Good afternoon. My name is Sherry. I will be your conference operator today. I would like to welcome everybody to Aptose Biosciences' Interim Clinical Update conference call. At this time, all participants are in a listen-only mode. After the speaker's remarks, there will be a question-and-answer session. If you would like to ask a question during this time, please press star one on your telephone keypad. You will hear a confirmation tone indicating your line is in the question queue. You may withdraw your call. Please press star two. As a reminder, this conference call is being recorded. I would now like to introduce Dan Ferry of LifeSci Advisors. Please go ahead. Thank you, Sherry. Good afternoon. 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; Dr. Raphael Behar, Senior Vice President, 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. Behar, 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 Behar, Aptose's Resident KOL and Chief Medical Officer. Today, I'll begin with the highlights and overviews, then Dr. Behar will present our new datasets, and then I'll wrap up with our vision for the future applications and commercializations of tuspetinib. First, I'll remind you again that today we will make certain forward-looking statements. 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 four 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. TUS has maintained a highly favorable safety profile. We believe TUS can be the ideal drug for combination therapy in frontline, second-line, and third-line patients. We view accelerated approval paths as feasible in second-line AML and in the more treatment-experienced relapsed or refractory population. We believe this profile supports a billion-dollar market potential in AML, plus additional commercial potential in MDS. Our secondary agent, luxeptinib, or LUX, as we'll 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 Three, 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 and achievements, including the European School of Haematology 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 four dose levels and with no observed DLTs at 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%. 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 mg once daily was selected. We learned that all potential development paths remain available, including the single-agent arm accelerated approval path. We learned that no extraordinary CYP450 metabolites or QTC prolongation monitoring will be required going forward. 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. We get many questions about the TUS-VEN doublet. To date, it's been well tolerated. All patients remain on study. Preliminary CR activity has already been observed. Dr. Behar will speak more about this in a few moments. 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 multidrug 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 KIT kinase, and the RSK1 and RSK2 kinases. All are inhibited roughly equally in the 0.5 nm- 6 nm range. This allows TUS 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 achieve clinical responses through simultaneous inhibition of the target kinases by 40%-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 a tuspetinib, venetoclax, or TUS-VEN doublet combination to achieve accelerated approval in second-line AML, the potential for triplet combination approval in frontline AML, and maintenance therapy to prevent patients from relapsing after achieving a complete remission by stem cell transplant or by drug therapy. This represents our near and long-term commercial strategy for TUS. I want to change gears and review our timelines 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 Pharmaceutical. We quickly added clinical sites and accelerated the enrollment, 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, only had four to five months of new data, the dataset was truly incremental. 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. This is when other companies began to notice the 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. 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 a TUS-VEN doublet. At the end of May, we also announced the completion of a $25 million financing. 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-VIN- HMA triplet combo pilot study in frontline AML patients. From there, we will refine our strategies for potential accelerated approval trials and for a TUS-VIN doublet phase II randomized registrational trial. our plate is full for the remainder of the year. I now want to turn the slides over to Dr. Behar. Raf? Thanks, Will, 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 had an optimal dose design. This allowed us, when we recently met with the FDA, to select, as Will mentioned, 80 mg as a 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 stereotypes. We hope to test enough patients in the monotherapy to also get information about patients with other select mutations, including patients with RAS mutations that turn out to be resistant to 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. As I'll tell you shortly in greater detail, we've already begun dosing patients and now have achieved rapid accrual in this doublet, exciting doublet study. Later this year, we do plan to proceed to a tuspetinib, venetoclax, HMA triplet combo in a frontline 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. The tuspetinib, venetoclax doublet would allow us to treat patients in earlier lines of therapy, including second-line therapy, which also could include a potential for accelerated approval. Finally, the triplet study in frontline could lead to a confirmatory randomized trial to seek approval in that indication. For more detail about what we've done during dose escalation, here we show you the different dose levels that have been tested, 20 mg all the way up to 200 mg, and then the four 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. 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. As you'll see, the most common treatment adverse events are those things that are not unusual for patients with leukemia. There is some cases of nausea and diarrhea that are probably the most notable side effects of tuspetinib, but the majority of those cases are grade one and two, with only a single case of treatment-related nausea being grade three. The key features here again are that 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 that it sets up tuspetinib to be an ideal drug for combination, especially with drugs that might have overlapping toxicities. Here are some data that help explain why we selected 80 mg 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 mg dose level. CRcs 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 achieve the exposure required for response. At 80 mg, more than 80% of patients were achieving this by day 15, whereas at 40 mg, where we did see signs of clinical activity, only about 50%-60% of patients were achieving the minimal dose level required for response. Together, it seems that 80 mg was the dose level with not only the greatest activity, with a substantial number of patients reaching the level needed to acquire a response, but also with the greatest safety profile. For that reason, the 80 mg dose is our recommended phase II dose for monotherapy. 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. 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 at 120 mg and patients at 40 mg. Again, showing the activity of this dose level that is below our recommended phase II dose, giving us a wide margin of activity that in order to treat patients with a wide therapeutic window. Here's an updated swimmer's plot of those patients with signs of response in the study. As always, I'll keep making the point that patients who achieve a response, who clear their blasts, often have incomplete count recovery at the time of that initial response. 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, that once patients have their leukemia cleared, the drug can be continued, and patients see their 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. You can see that patients over time who stay on study 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. Finally, as always, we note that a large number of patients were able to go on to stem cell transplants, 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 160 mg 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, the splicing factor U2AF1, and in SETBP1. This 55-year-old male had refractory AML with MDS-related changes and had already been failed by induction chemotherapy and by salvage therapy with additional chemotherapy. Starting at 160 mg of tuspetinib, the patient achieved a CRh at cycle one and then matured over time with continuous dosing. That became a CR by cycle five 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. To highlight that, I want to show the patient's blood counts over time here. 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 stays fairly stable until, as the response matured in cycle two, cycle three, cycle four, and cycle five, 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. You can see that over time, the 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 when count recovery or blast clearance has been obtained. In purple, you can see the bone marrow blast falling quickly, going from detectable levels at the start of therapy down to undetectable levels by cycle one, day eight. Again, compatible with the patient's quick response after one cycle of therapy. 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 any 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 who might otherwise be cleared of their leukemia. I also want to again highlight the diversity of mutations in our responding patient population. Not only in your substructure mutant and substructure wild type, we see a lot of adverse mutations in these responding patients. Mutations in RAS, as we highlighted before, mutations in TP53, as we've now seen, in two examples here in this plot, as well as other members of the, of the RAS pathway, PTPN11, CBL, and multiple different splicing factors, being more MDS-like in that mutational pattern than, say, traditional de novo AML. That gives us confidence that patients who don't have those three mutations, who have more MDS-like patterns, say, patients with higher risk MDS, might be potential beneficiaries of 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, five were FLT3 wild type. Again, suggesting broad activity beyond the FLT3 mutated population alone, and that we did see responses in those really tough-to-treat TP53 mutation patients. 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 four different dose levels with no dose-limiting toxicities, including CR/CRhs, CRcs, and PR in mutation-diverse patients, including the TP53 and RAS mutant patients that 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 a monotherapy and refine the way that we give this drug to patients in the trial. This, despite additional patients being brought on, maintains a favorable safety profile with no drug-related severe adverse events, deaths, differentiation syndrome, or QTC prolongation. As I just described, no overt myelosuppression with prolonged dosing in patients that have achieved a remission. Now I want to go on and talk more about our APTIVATE study that we began earlier this year, including the first report of data from our combination with venetoclax. In the APTIVATE study, we have now treated 14 patients in that tuspetinib monotherapy arm, including patients in those tough-to-treat copopulations that we're hoping to enrich. We treated 12 patients in the double combination of the tuspetinib and venetoclax. As we talked about earlier, we plan to expand the indication for this trial, including patients with relapsed/refractory MDS, and begin moving into frontline and triplet 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 are FLT3N mutated, with two with FLT3 mutation. Importantly, we see no concerning safety signals to date from this patient population. The doublet has been well-tolerated in what is generally a 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 a response, to develop a response, to gather the data, and so on, but we do want to share with you a couple of examples where we've seen data that includes CRs. They do await confirmatory assessments to make sure we understand the duration and depth of these responses. 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 characteristic. This patient had not responded to frontline chemotherapy or salvage therapy with hypomethylation and venetoclax. Despite this prior venetoclax exposure, this patient achieved a CRi at cycle one, day 15, and they are currently awaiting count recovery, as is planned per protocol. They will undergo a repeat marrow evaluation, again, to confirm their response down the road. Their response wasn't trivial. These neuroblasts fell from 18% at the time the study started, down to 0% by cycle one, day 15. Again, highlighting the potential quick activity of a 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. To summarize where we are now: completed phase I dose escalation and exploration, have begun the APTIVATE study, begun dosing not only in the monotherapy, but in the tuspetinib venetoclax doublet, and are planning to add additional groups, including the triplet frontline and MDS in the relapsed/refractory setting. Now I want to switch gears a little bit and talk to you about some additional preclinical work that 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. In this study, the goal was to develop tuspetinib-resistant AML cell lines in the lab, and this was done by exposing them to greater and greater concentrations of tuspetinib over time, until the drugs required much more drug in order to be... The cells required much more drug in order to be affected by the drug. You can see in the graph on the right that the concentration required to kill these 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 to drugs like sorafenib, where we saw no change in sensitivity. The most striking finding was that when we treated these resistant cells with venetoclax, they became 2,000-fold more sensitive. Resistance to tuspetinib engendered what we call a synthetic lethality, a hypersensitivity to a drug that they weren't that sensitive to at the beginning. venetoclax being very active, even as a single agent in these cell lines, suggests that the combination of tuspetinib and venetoclax could help prevent resistance to both of these agents, as the mechanism of tuspetinib resistance apparently engenders 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. I want to talk a little bit about luxeptinib and give you an update on where we always have. Just a reminder, luxeptinib is a tyrosine kinase inhibitor with activity against the 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 a patient who had a complete metabolic response and BIAC negative about now, 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 two follicular lymphoma patients. 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. The challenge with this agent has always been the maximum exposure that we're able to achieve with the original formulation. For that reason, we developed the G3 formulation that we hoped would be more active on a per milligram basis. That certainly has been borne out by the PK data we've seen to date. Here on the right, we're showing the PK exposures at multiple different dose levels for the original G1 formulation, including the 900 mg twice a day dose level shown there in purple. 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. You can see that it essentially overlaps exactly. That this 50 mg twice a day, which is again, 18-fold less drug, has identical exposures to 900 mg. That's exactly where we wanted to be for our first dose level, where we didn't exceed prior exposures. Now that we have safety data accumulating for the patients treated continuously with 50 mg, we plan to dose escalate soon to explore what kinds of exposures we can achieve at higher dose levels and whether this will translate into greater activity in our AML patient study. To summarize for luxeptinib, a broadly active kinase against multiple hematologic significant and validated targets, and that has delivered activity as a G1 formulation, including an MRD negative CR AML and diverse responses in B-cell 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 will 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 to explore further in the future. For now, I'll pass it back to you, Will, to complete the wrap-up. Thank you. All right. Thanks, Raf, for reviewing the data, you know, particularly the patient receiving the TUS-VEN doublet. Now I'd like to wrap up the presentation by sharing our vision of what we perceive 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 a distinguishing feature, and we hear that continuously from clinical investigators and our counterparts at other companies. 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, is our finding that fully 50% of the patients with the composite CRs were 50% FLT3 mutated, and 50% were FLT3 unmutated. What does all this mean? It means that TUS has sizable commercial potential in AML and then potentially more for 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 is to serve as the foundation for a mutation-agnostic combination therapy and to 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 proto- 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 is exceeding our expectations, particularly in the TUS doublet, and that LUX is moving forward toward higher doses and likely with higher exposures. With that, we look forward to presenting additional data as the trials mature, rather. With this, we'll end the slide presentation today, and operator, if you could please cue the questions. Thank you. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For a participant choosing speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Our first question is from Gregory Renza with RBC Capital Markets. Please proceed. Hi, Will and team. It's Anishan 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 BAX? To what degree might this hypersensitivity apply to other FLT3 inhibitors, such as those mentioned in your analysis, such as, gilteritinib and quizartinib as well? Appreciate it, and thanks again. All right, thanks for the question. Yeah, thanks. I'll give a couple of comments, and then, Raf can jump in. These studies were performed in a third-party laboratory, the laboratory of Dr. Stephen Howell at UCSD. These are in vitro studies, and it was quite the surprise to see the synthetic lethal with that magnitude of hypersensitivity to venetoclax. We're in the process of studying the various pathways, phosphoproteasome 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 sensitivity, as you mentioned, some of the other FLT3 inhibitors and a variety of other agents. We're not prepared to present that yet. It will likely be presented at a future scientific meeting. Dr. Behar, did you want to add to that? Right. The only thing I wanted to add is that I don't think it's necessarily 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. 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. 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. Great, thanks. Really appreciate it. Our next question is from Li Watsek with Cantor Fitzgerald. Please proceed. Hi there. This is Rosemarie on for Li. Thank you so much for taking our questions, and congratulations on the update. Just a couple from us. On the RP2D, would you be able to give us some color on why you picked 80 mg? Why do you think the monotherapy response in the escalation exploration portion seems to decrease at the higher doses? 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? Thank you. Thanks, Rosemary. Those were about 17 questions there, and so I'm gonna pass that over to Dr. Behar to answer. Sure. Let me see if I can take them at a 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. As you know, with targeted therapies, there reaches a threshold at which additional drug doesn't necessarily engage the target harder, but does begin to engage other targets that could contribute to toxicity. There was, you know, as we saw with our DLT at the 200 mg dose level, the possibility of encountering toxicity at these higher dose levels. We didn't think we were sacrificing any activity by moving down to 80 mg since we saw a similar engagement at 80 mg as, 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 them to one of these dose levels. You have to move sequentially through them. Earlier on in the study, we, even during the conduct of the study over the last three years, the standard of care for AML has changed. I could imagine that later, patients that are brought on, are actually even more treatment exposed or treatment experienced with other prior agents and so on. The nature of the patients that we're seeing actually could have changed over time. That said, we saw activity at all the different dose levels. That one highlight patient that we described as a 160 mg patient that has an absolutely beautiful response and tolerated that drug, continues to tolerate that drug for over a year. What is the bar? I think was another one of your questions. Could you repeat that aspect of it again? Oh, yeah. This is regarding the duration of response. That's right. Yeah. You're absolutely right that if you're gonna 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 six months or so would be doubling the expected overall survival of that patient population. I would like to see responses that at least last, you know, three months or so, three or six months, in order to be clinically meaningful. As we saw in our study, allow some patients to move on to other potential life-saving therapies like transplant. Got it. Thank you so much. Thanks, Rosemary. Our next question is from Matthew Biegler with Oppenheimer. Please proceed. Hey, great. Thanks, guys. This is Matt Hagar on for Matt. Maybe just to build on the last question, I'm curious, following your interactions with the FDA, if you have a sense for where the bar for activity is in those tough-to-treat, you know, single-agent, those tough-to-treat subpopulations 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 trial things? Thanks, Matt. Once again, I'm gonna ask Dr. Behar to address the bar of activity and also the difficulty of establishing a control for the null hypothesis in these populations. Raf? Yeah, I think that point you just made, Will, is a key point, 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. Getting the data to describe what would happen to these patients absent your experimental intervention is really quite important, and that form is what we would call the null hypothesis. What is the expected activity in the standard of care today? 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 onto 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 is challenging to get. 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. That is something that we would have to build up and build into the, 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 rates and very, very short overall survival, measured, as I mentioned before, in just a handful of months, somewhere between two and three months on average. 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 would increase the response rate to something where it would be easier to make that case, that you're substantially better than that, than whatever the standard of care happens to be today. Got it. I'll try to look. Okay, so go ahead, because one of the points that he said there, it really will differ among the different patient subpopulations, the mutational profile. I know a lot of people are looking at the NPM1 mutant patient population, and they tend to respond at a certain rate to a variety of drugs. 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. Also now patients who have failed venetoclax, that most of the patients now coming along will have failed venetoclax. They're also gonna be much more difficult to treat with a single agent. We'll have to work with the FDA to establish what those bars are with each patient population. Okay. Got it. I mean. Did we answer your question? Cool. 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 mg dose? Right. I would say the 80 mg dose is our P2D for monotherapy without mention of dose escalation. I think in the study, we are exploring whether dose escalation has a benefit, so that is something that is built into the protocol. 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, say, quote, "approved tactic," so to speak. That would require additional data that we would then share with the FDA. 80 mg is recognized as a monotherapy dose, and if we wanna include the dose escalation into that strategy, we'll have to generate the data, which is what we're doing in APTIVATE. Got it. By the way, 80 mg is also the dose we're using in our drug combinations with venetoclax. Got it. Sounds good. Thanks, guys. Bye. Our final question is from Soumit Roy with Jones Research. Please proceed. Hi, good afternoon, everyone. I would love to get a little sense from the FDA interaction, how they're 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, et cetera, approval path. 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? Thank you. 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 were asking is, what the FDA left with? Yeah. What will compel FDA to actually go ahead with the accelerated approval single arm part? What are they really looking for? Yeah, I think that the. 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, what the standard of care would be able to provide patients, so that there is a reference for which to compare. You set up that null hypothesis, and then you set up the trial, and you power it appropriately to demonstrate that increased benefit, if it is there. The challenge there is defining that standard of care in the absence of data. The field of mRNA has been pretty dynamic over the last three or four years, with the standard of care changing dramatically over that time. 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 it's an easier argument to make if you are doing a study with a randomized arm. If you're doing a two-arm study, then you can make a direct comparison to the patients that you enroll simultaneously. Of course, if you have a more active agent, then it's easier to enroll that study and to demonstrate that difference. We'll see what the data show us with the combination with venetoclax. If that activity is substantially better in this very tested treat patient population, we'd have to consider whether that might be the more viable approach. Yeah, let me just add to it. 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 null hypothesis and for each patient population we'd want to look at, whether it's TP53, RAS, previously, FLT3 inhibited. It is extraordinarily difficult, as Dr. Behar said, to get the control data for in the relapsed refractory population. Very little is published there, and it's very difficult to get the patient-level data, but that's the process, and we'll work through that. Thank you again for taking the question. Anything else, Soumit? No, that was... Totally get it. All right. Thank you so much again. Thanks for coming up. 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 wanna thank all of you for taking time out on your Saturday, especially those who are here at in Frankfurt at the EHA meeting, to share the time with us. 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. For now, thank you and safe travels. 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.