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

Greetings. Welcome to Aptose Biosciences Corporate Update Call. [Operator Instructions] Please note this conference is being recorded. I will now turn the conference over to your host, Dan Ferry. Thank you. You may begin.

Thank you, operator. Good afternoon. And welcome to the Aptose Biosciences corporate update call in conjunction with the company's participation at the 2020 ASH Annual Meeting. I am Dan Ferry, Investor Relations representative for Aptose Biosciences. Joining me on the call today are Dr. William G. Rice, Chairman, President and CEO; Mr. Gregory Chow, Executive Vice President and Chief Financial Officer; Dr. Jotin Marango, Senior Vice President and Chief Business Officer; Dr. Rafael Bejar, Senior Vice President, Chief Medical Officer. I will now turn the call over to Dr. Rice, Chairman, President and CEO of Aptose Biosciences. Dr. Rice?

Thank you, Dan. Good afternoon, all, and welcome to the Aptose Biosciences corporate update event to discuss our clinical results that have been presented during the 2020 ASH Annual Meeting. I'll remind you that today, I will make certain forward-looking statements. For the agenda, first today, I'll update you on the Phase I trial with APTO-253 in patients with AML and MDS. These findings were presented yesterday in a poster session during ASH. Then I'll speak to the Phase I trial of CG-806 in patients with CLL and non-Hodgkin's lymphomas, and much of these data were presented this morning in a poster session during ASH. And finally, I'll present new data from a Phase I trial of CG-806 in patients with AML. Afterwards, we will be delighted to entertain your questions in a Q&A session. For those of you less familiar with the company, Aptose is developing small molecule targeted agents for the treatment of life-threatening cancers of the bone marrow, blood and the lymphoid tissues. We have multiple pharmaceutical assets being developed across multiple cancer indications, which provide the company with optionality for value creation. Our first molecule, CG-806, is an oral kinase inhibitor that potently inhibits the wild-type and mutant forms of the BTK kinase, which, as you know, is the driver of CLL and non-Hodgkin's lymphomas. Because of this, we are developing 806 in a dose-escalating Phase I trial in these indications. In addition, 806 potently inhibits the wild-type and mutant forms of the FLT3 receptor tyrosine kinase, which is a driver of AML. And we're developing 806 in parallel in a dose-escalating Phase I trial in patients with relapsed or refractory AML. Our second molecule, APTO-253, is the only known clinical-stage agent that targets the G-Quadruplex regulatory motif in the MYC oncogene. And this molecule is in a dose-escalating Phase I trial for the treatment of patients with AML and high-risk MDS. So first, let's look at the data set with our APTO-253 MYC inhibitor. The MYC protein is a master transcription factor that's reported to regulate thousands of genes and is the most commonly dysregulated gene among all cancers, and its dysregulation tips the scale towards cell survival. The MYC protein does not have an active site and has been notoriously resilient to targeting with small molecule drugs. For this reason, it's been referred to as undruggable. However, 253 is not targeting the MYC protein, but rather, it targets the 3-dimensional G-Quadruplex DNA regulatory motif in the promoter region of the MYC gene, thereby preventing expression of the gene. This results in depletion of the MYC protein in the cancer cells and induction of apoptotic cell death. In this trial, AML and MDS patients receive a weekly IV infusion on a 28-day cycle. To date, we have completed the first 4 dose levels. And now dose level 5 is ongoing with 150 milligrams per meter squared, which is a 50% increase over the prior dose level. As shown in the swimmer's plot here, on Slide 8, we now have enrolled 3 AML patients at the 150 mg per meter squared dose level. You'll note the first patient discontinued early. As if AML isn't bad enough, this patient was at home, tripped and fell, hit his head and passed. So our heart goes out to that family as well as all families that are touched by AML. To date, 253 has been generally well tolerated, and we have observed no safety trends of concern as was presented yesterday in the poster session. I'll again remind you that following IV administration of the parent drug into patients, the parent drug of 253 can bind iron and form an iron adduct in the bloodstream. Both forms are active in the -- excuse me, both forms are active on the MYC gene, and we measure both forms in the plasma. Importantly, the iron adduct remains at 2 to 3 micromolar levels for 24 hours or more. This is important because we want 253 to act on the MYC gene during that first 24 hours. As shown to the right, we measure MYC gene expression in the total PBMC fraction in patients prior to dosing and then 24 hours after the first dose. And in most patients, there's a significant reduction in MYC expression. This is an important clinical pharmacodynamic response and demonstrates on-target activity. In this trial, 253 is targeting the MYC gene in an effort to treat AML and high-risk MDS patients who have failed standard therapies. To date, the safety and tolerability profiles have been favorable, and the PK profile has been encouraging, particularly with that iron adduct form of the drug. From a pharmacodynamic perspective, we've shown inhibition of MYC gene expression in the total PBMC fraction that includes both malignant and normal cells. We now are developing flow cytometry-based technologies to assess the MYC expression associated specifically with tumor cells. Separately, new research publications have heightened the interest in small molecule suppressors of MYC because even a transient reduction in MYC expression can sensitize tumors to other agents and this finding MYC precision 253 to be an agent that sensitizes hematologic and solid tumors to various other agents. And you can tell we believe in 253. We believe it can bring value to Aptose, and we plan to continue dose escalation and watch for potential responses. Now let's move to 806 and first address the Phase I trial in patients with CLL and non-Hodgkin's lymphomas. CG-806 is distinguished by its unique kinome targeting profile. It potently inhibits both BTK and FLT3, and both of these are clinically validated targets for cancer therapy. It inhibits the wild-type and mutant forms of both kinases, and it simultaneously suppresses multiple oncogenic signaling pathways while avoiding many of the kinases in the human kinome that can negatively impact safety. In this Phase Ia/b dose escalation trial, the patient population includes heavily pretreated CLL and non-Hodgkin's lymphoma patients who failed or are intolerant to multiple lines of established therapy. The patients received oral capsules twice daily over 28-day cycles and with an accelerated titration design that required only one patient at the first and second dose levels and then at 3 by 3 thereafter. And this was done in order to reach higher dose levels with higher plasma exposures as rapidly as possible. And as we progress through the dose escalation and increases in plasma exposures, we'll watch for leading indicators of clinical activity. We have completed the first 4 dose levels and now are treating patients at dose level 5 with 750 milligrams BID. From a PK perspective, on the left side of Slide 15, the graph shows that we've observed dose-related increases in plasma exposure during the first 24 hours of dosing, ranging from the first dose level of 150 milligrams shown in the green spheres to the fifth dose level of 750 milligrams shown in the blue spheres. And by the end of cycle 1, shown in the graph on the right panel, 806 is achieving steady-state trough levels by the end of cycle 1 in the range of 2 micromolar. Just so you know, 1,000 nanograms per ml is roughly equivalent to slightly greater than 2 micromolar. And this is the exposure levels we were hoping to achieve with the 750-milligram dose level. Now from a pharmacodynamic perspective, we have observed on-target activity against key kinases. To understand this relationship, we collect plasma samples from patients at various times either prior to or different times then following dosing with 806. We first quantitate the amount of drug in each sample and then ask if that drug load can inhibit the target kinases. For this, we bring the plasma back to the lab and placed on recorder cells for 6 hours, after which we lyse the cells and measure the level of kinase activity in the cells. Now we've shown you the -- previously the immunoblots at the bottom of the slides. So we then quantitated the level of phospho-kinase in each sample and related it to the plasma levels in each patient. As shown along the top, we demonstrated that as the exposure levels increased in the patients, the key BTK, SYK and FLT3 kinases demonstrated robust inhibition. And inhibition of these target kinases was the first leading indicator of clinical activity that we identified. Moving on to the other leading innovators of clinical activity. On the left-hand panel, we show the classic CLL patients that on-target lymphocytosis was achieved. And this is the second leading indicator of clinical activity. The CLL cells reside in the lymph nodes and spleens of the patients. And inhibition of BTK in these cells results in exfiltration of the CLL cells from the lymphoid tissues into the bloodstream with a resultant increase in the malignant cells in the peripheral blood known as lymphocytosis. We're confident this reflects on-target lymphocytosis and not merely disease progression because the lymphocytosis occurred immediately upon initiation of dosing and because the levels of lymphocytosis failed when study drug was withheld and then lymphocytosis returned when the study drug was reinitiated. Separately, on the right side, we provide case studies of 3 patients in which we measured modest reductions in tumor size as the third leading indicator of clinical activity of 806. In case A, a follicular lymphoma patient received 450 milligrams for 7 cycles, during which the tumors actually demonstrated some level of growth. The patient was then dose-escalated to 600 milligrams. And after 5 weeks or approximately 1 cycle on the 600 milligrams, the scan showed cessation of tumor growth. After 13 weeks on 600 milligram, approximately 3 cycles in total, the scan this week showed an actual reduction relative to the prior scan, albeit not to the level of a PR. This patient has maintained long-term dosing with 806 and is thrilled that their tumor is beginning to decrease at the higher dose level. In case B, an SLL patient received 450 milligrams of 806 and, after 2 cycles, showed a 10% reduction in tumor size. In case C, a 17p-deleted CLL patient demonstrated robust lymphocytosis immediately upon initiation of dosing with 600 milligrams and then showed a 27% tumor reduction with the scan after 2 cycles. The patient retained tumor reductions through cycle 4 and then chose to discontinue for apparently convenience reasons. Now let's discuss the CLL patients placed on the 750-milligram dose level thus far. I'm presenting the findings of -- as of the data cut date that were also presented during the poster session this morning, but nothing has changed since then. One CLL patient completed the first 28-day cycle and demonstrated steady-state trough plasma levels of greater than 2 micromolar, as shown by the green spheres in the PK graph. In contrast, 2 very ill and rapidly progressing CLL patients entered the study and did not complete even 1 week of dosing. The first patient experienced a Grade 2 dysarthria, which is manifested as difficulty in speaking and swallowing. This is a very puzzling case for us as the first off was a potential stroke. However, after an extensive diagnostic workup, there was no evidence of a stroke or any bleeds and no indication of nerve damage. Likewise, we've observed no neurological effects in any other patient treated with 806 at any dose. Interestingly, this patient had a history of enlarged lymph nodes in the neck area adjacent to the cranial nerve that's controlling these motor functions of speech and swallowing. But because there was no definitive and verifiable primary cause, the event was attributed as possibly related to study drug. The second patient was even more perplexing. This patient entered the study with rapidly accelerating disease and experienced Grade 3 and Grade 4 hypertensions. And it's important to note that this patient had been treated previously with 3 rounds of chemotherapy, anti-CD20 therapy, venetoclax, CAR-T therapy, ibrutinib on more than one occasion and most recently with a different non-covalent BTK inhibitor. Upon screening for our initial trial, and this was 2 weeks prior to receiving 806, the patient presented with a new onset of Grade 1 hypertension, as shown in the bottom left. 2 weeks later, on day 1 of the study, and this is prior to receiving any doses of 806, the hypertension had already progressed to Grade 2. Then on day 2, the patient reported Grade 3 hypertension prior to receiving doses of 806 on that day. The physicians considered the hypotension likely related to disease-associated pain or administration of IV fluids and adamantly wished to continue dosing because this patient entered the trial with such aggressive disease, so the dosing continued. Then on day 5, as shown over toward the right, the patient returned with a Grade 4 hypertension prior to receiving 806 on day 5. The patient was discontinued from the study. And upon scan, the patient had evidence of further disease progression as was anticipated at that time. Ironically, as shown in the red spheres in the PK plot, the exposure levels of 806 in this patient were very low on the order of 6x lower than the other patients on the 750-milligram dose level and actually lower than most patients on even lower dosage levels. In fact, we question if the patient actually took all of their intended doses. For the sake of thoroughness, we performed an analysis of all patients that had ever received 806 and found no correlation of the exposure level with any effect on blood pressure, neither hypotension nor hypertension in any patient at any dose. Unfortunately, the Grade 3 and Grade 4 hypertensions were scored as possibly related and therefore a DLT. While we may disagree with this attribution, we will honor the protocol and have expanded the 750-milligram dose level to 6 patients. And we will make lemonade out of this situation so that we can get more patients on the 750-milligram dose level. So now let's discuss the type of CLL patients that we're targeting for the 750-milligram dose level. This is an expanding population that's failed chemotherapy, anti-CD20 antibodies such as rituximab; the Bcl2 inhibitor, venetoclax; PI3K inhibitors; covalent inhibitors such as ibrutinib -- covalent BTK inhibitors such as ibrutinib and acalabrutinib; and even the recently developed non-covalent BTK inhibitors. These patients will likely have non-BTK escape mechanisms such as mutations in the RAS, ERK and MAP kinase pathways or the p53 pathway. They will be difficult to treat but in need of an agent like 806 that targets the wild-type and mutant forms of BTK as well as simultaneously targeting other escape pathways. So when do we believe we might expect 806 to deliver responses in these patients? While history teaches us that non-covalent BTK inhibitors typically deliver true PRs, and by this, we infer a 50% reduction in tumor size, in these relapsed or refractory CLL patients once a threshold plasma exposure is reached. Prior to reaching that threshold plasma exposure, as the drugs undergo dose escalation, the leading indicators of clinical activity evolve sequentially. These include, first, inhibition of BTK; followed second by on-target lymphocytosis; and then third by modest, less than 50% tumor reductions. 806 thus far during dose escalation has delivered these leading indicators of clinical activity. As -- and as 806 continues into higher dose levels, we may be approaching the threshold exposure that drive formal responses. We're gratified to see the dose -- the drug exposures continue to increase as we dose-escalate. And we are hopeful that true responses will emerge. To wrap up the CLL trial with 806. We now have accelerated the enrollment. And since the data cutoff date, we have dosed 2 additional patients and have consented 2 more patients. 806 has been generally well tolerated, and we've seen no toxicity trends to date that would prevent further dose escalation. I mentioned the 2 rapidly progressing patients that did not complete even 1 week of dose level 5. We will take advantage of this situation to gather more data with additional patients at the 750-milligram dose level. I also mentioned that plasma exposure levels generally increased as the dose increased. And at the 750-milligram dose level, 806 achieved a steady-state concentration. These are the trough levels that were sustained at 2 micromolar or greater. Our pharmacodynamic and pharmacologic findings are consistent with a march through the sequential leading indicators of clinical activity and trend toward responses. This includes inhibition of BTK and other key kinases, induction of on-target lymphocytosis in CLL patients and tumor scans that show modest reduction in tumor measurements. Three patients experienced modest tumor reductions. The maximum observed was 27% but not to the level of the PR, which requires a 50% decrease. Again, all leading indicators of activity are trending toward responses that may occur with the right dose and in the right patients. And we plan to continue dose escalation and identify the right patients toward that goal. Now let's turn our attention to the newest data from the dose-escalating Phase I trial of 806 in patients with AML. To place AML in context, this is a highly aggressive and deadly cancer. This year, approximately 20,000 cases will be diagnosed, and over half that number of patients will die. And once a patient becomes relapsed or refractory, their overall survival time typically is 6 months or less. The most common mutation in AML is the internal tandem duplication or ITD mutation that occurs in the FLT3 receptor tyrosine kinase. And you can see that I've shown that down on the bottom right. The ITD mutation turns the receptor on, sending an uninterrupted proliferation signal to the nucleus. And the mutated cell continues to divide nonstop. This mutation occurs in approximately 1/3 of all AML patients. And current FLT3 inhibitors do exist. Certain FLT3 inhibitors like midostaurin are dirty and hit so many kinases that this drug is limited by toxicity. Other FLT3 inhibitors like gilteritinib are more selective. A drug like this can extend the median overall survival in relapsed or refractory AML patients, as shown in this survival curve at the bottom left. But after 2 years, the curves meet, and only about 10% of the patients remain alive. So current FLT3 inhibitors are limited often by toxicity and by durability and also susceptible to additional mutations in FLT3 as well as mutations in p53 and RAS. Thus, there is a desperate need for a new class of drugs like CG-806. As we've reported in the past, 806 is highly potent against the ITD mutant form of FLT3, shown on the far left, with an IC50 of approximately 800 picomolar. 806 also retains potency against the wild-type form and all other mutant forms of FLT3, as shown in the table in the center. This includes the D835 tyrosine kinase domain mutation that is particularly nasty and difficult to treat in the clinic. Typically, if we're developing a molecule preclinically, we'll test the agent and determine if it can kill AML cell lines grown over many passages in cell culture, and this is done in the laboratory. These, however, may respond to a drug in a very different manner than AML's taken -- cells taken directly from an actual AML patient. And we wanted to understand how true AML cells would respond to 806. To do this, we turned to Dr. Brian Druker, who is best known for his role in the development of Gleevec. Dr. Druker's lab collected primary samples of AML cells directly from more than 200 AML patients. He then took those cells and exposed them to different concentrations of 806 and to all other available FLT3 inhibitors. He measured the IC50 of cell killing with each drug and with every patient sample and then transformed the data into a heat map in which the samples that were highly sensitive to a drug received a red mark while the samples resistant to the drug received a white mark. So red is good and white is bad. As you scan across the AML patient samples, those with the FLT3 ITD mutation, near the center right, were highly sensitive to 806. You can see the red. And remarkably, so are those AML patients with wild-type FLT3, designated on the slide as FLT3 ITD negative. Those are wild-type FLT3. Overall, 806 demonstrated greater potency in killing primary AML cells with FLT3 wild-type or FLT3 ITD than the other FLT3 inhibitors. And we were able to gain additional understandings from these AML patient samples because we have the genetic mutation profile and RNAC data from these samples. This allowed us to interrogate the data to look for mutations that might correlate with sensitivity or resistance to 806. As shown on the left-hand panel, the cells remained highly sensitive to 806 in the presence of NPM1 mutations or any mutation found in FLT3. Remarkably, cells remained sensitive even in the presence of IDH1, p53 and RAS mutations. These findings, along with the in vivo preclinical models of AML, give us the confidence to move 806 to the clinic to treat a broad range of AML patients, including those who failed other FLT3 inhibitors, IDH inhibitors or venetoclax, as well as those with mutated p53 or RAS. I'll also point out that other FLT3 inhibitors are directed only at the FLT3-positive AML population, which represents only 1/3 of the population. We believe we also can treat the additional 2/3 of AML patient population having wild-type FLT3 as well as patients that are unfit for intensive chemotherapy. So how did we move 806 into the clinic? Recall that we're performing a dose escalation trial in CLL patients, and this is shown on the left panel, and which we have treated them with dose levels from 150 milligrams to 750 milligrams. And we sought to identify a dose that would be safe and potentially active in AML patients. The dose level of 450 milligrams was selected as the starting dose for AML patients because we believe this was the lowest dose that may be clinically active in AML patients. From there, we plan to continue dose escalation to identify an optimal dose that may be able to treat a broad spectrum of AML patients. We currently are enrolling patients at the 450-milligram dose level. And the cohort is enrolled very quickly, with 4 AML patients enrolled to date. Note that the patients received a single dose on day 1 to allow us to characterize the 24-hour PK parameters and then received 2 doses per day thereafter. We have preliminary PK data from 3 patients thus far, as shown on the right panel. And we're gratified to see the exposure levels by day 22 of cycle 1 are consistent with the exposure seen in CLL patients at the same dose. I also wish to present a single case study of a heavily pretreated FLT3-positive relapsed AML patient who received the 450-milligram dose. The AML cells of this patient house mutations in NPM1, DNMT3A and FLT3 ITD. She is heavily pretreated with chemotherapy, received an allogeneic stem cell transplant and progressed on 2 FLT3 inhibitors, gilteritinib and crenolanib. During cycle 1 with 806, we observed a reduction in the percent blast in the peripheral blood from 93% down to 10%, indicating a true antileukemic activity. And this is shown in the graph on the right panel. Near the end of the cycle, the percent blast began to rise likely due to persistent AML clones not fully suppressed by this dose level of 806. And we hope that as we dose-escalate 806, we can identify an optimal dose that can clear persistent AML cells in future patients. For the key takeaway messages from this trial. We initiated dosing at the 450-milligram dose in AML patients, including FLT3 ITD and FLT3 wild-type patients. We rapidly enrolled 4 patients on study drug, and additional patients are awaiting a slot. The PK data are consistent with exposures observed at the 450-milligram dose level in CLL patients in our other trial. And we presented a case study of a FLT3 positive AML patient that have been heavily pretreated with and progressed on chemotherapy of bone marrow transplant and 2 FLT3 inhibitors. Likely this dose of 806 killed a sensitive subset of cells followed by outgrowth of persistent AML, yet the data demonstrate antileukemic activity on AML cells at the very first dose level of 450 milligrams. And now we plan to continue dose escalation to identify an optimal dose for the treatment of a diverse array of AML patients. In summary, we are a very science-driven company. And we always seek to understand and extensively characterize the chemical, biological, safety, PK and efficacy characteristics of our agents at the preclinical stage and then to seek to translate those lessons learned into the clinical setting. Our molecules are gaining momentum in the clinic and delivering the expected leading indicators that point to the potential emergence of true responses in heavily pretreated patients with relapsed or refractory hematologic cancers. We now plan to continue dose escalation to identify our optimal doses and watch for formal responses. Aptose retains an attractive value proposition as a pure-play orphan hematology company and further optionality into additional cancer indications. We are well funded into 2023, and we have no plans at this time to finance. We have a growing base of sophisticated investors, and we are poised to generate value-creating clinical updates during the first half of 2021. So with that, I wish to thank you, our employees, principal investigators and clinical staff, most importantly, our patients and their families for their participation in these clinical trials and our colleagues at CrystalGenomics. And now we'll be happy to address your questions.

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

Congratulations on the progress. Bill, I just, of course, wanted to start with the DLT in the hypertension. It sounds like you're thinking a little bit about a one-off. I think I heard you mention just some degree of being perplexed on that. But perhaps you could just provide a little more context how we should think about that occurrence of hypertension when it maybe compares to safety data, not just within -- in your program and how you're thinking about that, but with other BTK inhibitors. And as you expand those out, just potential impacts on the perception of the drug and how maybe these findings at this early stage may have hit or met your expectations.

All right. Thanks, Greg. So yes, you can sense our frustration on this one. So again, this patient was heavily pretreated multiple times with ibrutinib and then also another non-covalent BTK inhibitor immediately before coming on our trial. They were progressing very aggressively, and the physicians were pushing them to get into the trial quickly. Hypertension is associated with the BTK inhibitor class. We don't know if this was a cumulative effect from the prior treatments of the other BTK inhibitors, but it was already beginning to manifest itself several weeks before they ever saw our drug, progressing from Grade 1 to Grade 2 before they ever saw the drug, and then it continued to increase over the next couple of days. We did find this frustrating. But as we looked at across every patient at every dose level and every exposure, we found no correlation with hypo or hypertension. We do know this is a response that is associated with many of the drugs in the BTK inhibitor class, and we will watch for it going forward. But we question as to whether or not this truly was caused by our drug. So perhaps I can also ask our Chief Medical Officer, Dr. Bejar, to give a bit more of his perspective.

Thanks, Bill. I think you nailed it when you described that this was a finding that other BTK inhibitors can cause. However, it wasn't actually seen in the early clinical trials of those agents. This was a toxicity that was really learned about when we did larger studies with longer-term follow-up. And it became a late event for hypertension in these patient populations. Now it is a -- can be a significant problem in these patients. And a patient like this that has seen quite a bit of prior BTK inhibitor therapy could certainly have developed that even prior to coming on CG-806. So we thought it was very important to look very closely at the remainder of our patients on study both at this dose level and below to see if there was any association with hypertension or hypotension, including in patients who had preexisting hypertension. And we did not see that even after looking at considerations of exposure. So to date, this is the only patient that has had this as an issue. And as you noted, it happened almost immediately after starting dosing. And...

That's great. And just one more if I may. I'm just curious if you had anything -- unless I missed it, anything on baseline cytogenetics with patients and any associations between the normal reductions that you have discussed and perhaps C481S mutations. And maybe just in that population as we go forward with the patient population that you're selecting for, how should we think about that patient selection with respect to C481S?

So thus far, we don't -- we haven't identified any genetics associated with the patients who responded. In effect, what you see with the non-covalent BTK inhibitors, even the covalent, is as you continue to dose-escalate trials, you begin to hit these -- what we call these indicators of clinical activity. First, BTK, then lymphocytosis, then the reductions, the moderate dose reductions. These are more of a population-based effect. So you get to a certain dose level that a population of patients will have the BTK inhibition. A population will have lymphocytosis. A population will have nodal reductions. But that doesn't mean you're going to see it in every patient. And typically, what you see is when you continue to dose-escalate and you get to that threshold, that's when you begin to see the responses kick in. And we hope that to be the case. Yes, I find it interesting that -- I won't say which company, but there was another company developing a BTK -- a non-covalent BTK inhibitor. And once they reached a particular dose, I think their first patient was a DLT, that was -- I think that was frustrating for them. But then they expanded out, and that's when the -- that dose is what turned out to be their effective dose. May we be so lucky. But we'll just -- as I said, we have this DLT now. We don't truly believe that it was caused by the drug, but we'll expand out, try to get more patients on at 750 dose level and try to collect more data.

Our next question is from Tyler Van Buren with Piper Sandler.

I had a couple of questions, just one on -- for 806, one on CLL and then the second one on AML. The first one with respect to the CLL update is just wanted to get additional thoughts on just the evolution of the threshold exposure that you think will be required to drive formal responses. Previously, you had talked about it being above 1 micromolar. And at the 600-milligram dose, which is above that, if I'm not mistaken, it looks like we're seeing some tumor reductions and some lymphocytosis but just not enough to really drive formal responses. So at the -- and to be fair, we still need to evaluate the 2 micromolar with the 750-milligram patients. But do you think maybe 3 or 4 micromolar might be required? And then the second on the AML update, encouraging to see the antileukemic activity. Just wanted to get your latest thoughts on what you think the optimal dose the clear persistent AML cells might be based upon your preclinical work.

Thanks, Tyler. When we talk about the evolution of the various indicators until you get to that threshold, and you're talking about what exposures do we want to achieve, we've said all along, we wanted to get above 1 micromolar. At this point, we're double that at the 750. We are at 2 micromolar. And that's -- we've seen that sustained for multiple cycles. And -- but now we need to get additional patients on and watch long term to see what that exposure is going to be. It may be higher, it may be lower in some of the patients that we put on going forward. But the good news is once we reach that 600-milligram and getting the exposure level there, that's when we started to see the reductions in some of the tumors again, not to the level of a PR, but that gives us the confidence and the hope that as we continue to dose up. Is 2 micromolar going to be enough? We'll see. That's the trough level. And we'll see if some of the patients have even higher levels. And then if we dose-escalate to 900 milligrams, then we'll see what it is there. I'm gratified to see the 2 micromolar. I can't tell you what it is going to take to be able to treat these patients because remember, these are deep relapsed/refractory patients who have failed all the other therapies. These patients are actually deeper in terms of the relapsed/refractory format or their presentation than the patients put on other non-covalent BTK inhibitor studies. So they are going to be difficult to treat. We hope we're getting enough drug in for those patients at the 750 and possibly even the 900. In terms of the AML, we had said that we thought the 450-milligram dose level was just getting into that dose level that would give us exposures that -- where we might see inhibition or killing of the FLT3 ITD, the most sensitive population. And it will be safe and well tolerated. That's why we took that dose in the Phase I. And sure enough, that's what we've seen in the very first dose level. Now as we continue to dose-escalate, we have a good sense of what we will see in terms of exposures as we continue up in dose escalations. We know that the AML cells tend to be much more sensitive than CLL cells. So we're hoping that as we get in up toward the 600-, 750-milligram dose level in AML that we'll be achieving that exposure level, that threshold there that is able to treat the other persistent AML. That's why we're doing the studies, and we'll collect the data and share with you as soon as we can. Thanks, Tyler.

Our next question is from John Newman with Canaccord Genuity.

First question I had was, Bill, you've got 2 patients, I believe, that are on drug below the 750-milligram dose. I think you've got one at 600, and you've got another one at 600 -- at 450. I'm just curious if those patients could be escalated to 750 in order to give you more patients there. Also, I just wanted to clarify, I believe you said that patient A is still on drug and treatment is ongoing now in cycle 10. I just wanted to confirm that.

Hey, John. I think it's cycle 10. I'd have to look back to see the exact. So what's your first question? Kind of walk me through it again. So...

Sure.

What is it you're, first of all...

So you've got -- I'm just wondering, you've got a patient that continues to be on study at 450 milligrams that has NHL. You've also got a patient at 600 milligrams that has CLL or SLL that also continues to be on study. And what I'm wondering is could those patients...

When could we dose-escalate...

Yes.

Yes, okay. Yes. So according to the protocol, once we determine that a dose level is safe, then we can move patients up to that dose level. So we had completed the 600-milligram dose level, so patients were moved up to 600. We will have to complete the 750-milligram dose level before we can move patients up to that. If I recall the protocol, it required that we show at least 3 or more patients are -- safely completed the 28-day dose level. So perhaps Dr. Bejar can address that when we might be able to move the patients up.

Yes, that's right. We do have the capacity to do interpatient dose escalation on the study. And it's exactly, as Dr. Rice mentioned, that once the dose level is cleared, then we can dose-escalate patients at lower dose levels up to that most recently cleared dose level. So that patient who is on 600 could move to 750. The patient who started at 450 could move to 600 and then could move to 750. We also have included the ability to add patients to lower dose levels particularly when the dose escalation cohort is full. And that allows us to bring on additional patients, but we can only dose-escalate them to the dose levels that have been cleared in the dose escalation portion of the study.

And the good news is we're beginning to get a pickup in the enrollment of patients. So more patients, the types of patients are coming toward us. And so also, someone had asked -- I think maybe Greg Renza earlier had asked about C481S. So we are not excluding those patients, and we welcome those patients onto the study. But we believe they're becoming a little bit more rare as time goes on because venetoclax is able to effectively treat that patient population as are many of the non-covalent BTK inhibitors. So thanks, John.

Our next question is from Alethia Young with Cantor Fitzgerald.

Just a couple. I guess just going back to the CLL portion, you mentioned the hypertension, but when you looked at any other kind of labs or [ deem ] or anything, like did you see anything that would make you have some relativity? That's the first question. And then the second question is when you -- is there like a cumulative kind of hypertension risk that occurs with BTKs? Is that a thing? I mean there's a lot of BTK evidence out there. So I just wondered how known of an effect that is. And then my third question is just talking a little bit about this Fe(253) kind of biomarker discovered in the MYC program. How accepted is that biomarker? And how much kind of work do you have to do to kind of get that potentially validated to kind of look at what it means for PK?

So I'm going to address the first 2 very quickly, and then I'm going to come back and ask you about the third one again. So you asked about the CLL and the hypertension of that patient. Did we see any other labs that gave us concern on that patient? Not to my recollection. Dr. Bejar, can you recall?

Yes. There were no other Grade 3 or 4 events that I recall besides hypertension that were related to lab values. I believe that the person had headache as well that also resolved. So there was nothing else there that gave me pause, no end organ -- no permanent end organ damage or anything of that nature.

Yes. This was a very rapidly progressing patient. That was a train wreck coming in. All right. So you also asked about cumulative hypertension. Actually, one of our KOLs mentioned this to us recently that when you're having these multiple rounds of certain covalent/non-covalent BTK inhibitors, it looks like that cumulative effect can drive hypertension. Dr. Bejar, do you want to address that one?

Yes. So this is a problem that is coming more to the forefront now especially as we have more data on BTK inhibition in general and longer-term follow-up. There were some great presentations earlier during the ASH meeting about managing the complications of BTK therapy. And that was -- I think one of the major things that was highlighted there was the theory that progresses hypertension that occurs with cumulative exposure to primarily ibrutinib where we had the longest follow-up for that.

Okay. And the patient had been on ibrutinib for, I think, 3 different occasions. And then you asked about the MYC, and I thought I heard p53, but I didn't quite understand your last question.

Yes. Sorry, before I ask the last question, just to follow up on the 2. Okay. So it feels sort of like potentially a fluke, but just because you're in the early stage of a clinical trial, you just can't exactly technically rule it out from an investigator standpoint? Is that kind of a fair assessment here?

Yes, that's correct.

Okay. Okay. So on p53, I guess this iron adduct Fe(253), kind of that you're talking about that shows target engagement, I just wasn't very familiar with it. And I just wanted to kind of understand like a little bit more about it. And like is it something that's broadly accepted in kind of correlating to potential MYC reduction and MYC suppression?

So in terms of the iron adduct, we had actually published that, that 253, it's known to bind to iron. So we published that. And it's -- when you put it into blood, you have effectively -- you have some of the parent molecule as well as the iron adduct. We determined its structure. All of that is published. We also measured that and determined that both of them actually bind to this MYC quadraplex and the promoter of the MYC gene. And it turns off the MYC expression. So all of that is published, too. And so that's why we then wanted to make sure we understand both forms of the drug. So we had to develop the assays so that we can measure the parent end of iron adduct in the bloodstream of patients. And sure enough, that iron adduct does -- it hangs around, so it has a much longer half-life in the bloodstream. And so we're hoping then that, that will then deliver us responses or more dramatic -- and as we dose-escalate, not only more dramatic but also more consistent inhibition of MYC especially on day 1. So the other thing that we're trying to do there is when we measure the MYC inhibition in the bloodstream of these patients, the AML patients or MDS, we're just taking it to whole blood PBMCs, the abnormal and malignant cells there. So we're developing methodologies to pull out the PBMC -- the malignant PBMCs and just look at those and measure the level of reduction. It may be much greater than we're seeing in the total population.

Okay. Then I guess just a quick one, follow-up on that. So have you decided to go maybe past 210 since you didn't really see a lot of kind of safety events at 150?

Yes, we may. So right now, we need to complete the 150. Things are moving along well. We're -- for a period of time, it was a little bit slower getting patients on this study because it's an IV infusion. And during COVID, first, people were afraid to come into the hospitals. That's changed. So now we're getting again brisk enrollment there, too. Patients are interested in this study. So we hope to be able to complete the 150, move on up to 210 and then even further after that. And so yes, we're actually looking forward to this. And I'd also mentioned about a publication that recently came out. It was quite remarkable. What they demonstrated was that even transient reductions in MYC can remodel the tumors such that they become much more sensitive to drugs that induce apoptotic cell death. And this is also in solid tumors. So this makes it possible that 253, if we can show consistent inhibition of transient reductions in MYC, this can be a combination study -- combination drug for many different types of therapies. So we'll keep you posted on that, too.

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

Bill, I have 2 logistical questions and one crystal-ball question. So first, with regard to the earlier vein of discussion, does the AML arm of the 806 study also have the ability for intrapatient dose escalation once you have approved doses?

Yes.

Great. Okay. The second logistical question is, can you just tell us with regard to the formulation for 806, any ceilings we need to be considering at this point with regard to the size of the dose or needing to split it up if you get higher and higher?

Yes. So we're looking at that. So currently, it's a very simple formulation, and we know that the oral bioavailability, the percent oral bioavailability is low. And we've known that going into it. That's why we're using high doses and dosing twice a day. We're actually getting additional data in the AML trial. You may have noticed this, and you saw the blip on the first day of dosing in the pharmacokinetics in that AML patient. That was once-a-day dosing for the first day. and comes to pan out the half-life is longer than we thought. So it may be that we could go to once-a-day dosing in patients in the future. So we'll take a look at that hitting on the half-life. But at this point, we're not seeing really a ceiling driven by any problems in dosing of the patients. We haven't seen any gut discomfort that's associated with the doses as we dose-escalate. So we plan on completing the 750, and hopefully, we can go to the 900. If we chose to go up higher after that, then we can do so. And then on the AML, same thing. But the AML cells, they tend to be much more sensitive to a drug than the CLL cells. So it's quite possible -- and they react more quickly. It's quite possibly that the current dose levels that we're using in CLL may be very active in the AML.

That's helpful color.

And then one more logistical. Maybe we can get people to pronounce your name -- last name correctly.

So with regards to my crystal-ball question, going back to some of your prepared comments when you talked about the CLL study. And you said right dose, right patients. Obviously, the right dose is the empirical experiment that we're doing now in the clinic, that you guys are doing in the clinic. I guess I wanted to talk more about the right patient component about how you see this might play out.

Yes, that is more of a crystal ball. So it is clear C481S mutant patients are more sensitive to drugs than the wild-type BTK relapsed/refractory patients. That's been seen with other non-covalent BTK inhibitors, too. So as we go through this trial, yes, we would like to look at the 481S mutant patients. We'd like to see if we have activity there. But what we're really trying to have an eye on is what are the types of patients that we think are going to evolve in the future. And we talked about those that are having fewer BTK mutated effects and having more of the mutations in RAS, p53, ERK, MAP kinase, these types of pathways. And so we're going to be watching for those. We know those are more difficult to treat with our drug and every other drug. But we're hoping, as we get into these higher dose levels, we're going to have exposures that are able to treat those. And again, we're just seeing glimpses of that now as we're hitting the decreases in tumor volumes, albeit modest at this -- the 600-milligram level. And we hope the 750, which is twice as much almost in terms of the exposure level, will start getting there. But that is my crystal ball.

And our next question is from Matt Biegler with Oppenheimer.

So just curious if you can comment on if you're seeing any improvement in peripheral blood counts in addition to the reduction in tumor volume. I guess what I'm trying to ask is, theoretically, if you hit that 50% threshold, would that patient be considered a partial responder under the iwCLL criteria?

So you're talking about CLL patients.

That's correct.

So I assume you're talking about the lymphocytosis and the reductions there. So in these patients, it's great to see a reduction in the lymphocytosis once you induce it and then it drops down. But ultimately, you have to show that you're truly affecting the tumors, the lymph nodes and the spleen. And so that's what we're trying to achieve here. Perhaps Dr. Bejar would like to speak to that a bit more. And thanks, Matt, for calling in. Dr. Bejar?

Yes. That's a good question. So if the tumor reduces closer to 50%, the other components you're looking for response or improvements in blood counts like you mentioned, so far, we have seen some patients who show slight improvements in platelet counts, for example. Not all patients necessarily have low blood counts to begin with. So they don't need to improve further in order to meet those criteria. So it's hard to gauge, of those particular patients that we reported on, if they -- if all they needed was that 50% reduction, if that would be enough. I would imagine that as we reduce further, other aspects of their blood counts and everything would also change. So I don't have a definitive answer for you right now, but -- whether or not they would have met criteria otherwise. But we haven't seen anything that would make us think that, that might be an issue.

Yes. Okay. That makes sense. And maybe just one more if I could squeeze in about that AML patient. Super encouraging. I'm just wondering if that patient is still on the trial and whether they are going to undergo a marrow assessment.

So a couple of things on that. First of all, we gave you, I mean, real-time data on a patient. So that patient has left the study. As we mentioned, their counts were starting to rise, the percent blast counts there, near the end of Phase I. So when that happens in an AML patient, you need to move most of the trial and try to put them on something else. We are collecting samples both before, during and after the trial. We do not have the genetic analysis of these yet, but it's something we really want to know. For instance, if it's a FLT3-positive patient and we were able to kill the FLT3-positive cells, there may be still residual FLT3-positive cells but with also additional mutations or it could be additional mutations in FLT3 or in other areas. So we really want to know that so we know what to watch for in the future. But I gave you as much information as we possibly could. The good news is we did see activity, antileukemic activity, what we're hoping on this first dose level. And it was in a FLT3-positive patient. And now we just need to complete this level and move on up and try to hit the other -- what we call persistent AML cells. Dr. Bejar, did you want to add to that?

No, that's exactly right. We are very interested in what kinds of cells emerge during relapse or progression. And in this patient, this is a recent event. So we don't yet have those data.

Appreciate it. Congrats on the progress, guys.

Yes. Thanks, Matt.

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

All right. Well, this is Bill Rice again. And I just want to thank everybody for coming on this afternoon, taking time out of your life. We are proud of our people, the work that we're doing here. We appreciate the support of our shareholders, our analysts. And we look forward to continuing to provide you with updates as we go in -- especially the first half of 2021, we think that's going to be a critical time for us. And with that, we thank you, and everyone, we hope you have a good evening. Good night.

Thank you. This does conclude tonight's conference. You may disconnect your lines at this time, and thank you for your participation.