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

Good afternoon. I would like to welcome everyone to the Aptose Biosciences' clinical update and data review in conjunction with the European School of Hematology ESH Sixth International Conference. [Operator Instructions]. Joining me on today's call are Dr. William Rice, Chairman and CEO; Dr. Rafael Bejar, Senior Vice President, Chief Medical Officer; and our special guest and key opinion leader, Dr. Naval Daver from the MD Anderson Cancer Center. I will now turn the call over to Dr. Rice, Chairman and CEO of Aptose Biosciences. Please go ahead.

Thank you, and good morning, all. Today, we're coming to you from the European School of Hematology Conference being held in Estero Portugal. And it's my pleasure to welcome you to our clinical update and KOL data review for Aptose's lead agent, tuspetinib, that's being developed for the treatment of patients with relapsed refractory acute myeloid leukemia, or AML. And to contribute their expertise to the discussion today, we are joined by 2 KOLs, Dr. Naval Daver and Dr. Rafael BeJar. Dr. Naval Daver, our featured KOL, is Professor and Director of the Leukemia Research Alliance and the Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas. As a reminder, Dr. Daver is the lead investigator on Aptose's APTAVATE trial of tuspetinib, and he's a renowned hematology clinical investigator recognized for significant achievements and the development of Naval treatments for AML patients, in particular, as the architect of targeted double and triple combination therapies to deliver lasting responses and overcome mechanisms of drug resistance. Dr. Daver has published more than 150 peer-reviewed articles, serves on the editorial boards of numerous hematology-focused journals and service as a featured presenter of groundbreaking data at national and international conferences. Also joining us today is Dr. Rafael Bejar. Dr. Bejar serves as our Chief Medical Officer for Aptose and continues to serve as an Associate Professor of Clinical Medicine at the UCSD Medical Center. And we're very proud to call Dr. Bejar, one of our own at Aptose. So gentlemen, it's a pleasure working alongside both of you, and we thank you for joining us today. As for our agenda, I first will provide a brief background on tuspetinib. Next, Dr. Bejar will present clinical findings with tuspetinib administered as a single agent to relapse or refractory AML patients. And then he will present the most up-to-date clinical findings with the tuspetinib plus venetoclax or TUS/VEN drug combination inclusive of our preliminary data from the most recent data cut of last week taken on October 23. Afterwards, Dr. Daver will be available to answer your questions to provide insights into current as well as future treatments for AML and to discuss how tuspetinib can fit into those treatment strategies. So first, let's begin with the overview. Tuspetinib or Tus we often refer to it, is a once-daily oral kinase inhibitor. It already has demonstrated robust single-agent activity and an excellent safety profile as a treatment for relapsed or refractory AML. Because it's a kinase inhibitor, we're often asked, does it inhibit FLT3 and indeed it does. It's a very potent inhibitor, both wall type and the mutant forms of FLT3. But it's actually much more than a mere FLT3 inhibitor. It was designed also to inhibit the SIC kinase, the JAK1, JAK2 kinase so the JAK-STAT pathway, RSK II of the RAS/MAP kinase pathway. And so tuspetinib was designed to be a multikinase inhibitor to simultaneously suppress multiple oncogenic signaling pathways and have broad activity across many subpopulations of AML, but it was also designed to avoid hitting safety kinases, thereby allowing the tuspetinib to have a strong safety profile. So collectively, this makes tusbetinib, a multi-kinase inhibitor, but not a dirty kinase inhibitor. It's also this unique kinase inhibition profile that has allowed us now to extend beyond AML and to move into the larger indication of MDS. But this is important for us, but let's park the MDS discussion for now and move back to the AML. I believe that most of us are aware that the treatment paradigm in AML has shifted toward venetoclax containing combination regimens. And this has been a remarkable event for patients, giving them longer life expectancies, but it also has a bit of a dark side because we're seeing an emerging wave of venetoclax failure patients that are very difficult to treat. And by the way, I'll often refer to the VEN failure patients, venetoclax failure patients as VEN failures. So what does this have to do with tuspetinib?? Well, it turns out tuspetinib safety, efficacy, mechanism of action and conVENience properties make it an ideal drug for combination therapy, plus tuspetinib directly targets the mechanisms that AML cells use to create drug resistance to venetoclax. This means that test may mechanistically sensitized VEN failure patients to venetoclax and that tuspetinib may successfully treat these VEN failure patients. It also means that we may have a potential accelerated approval path for the TUS/VEN doublet and prior VEN failure patients. So today, you'll see a data readout from the October 23 data cut that was taken last week. You'll see all the preliminary data, both the source verified as well as the preliminary data that Dr. Bejar will be presenting today. But it's also important to know that we're going to have additional data readouts and events in the days, months, weeks ahead of us. As for the test then doublet, we will take an additional data cut at the end of November so that we could present these data at the ASH conference in December. And Dr. Daver will actually be presenting much of those data with us. Also for the tuspetinib doublet, we'll continue to collect data on these patients that are dosed as well as additional patients. And so that we're able to provide a bit more of a perspective on the duration of response as we go into the first quarter and second quarter of 2024. And then beyond the doublet, we're also planning a triplet study in which we combine tuspetinib with venetoclax as well as HMEs to treat frontline newly diagnosed AML patients. And we're planning on a pilot study in frontline patients for the first half of next year, and that's a very important study for us. We want to see the data, we know -- want -- large firms wants to see the data, so that's important for us. Likewise, we are going to -- we do plan to extend beyond AML into the higher-risk MDS patients as well as CMML patients, and we're positioned well to begin dosing those patients during the first -- fourth quarter of this year. So much ahead for us. So let me just focus now drill down a little bit on the recommended Phase II dose of tustetinib. It's 80 milligrams as the recommended Phase II dose as a single agent. We've seen that it's been highly active across diverse subgroups of AML patients. These are relapsed refractory AML patients and those patients with highly adverse genetics, including TP53 mutation, RAS mutations and others. And in patients who are naive to venetoclax, we've had very strong overall response rates, overall patients, 42% CR/CRh rate in patients with FLT3 mutations, 60% and in patients with FLT3 wild type, approximately a 30% response rates. And again, CR/CRh. And this -- it's very challenging for our Kinase inhibitor to have activity in both FLT3 mutated as well type. And so this is a real differentiator for tuspetinib because it has strong activity across the board in these patients. But I also want to point out that as we rose above the 80-milligram dose level in our dose-escalating trial, the response rate unexpectedly changed midway through the Phase I trial. As you can see on the table, as we dose through 20, 40 and then up to 80 milligrams of tuspetinib as a single agent, the response rate there was approximately 35% and those are CR/CRh, but then as we began to dose escalate higher, and as you can see in the 120-milligram dose level there, the response rate was 19%. So this was -- this created a cloud of confusion for us internally, for investigators and also for investors. But fortunately, that cloud has been lifted as we learned more about the patients. And it turns out the patient population that was enrolled at those higher dose levels, 120 milligrams and above was a completely different patient population. As you can see in the table, at 120 milligrams, over 80% of the patients now we had -- were been failure patients, whereas at 80 milligrams, it was only 30%. And that's responsible for the decrease in the response rate at the 120-milligram dose levels. And in fact, in the U.S. this year, we've seen over 90% of the patients coming to our trial have been VEN failure patients. And it's known that these patients are much more difficult to treat and have dramatically low response rates to single-agent therapies. But the good news is there's a silver lining to this cloud around the venetoclax failure patients. Although venetoclax, when it's administered single agent to these patients would have very little liquidy activity, we have learned that the addition of venetoclax to tuspetinib dumps the 19% overall response rate, as you can see in the table, up to 44%, demonstrating that the tuspetinib doublet can solve the problem. So how is it that tuspetinib can do that? Well, it turns out that tuspetinib directly targets pathways involved with resistance to venetoclax. Although venetoclax targets BCL2, the resistance mechanisms occur in multiple other pathways. And it turns out that by shutting down those additional SCATE pathways, tuspetinib may resensitize those prior VEN failure patients to venetoclax. So we'll see what it looks like on the right side of the slide here. So as you can see in the plasma membrane of the AML cells, you have the receptors. Those receptors then activate the cascade signal transduction pathways that are inside the cells. And those pathways then promote the growth and proliferation of the cell. So clearly, in AML cells, you see those pathways upregulated. And then over on the right side of the very far right of the slide in parallel, we have pathways that govern the sale death. And of course, AML cells want to avoid cell death. How do they do that? Well, very often they upregulate the BCL2. So that's why patients are treated with the venetoclax to inhibit the BCL2 and allow cell death to occur. But over time, as you treat patients with venetoclax, the AML patients develop just a panoply of mutations that occur in the other halfway. The FLT3 becomes mutated, KIT -- the KIT receptor becomes mutated. We see mutations in JAK as well as staff pathway and the RAS/MAP kinase pathway. So all of these then lead to enhanced growth and proliferation signals and that also increases the MCL-1 that then prevents the cell death from occurring. So what happens when we introduced tuspetinib? It directly inhibits the FLT3. The mutated forms of KIT and inhibits directly the SIC as well as JAK Kinases and the RSK in the RAS/MAP kinase pathway. And consequently, it reduces the MCL-1 expression levels, and that allows the cells to die. So this is concept. Do we have really any true clinical data to support that? Yes, we do. We've been dosing patients with the tuspetinib doublet all year in our APTIVATE trial. There was expectation that we -- by this time of the year, we would have dosed 30 patients. We're actually at 49 patients now as of this week that have been dosed with tuspetinib, and that's been driven by investor enthusiasm. There's a lot of data on this slide, but I'm going to focus your attention to the area that's circled by the green box. So we've been taking data cuts August 1, September 1, and then August -- excuse me, October 23. And as we went through this, we had more and more patients that became evaluable. First, it was 10 patients, then 15. And now as of October 31, 31 of the 49 patients have reached the valuable state. And in the patients who have failed venetoclax previously, you can see across the board, we're maintaining a 44% response rate. Yes, we have activity across the board in patients, wild-type FLT3 mutated FLT3 and thus a remarkable point here is that these VEN failure patients are responding to the test been doublet. And I also want to point out that many of these patients were just dosed in the last 2 to 6 weeks in September, October. So they're very early in their treatment, and we expect the responses to continue to mature as we go through the coming months. And Dr. Bejar can speak more about that in his section. But I want to have just one more slide here. I'll just point out, if you see the blue bar that indicates venetoclax and HMA and frontline therapy have a 66% response rate. But then over time, the patients are failing that frontline therapy. Many patients are getting treated in later lines of therapy. And when patients fail to venetoclax, the disease is highly refractory to salvage therapy. In fact, it's in the range of 4% to 15%. So we -- and it's because we're triggering all these additional pathways that make it difficult for other drugs to be active in these patient populations. So we absolutely need an improved therapy for these VEN failure patients and tuspetinib/VEN combination has shown already to be safe and active in these patients. With that, I'm going to turn it over to Dr. Bejar. Dr. Bejar?

Thanks, Bill. So I'll talk about the clinical experience with tuspetinib to date. I'll start with tuspetinib as a single agent where we've already demonstrated substantial single-agent activity and a very favorable safety profile. As you know, we had an end of Phase I meeting with the FDA that led to the selection of a recommended Phase II dose of 80 milligrams once daily and confirmed that all potential registration paths remain available. Then I'll talk about the ACTIVATE expansion trial and it began earlier this year, where we're treating patients with tuspetinib both as a single agent, but more importantly with tuspetinib in combination with venetoclax for the first time. And I'll share with you data from that, that shows that we continue to have a very safe favorable safety profile and increased activity, as Dr. Rice just mentioned. Finally, I'll summarize by talking about the impressive response rate we've seen with tuspetinib and venetoclax, particularly in the prior VEN AML treated patient population and how most of these patients are now actually prior VEN patients that are coming to our study. This may give us the opportunity for an accelerated approval development path we'll talk about at the end. So let's start with our experience with tuspetinib as a single agent and just do a quick recap. We began with the first-in-human study doing dose escalation at 20 milligrams going all the way up to 200 milligrams. And at every dose level where we saw signs of activity, we explored it further by adding additional patients at those dose levels. And you can see that we explored the 40, the 80 and 120 and the 160-milligram dose levels. We saw signs of clinical activity, including CRs at each of those different dose levels. And importantly, despite a large number of patients treated, saw no dose-limiting toxicities. In fact, there was only a single dose emitting toxicity in a study that occurred at 200 milligrams, 2.5x higher than a recommended Phase II dose. And take-home message for this is that we saw responses in a broad array of patients, as I'll show you, including patients with very adverse mutations. Let's talk about the safety of tuspetinib as a single agent. I think it has been impressive to date, you see the table on the right there from our September 1 data cut that shows that tuspetinib has been very well tolerated. Importantly, we haven’t seen side effects that might be common to other tyrosine kinase inhibitors, including no signs of QTC change or QTC prolongation, no drug-related nonhematologic severe adverse events and no drug-related deaths or discontinuations of drug due to adverse events related to the drug. We have not observed differentiation syndrome. And as I mentioned, no dose limiting toxicities all the way from 20 to the 160-milligram dose level. The 1 dose-limiting toxicity 200 milligrams occurred in a patient with high exposure that had a phenotype of muscle weakness, but importantly, not muscle damage. They had no rhabdomyolysis or no muscle breakdown, no elevations in muscle enzymes like CPK. Overall, tuspetinib has a very favorable safety profile that avoids some of the typical tacticities seen with other targeted agents. Now let's talk about the activity of tuspetinib as a single agent. This waterfall block shows the greatest reduction in bone marrow blast compared to baseline for patients treated at a variety of different dose levels shown in those different colors. And you can see that more than half of the patients treated had some reduction in their blasts and many had complete reduction of their bone marrow blasts. This includes patients with prior FLT3 inhibitors as shown by the little red triangles over the top there. And as you can also see that many responses came at 80-milligram dose level. As Dr. Rice mentioned earlier, as we increase the dose level, we saw that the patient population had begun to shift. We're seeing more and more patients that had received prior venetoclax. And as we saw the response rates were a little bit lower in that patient population. This is encouraging data nonetheless because it tells us that if we can combine with another active agent, we might see greater reductions in blast and greater responses, which I'll show you has been the case. When you break down the waterfall blast mutation status of the patients, you can see that the FLT3 mutant patients maybe have a slightly greater sensitivity to tuspetinib, not surprising given that they've mutated one of the critical paths that tuspetinib targets, but there is substantial activity even in the FLT3 unmutated or the wild-type population that I think differentiates tuspetinib from many of the other agents that are out there. So now let's talk about the responding patients on tuspetinib single agent. The swimmer plot shows those patients over time. And I want to make a couple of key points about this. First, the point that I just made about how patients with out FLT3 mutations can respond and several of our responders were in that category. But also how these responses evolve over time. You can see that patients with leukemia who have low blood counts often have an initial response that may be a complete remission with incomplete hematologic recovery. But as you can see, these responses that get checked over time can evolve and can improve despite continuing doses of tuspetinib, meaning that without any dose interruptions, the patients can see the accounts improve and the quality of these responses get better and remain in a good state for a long period of time as we've seen with a couple of long-term responders that did not go to stem cell transplant. That said, several of our patients did have early responses and were able to move to stem cell transplants that offer the best option for long-term survival with patients with realse refractory AML. Another question that we get about tuspetinib as a single agent is how does it compare to other existing agents? It's a difficult comparison to make because these agents were approved at a time when the landscape for treatment of AML was slightly different. Importantly, it didn't have a lot of patients receiving prior FLT3 inhibitors and didn't have a lot of patients or any patients that received prior venetoclax. However, we do have some patients that we think we can make an apples-to-apples comparison with. So for example, if we take our FLT3 mutated relapsed refractory AML population, identify those patients that were treated with tuspetinib at a recommended Phase II dose. We see that we had 5 of these individuals and 3 of them had a CR or CRh, a really excellent quality response. If you compare that to the experience with gilteritinib in its Phase III registrational trial treated at its commercial dose, the CR/CRh there is, as adjudicated by the FDA, was 23%. So I think we are as good, if not numerically better, despite small numbers than gilteritib in that target patient population of VEN-naive FLT3 mutant AML patients with relapsed disease. However, we think we -- if we look at the FLT3 wild time population, again, looking at those VEN-naive patients treated at a recommended Phase II dose, we see substantial and respectable activity in that patient population with 2 out of 7 patients achieving a CR/CRh whereas in the early phase studies gilteritib, the only time that they really treated FLT3 unmutated patients, the response rate was essentially 0 for the CRC rate responses, meaning that really tuspetinib has activity in a patient population where gilteritib seems to not have as much activity and in that sense, it makes it a better rating for those patients. Other important development work that we've done with tuspetinib shows that we're marching towards our registrational study. One of the key things that we needed to do was a food effect study. This is important because before this, we were limited to dosing tuspetinib in the fasted state. And when we want to combine tuspetinib with other agents, sometimes you would like to be able to take them at the same time. So for example, venetoclax must be taken with food. So we did the fed versus fasted study that confirms that there isn't any significant difference, no clinically significant difference in exposure when you give tuspetinib as a single agent in the fed state versus the fasted state. This will give us the flexibility to remove any fed versus passive requirements for taspetimib. So with that, let me move on to talk about Tus and then in the expansion trial where we give the 2 drugs in combination. I'll start with the safety profile, again, with the September 1 cutoff, where we treated a large number of patients with a Tus combination and compare that to our experience with tuspetinib as a single agent, as I've shown you earlier in the prior slide. The important message here is that we have seen no unexpected or new safety signals that have arisen from the Tus VEN combination. The combination is well tolerated. Importantly, we've seen no further increases of QTC prolongation. We see no differentiation in drug and no drug-related deaths. If you look at the table on the right, you see the one thing we do observe is a slightly higher rate of cytopenias and slightly higher rate of febrile neutropenia, which I would say is still favorable compared to other venetoclax containing regimens like HMA/VEN and VEN/GILT in prior studies where the published fabrile neutropenia rate is 40% or higher. Other studies we've done with the combination, if you look at the relative exposure of the 2 drugs when given in combination, the dose exposure of tuspetinib when given a combination of [indiscernible] is essentially unchanged comparing to when it's given as a single agent, meaning that we don't have to worry about any dose adjustments of tuspetinib when given in combination. The reverse also seems to be true that when we look at venetoclax exposures, they're very similar to what you would expect venetoclax was given as a single agent, comparing it to published data where venetoclax was given at the same dose. However, this data collection is ongoing, and we'll do further analysis down the road. But at the moment, it looks like there's no need to make large adjustments of the venetoclax dose and these 2 drugs are given in combination gives us the freedom to follow the label for venetoclax in our clinical studies. Now I want to summarize the activity that we've observed in the test bend doublet and compare it to what we've seen with tuspetinib as a single agent. So this table highlights the response -- the overall response rate for both of these different ways of giving tuspetinib. As a single agent, you'll see that our response rate in the VEN naive population was quite good, 34% response rate overall, which was even higher in the FLT3 mutated population, 55% and respectable in the FLT3 unmutated population that was VEN-naive of 22%. But as we mentioned earlier, the VEN pretreated patients had lower response rate. This is a very difficult to treat patient population with any agent, particularly a single-agent drug. However, when we combine tuspetinib with venetoclax in our doublet study, even the prior VEN-treated patients have an excellent response rate. We have a 44% overall response rate that's even higher in the FLT3 mutated population. We saw 5 out of 9 patients achieved an overall response and 38% in the FLT3 unmutated. This is a really promising result for this combination therapy that has been well tolerated to date and gives us the opportunity to pursue the combination as a potential registrational strategy in this difficult-to-treat patient population. Here is a simespot of the responding patients to the test than doublet. This looks somewhat similar to what I showed you earlier for test as a single agent, but I'll point out some key differences. First, we see that a lot of these patients, the vast majority have a V in that third column, reflecting the fact that they had seen prior venetoclax. Several of the patients also have an F, reflecting the effect that we've seen prior FLT3 inhibition. And like tuspetinib as a single agent, many of these patients have a FLT3 unmutated status while we have seen many ITD and TKD mutant patients here as well. The other difference is that there is greater myelosuppression with the combination with venetoclax as you would expect, with the addition of a myelosuppressive agent. And that right now, because of our rapid accrual in the last 2 to 6 weeks, the data are still early. So we hope to give you additional updates on this at ASH. In fact, the data approval has been quite quick over the last few months, where in August, we only had 5 patients on that some spot that was updated at September 1. And now with our October 23 data cut, you can see the great additional patients there. So again, at ASH will give you some more additional data with greater follow-up to better understand the quality and the nature of the responses that we've seen in the TUS/VEN doublet. So now I want to give you a preview of where we're headed with the combination therapy. As we showed you, we had a successful end of Phase I meeting with the FDA in the middle of this year, where shortly after we launched the ACTIVATE to set single agent arm for relapsed/refractory AML, we since launched the ACTIVATE TUS/VEN doublet, which will continue probably into the first or second quarter of 2024. We will gather all the data required to understand exactly how the drug is performing and how we will need to fashion a potential registrational study of test than in prior VEN AML treated patients. It will be a study that will include the potential for accelerated approval based on response rate but will be powered for overall survival. So the study itself, like the ATMO study can serve as a full approval study. In the meantime, we'll also be expanding the indications for tuspetinib. We'll be opening an arm for relapsed refractory higher-risk MDS and for CMML patients with refractory disease. This is important, I think, because many of the pathways that we've seen activated or mutated in patients with AML that have responded to tuspetanib are also active in patients with higher-risk MDS and CMML. So we're interested to see what kind of activity we'll see in this greater patient population. And I think most importantly, we are going to be combining to spend it with venetoclax and HMA as a triplet therapy or newly diagnosed untreated patients with AML. So we hope to launch sometime in the middle of 2024. That development will begin shortly after ASH. So we have a large program ahead for tuspetinib both as a single agent and in combination with venetoclax and additional data to share with you at ASH. But now we'd like to step back and take the opportunity to answer some of your questions. So with that, I'll pass it back to Bill.

Thank you, Raf. All right. So we're going to enter into the Q&A session so that everyone is able to ask questions at Dr. Daver. And as the operator is reading the questions for Dr. Daver, I want to ask you a question at first. So could you please describe for us this VEN failure patient population as they enter your clinic? How sick are they? What is the reservoir of normal bone marrow functions? And what is their expected life expectancy without salvage therapy or with current salvage therapies?

Yes. Thank you, Bill and Raf for the discussion question. So as you said, the HMA event as well as other VEN-based therapies in the frontline setting have been really important for our patients and have improved response rates and survival, which is good, but we are seeing a number of patients relapse, especially post HMA/VEN, we see that the median duration of remission is about 14 to 24 months. So in about 2 to 3 years, we're now seeing close to 50% to 70% of these patients relapse. And what has been shown by our group as well as others is that at the time of relapse, these patients tend to be very different from their frontline presentation with enrichment of mutations, including FLT3, TP53, RAS/MAP kinase involving mutations. And so they tend to be very resistant to standard therapies that usually do not cover these mutations well. The response rate that has been published by our group as well as others in the relapsed refractory setting post HMA/VEN is around 15% to 18% CR/CRi with whatever regimen you may use, cytarabine-based other HMA combinations targeted therapies and the median survival in our publication. This was in hematologic from MD Anderson a couple of years ago. post-HMA/VEN was about 2.8 months. 2 other groups have also now published similar data at about 2 months. So really a very difficult population, less than 20% response rates and about 2.5 to 3 months expected survival. So really a big ununmet need, probably the biggest unmet need, I think today, in the AML relapsed refractory setting to find something that can give us good response and outcome as well as good tolerability because as you mentioned, these patients also tend to be quite myelosuppressed and you need to have a regimen or a combination that does not cause very severe myelosuppression.

Okay. Thank you, Dr. Daver, for giving us the characterization of this emerging patient population. And now let me turn it back over to the operator for questions.

[Operator Instructions] With that, we will kick it off with our first question from Matt Biegler at Oppenheimer.

Thanks for walking us through this data, a nice update. I'm just wondering, I'm thinking ahead maybe to the front line here. Is there any way that you can leverage some of the recent FDA guidance under Project FrontRunner? And if yes, how is that kind of shaping how you're thinking about designing a trial that maybe you can get into the frontline setting?

I can start. I think that the project primarily does provide some guidance about how to bring therapies to the front line earlier. I think this [indiscernible] to treat the most sick and the most relapsed and most refractory patients first with an agent before he can bring into the front line can really prevent drugs from making it that don't have that kind of activity. Now fortunately, tuspetinib does have a single-agent activity we have been able to show and is highly relapsed refractory patient populations. But I think our greatest interest is to put it in that front-line setting, and we'll be moving forward with that as quickly as possible.

And we should ask Dr. Daver he's pretty much the architect of the triple combinations in frontline therapy, Dr. Daver.

Yes, absolutely. I think there is a huge unmet need in the front line as well. It was just another meeting we were sharing in London. And one of the comments that came out is that HMA/VEN has kind of become a crutch in a little way to the development of new treatments because people have become complacent, which we should not be because the 3-year survival was only 23% for all around fit with HMA VEN. So I think there's a huge recognition now that we need to improve on that and triplets are really the frontrunners there. And I think if we can leverage that, there may be potential ways and discussion with the FDA. They are looking more at TrueCR as well as MRD potentially for certain molecular subsets to look at early approval, maybe even potentially single-arm approval. So of course, we have to generate the data. But yes, I think with this triple especially looking at the profile of tuspetinib with less myelosuppression single agent showing better responses than what we had seen with Gilt in salvage as well as wild-type activity. I definitely think we would -- should think about potential rapid frontline triplet approval paths.

That makes sense. And then in the salvage setting, which I guess is kind of where we're going or what we're going for immediately. What kind of powering assumptions are you thinking for that doublet over standard? Or actually, what even would be standard of care? Would it just be like best supportive care, like what are you kind of thinking for the design of that trial to get this drug approved.

No, that's a great question. I think if you look at the options that patients have in terms of standard of care today after they've failed or been failed by venetoclax, there aren't a lot of things that are out there. There are some intermediate chemotherapy approaches. Some of these patients may be alterable for chemotherapy, so that could be one of the options. I think this could be run very similar to the atmost study, where you have a short list of potential therapies that one could give absent the experimental therapy and the physician would have to select prior to randomization, which when they would treat their patient with and the patient would be randomized and they would receive that therapy. And now Dr. Daver, if you have additional thoughts about the options that these patients could receive.

Yes. I mean, I think this is probably in the FDA's perspective, a huge unmet need, so post HMA/VEN population. And I think, yes, there is no standard of care. I mean there's nothing the NCCN gives us a whole list of different options. You can use cytarabine, HMA, hydroxyurea pallitive care. But yes, I think it would be very much what Dr. Bejar is saying that we would use the tuspetinib and we would give a list of 5 of the regimens people use, knowing that none of them really have more than 15%, 18% response because unfortunately, there is nothing that is there. And the endpoint here probably would be something like CR and OS. But I think this could be not a very large randomized study, especially if we continue to see the data we are with a potential early approval pad.

The next question comes from Soumit Roy at JonesTrading.

One, congratulations on the really solid data. I guess the summers link kind of fills the difference between relapsed refractory treatment and second line is markedly improved. A quick question on that is none of the patient in the VEN combo trial are going through HSC. Is that a good sign or a bad sign? Is it availability of donors or you could just give us some color?

I just think it's early. The decision to transplant a patient after treatment, will first it takes some time to do. And then ideally, you want to transplant them when they have a low level of disease. So it takes a bit to get to that point. So I think it still is a possibility for some of these patients.

Got it. On the febrile neutropenia front, are these patients getting treated prophylactically with GM-CSF? Or how is the management going and how much of a concern is there?

Yes. So for febrile netropenia is very common, obviously, in relapsed refractory AML population for a variety of agents. I think that this doesn't really stand out, I think, as being abnormal or unexpected for this patient population. The protocol doesn't require any form of prophylaxis, it really defers the institutional standards for that. But perhaps Dr. Naval you can put this into context for us?

Yes. Absolutely. I think that's a great question. And febrile neutropenia or neutropenia itself is probably the key side effect that we would be looking for in the salvage combination with VEN. And looking at VEN/GILT that we published, I was a lead author and JCO. We did see significant febrile neutropenia rates regimen is very effective, but had more than a 60%, 65% febrile neutropenia and even HMA/VEN doublets when used in [indiscernible] for intensive chemo, our group has published multiple times the expected febrile neutropenia rates are close around 50%, 55%. So the 26%, 27% febrile neutropenia here with the TUS/VEN granted, it's early, but does look like it's lower than what we have seen with VEN or HMA [indiscernible] could become an advantage if we continue to see that over time.

The next question comes from Joe Pantginis at H.C. Wainwright.

I wanted to continue on that theme with regard to febrile neutropenia. So obviously, you're quoting the rates in the other trials, whether it's with HMA or gilteritinib or what have you. So I guess I wanted to ask the question for the planned first-line setting, how you're going to be looking to hopefully mitigate the febrile neutropenia since you'll be combining with HMAs. And then secondly, any color you can add with regard to those on the call and beyond the underlying mechanism of action why TUS is having what appears to be a significant impact in the FLT3 wild type.

Yes, those are excellent questions. So I can address the first part a little bit, and then I'll have Dr. Daver comment. Since a lot of what we're doing is really based on this experience, putting these drugs together in first-line combinations. I think whenever you combine agents that bring toxicity to the table, you do have to do some dose adjustment. And I think that that's one of the things that we'll keep in mind that the label for HMA then is quite aggressive, where it's 28 days of venetoclax for a 28-day cycle, if you follow it exactly. But I think the reality is we're realizing that you need to reduce the venetoclax substantially in order to be able to get these patients to have significant count recovery. However, in the triplet side we would propose, we would do something that can do what we're doing in the doublet where we have patients have a bone marrow examination early on in the process. If they've cleared their blast, then we would hold a venetoclax to give them more time to recover. So it would be a little bit more of a dynamic dosing strategy. And we would, of course, be open to reducing the doses of the drugs if need be in order to combine them. That will be part of what we learned about in our triplet pilot. But I think that you -- that is the key point. I think being able to manage the cytopenias and the other side effects of the agents when you put them in a combination, is really important because if you don't get that right, getting patients into remission, they can't tolerate isn't going to be successful. So Dr. Daver, can you just share some of your experience?

Yes, absolutely. And as you mentioned, we've pioneered many of the triplets and these are moving forward. And the key issue here, of course, over the last 4 years, and we're working very closely with the FDA as well as other large corporate groups is mitigating mylosuppression. Nobody really doubts that if you combined biologically active drugs, you're going to get better activity. This has been shown very well by multiple myeloma, lymphoma, ALL over the last decade. So the key usually is optimal reducing it. And if you have a drug that does not have cumulative myelosuppression, that is a big advantage. So our approach has usually been to do an early marrow somewhere around day 14 or 21, which the FDA has actually agreed on multiple other frontline triplets to gate the stoppage of venetoclax once you've achieved either a remission or a marrow ablation hypocellularity, that we all agree that there's no point in giving VEN if your day 14 or 15 marrow shows that you have already achieved clearance of the disease and then you need to stop and allow content recovery. So this would probably be one approach. And with this approach with other triplets that we have shown the HMA/VEN with CD123, HMA/VEN and IDH, HMA/VEN FLT3 inhibitors, the myelosuppression has actually become quite manageable with count recoveries now below 35 days for all of these triplets, which is actually in line with what you get with doublet HMA VEN. And I think with the [indiscernible], at least in salvage, what we're seeing with maybe less pembrol neutropenia, less profound myelosuppression, this could get even better. The second thing, which I think is a very good question is why is this working the while time and this is always a question we have with many different TKIs. And often many years later, we started realizing that we may have just been focusing on one pathway of interest like FLT3, but there's other targets. And I think with TUS Is really interesting to see that it actually targets 4 or 5 of the major common resistance pathways event. So these are FLT3 TUS/MAP kinase, JAK-STAT TP53 and MCL1. These 5 are probably 90% of VEN resistant pathways. So that maybe, to some degree, good coincidence and maybe to some degree, the way the drug was designed, but this may really be why we're seeing very nice activity in combination with VEN, and we'll have to see how that pans out in the front line setting.

Very much.

Thank you, Dr. Daver for that. I wish I could have said it so eloquently. Thank you.

The next question comes from Greg Renza Gena RBC.

It's Anish on for Greg. Congrats on the continued progress. Just on the ESH posters and the 2,000-fold sensitivity of increase in sensitivity of test resistant cells to venetoclax. Just wanted to ask how you might be able to leverage these findings and translate them to the human population with regards to the clinical care regimen in terms of dosing, timing, et cetera. Congrats.

Thanks. We'll have Dr. Bejar address that one.

Yes. Thanks for mentioning that. We didn't talk about it in the slides, but we do have a poster here at this meeting that highlights some preclinical data where we created tuspetinib-resistant mines by exposing into tuspetinib for a prolonged period of time. And then we went to see what other things are they sensitive to or however their sensitivity has changed. The key finding is that these lines that have become resistant to tuspetinib are now 2,000 fold more sensitive to venetoclax than they were at baseline. That, I think, speaks to how these 2 drugs are work in concert. And the way we might leverage that clinically is what we're doing with the TUS/VEN combination, namely that if the mechanisms that lead to resistance TUS are then more sensitizing to venetoclax, putting these 2 drugs together could slow or prevent the emergence of that test resistance. So we think it's important from that standpoint. And I think in general, combination therapies that have very different mechanisms of actions offer you that opportunity to avoid the development of resistance. And that will be something that we explore in our patients as we go forward.

The next question comes from John Newman at Canaccord.

Thanks a lot for the very detailed data update. I just had 2 questions. The first one was, I'm just curious as to how you're defining venetoclax failures. I'm just wondering what portion of the venetoclax failure patients progressed on prior autoplex versus maybe discontinued, they couldn't tolerate the drug? And then second question, just a simple one. On the durability, it looks like you're measuring that in a liter cycles, if that's correct. Just curious as to the length of the cycle.

Yes. So for the test spend do we are measuring in terms of cycles, there's a little bit of flexibility in the cycle length as we will allow the cycle to be extended if patients see more time for account recovery, but cycles are on the order of 28 to 56 days at the most probably on average, closer to 42%. And then I would ask Dr. Daver if you could comment on the first question.

Yes, sure. Yes. So for VEN failure, terminology, which is being even much before the tuspetinib studies, it's basically refractory and/or relapse. So if they never achieved a CR, CRi, CRh, which is about 20%, 25% or so of HMM and frontline, that's refractory. And then, of course, relapse is those who achieved the CR/CRh, CRi and then relapsed. We don't see too many patients who just come off VEN because of intolerance, a lot of it is because we are -- we and many others have now through our publications and others have become familiar with the reduction of VEN duration. Yes, that VEN failure real is efficacy failure definition more than intolerance.

And that's our experience with the study participants. Most of them have seen a substantial amount of VEN HMA. It's not a simple cycle or something of that nature.

And we have, I think, one more. Analysts in the queue. The question will come from Li Wang Watsek at Cantor Fitzgerald.

I just wonder if you can comment on the CR/CRh actually for the doublet and whether you believe you can perhaps get approval based on the CRC rate and also looks like the 2 CRs occurred in the wildtype patients, wondering why do you think that's the case? Do you think it's mostly driven by their prior lines of treatment? Or they're more likely to respond to the doublet so they get a deeper response.

That's a great question. So I think it's early and that these responses evolve over time, just as they did for tuspetinib as a single agent. So I don't think I can make a strong comment about what the eventual CR/CRh would be. I think if you are looking for accelerated approval, it does have to be on that basis. I haven’t seen a lot of flexibility from the FDA about accepting responses that are other than CR/CRh. And then for the second half of your question about why do we only see the full CRs in the patients without prior venetoclax. I think that may have something to do with the bone marrow reserve of patients who have been through venetoclax. I don't know if Dr. Daver, if you have any insight into that?

Yes. I think it's hard to say exactly the mechanism there. I think among the wide type, there is activity because of the many different kinases that are being targeted, as we mentioned, RAS/MAP-kinase, JAK2, SRC that may be playing a role there. I'm not really sure. I think the numbers are too small right now to know for sure. But to the previous part of the question, I do think there is a potential for CRh or CR to be an endpoint in salvage studies and highest unmet need with no standard of care. This is kind of exactly the 3 or 4 things FDA would look for to consider single-arm approval. So I do think that if we continue to see that, but also has to have durability component. So if you have a good CR/CRh along with the durability component in salvage much beyond what can be shown by contemporary publications and controls for that similar population, this is definitely something that we could discuss. But we do need to get more durability data there.

Yes. Do you think that the patients with prior VEN exposure have a different hematopoietic reserve. Is it harder for them to recover counts in subsequent therapies?

I think yes. I mean, in general, the relapse patient population tend to have heavy prior treatment and more burned out marrows kind of the general term we use. But I also think they could be enriched with mutations like TP53 and RAS/MAP kinase, which also stunned hematological recovery. So I think it's probably a combination of those factors.

All right. Well, I believe we've hit our time limit now. So let me just thank both the -- all of the attendees, the listeners here for joining us today, but a really special things goes out to Dr. Daver. And so taking time away from your practice, your research, your family to be here with us today, we appreciate it so much. So a special thanks to you. Let me hand it over to Raf.

Yes. Let me echo that. So Naval thank you so much for joining us today. Your insight is extraordinarily helpful as it has been helping us navigate this drug through its clinical process, and we look forward to working with you further.

Yes. Absolutely.

Thank you. Yes, same here. I'm very excited to continue. And I will say the data as we get more and more patients is looking more and more robust and more and more confidence. So I'm very hopeful next year we'll really have some forward inroads with the test.

Thank you for the comments, yes. We always hear it takes more patients and more time. And so that's what we're doing. All right. Well, I'll turn it back to the operator now, but thank you so much again, Naval. We appreciate it. Operator?

Thank you, ladies and gentlemen. This concludes today's conference. You may disconnect your line, and have a wonderful day.