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

Greetings, and welcome to the Aptose Biosciences' Corporate Update Call. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Mr. Dan Ferry of LifeSci Advisors. Thank you. You may begin.

Thank you, operator. Good morning, and welcome to the Aptose Biosciences' Corporate Update in Concurrence with the 2021 EHA Conference. I am Dan Ferry, an Investor Relations representative for Aptose Biosciences. Joining me on the call today are Dr. William G. Rice, Chairman, President and CEO; Dr. Jotin Marango, Senior Vice President, Chief Financial Officer and Chief Business Officer; and Dr. Rafael Bejar, Senior Vice President and Chief Medical Officer. I would now like to hand the call over to Dr. Rice. Dr. Rice, the floor is yours.

Thank you, Dan, and a good morning and warm thanks to all of you for joining us online today as we host the Aptose Corporate Update Event in Concurrence with the European Hematology Association, or EHA 2021 Virtual Congress. It's a pleasure to welcome everyone to this event, and we're delighted to share our recent clinical findings with you. Today, we'll present highlights of the clinical status of luxeptinib, also known as CG-806 and also -- and often referred to merely as lux, and that's L-U-X. Lux is Aptose's oral first-in-class FLT3 and BTK kinase inhibitor, currently in 2 separate Phase Ia/b trials, one trial in patients with relapsed or refractory acute myeloid leukemia or AML, and the other trial in patients with relapsed or refractory B-cell malignancies. Because of full update of the clinical status of APTO-253, our small molecule MYC inhibitor in a Phase Ia/b trial in patients with relapsed or refractory AML or high risk MDS, was provided in a poster presentation earlier this morning. Our team today will focus exclusively on lux during this corporate update event, although we're happy to take and/or -- to answer any questions that you may have regarding APTO-253. Next slide. And I'll remind you that today, we will make forward-looking statements. Next slide, please. As you're aware, Aptose develops small molecule targeted agents for the treatment of life-threatening hematologic malignancies, including AML, myelodysplastic syndromes or MDS, chronic lymphocytic leukemia or CLL and certain non-Hodgkin's lymphomas. Collectively, these represent cancers of the bone marrow, blood and lymphoid tissues. While we have multiple assets addressing multiple cancer patient populations, as I said, today, we'll speak about lux that already has demonstrated formal single agent anticancer activity in a Phase I trial in patients with AML and has shown surgence of clinical antitumor activity in a Phase I trial in patients with certain B-cell cancers. Next slide. So now let me quickly explain why we were so eager to bring lux into the clinic. Next slide, please. What sets lux apart from other kinase inhibitors is its unusual kinome targeting profile, which we characterize as selectively inhibiting clusters of important kinases that are operative in a range of hematologic malignancies. Lux potently inhibits the wild-type and the mutant forms of the FLT3 receptor tyrosine kinase. This is known as a validated driver of AML. And lux potently inhibits the wild-type and mutant forms of the BTK intracellular kinase, and it's known as a validated driver of many B-cell cancers. And lux is the only kinase inhibitor known to potently inhibit both FLT3 and BTK. But lux really is more than a FLT3 BTK inhibitor. It simultaneously and directly suppresses other oncogenic kinases such as SYK, TRK, CSF1R and others, while also inhibiting additional downstream oncogenic signaling pathways, such as STAT, ERK, AKT and MYC expression. And all the while avoiding many of the kinases that can negatively influence safety. Such a kinase inhibitory profile should enable lux to impact a broad range of lymphoid and myeloid cancers and may enable lux to avoid rapid emergence of drug resistance in these very distinct disease indications. Next slide. To gain a true sense of the potential breadth of lux on hematologic malignancies, before we took lux to the clinic, we ask how well it can kill cancer cells that are sampled directly from heme cancer patients. Dr. Brian Druker and his team collected 675 primary samples from AML, MDS, CLL, CML, ALL and MCL patients and then tested each sample for sensitivity to lux. They measured the IC50 against each sample and expressed the data in a scatter plot as shown on the top left panel. As you can see, lux effectively killed a broad spectrum of hematologic cancer cells directly derived from patients in the submicromolar range. In a direct comparison of lux to ibrutinib on CLL patient samples, and this can be shown on the bottom left panel, lux has seem to directly kill the cells more effectively than ibrutinib and it did so through a mechanistically distinct action. You also can see in the top center panel that lux was equally effective on cells from subclassifications of AML patients. In separate studies, shown in the center bottom panels, lux is more potent than other FLT3 inhibitors, including gilteritinib, quizartinib and midostaurin on AML patient cells having the wild-type form of the RAS kinase. But RAS is often mutated in AML patients as a mechanism to circumvent the FLT3 inhibitors. Remarkably, lux maintained potency against AML patient cells having RAS mutations, while the other FLT3 inhibitors lost potency into the micromolar range. This suggests that lux may be able to treat AML patients with RAS mutations that failed other FLT3 inhibitors although it likely would require higher doses of lux to treat patients with RAS mutations than patients with wild-type RAS. But that's the biology, and it guides us to continue exploration of the higher dose levels of lux in our clinical trials. And finally, as shown on the far right panel, we perform drug combination studies using lux with the BCL-2 inhibitor, venetoclax, on AML, MDS, CLL and ALL patient samples. In every case, lux combined effectively with venetoclax, even in cancers where venetoclax alone had only minimal activity. Together, these studies demonstrated the broad potency of lux on different types of hematologic cancer cells, demonstrated lux acts in a mechanistically distinct manner relative to other agents, showed that lux is resilient to mutations that undermine other drugs and illustrated that lux combines well with other important drugs used for the treatment of heme cancers. Next slide. Currently, lux is being developed, as I said, in parallel for the treatment of patients with B-cell cancers, including lymphomas and CLL as well as for patients with AML. Next slide. And now I will ask Dr. Rafael Bejar, Aptose's Chief Medical Officer, to present our recent findings from these clinical studies. Dr. Bejar?

Thanks, Bill. I'd like now to share with you our clinical experience with luxeptinib in B-cell malignancies and in AML. We'll start with our study in B-cell cancers. So I'll summarize how this trial is being conducted. We are looking at a relapsed or refractory CLL, SLL and non-Hodgkin's lymphoma population, who has failed or has been intolerant to 2 or more lines of established therapy or for whom no other treatment options are available. In the dose escalation phase, patients are receiving oral capsules twice daily on a continuous 28-day cycle. We have a plan to escalate through 6 dose levels followed by expansion cohorts with an accelerated titration design. And I'll remind you that this study has broad eligibility. In other words, patients can have received a wide variety of prior therapies, including prior prevalent BTK inhibitors such as ibrutinib, BCL-2 inhibitors, anti-CD20 therapy, PI3 kinase inhibitors, cytotoxic agents and even experimental noncovalent BTK inhibitors. The study includes a wide variety of B-cell malignancies as potential diagnosis, including patients who've had Richter's transformation and patients with significant unmet needs, including treatment-refractory diffuse large B-cell lymphoma and treatment-refractory follicular lymphoma. This is a snapshot of our dose escalation to date. We have 6 dose levels, of which we have completed 4. We're currently ongoing in the 750-milligram BID dose level. And as I'll show you, we have already demonstrated target engagement with dose-dependent inhibition of phospho-BTK. We've observed treatment-related lymphocytosis in patients presenting with classical CLL, and we've seen modest tumor reductions across a different set of B-cell malignancies, including follicular lymphoma, CLL and SLL. This is a swimmer's plot demonstrating the patients that we've enrolled on study and their time on drug. As you can see, there's quite a wide variety of patients with different diagnoses. The table on the right gives you an example of the demographics. I will point out that the table on the right is drawn directly from our poster presented at the EHA meeting, and it has a data cut of April 22. For this call, we have collected additional data, and the swimmer's plot shown on the left has a data cut of June 7. So there may be small discrepancies between those 2 measures. The colors on the swimmer's plot demonstrate the dose level that the patients were begun on and then subsequently dose escalated to, if you see, the color change. And you can see at the bottom that we are now treating patients at the 750-milligram dose level. These 2 tables, also drawn from our poster presentation at EHA, comment on the safety of the drug to date. On the left is a listing of treatment-emergent adverse events, all as well as those that are related. And you can see, particularly for the related treatment-emergent adverse events, that the majority are of low grade, including nausea, vomiting, diarrhea as being the ones that occur most often in fewer than 1/4 of patients. And typically, not dose-limiting and not something that would require a change in dose or holding a dose. Most of those events are short periods of time. There were a couple of grade 3, 4 events that you can see on the table there. And when we look at the summary on the table on the right, we can see that these are patients with significant comorbidities and disease-related concerns, and you can see that the treatment adverse events were present in the majority of patients, including grade-3 events, but the majority of these did not lead to discontinuation or other concerns with the study drug. So again, as I mentioned, the stage -- the data cut verification was of April 22. Additional patient data will be presented here as it goes through June 7. And so far, we've treated 23 patients across 5 cohorts, 6 patients remain on study. Many of these patients will point out were heavily pretreated with as many as 12 prior therapies. To date, we have not observed any safety trends that would prevent further dose escalation. This slide shows the dose-dependent increases in the steady state or trough pharmacokinetic dosing of patients with relapsed or refractory B-cell malignancies. So on the left, you can see the PK profiles through the first cycle of treatment. And each of the colors represents a different dose level. For the highest dose level of 750 milligram shown in blue, you can see that by the end of cycle 1, we're achieving consistently doses that are in the greater than 1 micromolar range, approaching 2 micromolar or greater. The plot on the right shows the PK exposure at the different dose levels through the course of therapy. And once more, you can see that with our highest dose level, we are achieving higher exposures in patients. This gives us confidence that as we dose escalate, we should see additional increases in exposure and perhaps broader activity of CG-806 amongst the different targets that it can target. This slide shows the pharmacodynamic activity of luxeptinib, targeting BTK and SYK in the 2 plots. These are -- come from PIA assays where patient plasma is collected from subjects in the study, brought back to the lab and then treated cells with -- to expose them to the drug that patients had in their serum. And you can see that with increasing doses of CG-806 in the plasma, we see increasing inhibition of phospho-BTK at the Y551 position in a dose-dependent manner such that the higher doses have almost complete inhibition of phospho-BTK. There's a similar pattern with SYK, with substantial inhibition of SYK shown in the range that we are achieving in patients in the clinic. Now I'd like to show a waterfall plot of best responses in patients on the B-cell malignancy study. On the left, we see the best response achieved by patients colored by the different dose levels at which they began the study. I will point out that some of these patients did dose escalate during the course of treatment. As I mentioned before, these are heavily pretreated patients with a range of 2 to 12 prior regimens. Many of the patients were actually progressing rapidly prior to coming on study. We have observed a trend of tumor growth shortly after enrollment in the study that has then turned around in several patients, such that the waterfall plot actually underestimates the degree to which tumors have changed over time during the study. There's more of a dynamic process going on there. We've demonstrated that by showing these red lines. The red lines in the waterfall plot corresponds to the peak tumor volume that was achieved by the patients prior to their best response. So for example, if you look at the middle patient with SLL in green, they had a small increase in their tumor size prior to a subsequent decrease that was actually below their baseline measurement. To highlight this point, I would like to focus on 1 patient in particular. This is a follicular lymphoma patient, highlighted by the star in the upper left-hand quadrant. This is a patient that began the study at 450 milligrams BID. And as you can see on the plot in the middle bottom of the slide, their tumor growth -- their tumors actually grew during the first several cycles of therapy at the 450-milligram dose level. By the time that the patient reached cycle 7, the next highest dose level had been cleared and the patient was eligible to dose escalate. At that point, their doses increased to 600 milligrams BID. And subsequent scans showed that their tumor size had actually begun to stabilize and then shrink dramatically, ultimately actually falling below their baseline measurements at the start of the study. The images in the middle of the panel showing the PET/CT results from this patient are comparing their peak tumor volume at cycle 7 day 1 to their eventual best response at cycle 15 day 1. And as you can see in the left panel, all those black areas represent PET-avid or metabolically active disease, including extensive disease scattered throughout the neck, mediastinum and abdomen, which subsequently was substantially decreased in the cycle 15 day 1 scan. You can see this again with CT -- PET/CT cuts through the neck in the upper right, where many of the lymph nodes in the neck had completely shrunk or quieted their metabolic activity by cycle 15, day 1. And below that, you can see cuts through the abdomen, showing a very large, very PET-avid tumor present in cycle 7 day 1 that had been fragmented and become much less metabolically active by cycle 15 day 1. I will point out that not every tumor responded in this patient. As you can see, there is some residual activity left, but it was a dramatic decrease from baseline that isn't quite captured in the waterfall plot when we're simply comparing their starting point to their ending point as they did have this dynamic variation prior to the dose escalation. So to summarize, intermediate dose levels to date have delivered leading indicators of clinical activity. The drug has been well tolerated across 5 dose levels and multiple disease types. We've seen target engagement with dose-dependent inhibition of phospho-BTK, treatment-related lymphocytosis and a variety of tumor reductions across B-cell malignancies. We've also seen patients who have then subsequently improved their response as their dose has been escalated. This gives us the motivation to continue to higher doses and longer exposures to tackle this increasingly challenging patient population. And I'll point out that these are patients that have failed or been failed by several prior therapies and are actually more clinically challenging than patients who have been treated in comparable studies in the past as most of these have seen some of the more novel agents, including experimental agents that are in development. So we hope to achieve higher drug dose and longer exposure, as we continue our dose escalation. And as we mentioned, there are no particular safety signals that we think would preclude us from doing so. We'll continue to explore multiple different lymphoma subtypes, in line with our anti-tumor activity as we move closer to expansion studies in the future. Now I'd like to switch and talk more about luxeptinib in our Phase Ia/b trial for patients with acute myeloid leukemia. This study is being carried out in a similar fashion to the B-cell malignancy study in that patients are dosing twice daily in continuous 28-day cycles. As Dr. Rice explained, we have strong reasons to believe that this drug should be active in AML, given its activity against FLT3 and other related kinases. And unlike the B-cell malignancy study, we were able to start the AML study at a higher dose level based on the information that we learned from patients in the B-cell malignancy study, particularly that we were achieving a tolerable dose at 450 milligrams and exposures in the plasma that were able to inhibit the target kinases in our in vitro study. The study was begun at 450 milligrams. That dose level has now been completed as has the subsequent 600-milligram dose level, and the 750-milligram dose level is currently ongoing. The trial is broadly inclusive. It includes a wide variety of relapsed and refractory AML subtypes, including patients with CML and blast crisis. It doesn't have any preconditions for prior therapy, in that patients may have received prior FLT3 inhibitors, other targeted agents, venetoclax. It includes very challenging patients that already have mutations that are associated with resistance to many types of therapy, including mutations on TP53 mutations and RAS, and is not designed to be selective by genotype that is the patients who have FLT3 mutations or who have wild-type FLT3 are both eligible. This also includes patients who have had prior allogeneic transplants, which we have several on this study. This is the swimmer's plot showing the number of patients and the duration of treatment on study showing -- divided by the dose level. Note that 60% of the patients had a FLT3-ITD. And the table on the right gives further information about the demographic nature of the patients. I will point out that most of these patients have seen multiple prior therapies, including several prior FLT3 inhibitors. Many have been treated with hypomethylating agents, received venetoclax or other targeted or immunotherapy. These tables summarize the safety and tolerability profile of patients in the AML study. On the left, you can see those treatment-emergent adverse events as well as those that are greater than grade 3 or more, and those that led to discontinuation or death. On the right, you can see a summary of these events. As with before, most of the events are low-grade events, although -- and those that are grade 3 or 4, tend to be hematologic in nature. There's 1 exception. There was a patient in the 450-milligram dose level, developed a grade 3 pericardial effusion midway through-cycle 1. This was considered to be possibly associated with luxeptinib. I'll point out that this patient entered the trial with a history of gilteritinib-associated myopericarditis and actually had a relapse of this shortly prior to entering the study. The patient was treated with corticosteroids, clinically improved and entered our study while still tapering off of those corticosteroids. At about the midway through cycle 1, as I mentioned, the patient did develop a grade-3 pericardial fusion, that was also consistent with a potential differentiation syndrome. But unfortunately, the patient withdrew from the study before this determination could be made. And the protocol required that this be assessed as a possible DLT related to study drug. This led us to expand the cohort to a total of 6 patients. At the end of that period, there were no DLTs in the other 5 patients. The clinical safety review committee assessed the protocol mandated DLT and went on to approve dose escalation of cohort 2. I'll point out that we have not seen pleural or pericardial effusions in any other patient, both in AML study and in our B-cell malignancy study. Cohort 2 was on eventful. There were no DLTs or other safety concerns reported in 4 patients supporting dose escalation to cohort 3. I will point out that the protocol permits the enrollment of up to 4 patients at each dose level. After 3 have completed cycle 1, they are eligible for safety review and opening of the next highest dose level. And currently, we are at cohort 3, which is ongoing. This plot shows the steady state trough PK in patients with AML. You can see the 2 different dose levels in different colors shown on the left through cycle 1. And you can see the broader PK experience with the patient at 450-milligram dose levels beyond cycle 1 on the right. This is very comparable to what we observed in our B-cell malignancy patients with slightly increasing exposures at the higher dose levels and in the just sub to 1 micromolar range for the 600-milligram BID dose level. This is the range that we would expect to see clinical activity based on our preclinical studies. As we did with the B-cell malignancy study, we collected patient plasma, brought it back to the lab, exposed reporter cells to the plasma with the drug in it to see what kind of engagement we have of our target kinases. So a variety of western blots are shown here, looking at the activity of the drug against phospho-FLT3, phospho-STAT5, phospho-ERK, c-Myc, phospho-BTK, phospho-SYK and PDGFR-alpha. And as you can see, there's significant inhibition to all of these different targets. Some are direct targets of luxeptinib, others are indirect targets that are downstream of those more direct targets. In the scatter plots in the middle, you can see the activity of the plasma containing luxeptinib in -- against phospho-FLT3 at the position of 591. And you can see the very dose-dependent decrease with almost 100% inhibition after about 0.3 micromolar. The inset plot shows the same data on a log scale, showing the dose dependency below 0.1 micromolar. A similar plot below for phospho-SYK showed significant inhibition with luxeptinib in patient plasma at increasing dose levels. So to summarize, we have seen target engagement by luxeptinib in the PI assay, both -- in both cohorts in the AML study as we expected based on our data from the B-cell malignancy study. Steady-state plasma levels offer 100% inhibition of FLT3 phospho Y591, and there's dose-dependent inhibition of downstream signaling, including phospho-STAT5, phospho-ERK and c-Myc. We also see dose-dependent inhibition of non-FLT3 dependent survival pathways, including phospho-SYK, phospho-BTK and PDGFR-alpha. Now I'd like to take a moment to study individual patients in the 450-milligram dose level that showed evidence of clinical activity. The first is a very heavily pretreated FLT3-ITD patient with -- who had de novo AML. This 36-year female had 8 prior therapies, including induction chemotherapy and salvaged with azacitidine, venetoclax, allogeneic transplant, and treatment with prior -- with other FLT3 inhibitors, including gilteritinib and crenolanib. The patient had multiple mutations at study entry and had aggressively progressing disease prior to lux treatment. Her blasts increased from about 0.3 per 1,000 to over 6 per 1,000 at cycle 1, day 1. During the course of treatment, during cycle 1, there was a 90% reduction of blast before ultimately disease progression in cycle 2. And not only did the absolute number of blasts fall, but as shown on the plot to the right, the percentage of blasts were substantially decreased. There was a small decrease in the FLT3-ITD variant allele frequency. But as you can see, there was persistent FLT3 disease at the end of cycle 1, and ultimately, the patient did go on to progress as they had a persistent clone at this initial dose level. The second patient I'd like to discuss is another patient with FLT3-ITD relapsed in AML. This is a 76-year-old male that was deemed unfit for induction chemotherapy and have received 2 prior therapies with azacitidine and then subsequently azacitidine, venetoclax. They had multiple additional mutations detected at screening beyond the FLT3-ITD and again also showed progression of disease prior to lux treatment. During the course of treatment, the patient did have a small decrease in the peripheral blood blasts and importantly, when we look at the mutation data, we see that there was a significant decrease in the FLT3-ITD variant allele frequency, falling more than 80% from 0.62 to 0.12 at the end of the treatment in cycle 4. Some of the other mutations that were likely traveling with this clone were also decreased. And you can see that there was 1 clone not detected at screening that ultimately was present at the end of treatment is the PTPN11 mutated clone. This is a gene involved in RAS signaling pathway that had increased at the end of therapy there. The summary is that this patient at 450 milligrams BID showed evidence of activity against the FLT3-ITD mutated clone over multiple cycles of treatment. Next, I want to talk about a patient with an MRD-negative complete response. This is patient #5 in the first cohort at 450 milligrams BID. This is a 46-year-old male with a significant prior therapy for his AML, including induction chemotherapy followed by salvage chemotherapy with sorafenib as a FLT3 inhibitor, and a subsequent allogeneic hematopoietic stem cell transplant. 2.5 years later, the patient relapsed, was treated with decitabine, venetoclax and again with sorafenib, followed by a second transplant. And unfortunately, 8 months after the second transplant, the patient relapsed with extramedullary disease near the spine and increased bone marrow blasts. The extramedullary disease was treated with focal radiation prior to entering the study, and then the patient began treatment with lux. At that time, the patient had bone marrow blasts of 5.2%, and by cycle 2 day 1, it had decreased to 0.6% and remained below 1% thereafter without evidence of myelosuppression. The bone marrow FLT3-ITD variant allele frequency, which had been 10% at study entry, falling below the level of detection at cycle 2, cycle 4 and cycle 5 measurements. And importantly, high sensitivity flow cytometry performed at cycle 4 day 1 and cycle 5 day 3 failed to detect abnormal blasts in the bone marrow, indicating that this was an MRD-negative complete response by high sensitivity flow cytometry. The patient continues treatment in cycle 7. If you look at the plot on the right, it shows the patient's bone marrow blasts over time in the purple line, with the call outs indicating which percent of variant allele frequency the patient had at study entry and noting the 0% abnormal phenotype in cycle 4 and cycle 5. Below that is a table of the patient's blood counts at each of these evaluation points. The patient did start with near-normal accounts with the hemoglobin of 10, platelets 174 and an ANC of 1.31. And these remained largely unchanged or improved over the course of treatment despite early significant exposures to this patient. So to summarize our experience of luxeptinib in AML to date. We've treated 2 dose cohorts that delivered encouraging antileukemic activity. We've seen a durable MRD-negative CR in a FLT3-ITD mutant AML patient who had failed 2 prior allogeneic transplants and exposure to a FLT3 inhibitor. We've seen meaningful antiblast activity in patients with FLT3-ITD mutations, including reductions in the FLT3-ITD blasts in 1 patient and achieved steady state PK levels and PD inhibition of target kinases that are consistent with our prior experience. We've completed the 450-milligram and 600-milligram cohorts with no concerning safety trends. And this includes toxicities that might have caused problems for other agents in this class. We have not seen, for example, evidence of QTC prolongation. We've not seen evidence of peripheral edema, bleeding disorders or increases in the creatine phosphokinase or evidence of myocardial toxicity. Even though we had 1 patient with potential differentiation syndrome and pericardial effusion, we have not observed that in other patients in this study or our -- the B-cell malignancy study. So currently, we are in the 750-milligram cohort for the AML study, and we plan to dose escalate further. We believe that at higher doses, we'll be covering a broader set of kinases that might lead to activity even in the FLT3 wild-type patients. And we expect to select an expansion dose level and expansion cohort strategy in the latter half of this year. We hope to explore this drug in the different AML genotypes, which are quite varied and both under monotherapy and subsequent combination therapy. So to close, I'd like to acknowledge our site PIs and site staff as well as the patients and their families that have contributed to these studies. The investigators that have put patients on study are shown here both for the B-cell malignancy study as well as the relapsed/refractory AML study as well as all the members of Aptose and our consultants that have made this study possible. So with that, I will end, and thank you for listening to our talk. We will be entertaining questions at this time.

Thank you, Dr. Bejar.

[Operator Instructions] Our first question comes from the line of Gregory Renza with RBC Capital Markets.

Maybe for Dr. Bejar, just focusing on the AML side. I'm just curious if you could comment a bit on what the clinical significance is of seeing that complete response for a patient with a profile that CR with a FLT-ITD mutation one who progressed from transplant and sought prior FLT3 inhibitors?

Yes. No, thanks for the question. I think, obviously, for the patient is extremely meaningful to see that their disease is not only in remission, but in a fairly deep remission. As you know, achieving an MRD-negative state is associated with superior duration of response and better outcomes. So we're encouraged that we didn't just see a reduction in blasts, but we saw a significant reduction beyond the level of detection with high sensitivity flow cytometry. I think that going forward, we're going to be using that kind of measurement more often to assess our patients after treatment, particularly when making decisions about subsequent therapies for those patients in whom those options exist.

So Dr. Bejar, perhaps you could say something else about the lack of myelosuppression of that patient and not seeing some of the other typical toxicities that we see with other drugs?

That's right. So again, I'll remind you that, that patient was treated at our lowest dose level in the study thus far, and we were encouraged to find that they were able to decrease their burden of disease without affecting other cell lines. So the patient didn't have significant anemia, thrombocytopenia, neutropenia, which can complicate the treatment of patients with AML. So I think it's an important and encouraging finding.

Got it. Maybe just a couple more, if I may. Just based on that clinical data so far, any expectations around serum levels that will be needed to be therapeutically active in the FLT3 wild-type patients? And could those levels perhaps be achieved and what's planned so far in the trial?

Yes, that's a good question. We do know that some of the other kinases will require higher dose levels to be inhibited. So we wish to explore that further as we get to these higher dose levels in the wild-type AML population. It is quite a heterogeneous population. So it's hard to say with any dose escalation, we're going to be able to completely understand the activity of the drug in the patient population. But we do hope as we get to higher dose levels, we'll see broader activity. Bill, did you want to add anything more?

No. I think you covered it very well. It's -- we always expected that the -- that FLT3-ITD patients would be kind of the low-hanging fruit, the most sensitive. We're seeing that even at the lower dose level. But we always said we want to dose escalate as high as possible so that we can get as much drug in safely, so that we can hit as many of these pathways as possible and be able to affect the other patients. So Greg, did that answer your questions? And thanks for being on.

Yes, it sure did. And maybe I'll sneak in 1 last one, just on that B-cell side. Just curious if you could comment just a bit or maybe just add some context on your thoughts or implications for moving forward around just that best response underrepresentation that you noted on the antileukemic effects. And how you would think about strategies moving forward or incorporating those learnings into your next steps here?

Dr. Bejar, please?

Yes. No, that's a great question. It's something that we're thinking quite a bit about. One of the simple things that it does is it does encourage you to keep patients on study. These patients are often progressing rapidly. And before your drug has a chance to even reach steady state, the patients kind of already progressed to a significant degree. So we want to make sure the patients are on say long enough. I think it also teaches us that single-agent BTK inhibition and these B-cell malignancies doesn't result in responses the way that it might in FLT3-mutant AML patients, these responses take time. And we want to make sure the drug is safe enough to be able to dose continuously so that we can achieve those responses over time. So part of our strategy here will obviously be to encourage investigators to continue to keep patients on study as they are tolerating drug well, so that they can benefit from these later improvements in their tumor size and see those tumor reductions. I think it also question -- demonstrates to us that dose matters, that as we go to these higher dose levels, we see increasing activity, and that may be partially responsible for that effect that we're observing. And finally, we are also questioning whether or not the mechanism of action of luxeptinib maybe a little different than some of the other more narrowly focused BTK inhibitors, in that it may be causing cell death in a different way. It might be more inflammatory, it might be producing evidence of pseudoprogression or tumor flare. And there have been examples of that with other BTK inhibitors, and that's something that we need to explore further. Because if that is the case, these early milestones may not be accurate markers of what patients are likely to do down the road.

Our next question comes from the line of John Newman with Canaccord Genuity.

I just wanted to confirm, I believe you showed this in the slides, but the patient with the previously reported CR is still in response? And I also just wanted to confirm the genotype for that patient?

Yes. Thanks, John. Thanks for coming on this morning. And I'll ask Dr. Bejar to address that question also.

Sure. Yes, that patient with the MRD-negative CR does remain on study, that is the same patient that we referred to earlier. And that patient was FLT3-ITD mutant, so they did carry the internal phantom duplication of FLT3.

Okay. Great. I also wondered, I know that we're dealing with relatively small numbers of patients here. But I'm wondering if you are seeing a correlation between the average blast reduction in the dose, so that as you increase the dose level, I'm curious if you're seeing a trend there that the blast reduction is larger and maybe perhaps that the blast reduction occurs maybe a little bit sooner at higher doses? Just curious there.

No, it's a good question. We certainly want to look at the dose dependency of the drug's activity. But to your point, I think we just have too few patients in the study to really understand that very well. Even within a dose level, there was some variation in exposure, and that certainly may come into play.

Just to add to that a little bit, we know the -- even within a single patient, there's a tremendous amount of heterogeneity of the different cell types that are in there. And some of these will be more sensitive to lower dose levels. And so you're going to see differences from patient to patients and even within a patient.

Okay. Just 1 additional question and that is, once you complete the 750-milligram BID dose level, I'm curious if you would look to dose-escalate patients from lower dose cohorts? Or if you would wait until you decide on a specific dose to do expansion?

I'll start on this and then maybe -- perhaps, Dr. Bejar can jump in. But we already have it established so that we have intra-patient dose escalation. So for instance, a patient who is on 450, as soon as we clear 600, they could be moved up to 600. And the same is true once we clear 750, they could be moved up from 600 to 750. So the intra-patient dose escalation is possible. Because we always want to get -- maintain the patients on the highest drug level when it's possible. Dr. Bejar, do you want to add to that?

Yes. No, that's exactly right. We want to give these patients the best chance to respond. So if we have the opportunity to dose-escalate them, we will offer that to the investigators.

Our next question comes from the line of Alethia Young with Cantor Fitzgerald.

This is Emily on for Alethia. I'm just wondering with the safety profile that you've seen so far, how much more do you think you'd be able to dose escalate? And maybe when do you expect to give your next data readout? Is it probably going to be around ASH in December? Or do you expect to give updates more often throughout the year?

I'll start on that. Thanks, Emily. So in terms of safety profile, that has gone well. But when we would expect to provide additional data? Traditionally, we make sure that we have completed each dose level before we then collect the data, analyze the data and then report on it. That's traditionally what we've done. So the next major data release would be toward the end of the year at ASH. But between now and then, especially as we complete dose levels, we would expect to then provide some level of information to the market. Perhaps I'll ask Joti if he -- Dr. Marango, if he wanted to add to that.

No, nothing to add. Thank you. Bill summarized it quite well. That's what we've historically done, and that is a playbook that we'll continue to stick to. Thank you.

Thank you.

Our next question comes from the line of Matt Biegler with Oppenheimer.

Bill or Dr. Bejar, maybe just hoping you could comment on the variability that you're seeing in plasma exposures. Certainly nice to see something of a dose response so far. But are the exposures generally consistent from one patient to the next and do things like fasting state influence PK. And I think I read an article on some FLT3 inhibitors maybe being influenced by SIK induction. So just any comments there would be helpful.

I'll start on that and then perhaps Dr. Bejar can jump in. So thanks, Matt, for the question. So even the best of drugs, a commercialized drug that's oral and well-behaved, has a coefficient of variability of around 30%. So are we seeing variability? Yes. Any oral drug, you're going to see variability from patient to patient. And then even within a patient, you'll see variability over time. But we are seeing dose-dependent increases as we go from level to level. And we were gratified to see some of the increases, particularly when we went from 600 to 750 in the B-cell trial, that gives us confidence that we're definitely getting more drug in as we escalate, then it gives us confidence then to go on up to the 900-milligram dose level after it. In terms of fasted and fed, we performed such studies in dogs. We didn't see a difference really in dogs. But we are going to continue to look at fasting versus fed as well as different formulations of this drug. And in terms of SIKs, many of the drugs out there are affected by SIKs, whether they be FLT3 inhibitors or other types of drugs. So we will always continue to look at that as to how much of an effect might there be. We can get hint of that, especially in patients who are treated with antifungals, which often are SIK3 inhibitors also. But it's something we will always have to watch for because you have to think of safety first for patients. So anytime you're giving patients a particular antifungals and these azos that are SIK inhibitors, you have to look and see how you would adjust the dose of this drug and other doses. We'll continue to look at that as we go forward. And as we collect the data on that, we'll provide it to the Street.

Got it. Maybe I'll just sneak in a quick follow-up. I had a question on just FLT3 inhibitors in general. Can you kind of set some expectations for how quickly responses develop on average, maybe using quiz or gilteritinib, as examples? And do we typically see responses deepen over time?

I'll start on that, and then I'll let Dr. Bejar jump in. So you're trying to put a time line based on different patient populations. For instance, if you look at the prior studies with -- and I don't typically like to name the other drugs, but gilteritinib, that was a patient population that effectively was FLT3 inhibitor naive. And they showed that they would see responses over a certain period of time. You start seeing typically reductions in the first month. And by the third month, you get CRs if you're going to get them in the patients. The patient population now, most of them have already failed those types of FLT3 inhibitors. They're much more resistant and with various mutations. So it easily can take longer. In the patient where we saw the complete response, during at the end of the first month, the first cycle, we were seeing dramatic reductions. But then we didn't even take bone marrow valuations until a couple of cycles out from that. So it's going to vary from patient to patient, depending on the tumor status -- I mean, the mutational status of the patients, and they're all different. And again, most of these patients have seen so many different drugs that it's going to vary from patient to patient. So I wouldn't put a specific time line on different drugs. But Dr. Bejar, would you like to address that and possibly differently?

No, no, I agree with you, Bill. I think that in patients who do have a lot of circulating blasts and carried FLT3-ITD mutation, when treated with FLT3 inhibitors, we'll often see a reduction in that blast count relatively early on, but they don't necessarily achieve their best response until sometime later. I think the example of the patient that we showed is a good one in that at that cycle 2 day 1 period, there were still immunophenotypically abnormal blasts detected by flow cytometry. The patient, even though the variant allele frequency is below the limit of detection, I'm sure that with more sensitive methods that would still be detectable. It was only until cycle 4 when we really saw that MRD-negative CR. So those responses can certainly deepen over time.

[Operator Instructions] Our next question comes from the line of Matthew Cross with Alliance Global Partners.

First was, I just wanted to focus on the B-cell malignancy data. And this observation that you've seen some pretty substantial tumor growth before people ultimately are falling below baseline. And trying to reconcile that with what you saw in the plasma inhibitory assays, which, as you said, are taken at steady state. So I was curious, just if you could remind us the kind of average time to steady state across these doses as maybe a possible explanation for why you see that initial growth and then the significant come down? Or -- just to get some kind of possible assurances that dosing higher and reaching those optimal concentrations sooner might start to see that pattern change?

Okay. Thanks, Matt. This is Bill. I'll start with it, and then I'll ask Dr. Bejar to jump in. The plasma inhibitory assays, they give you a sense of whether there's enough drug in the plasma in that patient at that period of time to inhibit these various kinase pathways. And so it gives us a snapshot as to whether or not there's an effective drug concentration there. Now even before we started this trial, I had highlighted the fact that I would expect to see some element of tumor growth early on when we start the treatment with these patients. Because as Dr. Bejar said, there may be the phenomenon known as pseudoprogression. Now that may be part of it in which when if we are killing the cells. So again, if you look at many of the other BTK inhibitors, they work through changing the signaling between the CLL cells and the micro environment. And that causes the CLL cells to leave the compartment, the lymphoid tissues, going to the peripheral blood, so you'll see the shrinkage relatively quickly. We think our drug has a different mechanism. We believe it can directly kill the cells much better than ibrutinib and some of the other drugs. And we actually showed that on one of our graphs here, where we're looking at the IC50s of ibrutinib versus luxeptinib. And so what you would expect then possibly is cell death of some of those cells in the lymphoid tissues and that would cause the infiltration of potentially the inflammatory cells. Now we do not have biopsies of these patients so we can't say that is true, but that is something that we were considering that could happen. And with many of these patients, we actually have seen increases when we start dosing. Part of it could be due to that pseudoprogression or it could just take time for these tumors to respond. Yes, we're achieving steady state around 2 weeks or so of dosing by halfway through the first cycle, but then it takes time for these cells to respond, it may take months. And we also may be seeing an effect of that as well as some of these patients are getting dose -- intra-patient dose escalations, like when moved from 450 to 600, that was when the patient really started -- that patient that we showed really started seeing a decrease. So it shows both a dose dependency, a time dependency and also a mechanistic potential reason for some of this. But the good news is that if we're able to maintain patients on study drug, even though they're getting some level of increase in tumor size early on, we are seeing kind of a consistent reduction in later and it's underestimating the effect of the drug. Perhaps Dr. Bejar wanted to add to that?

No, I think that's a great summary. I will point out that the screening scan is done within 28 days of starting the study and often patients at that time were washing out from the prior therapy if they were on one. So some of these rapidly progressing patients, if you were to test them on cycle 1 day 1 would already have shown some degree of progression from that baseline scan. So there is some element of sort of simple just normal disease progression that contributes to this as well. But I think all those other mechanisms that you mentioned, Bill, are potential contributors here. And even though the drug might reach steady state in the plasma in a couple of weeks, there are other compartments, including disease compartment that we don't have the opportunity to measure directly. So they may also play into how long it takes for these patients to ultimately respond.

Yes. And it also encourages and guides us to continue the dose escalation to get as much drug as we can into as many of these pathways as possible, which is what we're trying to do, Matt.

Got it. That's very helpful additional insight. And just if I can squeeze in 1 more quick 1 on AML. I appreciate the level of detail you had on this MRD-negative responder. It was interesting, though, but I guess, they were quite young, I believe, in their 40s, if I remember from your slides, and I think we're just north of 5% blast counts at baseline. So I'm curious if maybe you could remind us if it wasn't in the slides and I missed it, what kind of the median or mean blast that baseline have been, whether that's peripheral or bone marrow? And how some of these patients that are already quite low and are almost in CR at least on that parameter, sneak into the trial? And whether that's indicative of your activity here?

Sneaking into a trial, these are very sick patients, and they're going to have -- some of them may have lower blast counts in the bone marrow, some may have higher, but they have extensive disease throughout the body. And you're just going to see a myriad of different parameters in these patients. Dr. Bejar, did you want to add to that?

Yes, you're right. There's quite a variety of patients in relapse who present. Some of them present after -- early after relapse, which I think this patient did in part because of the pain that led them to discover this extramedullary relapse after transplant. Other patients who were refractory to primary therapy, for example, may have a tremendous burden of disease and may present very differently with high circulating blasts. So I -- you're right that, that patient already met many of the CR criteria in terms of blood counts and blast, but the degree to which that they reduce their disease burden down to being MRD negative, I think, is what was more compelling about that story. Other patients that have seen blast reductions were again treated at our lowest dose level. So we'll have to explore this higher dose levels to see what we can achieve there.

Ladies and gentlemen, this concludes our question-and-answer session. I'll turn the floor back to Dr. Rice for any final comments.

Thank you. I think just 1 -- a couple of quick comments on luxeptinib. We now know it's an active drug. We're treating very difficult patients, B-cell malignancies, AML patients. We know it's an active drug. We're at some of the lower dose levels, particularly in AML. We have predicted that the low-hanging fruit would be the FLT3 positive patients, and we're actually seeing that play out. We're getting hints of activity elsewhere. And so we will continue then to dose escalate as high as possible so that we can hopefully get activity in the FLT3 positive as well as in the FLT3 wild-type patients with these diverse mutations throughout the diversity of AML patients. Same true on the B-cell malignancies. It's -- early on, people were saying, why didn't you get the C481S patient population in there to show that your drug's active? Well, guess what, that patient population is becoming very rare because other drugs are handling that population. So now it's a more difficult population that's emerging. These have the wild-type BTK with activation of a variety of other pathways. We're now seeing as we dose escalate, yes, we're hitting the BTK. Yes, we're hitting these other pathways continue to dose escalate and also watch these patients for longer-term to see if we can see the tumor reductions. But we're seeing activity there. We're happy with where we are, with the way this has flowed out. We also know that we have had a delay in the timing of some of these trials. We know because we had an apparent DLT in the earlier B-cell trial. We had -- and that raised a question there for us. We had to resolve that, make sure that we identified the fact that, that patient -- we didn't believe it was associated with our drug, gain confidence there for ourselves and the investigators. Now we have that confidence in the safety profile. We have not seen the typical toxicities you see with BTK and FLT3 inhibitors. We don't see the bleeding, the QTC prolongations and many of the other side effects that you see with the other drugs. It's difficult-to-treat population. But we believe in luxeptinib. We're going to continue driving through. With that, what I want to do is then, I just want to thank everybody for being on here today, getting on early, taking time away from your -- from the other companies that you're covering and the other drugs. We really appreciate you being here. We're thankful to all the patients, the clinicians. I'm thankful that Dr. Bejar is here, Dr. Marango. It's a great team. And so what I will then do is say thank you for coming on here today. I wish you a wonderful EHA event and a wonderful day. And with that, we will end the call. Thank you so much.

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