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

Good afternoon. My name is Sherry, and I will be your conference operator today. I would like to welcome everybody to Aptose Biosciences Interim Clinical Update Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to introduce Dan Ferry of Life Science Advisors. Please go ahead.

Thank you, Sherry. Good afternoon, and welcome to the Aptose Biosciences interim clinical update conference call. Joining me on today's call from EHA 2023 are Dr. William G. Rice, Chairman, President and CEO; and Dr. Rafael Bejar, Senior Vice President and Chief Medical Officer; and Mr. Fletcher Payne, Senior Vice President and Chief Financial Officer. After today's prepared remarks made by Dr. Rice and Dr. Bejar, there will be a question-and-answer session. Before we proceed, I would like to remind everyone that certain statements made during this call will include forward-looking statements within the meaning of U.S. and Canadian securities laws. Forward-looking statements reflect Aptose's current expectations regarding future events. They are not guarantees of performance, and it is possible that actual results and performance could differ materially from these stated expectations. They involve known and unknown risks, uncertainties and assumptions that may cause actual results, performance and achievement to differ materially from those expressed. To learn more about these risks and uncertainties, please read the risk factors set forth in Aptose's most recent annual report on Form 10-K in the SEC and SEDAR filings. All forward-looking statements made during this call speak only as of the date they are made. Aptose undertakes no obligation to revise or update the statements to reflect events or circumstances after the date of this call, except as required by law. I will now turn the call over to Dr. Rice, Chairman, President and CEO of Aptose Biosciences. Dr. Rice?

Thank you, Dan. Good afternoon all, and welcome to the Aptose interim clinical update being held in conjunction with the 2023 European Hematology Association Congress. I'm Dr. William Rice, Chairman and CEO of Aptose and I'm joined here in Frankfurt and on the call today by Dr. Rafael Bejar, Aptose's resident KOL and Chief Medical Officer. Today, I'll begin with the highlights and overviews. Then Dr. Bejar will present our new data sets, and then I'll wrap up with our vision for the future applications and commercializations of tuspetinib. But first, I'll remind you again that today we will make certain forward-looking statements. And I'll remind you that Aptose is a precision oncology company, developing oral targeted agents to treat hematologic malignancies. Our lead agent is tuspetinib or TUS, as we call it. TUS is a once-daily oral kinase inhibitor being developed to treat acute myeloid leukemia or AML. TUS already has received orphan drug designation and fast track status from the FDA. TUS has delivered complete remissions or CRs across 4 separate dose levels and with no dose-limiting toxicities at any of those doses. In fact, TUS has demonstrated single-agent clinical activity across a broad range of difficult-to-treat relapsed or refractory AML patients harboring a diversity of adverse mutations. Yet TUS has maintained a highly favorable safety profile. We believe TUS can be the ideal drug for combination therapy in front line, second line and third line patients. We view accelerated approval paths as feasible in second line AML and in the more treatment in coherence relapsed or refractory population. And we believe this profile supports $1 billion market potential in AML plus additional commercial potentials in MDS. Our secondary agent, luxeptinib, or LUX as we will call it, is an oral lymphoid and myeloid kinase inhibitor that already has demonstrated clinical activity in patients with AML, follicular lymphoma and DLBCL. In an effort to reduce pill burden and increase exposures, we developed a Generation 3 or G3 formulation that is showing promising absorption, and we plan to dose escalate soon to explore the PK properties of a higher dose level. Among our TUS and LUX programs, there are multiple near-term opportunities to report additional clinical responses, responses and achievements, including the European School of Hematology and the American Society of Hematology Conferences during the second half of this year. I now want to highlight a few of the key headlines related to our tuspetinib program. First, we recently announced a $25 million financing with Keystone Capital. This is a common stock deal with no warrants and the proceeds are planned to support the TUS development program. Second, we completed the dose escalation and dose exploration trial with TUS in relapsed refractory AML patients, and we dosed 77 patients in this study. Complete remissions or CRs were achieved with once-daily oral tuspetinib, across 4 dose levels and with no observed DLTs at any of the active dose levels, illustrating the highly favorable safety profile of TUS. These clinical responses were observed across mutationally diverse populations of relapsed or refractory AML patients, including TP53 mutated patients with a CR/CRh rate of 20% and RAS-mutated patients with a CR/CRh rate of 22%. And these are among the most difficult patients to treat. Third, we held a successful end of Phase I meeting with the FDA, in which the recommended Phase II dose of 80 milligrams once daily was selected. We learned that all potential development paths remain available, including the single-agent arm accelerated approval path, and we learned that no extraordinary CYP450 metabolites or QTC prolongation monitoring will be required going forward. And finally, we initiated the APTIVATE expansion trial with TUS in which high-risk patients will be enriched to receive TUS monotherapy and will be combined with venetoclax called TUS-VEN to assess doublet activity in the relapsed/refractory patients who previously failed VEN and other agents. Enrollment has been brisk with greater than 25 patients already dosed, and we get many questions about the TUS-VEN doublet. To date, it's been well tolerated. All patients remain on study and preliminary CR activity has already been observed, and Dr. Bejar will speak more about this in a few moments. Now I want to discuss the kinase inhibition profile of TUS and how that guides the commercial opportunities. It's important to understand the mechanism of TUS and how that differs from other kinase inhibitors. We view TUS as a multi-drug therapy in a single tablet. TUS potently inhibits the mutant and wild-type forms of the FLT3 kinase, the SYK kinase, the JAK1 and JAK2 kinases, mutant forms, but not the wild-type form of cKIT kinase and the RSK1 and RSK2 kinases. All are inhibited roughly equally in the 0.5 to 6 nanomolar range. This allows us to simultaneously suppress these specific kinases that operate oncogenic signaling pathways that can drive proliferation and resistance to various drugs. On one end of the spectrum, dirty kinase inhibitors must achieve exposure levels to hit the kinases important in the disease process, but they also hit an array of safety targets and have toxicity issues. On the other end of the spectrum are highly selective kinase inhibitors, like certain FLT3 inhibitors that specifically target FLT3. These agents must achieve exposure levels that deliver near complete inhibition of FLT3 in the AML cells, but that comes at a price because those exposure levels also fully inhibit FLT3 and other kinases in normal cells that can cause toxicities. In contrast, TUS can achieve higher exposure levels and fully inhibit FLT3, JAK and other kinases, but it does not need to do so. Rather, lower exposure levels of TUS in the bloodstream achieved clinical responses through simultaneous inhibition of the target kinases by 40% to 70%, thereby avoiding higher exposure levels and avoiding common toxicities of other agents. This potency and safety profile that is quite unique among kinase inhibitors makes TUS the ideal drug for monotherapy, combination therapy and maintenance therapy applications. In fact, the safety and potency profile positions tuspetinib to address multiple AML populations and commercial opportunities. This includes the potential for a single-arm accelerated approval in relapsed/refractory patients, the potential for tuspetinib-venetoclax or TUS-VEN doublet combination to achieve accelerated approval in second-line AML, the potential for triplet combination approval in front-line AML and maintenance therapy to prevent patients from relapsing after achieving a complete remission by stem cell transplant or by drug therapy, and this represents our near and long-term commercial strategy for TUS. Now I want to change gears and review our time lines of recent events and our catalysts going forward. On this slide, I'm illustrating achievements from the beginning of 2022 on the left side through May of this year on the right side. In January of 2022, on the left, Aptose assumed full responsibilities of the tuspetinib dose escalation and dose exploration trial after licensing TUS from Hanmi Pharmaceuticals. We quickly added clinical sites and accelerated the enrollment. And at the same time, TUS received fast track status from the FDA. Moving to the right, we presented incremental data at the EHA conference last year. We only had taken control of the trial earlier in the year and only had 4 to 5 months of new data. So the data set was truly incremental. But later at the end of 2022, at the ASH conference, we illustrated the broad activity of TUS against a range of mutational populations and highlighted the favorable safety profile. And this is when other companies began to notice a unique profile of TUS. Moving into 2023 toward the right side of the slide, we completed the original dose escalation and dose exploration trial with TUS and submitted our data to the FDA. Then at the end of May, we had a successful end of Phase I meeting with the FDA. Looking below the line, in parallel during the beginning of 2023, we also initiated the APTIVATE trial and began dosing relapsed/refractory AML patients with TUS as a monotherapy and as the TUS-VEN doublet. Then at the end of May, we also announced the completion of a $25 million financing. Now moving on to June of this year on this slide, here at EHA, we are presenting the totality of data from the TUS dose escalation and dose exploration trial and preliminary activities from the APTIVATE trial. Moving to the right, we plan to present a maturing data package from the APTIVATE trial at the ESH conference in October and then a much more mature data package at the ASH conference in December. Looking below the line, we also aim to introduce MDS patients into the APTIVATE trial and then prepare for a TUS-VEN HMA triple combo pilot study in front-line AML patients. From there, we will refine our strategies for potential accelerated approval trials and for a TUS-VEN doublet Phase II randomized registrational trial. So our plate is full for the remainder of the year. I now want to turn the slides over to Dr. Bejar. Raf?

Thanks, Bill, and thank you all for joining us on the call today. I'm going to be telling us more about the clinical journey and what we've done so far to get to the point where we have. I'll start with our completion of our dose escalation and exploration portion, where we tested various levels of tuspetinib to determine safety profile and to explore it in a greater number of patients to make sure we hit an optimal dose design. This allowed us when we recently met with the FDA to select, as Bill mentioned, 80 milligrams as the recommended Phase II dose. Now in the APTIVATE portion of the study, where dosing is ongoing with tuspetinib as monotherapy, we'll be exploring its activity in select patient populations. This includes patients with FLT3 mutations that have been exposed to prior FLT3 inhibitor therapy as well as patients with adverse features like TP53 mutations and complex karyotypes. We hope to test that up patients in the monotherapy to also get information in patients with other select mutations, including patients with RAS mutations that turn out to be resistant mutations to many other therapies, including other tyrosine kinase inhibitors and venetoclax. In parallel, we'll be testing patients with tuspetinib and venetoclax as part of our doublet combo therapy. I will tell you shortly in greater detail, we've already begun dosing patients and now have achieved rapid accrual in this exciting doublet study. Later this year, we do plan to proceed to tuspetinib-venetoclax HMA triplet combo in a front-line setting to further explore the potential of tuspetinib in combination therapy. Each of these different strategies will allow us to investigate a potential registrational path. Monotherapy in very high need clinical populations could lead to a single-arm accelerated study with tuspetinib-venetoclax doublet will allow us to treat patients in earlier lines of therapy, including second line therapy, which also could include a potential for accelerated approval. And finally, the triplet study in front-line could lead to a confirmatory randomized trial to seek approval in that indication. So for more detail about what we've done during this escalation here will show you the different dose levels that have been tested, 20 milligrams all the way up to 200 milligrams and then the 4 dose levels that were explored in further testing at the active dose levels where we saw additional responses and no additional DLTs with a large number of patients treated. In total, 77 patients received tuspetinib in the Part A Part B dose escalation, dose exploration portions of the study. And as I'll go into greater detail, this has been very well tolerated. There have been no drug-related severe adverse events, deaths, differentiation syndrome, QTC prolongation or evidence of muscle damage. We have some estimates about the PK being approximately 40 hours, which is compatible with once daily dosing. And as I mentioned before, no dose-limiting toxicities. Here is an updated summary of the safety of the drug to date, again, including the 77 patients treated, and you'll see the most common treatment adverse events, other things that are not unusual for patients with leukemia. There is, in some cases, of nausea and diarrhea, that are probably the most notable side effects of tuspetinib. But the majority of those cases are Grade 1 and 2 with only a single case of treatment-related nausea being Grade 3. So key features here, again, are the drug is well tolerated across a broad range of doses that we see no evidence of adverse events that have compromised the development of other agents in this class. And it sets up tuspetinib to be an ideal drug for combination, especially with drugs that might have overlapping toxicities. So here are some data that help explain why we selected 80 milligrams as the recommended Phase II dose. In this graph, you see several bars that represent different response rates in the population. The yellow bar is the overall response rate, which you can see was greatest at the 80-milligram dose level. CRC and CRh are represented by blue and orange lines, respectively, and partial responses are in purple. The line that you see going across the top here represents the proportion of patients in each dose level that achieved the exposure required for response. And at 80 milligrams, more than 80% of patients were achieving this by day 15, whereas at 40 milligrams, where we did see signs of clinical activity, only about 50% to 60% of patients were achieving the minimal dose level requires a response. So together, it seems that 80 milligrams was the dose level with not only the greatest activity with a substantial number of patients reaching that level needed to acquire a response but also with the great safety profile. And for that reason, the 80-milligram dose is a recommended Phase II dose for monotherapy. Now let's talk a little bit about the activity of the drug. We've shown plots like this before that note the decrease in bone marrow blasts compared to baseline. On the left are shown those decrease in bone marrow blasts for all patients. And on the right, they're broken down by the FLT3 mutation status. The addition to this graph, since the last time we showed something like this is the additional patients that want 20 and patients at 40 milligrams, again, showing the activity of this dose level that is below our recommended Phase II dose, giving us a wide margin of activity in order to treat patients with a wide therapeutic window. Here's an update for response of those patients with signs of response on the study. And as always, I'll keep making the point that patients who achieved a response who cleared their blasts often have incomplete count recovery at the time of that initial response. But with continuous dosing of tuspetinib, we see improvement in their counts over time. This is a strong indication that continuous exposure to tuspetinib is not uniquely myelosuppressive. Once patients have the leukemia cleared, the drug can be continued and patients see the response mature from complete remissions with incomplete recovery shown in the triangles to complete remissions with partial or complete count recovery shown primarily in the diamonds, the orange and the red diamonds there. And you can see that patients over time to stay on study to see improvements in their counts. We also note the diversity of responses in patients with and without FLT3 mutations, again, arguing that this drug has activity well beyond the FLT3 mutant population, making it more agnostic to that mutational status than perhaps other agents in this class. And finally, as always, we note that the large number of patients were able to go on to stem cell transplant, which is the only potential curative option for patients in these late-line therapies with AML and something that is very difficult to do if the patient doesn't achieve a clinical benefit. I want to highlight one patient in particular. This is the patient at 150-milligram dose shown by the star there. This is given in greater detail in this case study here. This is the FLT3 unmutated patient who does carry mutations in NRAS, BCOR, splicing factor U2AF1 and [ INCETBP1 ]. This 55-year-old male have refractory AML with MDS related changes and had already been failed by induction chemotherapy and by salvage therapy with additional chemotherapy. Starting at 150 milligrams of tuspetinib, the patient achieved a CRh at cycle 1 and then matured over time with continuous dosing. That became a CR by cycle 5 and allowed the patient to become transfusion independent. This occurred without any dose-limiting toxicities, no drug-related severe adverse events and importantly, no prolonged myelosuppression over time. And to highlight that, I want to show the patient's blood counts over time here. So I'll walk you through each of these lines. The red line at the top shows the patient's hemoglobin over time. And you can see, despite the presence of leukemia and ongoing dosing, the hemoglobin stayed fairly stable until as the response matured in cycle 2, cycle 3, cycle 4 and cycle 5, the hemoglobin actually improved over time. The green line represents the patient's platelet count shown on the right-handed axis there. That was quite low at the beginning, being approximately 40,000 per liter. And you can see that over time, platelet count also rose despite the drug being given continuously, in the blue line, we see the neutrophil count rise over time as well, again, ensuring that this drug doesn't cause myelosuppression in count recovery, last clearance has been obtained. In purple, you can see the bone marrow blasts falling quickly going from detectable levels at the start of therapy down to undetectable levels by cycle 1, day 8, again, compatible with the patient's quick response after 1 cycle therapy. So this is encouraging. This is exactly the profile you would like to see for a drug that could be used, for example, in a maintenance setting where it's important to not cause additional myelosuppression and toxicity as well as in combinations where you don't want to bring additional myelosuppression or toxicity to the table as this is what is most life-threatening to patients, we might otherwise be clear that they're looking at. I also want to gain to highlight the diversity of mutations in a responding patient population. Not only are [indiscernible] wild type, we see a lot of adverse mutations in these responding patients, mutations in RAS as we highlighted before, mutations in TP53, and we've now seen 2 examples here on this plot as well as other members of the RAS pathway, PTPN11, CBL and multiple different splicing factors being more MDS like in that mutational pattern than a traditional de novo AML, and gives us confidence that patients who don't have FLT3 mutations who have more MDS-like patterns, say patients with higher-risk MDS might be potential beneficiaries with a drug like tuspetinib. I would also like to point out that of the patients who achieved a composite complete remission that of these 10 patients, 5 were FLT3 wild type, again, suggesting productivity beyond the FLT3 mutated population alone and then we did see responses in this really tough to treat TP53 mutation patients. So to summarize, we completed the tuspetinib monotherapy Phase I dose escalation and dose exploration trial, treating 77 tough to treat relapsed/refractory AML patients. We've seen dose-related PK exposures both for single doses in a steady state and that monotherapy achieved activity across 4 different dose levels with no dose-limiting toxicities, including CR/CRhs, CRCs PR-mutation-diverse patients, including the TP53 and RAS mutation patients as Bill mentioned at the beginning. Importantly, we now have a recommended Phase II dose. This will allow us to do additional exploration with tuspetinib as monotherapy and refine the way that we give this drug to patients in the trial. Despite additional patients being brought on, maintains our favorable safety profile with no drug-related severe adverse events, dose, differentiation and no QTC prolongation. And as I just described, no adverse myelosuppression with prolonged dosing the patients that have achieved a remission. So now I want to go on and talk more about our APTIVATE study that we've been in earlier this year, including the first report of data from our combination with venetoclax. So in the APTIVATE study, we have now treated 14 patients in the tuspetinib monotherapy arm, including patients in those tough to treat co-populations that we're hoping to enrich and we treated 12 patients in the doublet combination with tuspetinib and venetoclax. As we talked about earlier, we plan to expand the indication for this trial, including patients with relapse refractory MDS and began moving into front-line and triple therapy down the road later this year, which will allow us to expand the scope of the APTIVATE study to explore further indications for tuspetinib. To date, enrollment in the tuspetinib-venetoclax doublet have been really brisk. In a short period of time, we've enrolled 12 patients quickly, 10 of them were FLT3 unmutated with 2 with FLT3 mutation. And importantly, we see no concerning safety signals to date from these patient populations. The doublet has been well tolerated in what is generally very critically ill and aged population. All of these patients that enrolled have remained on study as of today. And we've seen signs of preliminary efficacy. It takes time to confirm the response, to develop a response, to gather the data and so on, but we do share with you a couple of examples where we've seen data that include CRs. They do await confirmatory assessments to make sure we understand the duration and depth of these responses. But in this example, we have a 65-year old with mutations in RUNX1 ASXL1, and several other genes that again are very MDS-like in their nature. This patient also has an AML with an MDS-like characteristics. This patient had not responded to front-line chemotherapy or salvage therapy with [indiscernible] and venetoclax. And despite this prior venetoclax exposure, this patient achieved a CRI at cycle 1, day 15, and they are currently awaiting count recovery as is planned per protocol. He will undergo repeat marrow valuation, again, to confirm the group's response down the road. But the response wasn't trivial. These narrow blasts fell from 18% at the time of study start, down to 0% by cycle 1 day 15, again, highlighting the potential quick activity of tuspetinib-venetoclax combination. These are encouraging preliminary findings, and they suggest that even patients with prior venetoclax exposure are capable of response. We hope with additional data to better characterize that and understand the breadth of patients who might benefit from a combination like this. So to summarize where we are now, completed Phase I dose escalation and exploration, have begun the APTIVATE study and began dosing not only in the monotherapy but in tuspetinib-venetoclax doublet and are planning to add additional groups, including the triplet front-line in MDS in the relapsed/refractory setting. So now I want to switch gears a little bit and talk to you about some additional preclinical work is one of the abstracts that we submitted here to the EHA conference. I think it's very interesting to describe the potential interaction that tuspetinib has with venetoclax. So in this study, the goal was to develop tuspetinib resistant AML cell lines in the lab, and this is done by exposing it to greater and greater concentrations of tuspetinib over time until the cells required much more drug in order to be affected by the drug. And you can see on the graph on the right that the concentration required to kill the cells shifted substantially to the right. In these stably resistant cell lines, we could then explore their sensitivity to other agents. We tested them against drugs like tuspetinib, against luxeptinib for example, where we saw no change in sensitivity [indiscernible] where we saw the change in sensitivity. But the most strict finding was that when we treated these resistant cells with venetoclax, we became 2,000-fold more sensitive. Resistant to tuspetinib in general what we call a synthetic lethality, a pathway sensitivity to a drug, but they weren't that sensitive to at the beginning. So venetoclax being very active, even as a single agent in these cell lines suggest that the combination of tuspetinib-venetoclax could help prevent resistance to both of these agents as the mechanism of tuspetinib resistance apparently generates hypersensitivity to tuspetinib in this model. This reinforces the potential synergistic activity of tuspetinib and venetoclax that we hope we're starting to see in the clinic today. Now I want to talk a little bit about luxeptinib, giving you an update on where we always have. Just a reminder, luxeptinib as a tyrosine kinase inhibitor with activity against both BTK, FLT3 and several other important targets that's being developed both in AML and MDS as well as in B-cell malignancies. We have already seen substantial activity in the B cell study, including complete metabolic responses, a complete remission response in the patients who had a complete metabolic response and biopsy negative [indiscernible] and several signs of additional activity as shown in the waterfall plot on the right, where we saw a PR and a near PR in 2 follicular lymphoma patients. In AML, we've also seen signs of activity with an early patient achieving an MRD-negative CR that was quite durable lasting over a year, and we have seen blast reductions in this patient population as well. But the challenge with this agent has always been the maximum exposure that we're able to achieve with the original formulation. And for that reason, we developed the G3 formulation that we hoped would be more active on a per milligram basis, and that [indiscernible] has been borne out by the PK data we've seen to date, here on the right are showing the PK exposures at multiple different dose levels for the original G1 formulation, including the 900 milligram twice a day dose level shown there in purple, and we're overlaying the exposures that we've seen in patients that are treated with 50 milligrams of the new G3 formulation twice a day. And you can see that it essentially overlaps exactly this 50 milligram twice a day, which is, again, 18-fold less drug has identical exposures to 900 milligrams. And that's exactly where we wanted to be for our first dose level, but we didn't exceed prior exposures. Now that we have safety data accumulating for the patients treated continuously with 50 milligrams, we plan to dose escalate soon to explore what kind of exposures we can achieve at higher dose levels and whether this will translate into greater activity in our AML patient study. So to summarize for luxeptinib, with broadly active kinase against multiple hematologic significant and validated targets and that has delivered activity as a G1 formulation, including an MRD-negative CR in AML and diverse responses in B cell moving diverse tumor shrinkage and responses in B-cell malignancy patients. The G3 formulation looks very promising. And again, we expect to increase that dose level soon, and we hope that these increased dose levels translate into greater activity, not only in our AML study, but eventually B-cell study should that exposure be realized. I'll remind you that luxeptinib also has activity against BCR pathways that are important in other conditions, including potential autoimmunity and inflammation conditions, and that's something that we hope explore further in the future. So for now, I'll pass it back to you, Bill, to wrap up.

All right. Thanks Raf for reviewing the data, particularly the patient receiving the TUS-VEN doublet. So now I'd like to wrap up the presentation by sharing our vision of what we foresee for TUS. We believe TUS will become a bedrock ingredient in combination therapy for AML. TUS is convenient, conveniently administered as a once-daily oral tablet. TUS has a favorable safety profile that truly is distinguishing feature, and we hear that continuously from clinical investigators and our counterparts at other companies, plus TUS has a broad range of efficacy in patients harboring a vast array of adverse mutations, including the most difficult to treat TP53 and RAS-mutated patients. Another indicator of the breadth of TUS activity, as was mentioned by Raf a few minutes ago, we are finding that fully 50% of the patients with the composite CRs were FLT3 mutated and 50% were FLT3 unmutated. So what does all this mean? It means that TUS has sizable commercial potential in AML and then potentially more for our application to MDS. We believe the AML market can exceed $1 billion as TUS serves as a monotherapy and in combination therapy across third line, second line, front-line and maintenance therapy. Our goal for TUS to serve as the compound for a mutation-agnostic combination therapy and then to move into MDS. TUS now is looking like a big pharma drug with a sizable commercial potential, driven by the safety, breadth of activity, convenience and ability to effectively combine with other agents. Because TUS is emerging with clinical properties that fit the large pharma profile, we have engaged our clinical development plan to position TUS accordingly. Rather than repeating the details on our final slide, I'll just note that the recent financing eased pressure on our development plans with tuspetinib that TUS, second, that TUS is exceeding our expectations, particularly in the TUS-VEN doublet and that LUX is moving forward toward higher doses and likely with higher exposures. And with that, we look forward to presenting additional data as the trials mature. With this, we'll end the slide presentation today. And operator, if you could please queue the questions.

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

Bill and team, it's Anish on for Greg. It's great to see the data today and thanks for the time. Just wanted to ask on the in vitro data and the exposed lethal vulnerability of TUS-resistant cells to venetoclax. What might be the mechanistic rationale behind this sharp change in cell profile and increase in [ BACs ]? And to what degree might this hypersensitivity apply to other FLT3 inhibitors, such as those mentioned in your analysis, such as gilteritinib and [ crizotinib ] as well.

So I'll give a couple of comments and then Raf can jump in. So these studies are performed in a third-party laboratory, the laboratory of Dr. Stephen Howell [indiscernible]. These are in vitro studies. And it was quite a surprise to see the synthetic lethal with that magnitude of hypersensitivity to venetoclax. We're in the process of studying the various pathways, also proteasome pathways. We're looking at all the cell death pathways to try to understand what exactly has changed here. We presented some data regarding this, but we also have been collecting additional data to look at this mechanistically of how this can occur and what is the impact of it. We also have now performed additional studies with other molecules to look at the sensitivities. You mentioned some of the other FLT3 inhibitors and a variety of other agents. But we're not prepared to present that yet, [indiscernible] will be presented at a future scientific meeting. Dr. Bejar, did you want to add to that?

Right. The only thing I wanted to add is that I don't think it's necessary universal to all the tyrosine kinase inhibitors. I think it's interesting that luxeptinib, which also has activity against FLT3 that's quite potent, retained its ability to kill these tuspetinib-resistant cells, suggesting that the mechanism of resistance was specific for tuspetinib. And it's not clear to us if you were to make a resistant cell line with one of these other agents that it would share that same hypersensitivity to venetoclax. So it may be a class effect, but it's certainly not the same for every single drug, and it's an exciting finding for us, I think, to justify the combination that we have put together.

Our next question is from Li Watsek with Cantor Fitzgerald.

This is Rosemary on for Li. Congratulations on the update. Just a couple from us. So on the RP2D, would you be able to give us some color on why you picked 80 milligrams? And why do you think the monotherapy response in the escalation exploration portion seems to decrease at the higher doses? And then on duration, I know it's really early, but do you have any comments on the durability in your patients? What do you think the bar is? And what would you say, given that some of the patients have gone on to transplant?

Thanks, Rosemary. There about 17 questions there and so over to Dr. Bejar answer.

Sure. So let me see if I can take it up at the time. I'll start with the selection of the recommended Phase II dose. That was part of our end of Phase I meeting with the FDA. The goal there was to defend the, I would say, most active, most safe dose or the minimal dose required for activity. And as you know, with targeted therapies, there reaches a threshold at which additional drug doesn't necessarily engage target harder, but does begin to engage other targets that could contribute to toxicity. So there was, as we saw with our DLT at the 200-milligram dose level, the possibility of encountering toxicity at these higher dose levels. And we didn't think we were sacrificing any activity by moving down to 80 milligrams since we saw a similar engagement at 80 milligrams is, say, for example, 120 and so on. To your point about the decreased activity 120. Some of this is stochastic these are small numbers. But you remember that these dose levels aren't randomized at the beginning. It isn't like you bring on a patient, you randomize into one of these dose levels. You have to move sequentially through them. And earlier on in the study, even during the conduct of the study over the last 3 years, the standard of care for AML has changed. So I could imagine that later patients that are brought on are actually even more treatment exposed or treatment experience with other fire agents and so on. So the nature of the patients that we're seeing actually could have changed over time. That said, we saw activity all the different dose levels that one highlight patient that we described to the 160-milligram patients that has an absolutely beautiful response and tolerated that drug continues to tolerate that drug over a year. What is the bar, I think, was another one of your questions. And could you repeat that aspect of it again?

Yes. This is regarding the duration of response.

That's right. Yes. So you're absolutely right that if you're going to have a response in AML, it can't be a fleeting response. It really has to be durable enough to be meaningful to patients and to be clinically significant. I think given the life expectancy of late-line AML patients, even a response duration of 6 months or so would be doubling the expected overall survival of that patient population. So I would like to see responses that at least last in 3 months or so, 3 to 6 months in order to be clinically meaningful. And as we saw in our study, allow some patients to move on to other potential life-saving therapies like transplant.

Our next question is from Matthew Biegler with Oppenheimer.

This is Matt Hagood on for Matt. Maybe just to build on the last question, I'm curious following your interactions with the FDA. Do you have a sense for where the bar for activity is in those tough to treat sub-populations you're going for as a single agent. And if there's a general number of patients you think you might need to enroll to give you confidence to move forward with those trials?

Thanks, Matt. Once again, I'm going to ask Dr. Bejar to address the bar of activity and also the difficulty of establishing a control from the [indiscernible] population. Raf?

Yes. I think at that point you just made, Bill, is a key point that that especially for single-arm studies where you don't have a comparative built into the study, you have to have some frame of reference for seeing the benefit that you see in your patient population. So getting the data to describe what would happen to these patients absent your experimental intervention is really quite important. And that one is what we would call the no hypothesis. What is the expected activity in the standard of care today? And then how much better than that do you have to be. In general, if you can establish what you think that is setting a response rate and adding enough patients under the study that would allow you to exclude that comparator as being within the confidence interval, I think would be the way you would design that from a statistical standpoint. What that number rate is challenging to get. So I don't think I can quote you today exactly what the standard of care response rate would be as the data just aren't quite there yet. So that is something that we would have to build up and build it in the nature of the study. That said, I think in those patient populations that we just described, the TP53 mutant and the FLT3 inhibitor-treated patient population, that bar is quite low. I think those patients, as we've seen in the limited amount of data that are available have incredibly low response rate in very, very short overall survival measured because I mentioned it before, in just a handful of months, somewhere between 2 and 3 months on average. So that's about the bar that we're dealing with that patient population. Another approach would be to see what the activity is with the doublet. And there, you would hope the addition of synergistic activity will increase the response rate to something where it would be easier to make that case that you're substantially better than whatever the standard of care happened to be today.

I would say let me as one of the points that he said there. It really will differ among the different patient subpopulation, the mutational profile. I know a lot of people are looking at the MP1 patient population, and they tend to respond at a certain rate to a variety of drugs. But when you start looking at the TP53 mutant patients, the patients who have failed prior FLT3 inhibitors, the RAS mutations, these are among the least responsive to any drug. And also now patients who have failed venetoclax, that most of the patients now coming along will have failed venetoclax. And so they're also going to be much more difficult to treat with a single agent. And so we'll have to work with the FDA to establish what those bars are with each patient population. Okay. Did we answer your question?

You did. I just wanted to ask one more on the APTIVATE trial. Do you still have the optionality to bump patients up to a higher or lower dose based on exposures? Or are you now pretty locked into that 80-milligram dose?

I would say the $80 million dose is our RP2D for monotherapy without mention of dose escalation. I think in the study, we are exploring where the dose escalation has a benefit. So that is something that is built into the protocol. But until we demonstrate that, I don't think we can call that strategy of starting at one dose level and escalating to another in the absence of a response, a approved tactic, so to speak. That would require additional data that we would then share with the FDA. So 80 milligrams is recognized as a monotherapy dose. And if you want to include the dose escalation into that strategy, we'll have to generate the data, which is what we're doing in APTIVATE.

And by the way, 80 milligrams is also the dose we're using in our drug combinations with venetoclax.

Our final question is from Soumit Roy with Jones Research.

I would love to get a little sense from the FDA interaction, how they are thinking about potential for the accelerated trial part? And also, like what bars they want to see or what would compel them to go with the single arm accelerated approval path? And from your point of view, like are you thinking that's a real feasibility or the most feasible path is actually doublet or triplet setting with a randomized arm...

Raf, why don't you start out and then I may add...

Sure. I missed the very first part, Soumit, but I think what you're asking is what is the FDA left...

Yes. What will compel FDA to actually go ahead with the accelerated approval single-arm point? What are they really looking for?

Yes. I think that you can petition the FDA for a single-arm registrational study. If you have a very good understanding of what the response rate is likely to be again in the absence of your therapy with the standard of care would be able to provide patients so that there is a reference for which to compare. So you set up that no hypothesis and you set up the trial, you power it appropriately to demonstrate that increased benefit if it is there. The challenge there is defining that that standard of care in the absence of data, the field that [indiscernible] has been pretty dynamic over the last 3 or 4 years with the standard of care changing dramatically over that time. So I think that's actually one of the bigger hurdles. It isn't necessarily the activity of the drug. It's proving that the activity drug is better than what you could achieve otherwise. I do think that's an easier argument to make if you are doing a study with a randomized arm. So if you're doing a 2-arm study, then you can make a direct comparison to the patients that you all simultaneously. And of course, if you have a more active agent, then it's easier to enroll that study and to demonstrate that difference. So we'll see what the data show us with the combination with venetoclax. if that activity is substantially better in this very tough to treat patient population, we'd have to consider whether that might be the more viable approach.

Yes, let me just add to it. So it's clear that the single-arm accelerated approval path is still open and available to us. But the burden of proof is upon us to be able to establish the control data for the no hypothesis and for each patient population we'd want to look at, whether it's GP53, RAS previously FLT3 inhibited. And it is extraordinarily difficult, as Dr. Bejar said, to get the control data in the relapsed/refractory population. Very little is published there, and it's very difficult to get to patient-level data. But that's the process, and we'll work through that. Anything else Soumit?

We have reached the end of our question-and-answer session. I would like to turn the conference back over to Dr. Rice for closing comments.

All right. Thank you so much. Well, I want to thank all of you for taking time out on your Saturday, especially those who are here in Frankfurt at the EHA meeting to share the time with us. And as you can hear, we're very excited with the performance of TUS and with our path ahead, and we look forward to speaking with you again. But for now, thank you and safe travels. And operator, if you could please close out the meeting.

Thank you. This does conclude today's conference. You may disconnect your lines at this time, and enjoy your weekends.