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

Greetings. Welcome to the Aptose Biosciences Corporate Update Call. [Operator Instructions]. Please note, this conference is being recorded. I will now turn the conference over to your host, Chairman and CEO, Dr. William Rice. You may begin.

Good afternoon, everyone, and welcome to our call for the Aptose corporate update event held in conjunction with the 2021 ASH Annual Meeting. As always, I'll remind you that today I will make certain forward-looking statements. As many of you already know, Aptose is a clinical stage company, a biotech company that develops oral kinase inhibitors for the treatment of orphan hematologic malignancies. Our lead molecule is the recently in-licensed HM43239 or 239 as we will call it. First and foremost, 239 is a clinically validated myeloid kinome inhibitor that potently inhibits a constellation of kinases, including the sixth FLT3 mutant forms of c-KIT and other kinases operative in myeloid malignancies such as AML. Already, multiple patients have achieved a complete response with 239 treatment in an ongoing Phase I/II trial with relapsed/refractory AML patients and 239 delivered meaningful clinical benefit in all responders, either through bridging them to a stem cell transplant or by providing durable responses over time. Even more impressive, 239 delivered complete responses and a diverse set of AML patients. Composites were achieved in patients harboring the ITD or tyrosine kinase domain mutant forms of the FLT3 kinase, including those patients with prior failure of venetoclax and failure of the FLT3 inhibitors such as gilteritinib and midostaurin. Complete responses also were observed in patients with complex caryo types, mutated NPM1, mutated p53, mutated RAS, mutated IDH and other genes. And momentarily, you'll hear more of the details related to 239. Our second molecule, luxetinib, also known as lux, is an oral kinase inhibitor characterized as a dual myeloid kinome inhibitor and a lymphoid kinome inhibitor. Lux inhibits FLT3 and a constellation of other kinases operative in AML and as well as BTK and a constellation of other kinases operative in B-cell leukemias and lymphomas. Lux is in a Phase I dose escalation trial for the treatment of patients with relapsed or refractory AML and monodysplastic syndrome and separately in a Phase I dose escalating trial for the treatment of B-cell malignancies. Importantly, lux is showing anti-tumor activity and heavily pretreated AML and B-cell cancer patients who are resistant or refractory to standard of care and experimental therapies. The Aptose leadership has a depth of experience and know-how in kinase inhibitors and in the development of heme cancer drugs. Likewise, our Scientific Advisory Board is composed of distinguished key opinion leaders that are icons in the treatment of cancer patients with kinase inhibitors, including Dr. Brian Druker, who is the Chair of our SAB. He most notably is renowned for his role in the development of Gleevec, the first kinase inhibitor treat for the treatment of cancers. The SAB members help us identify and triage new molecules for in-licensing they anticipate the therapeutic needs of patients in the future and to help guide the development of our pipeline molecules. Our pipeline consists exclusively of small molecule targeted agents. This includes 239, our new program for the treatment of AML; lux that we are developing for patients with relapsed or refractory AML, high-risk MDS and B-cell cancers; APTO-253 being developed for the treatment of AML, MDS and certain MYC-driven B-cell cancers; and our early-stage kinase inhibitor, APL-581 that has been partnered out to another company. We clearly have a diverse range of options and the ability to make multiple shots on goal. All of our agents engage clinically validated targets directed at orphan heme cancers, yet also has the potential to address certain solid tumor indications in the future, plus 239 now brings Aptose a confirmed clinically active and more mature agent to our pipeline. Not surprisingly, we've been asked why did we license 239 what is 239, and why did we execute the license now. So I thought I would address each of these questions directly. The first is why we license 239. Our vision has been to grow the pipeline by in-licensing kinase inhibitors for hematologic cancers. 239 is an ideal fit for our corporate vision and to complement lux and acquiring 239 to end the pipeline with a more clinically advanced drug to increase the likelihood of pipeline success. The second question is what is 239. Most importantly and simply, this is an active drug. It already is a clinically proven drug for the treatment of AML with once-daily oral dosing. It targets a constellation of kinases distinct from lux and competitor regions and it expands our ability to cover additional genotypes and stages of AML populations and in so doing, address a larger fraction of the market. And the third question is why now. To be clear, this was not a spur of the moment or risk decision. Rather for 2 years, we've observed as Home Advance 239. We learned the details of its kinase inhibitory profile, and we evaluated the strong preclinical data. Over time, the clinical program matured as a preclinical data translated into convincing clinical findings with multiple single-agent complete responses and a broad array of AML patients. Plus, we wanted to participate in the clinical oversight and crafting of the clinical development plan. And we wanted to close the deal prior to public release of the high-impact clinical data contained within the ASH abstract that was released on November 4. In that regard, the bulk of the clinical data set for 25239 was provided in that ASH abstract released on November 4. And Dr. Naval Daver, the lead investigator for 239 clinical trial, delivered an oral presentation to ASH Annual Meeting today and in which we provided a clinical update for 239. Because not everyone is able to view that presentation, we will recap the key messages for you. Also, Aptose will assume control of the 239 program in just a few weeks on January 1 and we then will continue to update you further during Q1 and beyond in 2022. Now let's take a peek at the kinase inhibitory profiles of 239 and of lux. In these kinome tree representations, we highlight the overlapping and distinctive constellations of kinases inhibited by each molecule. As shown previously with lux on the right, lux inhibits the FLT3 track, MAP kinase and Aurora kinase clusters operative in AML as well as the BTK and MAP kinase clusters operative in B-cell cancers. In contrast, 239 on the left is a more selective agent with potent and focused activity on a different set of kinases in the FLT3 and adjacent clusters. With that introduction behind us, I will ask Dr. Rafael Bejar, our Chief Medical Officer and physician scientist, to walk you through the clinical data with 239 and then with lux. Raf?

Thanks, Bill. I'd be delighted to share the clinical results for these 2, and we'll start with 239. As you may have seen Dr. Naval Daver, the lead investigator for the HM43239 Phase I/II trial, presented clinical findings today at the 2021 ASH Annual Meeting during an oral session. We described the first in-human study of 239 as a single agent in relapsed/refractory AML patients, including data about the safety and clinical activity in this difficult-to-treat population. The study began an accelerated dose titration design with one evaluable patient in each of the lowest 2 dose levels. When the third quarter was reached, the study adopted a standard 3x3 design with a preplanned expansion cohort at the end of each subsequent dose level. The dose escalation portion of the study has cleared the 80-, 120- and the 150-milligram cohorts and patients are being treated at the 200-milligram dose level, including the expansion arm. A total of 20 patients have been treated at the 80-milligram dose level in both the 120- and 160-milligram expansion cohorts are open to enrollment. As you can see, we did observe several responses, which we will discuss in just a moment. Here are shown correlative data from the study, including PK drug concentrations for each dose level and target engagement as a function of plasma 239 concentration. Higher dose levels generally produce greater plasma concentrations of 239 and greater inhibition of phospo FLT3 and on 14 PIA assays with the higher dose levels achieving greater than 75% inhibition of FLT3 phosphorylation. This slide summarizes the significant clinical activity observed in the study. Several complete responses have been observed at the 80-milligram once-daily dose level and included a diverse array of animal patients. Responders were not solely those with the FLT3-ITD mutation, one patient with a FLT3 tyrosine kinase mutation achieved a complete response even after prior exposure to both midostaurin and gilteritinib. Then to patients with unmutated FLT3 achieved complete responses, including one with a highly adverse genotype defined by TP53 mutation and complex carotid lata duration of response that exceeded 1 year. Overall, responding patients harvest several important driver mutations such as NPM1, RUNX1, as well as NRAS and KRAS that have been associated with resistance to tyrosine kinase inhibitors, along with TP53. It's important to note that 4 out of the 5 patients who achieve a complete remission were able to undergo allogeneic stem to transplantation, a potentially curative procedure. This table summarizes additional details about each of the responding patients, including their FLT3 status and presence of other driver mutations and carry-type abnormalities, time to response and duration of response with the caveat that most patients left the study while still responding in order to receive a stem cell transplant. This is considered a huge win for these patients. To summarize, the HM43239 study in relapsed/refractory AML patients have enrolled both FLT3 mutant and FLT3 unmutated patients at the 20, 40, 80, 120, 160 and 200-milligram dose levels, with expansions at 120 and 160 ongoing. 239 has demonstrated exposure-related target inhibition of phospho FLT3 and clinically has favorable -- has a favorable safety profile. Importantly, we've observed durable clinical benefits in several treated patients with a relatively low dose level of 80 milligrams once daily. This includes 25% of allocations treated in this cohort with 37.5% of the FLT3-ITD and PKD patients achieving a complete response. And I should note, this is among all treated patients at this dose level, not nearly those considered evaluable for response. While we continue to dose escalate, the 80-milligram dose level already represents a potential go-forward for subsequent studies. In 2022, we plan to continue the study to learn which AML genotypes in patient categories to focus on the subsequent expansion while planning for registrational trials. In addition, we plan to initiate combination studies to further explore the clinical benefit of 239 and to accelerate its development. So now let's turn to luxeptinib or lux, our oral lymphoid and myeloid kinome inhibitor previously referred to as CG-806 that is being developed across a broad array of hematologic malignancies. Lux had several relevant kinases, including the validity targets BTK or Bruton's tyrosine kinase, a lymphoid tumor driver; and FLT3, a myeloid tumor driver most often associated with AML. Lux is currently being studied in 2 separate Phase Ia/b clinical trials where a dose continuously twice daily in 28-day cycles. As I will show, both studies have continued dose escalation and are currently treating patients in the 900-milligram BID dose level. Let's focus first on Aptose CG-80601, our study of lux patients with B-cell malignancies, a summary of which was presented by Dr. Samaniego of The MD Anderson Cancer Center during this ASH meeting. This study is open to relapsed or refractory B-cell malignancy patients, including those with CLL, SLL and a variety of [ nonhouse ] and lymphomas. The study began with an accelerated titration design treating single patients in cohorts 1 and 2, followed by a 3-wave redesign thereafter. The study has now completed dose escalation through the 750-milligram BID dose level and is treating patients at the 900-milligram BID. Additional patients have been backfilled into lower dose levels or in a bioavailability cohort comparing different formulations of lux. The service pump shows the number of patients treated at each dose level, in any dose escalations they might have received. Black arrows represent patients that remain on study. In total, 29 patients have been dosed and represent a very heavily pretreated population with more than half having received prior BTK inhibitor therapy. This slide summarizes the clinical activity observed in patients with various B-cell malignancies. On the left is the waterfall plot presented at the 2021 EHA meeting in June. And on the right is an updated version as of December 6, 2021. You can see that additional patients develop greater tumor reductions and to achieve a complete metabolic response on PET imaging, including 1 follicular lymphoma patient was just shy of a formal partial response. These are represented as images from that patient who experienced a 47% reduction in SPD from baseline by cycle 5 day 1. To be considered a formal partial response to PR, the patient would need a 50% reduction in FPD measurements. Similarly, the patient experienced a 29% reduction by the SLB measurement criteria that would have required a 30% decrease to be considered a formal PR. This is a [indiscernible] lymphoma. We began a study at 450 milligrams BID. They received several prior lines of therapy, including immunomodulatory agents, antibodies and E3 kinase inhibitor. The patient had multiple posted disease in the next and abdomen, an example image which is shown here, noting the near complete resolution of pathogenic retrocede lymph node. Importantly, head scanning demonstrating a reduction in metabolic activity at all [indiscernible] was consistent with a complete metabolic response. Here is another example of a patient with a meaningful improvement in the tumor burden occurred after the dose of lux was increased from 450 milligrams to 600 milligrams BID. This 60-year-old woman with follicular lymphoma and a heavy burden of disease noted slow tumor growth until cycle 8 when our doses increased to 600 milligrams. Thereafter, she experienced rapid reductions in tumor size that eventually fell to 12% below our baseline by SPD and 43% from our peak tumor site by cycle 15, represented a [indiscernible], which is highlight the clearance of most tumors by cycle 15 in treatment. Again, this is clear evidence of clinical benefit from her exposure to luxeptinib. Interestingly, we observed a pattern of initial tumor growth, followed by subsequent reductions in several patients, many of whom had rapidly progressive disease at the time of study entry. This was particularly notable in patients who discontinue a BTK inhibitor and experience sudden increases in disease activity. This initial growth Kacar after screening and prior to the first scan underestimates the activity of lux. Therefore, we've made an informal calculation of tumor reductions as measured from the prior peak tumor size to highlight this anti-tumor activity driven by acceptance. To summarize the B-cell study with lux, we continue to treat a population of highly refractory patients now with a 900-milligram BID dose level. Lux has generally been well tolerated through the 750-milligram dose level and has demonstrated encouraging clinical activity across a variety of B-cell malignancies, including 2 patients with complete metabolic responses. In 2022, we plan to continue to have escalation and to identify the optimal go-forward dose with which to further explore and select populations. We plan to initiate single-agent expansion studies as well as studies in combination with approved agents. Finally, we will explore the new G3 formulation of lux that we will tell you more about shortly. Now I want to talk about lux in our mutation-agnostic AML study, Aptose CG-80603 in relapsed or refractory AML patients. Dr. Aaron Goldberg from the Memorial Sloan-Kettering Cancer Center presented the summary of the study at this year's ASH meeting. The patient population in the study includes a wide variety of AML patients regardless of the 3 mutation status who have relapsed, after or have been refractory to at least one line of prior therapy. As with the B-cell study, the lux AML study has recently cleared the 750-milligram BID dose escalation cohort and is now dosing at 900 milligrams BID, with the option to backfill patients at lower dose levels. This slide shows the status of the study as of the data cut on October 6, 2021. This includes 16 patients -- apologies it's December 6, 2021. This includes 16 patients treated across 3 cohorts, including 12 use patients and 4 FLT3 wild type. The majority of patients have received prior treatment with vitritinib and other FLT3 targeted kinase inhibitors. Several patients have participated in the drug interaction study with azole antifungals to explore the effect of FLT3 inhibition on lux exposure levels. Since the data cutoff, as you've seen, we have treated 2 patients with the 900-milligram dose lot. Today, even durable measurable disease negative complete response in a patient treated at the 450-milligram dose level that we reported earlier. However, there have been other signs of activity, including a reduction in the 3 clone size in one patient and blast reductions and several others. While blast reductions are not clinically meaningful to patients that they don't resume the complete response, they can be signs of activity and we're often asked about whether we see them in this study. So here are 3 examples of FLT3 mutant patients who experienced both relative and absolute reductions of blast during the first cycle of treatment. This slide shows the details of the 46-year-old man who underwent 2 prior allogeneic transplants for relapsed FLT3-ITD and AML was treated with lux at the 450-milligram BID dose level. He achieved a complete response with normal blood counts and no measurable residual disease by high-sensitivity pose-atometry as measured in cycle 4 and confirmed in cycle 5. This response has been durable. He remained on study and is currently in cycle 1 and participating in the solid interaction substudy with loss. Despite only taking 150 milligrams of lux once daily while on [indiscernible] in the past several months, he has achieved plasma levels of lux in the 2 to 4 micromolar range that represent the highest levels observed in this study to date. This suggests that FLT3 84 inhibition as one mechanism for increasing less exposure while decreasing both the till burden and dosing frequency. On that note, I'd like to pass it back to Dr. Rice, who will tell us more about efforts to improve the absorption exposure of box with the new formulation. Bill?

Thank you, Raf. I now will jump back in to discuss the new formulation that we plan to test clinically for lux. The original first generation or G1 formulation being used in the clinic now has been safe and well tolerated and has allowed us to show clinical antitumor activity in B-cell cancers and AML. And now we have developed a third-generation or G3 formulation that we believe can deliver improved absorption reduced to pill burden, reduced total drug substance administered and particularly increased exposures of luck in the bloodstream. The reason we developed the G3 formulation is because we always understood and reported that the original formulation had limited absorption. And now we are gleaning clinical data that can help guide our needs. Clinical PK characteristics with the original G1 formulation are illustrated on the left-hand figure. While we observed significant increases in exposure at the lower dose levels, and consistently reached micromolar levels in the plasma with the 450-milligram dose. The increases in plasma exposure from 450 to the 750-milligram doses have been more incremental in nature and yielded exposures in the 1 to 2 micromolar range. We had expected the exposures to reach into the 4 macro mobile range are even higher at these doses. I'll remind you, Dr. Bejar just highlighted that our AML patient who received -- who achieved an MRD-negative complete response, reached plasma levels in the 2 to 4 micromolar plus range, actually greater than any other human who has received luck to date teaching us that a higher exposure levels of locks are both clinically safe and clinically active. So now our goal is to learn from this patient and to seek ways to achieve higher exposure levels and to do so consistently. One way to address the exposure needs is to develop an improved formulation. We, in fact, began formulation development activities more than 2 years ago. And this ultimately led to G3, an oral self-emulsifying drug delivery system designed to improve oral bioavailability. In preclinical studies, G3 was compared to the original G1 formulation in mouse, rat and dog. And the PK graph in the right-hand figures demonstrate that G3 outperforms significantly the G1 formulation in all 3 species. G3 capsules have been manufactured at 2 strengths under GMP conditions. They have demonstrated stability under different atmospheric conditions, and we plan to introduce G3 in the patients after the first of the year. This has been a long time in the making, and we're excited to see how GI performs in humans. To wrap up our discussions on lux, this oral kinase inhibitor has been well tolerated to date and has delivered encouraging antitumor activity in B-cell cancers and AML. Clearly, this is an active molecule and worthy of developing new approaches to deliver higher levels of drug exposures consistently. We're testing the 900-milligram dose of the G1 formulation now in B cell cancer and AML patients, and we may escalate further if warranted. Separately, we plan to explore the new G3 formulation that I just described. Plus, we are considering testing a once-daily lower dose of lux code-administered with a SIK3 or 4 inhibitor because our AML patient with a complete response has maintained the 2 to 4 micromolar plasma exposures when an azole antifungal is administered with 150 milligrams of G1 formulation delivered only once daily. Clearly, we have multiple paths to enhance the exposures of lux so that we may choose the best formulation conditions and dose to move into the appropriate expansion studies. With that, I will now turn the slides over to Dr. Joti Marango, our Chief Financial Officer and Chief Business Officer. Joti?

Thank you, Bill. After reviewing at a high level some of the ASH data from our 2 kinome inhibitors, lux and 239, we wanted to take the opportunity to place some of the data in a bigger picture and begin to share with you how we see lux and 239 complement each other. In our view, lux and 239 help us cover meaningfully more territory in the hematology spectrum in both lymphoid and myeloid malignancies after segmenting them by diagnosis as well as genotypically. Specifically, our clinical findings continue to support development opportunities for lux across the spectrum of B-cell malignancies, not only in indications which have typically been associated with BTK inhibitors, such as CLL and MCL, but also in indications which have historically been impervious to more traditional BTK inhibitors, such as follicular lymphoma, where there continues to be a shortage of genotype-agnostic and tolerable oral therapies. Our findings to date from the study of lux in B-cell malignancies continue to point us towards these additional opportunities beyond just CLL, and we intend to continue exploring these other lymphoid indications further and in parallel. To date, we have also seen clinically meaningful activity from lux in FLT3 mutant AML, which is consistent with this agent's preclinical profile and begins to sketch at least one potential direction or genotype silo for the entry of lux into AML. Now let's turn to 239, an asset with more mature data from its study in AML. Our clinical findings so far support the further exploration of several key genotype groups within the AML population. These are all genotypes that either represent meaningful portions of the AML population. For instance, NPM1 mutant account for close to 1/3 of AML patients, similar in scale to FLT3 mutants, or they are genotypes that are historically associated with challenging disease, which is typically unresponsive to other targeted therapies. For instance, TP53 mutation is an extremely poor prognostic factor. As Drs. Rice and Bejar noted earlier, we are now deep enough into the 239 study that we have identified a potential go-forward dose, and the collective efficacy data to date begins to catch potential directions or genotype silos for development of 239 in AML. These directions extend our coverage of AML well beyond the territory covered so far by lux. In the new year, we look forward to sharing with you more clinical data as it emerges from the ongoing studies, which may continue to bring into focus these as well as other potential opportunities for our pipeline within the spectrum of hema malignancies. We will conclude by reminding you of some of our top line messages from today. This year, Aptose has continued to advance its expertise and work on kinome inhibitors and hema malignancies. We currently have multiple ongoing open-label clinical studies, which we expect to deliver clinical updates through 2022. HM-239, our newest agent, is now also our most advanced agent. It has already shown meaningful clinical benefit in AML across several genotypes, which may offer separate parallel expansion opportunities. Lux, our other agent, continues to mature in 2 ongoing studies, and data from these studies continues to suggest broad opportunities for development. Importantly, the profile of the activity to date in our view, warrants continued effort forward towards higher exposure. Together, we believe that these oral small molecule agents together offer us a broader coverage of tough-to-treat diseases and genotypes. And importantly, they create near, medium and long-term opportunity for development and value creation. With that, we thank you all for joining us today on the call, and we will be happy to take any questions that you may have. Operator, you may open the Q&A session.

[Operator Instructions] Our first question is from Alethia Young with Cantor Fitzgerald.

Congrats on the progress programs here. One -- well, my question is -- and I just -- maybe I missed it, but I just want to maybe talk a little bit more about plans you have with dose escalation with the G3 formulation and when you think you'll kind of be able to go into clinic there? And the second one kind of dovetails with that, which is kind of -- should we be thinking that kind of these 2 formulations will run concurrently and you'll kind of select the better? And I guess, in particular, with the SIP combination, is that how you're thinking about it? Or are you already thinking you'll just go with the G3 combination?

Alethia, this is Bill. So a couple of questions there. So first of all, let's talk about the G3 dose escalation. Our plan is to get it into the clinic into human right after the first of the year. So that is our plan. We hope to be able to do that, and we're on track for that now. Everything thus far is in place, so that addresses when. So how we plan to do that is put it in single agent initially, get a sense of the PK properties over, say, a 72-hour period, take a look at 2 different dose levels there and then do the modeling, and then we hope to be able to then go into continuous dosing. Once we identify a dose that should take us at the same level of exposures as we're currently at with the G1 formulation. So what that means is it answers your second question. Yes, we are going to be performing this in parallel. We're going to continue to dose patients with the G1 while we bring along the G3. But starting with G3 is not starting over. So again, we'll try to get the PK data as quickly as possible with single agent, do the modeling and then transition that into the same exposure levels as we have with G1 and then hopefully be able to dose escalate from there with the G3. As regard to the SIP program, that's more of an earlier prospect. So we had noted that in the patient but it's not the only thing in that patient because you have to remember that patient that had the complete response, they had the 2 to 4 micromolar levels when they were receiving just lux alone. And then later, and that was at the 450-milligram dose level. So they achieved higher levels than any other patients. So it's more of a patient dependent process. But even when we then they wanted to -- the physicians wanted to put that patient on the azoles to antifungals, we reduced the drug down to 150 milligrams once a day and they still maintain the 2 to 4 or even 4-plus micromolar levels. So that says SIP may be playing a role in it. But this is more of, I think, a patient dependent process, and I believe that G3 is the more important factor here. But we are building the foundation for the potential coadministration of a SIP inhibitor. We're doing the preclinical studies now and building that profile. Did that answer your questions?

Yes. I'll just like a follow-up. So just to make sure I'm clear. So basically, G3 kind of you'll be at levels probably there are efficacious much faster because of the formulation difference. So you'll kind of be able to kind of raise the 2 of them at the same time to see what the distinctions may be? And then the other part, the follow-up is just, should we be thinking kind of by the time we get around to ASH next year that you would be able to kind of have clarity on like which formulation wins here?

Yes, we do plan to, as you said, raise these in parallel. So we are hopeful that we can get the G3 quickly that we get good absorption. We actually hope we can administer much lower doses of the drug and achieve equivalent or higher exposures quickly. And then we'll continue to do that dose escalation. We will select the one that's the best. It may turn out that -- now we're at 900 milligrams, it may turn out that we began to see activity in the 900 milligrams and even and PK increases and we may go beyond that, but we have to see the data, the PK data and the response data at 900 milligrams before we can make that decision with the G1, but again, try to push forward the G3 as fast as possible. We believe this is a meaningful step for lux and we hope it can deliver the higher exposures. And we absolutely would expect them to have that answer before ASH next year, absolutely.

Our next question is from Joe Pantginis with H.C. Wainwright.

First, I want to ask a question about the swimmers plot for 239, the responses and the kinetics around these responses. Obviously, you're seeing these CRs and CRIs within the first 2 cycles according to the chart. So I guess I wanted to see if you can glean anything from, say, patient 2 when you initially starts out refractory on treatment, but then goes to CRI and then even patient 6 that initially sees the PR. Is there anything, I guess, I shouldn't say biomarker observational wise that you could see that, that PR patient might translate to a CR with a little more time?

All right. So let me start out, and then I'm going to have Dr. Bejar address the question. So for the 239 program, we're going to have to be able to limit the comments to the data released by Dr. Daver today with the data cutoff at August 31. Now once we pick up the program on January 1, we'll be able to prepare additional data for updates and provide those to you, but we are going to restrict our comments to those data that were presented today by Dr. Daver. And so now I'm going to ask Dr. Bejar also to address the question.

Yes, it's a good question. So patients don't always respond in cycle 1 or 2, we typically get some signs with their head in that direction, blast reductions can be a sign of that in some patients. And on the lux study, for example, the patients that achieved a CR that wasn't confirmed until cycle 4, for example. So it is true that patients can have a CRI or even less than a CRI initially and then have their response mature over time and become more solidified that is in the case of every patient. Some patients may have early signs of response have been turnaround later and unfortunately don't come about. So it's -- I don't think it's really possible to predict that in that first cycle if a patient has an achieved a response where those are absolutely going to just need to continue to dose and see what happens.

Got it. That's helpful. And then I guess maybe just a logistical question on the lux study in B-cell lymphomas. I guess how is patient screening or identification going? And I guess, maybe a little bit of devil's advocate because everyone is chomping at the bit for more data all the time is it appears not appears, it says the data cutoff is September 29. Just curious how come there wasn't closer-term follow-up.

Sure. [ The tumor spot ] has a more recent cutoff. The [ tumor spot ] there had a cutoff of December 6, and you can see the were dosing patients at the 900-milligram dose level. Those patients aren't immediately evaluable for response, right? The first response assessment in the study doesn't happen until much later after study start. So the -- there is a little bit of a lag between what we see there. And then often patients don't necessarily have their best response at the first assessment, or so it does take a little bit of a while. Does that address your question?

It does. And I guess maybe just a general comment on how identification and screening is going?

Yes. No, I think it's going reasonably well. In addition to the patients at the 900-milligram dose level, we also have the ability to backfill patients and put patients on a sub-study to compare different formulations of lux, and we've been able to accrue all of those categories.

Our next question is from Matt Biegler with Oppenheimer.

I was hoping you could speak to 239 safety profile and how that compares to other FLT3 inhibitors like gilteritinib, just more data from that at ASH. I guess maybe talk about the importance of a clean safety profile in this particular patient population, especially as it relates to things like neutrophil counts when I think the goal for many of them is to get to transplant. So if you could just discuss that, that would be helpful. And then I have a follow-up.

Okay. I'll begin and Dr. Bejar can jump in again. So one of the most notable things about this molecule is that even at the lower dose levels, when we began to see responses, 4 out of 5 of these CRs went to transplant. And that's really the best that you could ask for at this time. The one that did not go to transplant was an older patient, and that patient was mentioned today by Dr. Daver. The other thing that Dr. Daver mentioned today during his presentation at ASH was the fact it was a very well-tolerated drug. And so at this point, there have been no discontinuations due to drug toxicities. I'm going to ask Dr. Bejar then to give perspective on how important that is in this patient population.

Yes. I would echo Dr. Daver's comments and his personal experience with treating patients with the drug. It really has seem very safe. Of course, in patients who have AML you're willing to tolerate some additional toxicity in this friction population in order to see clinical improvement. And things like Grade 1, 2 to 0 diarrhea are not uncommon and are not necessarily that problematic, but the more important Grade 3, Grade 4 things that might actually limit your ability to escalate or limit your ability to treat patients or the things that we look for. And we haven't seen those classic things that you often worry about with tyrosine kinase inhibitors, including effects on QTC, for example, effects on muscle creatine kinase or cardiac problems. So those have not been safety signals in the study, and we don't really have a particular concern that would prevent us some further deescalations we choose to do it. So from that sense, I think it's been very positive. And it is a really important thing in part not only are these frail patients and you don't want to add to their burden of disease with side effects induced by a drug, but you want to combine these drugs with other agents. And if you can combine these drugs without having overlapping toxicity, you're more likely to be successful and sustain the intensity of therapy, which is going to be important, I think, for response in the end. So the safety profile of these agents is really critically important. It increases the number of patients you can treat and how you can treat them when you start getting into combinations.

Yes. That makes sense. I wanted to just ask quickly about some of the newer data that was presented today versus what was in the abstract. We saw some data from the 120 mg cohort, one partial response, no complete responses. Do you think that just boils down to small patient numbers at this point? Or is there something inherent about the drug that you think it could have a plateauing effect as you get to higher doses?

That's a good question. The thing that I would worry about if we were giving higher doses and not seeing anything would be whether there was toxicity that preventing you from dosing those patients appropriately and that really hasn't been the issue. So I think it really is what we just suggested is that the cohort at those higher dose levels are not very mature right to dose escalation cohorts only have 3 patients and even the dose expansions have not yet been completed at those levels. So there is -- there could be some [ stick afters ] in terms of which patients happen to get on study at a particular dose level, but so far, the numbers are relatively small, above 80.

So more of a game of numbers.

Our next question is from Ted Tenthoff with Piper Sandler.

Congrats on the update on the programs. With respect to 239, impressed by the data set. It looks like a really nice asset. I was intrigued by kind of the breadth of activity that you were showing there, both in FLT3 wild type and MP. And I wanted to get a sense sort of how you're thinking about casting the net here to develop 239 broadly? Do you envision multiple expansion cohorts, kind of what's your thinking? And are we taking different lines of therapy. Maybe you can share a little bit light on that?

So let me begin, and then I'll have Dr. Bejar coming in. So thanks, Ted, for coming on and asking questions. It's a good question. One thing we -- when we -- first, again, looking at this molecule 2 years ago or so, we were struck by the fact that it was being called the FLT3 inhibitor, but it was actually much more than that. So yes, it's great to inhibit FLT3. We think that's a major part of the activity here, but there's a clear activity beyond just the FLT3 mutated patients. So we'd love to be able to move toward, yes, FLT3 ITD in tyrosine kinase mutated patients, particularly those who have failed prior TKIs, and Dr. Bejar will speak about that in a minute, but we've also seen these other patients that have FLT3 unmutated, but they have the p53 mutations, for instance. And that is just a terrible mutation in prognostic value. So if we can go after also the single-agent expansions and then toward that path of p53 mutated patients, complex caryo types, single agent, that's a real path forward. So we want to look at this well beyond being just a FLT3 inhibitor. Dr. Bejar, please, you can say that far more eloquently.

Yes. I think the breadth of activity is something that impressed me too, when we were doing our diligence on this asset. It really does open up the number of patients you can treat. I think when you look at them, the ones that stand out are the ones that have the greatest need. So those patients that have been previously treated and failed by tyrosine kinase inhibitors like gilteritinib really have nothing available to them in the standard of care. And even very little available to them in the approved setting of drugs even well off label. So I think that's an important patient population to try to single out and make sure that we understand the activity of this drug better in. The other [ obviously ] p53 wild -- FLT3 unmutated patients, those patients also have every dismal prognosis and do very poorly with rapid relapses if they respond at all. So that's another patient population that we would want to make sure that we explore in order to see if that population has any benefit that we could then translate into a more robust and potentially registrational study, but that isn't the only group that we want to look at. There certainly is a wider breadth of AML that we want to explore in this Phase I study. And those studies will help guide us in terms of what patient populations we should narrow in and focus on down the road if there are such populations. But at the same time, we'll be interested in combinations, which may also broaden the breadth of activity to include patients that maybe are not as well served by single agent alone.

Let me just add. That's a really important point, Dr. Bejar. Yes, so continuing to look at a breadth of patients in this dose escalating phase trial gives us a better sense of what patients we would be able to treat and go after later. It also gives us a better chance to identify, and as Dr. Bejar called it, the optimal dose. Yes, we have already seen a dose, the first dose that we could use as a go-forward dose, but we want to make sure we've identified that optimal dose and that we understand the patient populations going forward. And the FDA also was insisting the companies perform more activity around the dosing in the Phase I so that you fully understand your dosing going forward. So Ted, does that answer your question?

Our next question is from Matthew Cross with Alliance Global Partners.

Happy ASH, and thanks for the detailed update. Just a couple for me. First off, for 239, I was curious kind of in follow-up to your point, Bill, about the 239 not being just a FLT inhibitor and the fact that you're seeing responses in wild-type patients and a variety of different other forms of mutation. But I guess, in contrast to that, it seems like one of the focuses of Dr. Daver's presentation today was the activity and then the PIA assays for FLT3 in patients. I was curious, I know you're kind of limited for now to the details from that presentation, but is there anything you can say about whether you've seen similar results in PI assays for kind of these other key kinases the 239 hits such as SIK? And any kind of detail you can give at this point as far as that. And then on the lux side of things, obviously, we're thinking about a couple of different approaches here to extending exposure into the levels you're hoping to see. I was wondering because I guess most of the data we've seen across the AML and B-cell studies has been kind of grouped as one overall safety population. I was curious if you've seen any trends in safety concerns of note, I guess, particularly neutropenia as we're thinking about what exposure and then pushing that level could result in from a safety perspective with new formulations or other methods of doing so? Anything you saw maybe in this single patient who was on azoles as well?

Wow, that was a lot. So I'm going to respond to the first one, talking about the different kinases in the PI say. Then I'll ask Dr. Bejar to jump in on any potential safety trends. So yes, you picked up on something that -- one of the questions to Dr. Daver today and then his response. So clearly, many people see this as a FLT3 inhibitor. And so the company, Hanmi Pharmaceutical that originally developed this molecule they viewed it primarily as a FLT3 inhibitor. So early on in the clinical trial, all the PIA assay development work was done against FL3. And they clearly showed that the plasma from patients, as you dose escalate, does inhibit FLT3, but that doesn't explain everything. So it's clear it will inhibit PL3. And in those PI assays where you bring the drug back in the lab, putting on reporter sales, you can show that you got -- the -- as you increase the doses in the patients, the plasma will increase the inhibition of FLT3. But something that we wanted to look at, for instance, is what about the other pathways. So although we have not had clinical samples yet to work with, plasma from patients, we have looked at the drug itself, the 239 itself, and we've looked at other pathways. And we can clearly see it turn off some of these other pathways. For instance, Dr. Daver was asked about the SIK. And we can see that SIK is turned off the pathways in the cell and some of the downstream pathways there from. So we know that we're hitting multiple targets with this drug. We can measure those in the cells. We believe that is having impact in the patients. It's just to date, the PIA assay has only been evaluated with FLT3. But as we go forward, we'd like to look at some of those other targets in the PI assay once we take over. Now I'm going to turn it over to Dr. Bejar and let him talk about any potential safety trends.

Right, and the question was specifically about concerns with the lux program. The toxicity you would expect from a drug that inhibits FLT3 and other related kinases is myelo suppression. And of course, in AML, that's a little bit less of a concern since that's something that comes in part of the disease and is easily managed. I'll say that while we have seen in the B-cell study some neutropenia that's often transient, and there are many patients who dose continuously without any really significant neutropenia. It looks like if a patient has an intact bone marrow, that wild-type FLT3 inhibition doesn't seem to be that much of a problem even at sustained dosing. So we haven't really seen that as a concern that might be something that limits our ability to dose escalate in the B-cell study, for example. And of course, in the AML study in this patient who didn't have a response, they continue to dose with very high exposures and did not see myelosuppression once their marrow had established itself and recovered. So in that sense, I'm not worried so much about the my suppressive sign being dose limiting. As far as other toxicities, as you know, we have seen other toxicities in study, none of them really recurrent or such that I think they would preclude further dose escalation or exposing patients to higher levels of drug as we plan to do with the new formulation.

Our next question is from John Newman with Canaccord.

I apologize if this was already asked. But when you start dosing with the G3 formulation for lux next year? Will you also, at the same time, be testing further inhibition of metabolism by giving things like the antifungals or would that be done at a different time?

John, good to hear. The G3 dosing, it's -- initially, it's going to be -- it's planned to be a single agent dose where we just measure the PK over the first couple of days, and then we put them on the G1 until we have a understanding of the pharmacokinetics of the G3, the new G3 and then we can transition them to longer-term dosing. So that's primarily what we'll do with the G3 and we are hoping that we are able to get much greater exposure levels with far less drug. As for the azoles, Dr. Bejar, did you want to address that and how the those are being used clinically?

Sure. I think the reason for doing that azole study, which we will continue to do in parallel, was really to allow those patients in the AML study to receive those drugs and they needed them. So they're not allowed during that first cycle of treatment. We really want to understand any signs of toxicity that are associated with the drug itself at more predictable exposures. After that first cycle, patients can go on an azole antifungal and participate in what we call our drug-drug interaction sub-study where they get additional PK measurements to help us understand those interactions, and those will continue as part of that study. I think what you might have been referring to as Bill's comment that in addition to that, we're also doing work in parallel preclinically to try to understand how a SIK3 or 4 inhibitor might be best combined with lux. I think one of the challenges in doing it in the clinical setting with 2 different agents sometimes the patient does need that second agent, sometimes they don't. You don't want to give it to patients who don't necessarily need it. It's better to either co-formulate or give them in a more predictable manner. And that's what we're looking at preclinically.

Yes. And I would say we're exploring it is because we saw that primarily in that one patient, but that patient -- one patient also had much higher dose exposure levels even just when they got lux. So yes, we're going to study this preclinically. We'll take a look at the patients. We're also looking at the various antifungals that are strong SIK3 or 4 inhibitors and those that are modest SIK3 or 4 inhibitors. And maybe Dr. Bejar wants to add to that a little bit.

Right. So patients on the AML study have the option taking either. And what we've learned is that you do have to do a dose reduction with the strong inhibitors because there is an interaction. The moderate inhibitors like spoonful for example, may have much less of an effect, which actually would be nice because the patients could go ahead and take those agents without necessarily having to adjust their dose and we're seeing less drug interaction there.

Our next question is from Soumit Roy with Jones Research.

Congratulations on the progress. Could you give us a little detail on how many p53 mutants were enrolled among these 34 patients and -- or was it the first one that got responded? And second is, once you get a full charge of the program starting January 1, what would you do with the 239 if the enrollment would be geared towards earlier line patients or any specific biomarker positive to just to lay the groundwork for the rest trial? What can you do? And what can you tell us today?

Soumit, I'm going to ask both Dr. Bejar and Dr. Marango to possibly address that one. Dr. Bejar, do you want to start with p53?

Sure. So I don't have the data in front of me that the total number of p53 mutated patients in the 239 study to date. So I don't have a denominator for you there. I will say that we do want to definitely explore that patient population. And I think one of the things that we will do once we take control of the study is ensure that we design any further expansion cohorts to include a minimum number of those patients that we get a good signal there. In terms of what we do, we need to do that first in order to understand what we do next in terms of a potential registrational study. But in parallel to that, we'll begin moving ground for doing combination studies that will help address whether other agents can help synergize and perhaps improve the response rate or treat other number of patients will be doing those in parallel.

Got it. Should we expect that kind of details to be provided in the first week of January or this much later on in the year after you get some of the initial data out from 239?

Yes. I think we would be waiting until we have additional data to report. I don't think we're going to do a spot announcement the first week of January about where we are with the questions like the one you just asked. I think I'm not even sure exactly if all the samples have been sequenced in their entirety just yet. So at the next summarization point, I think we'll put together what we have, and we'll share data like that.

We have reached the end of the question-and-answer session. And I will now turn the call over to Dr. William Rice for closing remarks.

All right. Thank you, everyone, for joining us this afternoon. We believe that both 239 and lux are valuable assets that can bring significant value to Aptose and our shareholders, and we look forward to updating you more on our exciting and evolving pipeline in the coming months. Thank you so much for joining us today, and have a wonderful evening. Bye.

This concludes today's conference, and you may disconnect your lines at this time. Thank you for your participation.