as a very agnostic inhibitor. And I think lately the company's received a lot of attention within the B-cell malignancy space, and the potential there, given, you know, M&A and just developments in that landscape. But I guess what I'm curious to know and get your feedback on is whether maybe within the FLT3 and the relapsed/refractory AML market, an agnostic approach is even more in demand than something like CLL, where most of the kind of new single targeted agents are targeting pathways that are not mutation-driven and are more broadly survival or proliferation-related.
So just feedback on kind of the demand for between the physicians are looking for these kind of more agnostic approaches in AML and also the investment market.
Do you guys wanna comment from a clinical standpoint, if that's something that's differentiating for you?
I mean, I, I think very simply, we're, we're looking for the most effective therapies, whether they're, you know, targeted, you know, that obviously, if they're as marketed as a FLT3 inhibitor or not, we just wanna make sure that it's actually the patient, specific patient in front of me, you know, responds. I think what, what Eytan and I do, I think, in the clinic, is we always, you know, we think, who is this patient? You know, what can-- what are the, what are the goals of therapy? What can they tolerate? You know, how old are they? What's their organ function? What's their performance status? And then what is their molecular mutational landscape? And are-- can I use a specific targeted agent that might already be available, that they might have a response to, an IDH inhibitor, for example?
But if they fail that, then what, what other options, you know, are out there? And so I think there is an enormous opportunity for a more effective, you know, FLT3 inhibitor, for example, that could target-
... gilteritinib failures. But, to your question also, I mean, if this agent preclinically could have a activity even in non-FLT3 mutations, that would be outstanding. TP53, for example, I mean-
Mm-hmm.
These patients have the, the poorest prognosis. So I think, and that's really what the point of the, the early phase clinical trials is all about, is sort of to see. We're not gonna restrict, you know, to specifically to FLT3-mutated patients. We're gonna-
Right.
Ask your question, you know, who is the patient most likely to benefit from this? That's what future clinical trials will target.
So from a quote, "marketing perspective," we call it a FLT3 BTK inhibitor. People understand FLT3 and its application to AML. People understand BTK and its application to the B-cell malignancies. But it's more than that. So remember, that's the first thing I said today. It's yes, it's a reversible BTK inhibitor, but it's so much more than that. So it targets multiple pathways, key oncogenic pathways simultaneously. But how do you get that message out to everybody with a single word? So yes, we inhibit FLT3 and all mutant, wild type and mutant forms that we've tested it. Same is true for BTK, but it's those other pathways that we're hitting are just as important. Because if you're just hitting... I don't care if you hit all forms of FLT3, the cell will escape, AML will escape.
Yeah.
So, it's like Whac-A-Mole. Yeah, FLT3 is one of the Whac-A-Moles, but you have to hit all multiple ones simultaneously. That wasn't so good at marketing, but it's true.
Very helpful. Thanks, guys. The second one was just on, on your other, you know, kind of lead asset that wasn't really discussed today, 253. And now that you're, you know, getting kind of on the cusp of, of moving CG-806 into testing in AML, just if, if you could give any kind of comments on the positioning for 253, at the same time, also running an AML and MDS, and how those two may kind of interplay as you move both of them forward, kind of in lockstep.
253, we haven't spoken about it that much, but under the radar screen, we're continuing to dose escalate patients with 253. We're in dose cohort 4 now. So we dose this molecule once weekly. We've clearly seen 75%-80% reductions in c-MYC, so it, it suppresses the expression of c-MYC. That's in patients, both in AML and MDS patients. We're measuring the pharmacokinetics of that drug. We're clearly getting coverage over three or four days, but we want to dose escalate and maintain coverage over a week, if we can. So we hope, as we dose escalate, we'll get good coverage, we'll get MYC inhibition, and we'll see effectiveness in the AML, MDS patient population.
But now that we know it's a MYC inhibitor, we might be able to take it into other indications, too. But for now, we're progressing with that molecule, and very few people ask about it, so we haven't said much. But again, under the radar screen, we believe there's something there, so we're continuing to dose escalate.
Any other questions? Oh, one moment.
Thank you. Hey, Greg Renza from RBC Capital Markets. Thanks for the discussion and for taking the question. Just quickly for the panel, just wanted to hear your thoughts about the aspirational context of combinations of eight, oh, six with some of the treatments out there or in development that you think are potentially most interesting to you. Thank you.
We showed some examples of that in the talks. I think that venetoclax, as a drug that spans both B-cell and lymphoid and myeloid indications, similar to CG-806, might be a great partner because we could consider using it in combination in both those scenarios. But there certainly are other drugs that I think could work well with CG-806 in AML. Specifically, if we're thinking about there, we talked about the need for therapies for those unfit patients, and that the standard of care for those individuals now, I think, has really become hypomethylating agents plus venetoclax. Yet that isn't a cure either. So if we can either potentiate that therapy or combine with an HMA as another alternative for those individuals, again, agnostic to their mutation status, that might be another opportunity for pairing.
So this is, again, aspirational thinking down the road, but I think that we might have opportunities for multiple pairings where eventually, the treatment of AML may look more like the treatment of myeloma does today, where we're not doing single agents in serial use, we're actually combining them up front to get our most effective, most deep, most durable response at the get-go.
As you may know, we're involved in the Beat AML trial, sponsored by the Lymphoma Society, where we're treating newly diagnosed patients over 60 with a variety of currently single and some combinations. I'd very much like to see 806 with venetoclax for newly diagnosed, untreated patients, and quickly. One of the things that we've seen in our data is that venetoclax has an unusual property, and it sort of makes everything better. And on its own, it, it's not that great, but you add it to other things, like 806, azacitidine, it does much better. But again, even in our combinations, and I didn't show the heat maps for those, 806 venetoclax is a huge winner. And we're also looking at venetoclax ruxolitinib.
So again, there's some really interesting data, but I'd like to get this up front as quickly as possible, and hopefully, the company will support that.
There are other really interesting drugs out there-
that I think that could be potential partners, and this is just-
Yeah
... something we haven't dove into too much, but there are interesting drugs, including the Forty Seven has a very different approach for treating MDS and AML. APTO-253 is a very interesting compound that I think could synergize with some of these approaches. So I think there are multiple options for putting drugs together.
I've got another question. Can you talk a little bit about the, the clinical trial in terms of... I know you're testing it just broadly, but how it'll be set up or structured in terms of testing different subgroups and sort of the whole, the whole sort of constellation of what you need to try and identify in terms of patients, effect, different mutations. Can you sort of just put that in context a little bit in terms of a, a trial and what that's about?
I think. So there are obviously many different ways that one could go about a trial like this. I think what we'd like to do is really get into AML quickly with a dose that's effective. To do that, we're not gonna be very restrictive about what kind of patients come on. Relapsed/refractory AML patients, regardless of mutation status, are gonna be the types of patients we want to go into early. What we learn from that experience will influence what we do down the road, how we design expansion cohorts, whether we look at a particular target population. I think we have the advantage of actually being able to accrue more patients more quickly by staying broad at the very beginning. We are actually working with sites and asking for their input into how, what the protocol is going to look like.
We're not really in a position to talk exactly about what the details of the trial are gonna be, but that's the general philosophy that we're taking into this study.
So I'm also gonna have to note that Dr. Bejar and I have a hard stop right now. We have a plane to catch, so we're gonna have to sneak out. So, Greg, do you wanna-
Thank you. Thank you very much, everyone, for coming.
Yes, thank you.