Aptose Biosciences Inc (APTO) 2020 Q2 法說會逐字稿

Good afternoon. My name is Victor, and I will be your conference operator today. I would like to welcome everyone to the Aptose Biosciences conference call for the second quarter ended June 30, 2020. (Operator Instructions) Thank you. As a reminder, this conference call may be recorded.

I would now like to introduce Ms. Susan Pietropaolo. Please go ahead.

Thank you, Victor. Good afternoon, and welcome to the Aptose Biosciences conference call to discuss financial and operational results for the second quarter ended June 30, 2020. I'm Susan Pietropaolo, a communications 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; and Dr. Rafael Bejar, Senior Vice President, Chief Medical Officer.

Before we proceed, I would like to remind everyone that certain statements made during this call will include forward-looking statements within the meaning of U.S. and Canadian securities laws. Forward-looking statements reflect Aptose's current expectations regarding future events but are not guarantees of performance, and it is possible that actual results and performance could differ materially from these stated expectations. They involve known and unknown risks, uncertainties and assumptions that may cause actual results, performance and achievements to differ materially from those expressed. To learn more about these risks and uncertainties, please read the risk factors set forth in Aptose's most recent annual report on Form 10-K and SEC and SEDAR filings. All forward-looking statements made during this call speak only as of the date they are made. Aptose undertakes no obligation to revise or update the statements to reflect events or circumstances after the date of this call, except as required by law.

I will now turn the call over to Dr. Rice, Chairman, President and CEO of Aptose Biosciences. Dr. Rice?

Thank you, Susan. I'd like to welcome everyone to our call for the second quarter ended June 30, 2020. Separately, I do hope that all of you and your loved ones are safe from COVID, and I hope that all of you on the East Coast, in particular, are safely weathering the tropical storm. So please do take care.

And now back to Aptose. As you're aware, Aptose is developing 2 distinctive clinical assets: first, we have CG-806, which has become a high profile, first-in-class FLT3 and BTK kinase inhibitor; and second is APTO-253, the only known clinical-stage agent that directly targets the MYC oncogene and suppresses its expression.

Before I bring you up-to-date on both clinical assets, let me note that we remain firmly bullish on CG-806, and we understand the primary importance of successfully executing our clinical plan for 806. And indeed, we are executing on the original plan to first develop 806 for patients with chronic lymphocytic leukemia or CLL and other B-cell malignancies, to observe inhibition of BTK and lymphocytosis in CLL patients and to be on track to reach higher dose levels and deliver clinical efficacy by year-end.

In parallel, we sought to identify an appropriate starting dose of 806 that may be active in patients with acute myeloid leukemias, or AML, to obtain a new IND for the treatment of AML patients and to demonstrate clinical efficacy in AML patients by year-end. Plus, we wanted to build a strong balance sheet to support this expanding development plan. We now have built a foundation for success going forward, and we believe we can accelerate our pace of clinical development as we enter the second half of 2020 with doses of 806 that should deliver activity in both CLL and AML patients.

So today, I will provide a corporate update, and then our CFO, Mr. Greg Chow, will review our financials, after which we will open the call for your questions. But first, I'll address our most recent news.

A couple of weeks ago, we announced a public offering of 10.5 million common shares at a price of $5.25 per share, raising more than $55 million for the company. Mr. Chow will speak to the particulars of this recent offering, but I just wanted to express that we are pleased to have raised this capital and with strong participation from fundamental health care investors in a market environment with growing uncertainties.

More than 2 years of cash runway gives us a strengthened balance sheet and assurance that we have the right resources to press forward with the clinical development of CG-806 and APTO-253 appropriately. This includes the ability to perform multiple dose-escalating clinical trials, to initiate multiple expansion cohorts and to boost the global manufacture of drug substance and drug product to support the expanding clinical activities. Overall, the recent financing increases the likelihood of success of our molecules, the likelihood of delivering effective treatments for patients in our clinical trials and the likelihood of success for our investors.

Now let's turn to CG-806 and first discuss our ongoing Phase Ia/b clinical trial of 806 in patients with relapsed or refractory CLL and other B-cell malignancies. Since our last call, we presented 806 data at the European Hematology Association or EHA meeting, demonstrating that 806 was well tolerated in patients treated with 150 milligrams, 300 milligrams and 450 milligrams BID over multiple cycles, with no drug-related dose-limiting toxicities or serious adverse events. CG-806 treatment led to lymphocytosis in 2 classic CLL patients and delivered complete inhibition of phospho-BTK and multiple oncogenic survival pathways in all patients receiving the 300-milligram dose or higher, thereby demonstrating molecular and physiologic activity of 806.

Based on these data and subsequent data from our 450-milligram dose, we continued to dose escalate. And since our last call, we successfully completed the fourth dose level of 600 milligrams. This includes another classic CLL patient that also experienced rapid lymphocytosis and inhibition of phospho-BTK.

Just yesterday, we reviewed the 600-milligram data with our cohort safety review committee, and I'm happy to report that the committee agreed that we should escalate to the fifth dose level of 750 milligrams. So now we are actively screening for 3 patients at 750 milligrams. In keeping with our original development plan, this illustrates that we efficiently moved to the lower and intermediate dose levels with a minimum number of patients so that we now may focus efforts on the higher dose levels that are more likely to deliver responses.

As we move into our higher dose levels in CLL patients and begin to inhibit additional kinase-driven oncogenic pathways, we are hopeful that 806 will begin to deliver formal responses as patients remain on higher doses of drug for longer periods of time. Depending on the clinical activity in specific subgroups in this dose-escalation phase, we may enroll patients across expansion studies that may include subpopulations with different genotypic or phenotypic properties.

As of today, we have 23 U.S. clinical sites open for screening and enrolling patients for the study with additional sites scheduled to come on board. For more specific information on the B-cell malignancy trial and the clinical sites enrolling patients, please visit clinicaltrials.gov. Also, note that we plan to present more data at the higher dose levels during ASH later in the year, and we plan to do so in a separate corporate update event, much as we did last year. That allows us to provide a more extensive clinical data review and enter into deeper discussions with you.

Now let's discuss the application of CG-806 to patients with relapsed or refractory AML. Certainly, one of the most significant events of the second quarter was the FDA's review and allowance of our IND for the initiation of the Phase Ia/b clinical study of 806 in patients with AML, expanding the development of 806 beyond B-cell malignancies. AML is a cancer of the bone marrow and blood with a poor prognosis and an overall 5-year survival rate of a little more than 27%. Despite recent advances in the targeted treatment of AML, the majority of patients will relapse or remain refractory to current therapies, and there persists a tremendous unmet need for new therapies.

For example, as we look to gilteritinib, a FLT3 inhibitor recently approved in relapsed or refractory AML, the majority of patients who initially respond to treatment will relapse and, ultimately, their 2-year survival is no different than untreated patients. 806 is the only BTK inhibitor that also possesses strong FLT3 inhibitory activity, giving a broad therapeutic potential across the hematology spectrum, including both lymphoid and myeloid malignancies. Because of Dr. Brian Druker's strong preclinical evidence of 806's activity against AML, including demonstration of mutation-agnostic and genotype-agnostic activity, particularly compared with other FLT3 inhibitors as well as its ability to safely cure AML in mice, we believe 806 offers hope to the fragile and difficult-to-treat AML patient population.

Our strategy from the outset was to begin testing 806 in patients with B-cell cancers, including CLL and to dose escalate and seek responses in the CLL patients. Separately, we sought to identify starting dose of 806 that might be therapeutically active in the critically ill relapsed or refractory AML patient population, and we've done just that. Indeed, the FDA has allowed us to initiate this trial in AML patients with our desired starting dose of 450 milligrams BID.

Allowing us to start at the 450-milligram dose was a major success for Aptose and for 806. At this dose in humans, we already have observed steady-state plasma levels in the same range as the exposure levels observed in our preclinical work that led to cures of AML in mice and without any observed toxicities. Starting at the 450-milligram dose truly gives us an opportunity to begin seeing early anti-leukemic activity in these critically ill relapsed or refractory AML patients. The trial design is the traditional 3 plus 3 dose escalation, and the protocol allows us to enroll more than the minimum of 3 patients at each dose level, if appropriate.

I just want to mention here that we purposely kept this IND solely focused initially on treating AML patients. We believe that there will be additional opportunities for 806 in patients with myelodysplastic syndromes or MDS and in combination with venetoclax. We plan initially to treat only patients with AML in this study and then expand into MDS and into combination with venetoclax as appropriate. CG-806 is too important of a drug, and we will continue to take this thoughtful and deliberate approach in expanding its value footprint rationally and steadily toward the long term.

So where do we stand in getting this recently allowed AML clinical trial up and running? Currently, we are advancing the approved AML protocol through Institutional Review Boards or IRBs at key clinical sites and scheduling our site initiation visits. So while we are working to get our larger AML clinical sites on board, such as the Memorial Sloan Kettering Cancer Center and others of the same high caliber. We also are focusing on faster activation sites, including specialty regional cancer centers. We are taking actions to expedite the tedious parts of the trial start-up process, and we continue to target the third quarter for enrolling our first AML patient. We will want to enroll patients having AML cells with the FLT3-ITD mutation, often referred to as FLT3-positive AML as well as those patients with wild-type FLT3 with the help of demonstrating early clinical responses with the 450- or 600-milligram dose levels.

Just a quick aside. If you have not seen the KOL presentation from February of this year that featured Dr. Aaron Goldberg and Dr. Eytan Stein from the Memorial Sloan Kettering Cancer Center as well as Dr. Brian Druker of the Oregon Health & Science University, and our Chief Medical Officer, Dr. Rafael Bejar, it provides a great perspective on the treatment of AML in the age of targeted therapies. It's available on our website in the Presentations section.

To wrap up on 806, we continue to diligently execute on the plan we originally crafted, and we now have set the stage to move forward at an accelerating pace and with unreserved optimism. We're moving into higher doses with the right patients in both CLL and soon AML, and we have the resources we need. Finally, we hope to see you in December as we provide a more robust and detailed update on 806 at a corporate event during ASH.

Now on to APTO-253, our second clinical candidate and a first-in-class MYC inhibitor currently in a Phase Ib trial for AML and MDS. As we've mentioned before, the MYC oncogene is a major driver of cancer cell proliferation. In fact, its expression is estimated to be elevated and up to 70% of human cancers. As a MYC inhibitor, 253 may have a broader anti-cancer application among a host of hematologic malignancies and solid tumor indications. But as you know, our initial development focus is on AML and MDS. MYC inhibition has been an elusive clinical target in pharmaceutical development. So we've been gratified to observe evidence of MYC inhibition in this trial at all dose levels evaluated to date.

Just as a reminder, per our Phase I clinical protocol, 253 is being administered once weekly over a 28-day cycle at ascending doses in patients with relapsed or refractory AML or high-risk MDS until the maximum tolerated dose is reached. The study is designed to then transition as appropriate to single-agent expansion cohorts in AML and MDS.

Since our last call, we have completed the 28-day dosing in 3 patients on the 100 milligram per meter squared dose, which is dose level 4. On Friday of last week, we held our cohort safety review committee that allowed us to proceed to dose level 5. Because 253 continues to be well tolerated at these higher dose levels and still with no myelosuppression, we have amended the protocol to allow us to accelerate the dosing schedule. So we currently are screening patients who will be treated with a dose of 150, 150 milligrams per meter squared, which is a 50% increase over that of dose level 4 and also have identified a patient to begin dosing in this cohort.

We are still learning about this drug. At higher doses, we hope to see sustained MYC inhibition and clinical responses.

I will now turn the call over to our Executive Vice President and Chief Financial Officer, Mr. Greg Chow, who will review results for the quarter. Greg?

Thank you, Bill, and good afternoon, everyone. Let's start with the details of our recent offering, and then we'll review the quarter. On July 20, we closed on the previously announced underwritten public offering of 10.5 million common shares at a public offering price of $5.25 per share, raising $55.125 million to date and netting approximately $51.5 million. The underwriters have been granted a 30-day option to purchase up to an additional 1.575 million common shares in the offering under the same terms. As Bill mentioned, the offering gives us a healthy balance sheet and cash runway into 2023.

Let's now turn to the quarterly results. We ended the quarter with approximately $83 million in cash and cash equivalents and investments compared to approximately $90 million at March 31 of this year. During the quarter, we utilized approximately $7.2 million of cash in operating activities, which were attributable to activities surrounding 253 and 806 as well as G&A purposes. Based on current operations, cash on hand at June 30 plus the net proceeds from the recent offering, this provides the company with sufficient resources to fund all planned company operations, including research and development into Q1 of 2023.

Moving on to the income statement. We had no revenues for the quarter. Research and development expenses were $6.9 million for the quarter and attributable to 806 and 253 clinical trial costs, manufacturing our drug product for clinical trials, including continuing development on improving GMP formulations for both 806 and 253 and personnel costs for headcount supporting clinical trials and manufacturing activities and research studies. G&A expenses for the quarter were $9 million, of which $6.8 million is related to onetime stock-based compensation.

And finally, our net loss for the quarter was $15.8 million or $0.21 per share or excluding the onetime items, $8.1 million or $0.11 per share. More detailed information can be found in our filings on EDGAR and SEDAR.

With that, I will turn it back to Dr. Rice. Bill?

Thank you, Greg. I'll remind everyone that on the line, we also have with us Dr. Jotin Marango, our Chief Business Officer; and Dr. Rafael Bejar, our Chief Medical Officer. As we open the call for questions, please feel free to pose questions to any of us. Operator, if you could, please introduce the first question.

(Operator Instructions) Our first question will come from the line of Tyler Van Buren from Piper Sandler.

Congratulations on all the progress. I had a couple of questions with respect to 806. So I guess you mentioned that you completed dose level 4 and that you had the one CLL patient who also achieved lymphocytosis. Is that the same patient that you guys referred to at EHA? And if so, if you're able to clarify that, is there an update that you can provide on that patient?

And then the second question is with respect to the new higher dose cohort, the fifth dose level, is there -- I know that you guys are screening patients to enroll. Is there enough time to enroll those patients and potentially allow them to generate responses prior to the ASH data update?

All right. Tyler, thanks for coming on. So thanks for the compliment on the progress. For the first question, you -- we have mentioned an additional CLL patient that came on the 600-milligram dose. That's dose level 4. That was a separate patient that also underwent lymphocytosis. So it was immediate lymphocytosis and inhibition of phospho-BTK. So we're going to speak in terms of trends today rather than particular details on patients. But thus far, we've had patients at 300 and at 600-milligram dose levels. These are the classic CLL patients that entered the trial with some level of lymphocytosis. Those are the ones that if you have an active BTK inhibitor that you would expect to see [each group] lymphocytosis induced, and we have. So in all 3 classic CLL patients that have come into our study, we've seen drug-related inhibition of BTK and lymphocytosis.

Now with regard to dose level 5, the 750 milligram. We planned -- we just have allowance to move into that dose level as of yesterday. So we are screening for patients immediately. So the question is, will we have time to get the patients on study, and it usually takes at least 2 months if you're fortunate to see classic or formal responses in these patients. What I can tell you is, we're trying to focus on CLL patients at the higher dose level as best we can. We've informed the site that we do, in particular, have CLL patients. We want to get them on 750 as quickly as we can, and we hope that we will see responses. So we are very hopeful that we can get them on there, we can get them enrolled, get them dosing, and then we'll scan them after effectively 2 months, okay, so after each cycle. So that's effectively after 2 months. Yes. Did that answer your question?

Yes, that's very helpful color, especially because your quote -- noted the goal of delivering responses specifically in CLL patients. So I appreciate you taking the questions.

Our next question comes from the line of Gregory Renza from RBC.

Congrats on the progress here. I really appreciate it. Bill, maybe just building off of Tyler's question, I'm just curious if you could perhaps tee up some of those expectations certainly in focus for year-end and the event that you alluded to potentially having in December. Just curious if you could help frame those expectations a little bit on responses on patient counts perhaps. But then also how your disclosure plans could potentially evolve, certainly keeping to kind of the biannual disclosures on data, but just curious if there are any prospects for providing any efficacy updates prior to that December plan.

All right. Greg, thanks for coming along. A couple of good questions. So let's talk about the expectations for later this year, particularly at ASH. So we're looking effectively at year-end. So right now we just entered August. We will get as many patients on quickly as we can at the 750-milligram dose. The good news is we're able to get into our higher dose levels where we believe that we can start seeing responses. We have reason to believe that the drug is active. We're seeing, as I mentioned, mechanistic and physiologic activities. Even at 600 milligrams, we started seeing some differences that make us believe that we should start seeing something as we get into these higher dose levels, particularly at the 750-milligram level. But in reality, it's a -- we expect to get 3 patients as we move into dose level 5, to 750 milligrams.

So how are we going to get more patients on it? Well, we have an amendment from the FDA that's allowing us now to begin backfilling. So I think it's -- our Chief Medical Officer earlier today was talking about it, it's almost -- backfilling is almost like a mini expansion while you're doing the dose escalation. So yes, we'll get patients on the 750. We hope the majority of those are CLL patients and that we hope then by the time that we reach ASH later in this year that we'll be able to deliver responses.

In parallel, we'll also be trying to backfill patients at the 600-milligram level. And then when 750 is shown to be safe, if it is, then we'll move those patients at 600 up to 750. And I should also say we have a couple of patients then at 7 -- 450 now. They're going to be moved up to 600. So we're increasing the ability -- or increasing the likelihood of potentially demonstrating responses at ASH later this year.

So the second part of that -- and I'll ask Dr. Bejar, if he wants to add to that in just a moment. But the second part of your question was disclosures. Is there anything possibly between now and ASH, between these midyears? What I would say is, I wouldn't expect anything for us to be disclosing anything between now and then. The reason is we've just gotten into the 750-milligram dose, the higher dose levels. We need time to get the patients on to give them time to respond, and then hopefully, we'll see something by December in ASH. But separately, we're also going to try to get the AML patients up and on the trial. As I said, we still continue to target getting the first patient enrolled in the third quarter of this year. If we can do that and we can get a couple of patients on the 450-milligram dose level, get them through by the time we get to ASH and maybe have some patients on the 600-milligram dose level, then that gives us the opportunity to have responses in AML during this period.

And again, I'll remind you, AML is an acute leukemia. And typically, you're able to view what happens in these patients much more quickly. With CLL, it takes typically at least 2 cycles before you see anything, but it can take anywhere from 2 cycles up to a year -- 2 months up to a year, whereas in AML, you would expect to start seeing something, a reduction in the blast the first month and then possibly a response by the second or third month.

And I'm going to ask Dr. Bejar if he would like to add anything to that in terms of what to expect in patients.

I think that was a great answer, Bill. I think you answered it perfectly. That just putting on the patients now at 750, having that ability to backfill will give us more opportunities to see responses at these higher dose levels. And we're going to definitely push to do that. And I agree with your statement about AML, that's a disease that has very different response kinetics and that we should know sooner than we might for the B-cell malignancies that take much longer to demonstrate responses.

Yes. So the irony is that even though we started the B-cell malignancy trial earlier, it takes those patients longer to show responses. And it may be that even AML might show responses earlier, even though we're starting it later, but we are starting at a dose that we believe can show activity. So Greg, I hope that answers your questions. If not, let us know.

It sure has, Bill and Dr. Bejar. And actually, it also answered my follow-up question, which was around the backfilling. And just to confirm, so would we presumably -- given that the fifth dose cohort just recently cleared, is it safe for us to anticipate that there could be additional 600 mg patients that have since added prior to that clearance?

Not that are added prior to it because we had -- sorry, we have a lot of background. So in reality, the 600 milligrams, you have to get 3 patients and show the FDA -- or show, excuse me, not the FDA, CSRC, that you have 3 patients that have completed safely that cohort. You can then move up to 750. Only then can you start backfilling on the 600. So right now we're going to try to both get patients on the 750 immediately and the 600 as quickly as we can.

And our next question will come from the line of John Newman from Canaccord.

Good progress here on both of the agents and clinical trials. So I guess a question for Bill. Bill, you mentioned that it seems like there was an additional patient at the 600-milligram dose, where you saw some signs of lymphocytosis, which is great. I'm just wondering if you happen to notice any of the other changes that can go along with a response, for example, if you saw an increase in platelets, hemoglobin, if lymphocytes decreased in the bone marrow. Just wondering if you can tell us anything, maybe broadly speaking, if there were other markers that you noticed that seemed to confirm that there may be some activity there.

John, thanks for coming on and asking questions. So one thing I can confirm is that the lymphocytosis and the inhibition of BTK in the patients, it is due to the drug because we actually had an instance where we were able to dose-reduce and then take it right back up. In whom we dose-reduced, we actually saw the lymphocytosis decrease. So it is clearly a drug-related event.

And as for the other markers, I'm not able to address that. Perhaps Dr. Bejar can provide a little bit more information on that. But again, I don't want to get into too many specifics of any patient until we get later in the year. Dr. Bejar, was there anything else that you wanted to add to that?

Yes. I would just say, the simple answer is that this last patient that you're referring to has just recently finished cycle 1. So we haven't actually done any of the additional studies that you've asked about. So we don't know the answer yet to your question.

Fair enough. Thank you.

I just had one quick follow-up question, if I may, and that is just in terms of the type of AML patients that you're looking to enroll, I know that when you're dealing with the AML population, it's always a challenge almost regardless of the agent because you're dealing with patients that are very frail and fragile. Are there things that you're able to do in terms of your selection criteria just to give yourself sort of a reasonable chance to be able to answer the question? If your drug is active rather than sort of fighting a very frail state of disease?

Well, we are on the same page with you on that one. So the first and most important thing we did is we're starting the trial at a dose level that we think should be active. So that's the first thing that we're doing to give the drug the best opportunity to show responses.

Secondly, one of the most highlighted feature of this drug in terms of AML is the fact that we believe it can be developed for FLT3 positive as well as FLT3 wild-type patients. So again, about 1/3 of the patients have the mutated FLT3; 2/3 of the patients do not. They have wild-type FLT3. So we want to be able to treat those patients with the wild-type FLT3.

However, it is generally accepted that patient -- that the patients with the ITD mutation, FLT3-positive patients, would tend to be more sensitive to a FLT3 inhibitor. That's been shown with gilteritinib, quizartinib, some of the other molecules. So we absolutely want to get FLT3-positive patients on this trial as soon as possible. They are likely the, I'll use to phrase, low-hanging fruit that would most likely get us responses earlier. And again, starting at a dose that we think is going to be pharmacologically active in these patients, it gives us a great opportunity to show responses.

And again, well, that's where we are. And we hope that we're able to get both FLT3 positive as well as the wild type on. But again, most likely showing the FLT3-positive patients will show activity earlier, most likely. And then it may take some of the higher doses to show activity in the wild type. We won't know until we get the patients on. But thanks, John, for your questions.

And our next question will come from the line of Matt Biegler from Oppenheimer.

Can you shed any light, Bill, on how the exposures are tracking in the 600 mg cohort. Obviously, these were too premature for the EHA data set. But maybe high level, can you comment on whether we're still seeing kind of the linear increase that we saw between the 150 and 450 mg doses.

Yes. Matt, so when we -- so originally, we have 1 patient on the 150 dose level, 1 patient on the 300, and then we had 3 patients on 450 and then 4 patients on 600. So when you only have one patient per dose level, you really -- I mean you can draw a straight line between 2 points, but it's really meaningless. So what it appears as though is the 150 milligrams, it starts coming up over 24 hours and then begins to plateau. And it looks like that second patient at 300 milligrams, it looks like that was more the outlier because then as you go to the next dose level and you have 3 patients, it comes in about the same as the dose level 2 and then when you go to the fourth dose level, 600, what you can see is another increase. So what we are seeing is, as we increase the dose level, the initial uptake is more rapid, higher levels over that first 24 hours. So we're able to see more of a dose-related exposure level during that first 24 hours now. And then they begin to plateau off as we go forward.

But it's not necessarily a linear line yet because we only had one patient at 2 lower dose levels. But we're definitely getting meaningful exposure there at the 600 milligrams, and we're starting to see some effects that are giving us confidence that we're really having a physiologic effect. And it looks like it's more so than at the 450, which again is gratifying and so we expect even more at the 750.

So I would not call it linear, but we are seeing now more dose-related effects as we get more patients on. But it's also an oral drug, and you're giving it to patients of different sizes. So there will always be differences in the exposure from patient to patient even at the same dose level.

Right. Right. Understood. Okay. That's good to hear. I just want to be completely clear on cohort 4 in terms of the patients and what they had. So we know from -- that one was classical CLL, one with Richter's transform. Can you just confirm what type of (inaudible) that the third patient had the one (inaudible) that EHA cut off? Was that the patient with lymphocytosis you were referring to earlier?

So one patient that was on the 600 milligrams, that one clearly had lymphocytosis and the inhibition of BTK, we showed that. And then we have another patient that's gone on to 600 milligrams. That's a classic CLL patient. And they've also demonstrated the lymphocytosis. That's the patient who just completed the 28-day dosing recently. So it's clear we're able to induce lymphocytosis as well as the inhibition of BTK as we give them these higher doses to inhibit the other pathways, the kinase-driven pathways. And now as we get, hopefully, these patients stay on a little bit longer as we go forward on both the 600 and the 750 and it gives us the opportunity to then see responses. So perhaps Dr. Bejar might have something to add to that about the 2 CLL patients at 600 without details.

Right. So we had one CLL patient at the beginning of the cohort, and then we had the most recent patient complete the cohort. So 2 classic CLL patients with preexisting lymphocytosis were in this cohort.

Got it. Congrats on the progress, guys.

Thanks.

(Operator Instructions) And our next question will come from the line of Naureen Quibria from Maxim.

I guess the first one for me would be on the 253 program. It's been running sort of under the radar. Will you have any clinical updates shared at this year's ASH? And what kind of data would we be likely to see if so?

So thanks, Naureen. Yes, we do plan on presenting data at ASH. But you're right, to most people, it's flying under the radar screen, so we're not getting many questions about it. But as we mentioned, COVID was somewhat of a setback because that's an IV-administered drug. But once the clinical sites became accustomed to dealing with it, they were able to then start getting more patients on. We completed cohort 4 at 100 mg per meter squared. We're clearly seeing an increase and the PK exposure there now, getting into the range that we had hoped we would get into. That's both of the parent drug as well as the [iron add up]. We don't have all the data from that cohort yet, but we would plan to present data from all 4 cohorts this year at ASH. And then we're also now recruiting patients for cohort 5. That seems to be going well. We're getting -- we're actually getting quite a favorable response in terms of patients coming on 253 now. And we should be able to present data from cohort 5 at ASH.

Again, we'll be looking at the various biomarkers, the MYC expression and the PBMCs at different times throughout the different 28-day periods, the different cycles as well as PK, safety, tolerability. And we hope that as we go into the next dose level, the higher doses, that we're able to get PK coverage over greater number of days. Again, it's once-weekly dosing. So if we can get -- start getting coverage over 3, 5, 7 days and maintain suppression of MYC, that gives us the opportunity then to start seeing responses. So we hope to be able to show that as we're beginning to increase the doses, we're extending the time where you can measure adequate levels of drug in the plasma and hope to be able to see responses in the future.

Great. And then in terms of the CG-806 study in AML that you're about to start, you mentioned that you're going to have both FLT3 wild-type and mutated patients. But if I recall from your KOL talk back in February, there was a mention that 806 may also be active in the context of RAS mutations that may confer proliferative capacity in AML patients and that these RAS mutations may make patients resistant to the FLT3 inhibitor gilteritinib. So I was just wondering, are you going to actually test patients that are selected for the study, whether they also have RAS mutations. And will that information ultimately be shared with the public when the data is released?

So we absolutely want to get patients on there. So I can't promise they'll be on the first or second cohort, but we absolutely want to get patients on there that have failed gilteritinib, that have these RAS mutations, that are -- it's not just RAS. So there are a number of different mutations that give resistance to gilteritinib. So you've got the gatekeeper mutation in FLT3, you've got the RAS mutations, some of the p53s. So yes, we do want to get those patients on. We want to make sure that we get them genotyped and that we understand the sensitivity there, especially in the context of the particular mutations, and we will share that with the public.

That's one of the exciting things about this drug. We think it has the potential to treat those patients, whereas others don't. But that's also one of the reasons why we're going to specific institutions, cancer centers that have the capability to perform those analyses on the patients and understand the genotype, the underlying genetic background that are able to follow that genotype going forward as we begin to treat the patients and look at the clones and that also have patients who may have failed gilteritinib. So all of those are in the works. So good question. Thank you.

Got it. And just one last from me. So on the same drug, but CG-806 is a BTK player, shall we say. AstraZeneca and some of the larger companies are testing their BTKs in COVID patients. And I know that you don't have any plans to do that, but I was just wondering, have you had any anecdotal evidence of any of your patients actually getting COVID and how they may have performed on CG-806? I know it's not exactly a direct correlation, but I was curious if you have any anecdotal stories or evidence.

So we don't -- we are not aware of any of the patients on our study that acquired COVID and of any responses. But if you're asking us, is there potential for a drug like this (inaudible) COVID, there is a potential. Because if you're talking about the NLRP3 inflammasome complex and how it utilizes the cleaved caspase-1, releases IL-1-beta, IL-18, yes, we can measure those certain activities. We know how well our molecule would act there. So it is possible that the drug could be used in either this or inflammatory processes in the future.

But at this point in time, we have to remain focused on the AML and the CLL. We have -- our hands are full with those, and we don't want to lose focus. If something can emerge from this as a separate indication in the future, we'll do those companies on -- excuse me, we'll do those studies on the side, and we'll collaborate with groups, but we have to remain focused at this time.

So let me ask if Dr. Marango wanted to add anything to that. I know he's online.

No. Thank you, Bill. Bill captured it quite fully. Thank you.

We have a follow-up question from John Newman from Canaccord.

So Bill, I'm just curious for the patients that have shown evidence of lymphocytosis on CG-806, just trying to recall, I'm wondering if you can talk to us about whether those patients had -- all had previous exposure to other BTK inhibitors. And also, if you happen to know what the mutational status might be for those patients?

All right. So in terms of those patients, those are the classic CLL patients. I can tell you, they are so heavily pretreated with all different types of drugs. I'm going to ask Dr. Bejar, if he can give a bit of context as to the background in terms of what these patients may have seen. But again, they're all different. So a little bit of context.

Sure. I think you're exactly right, Bill. These patients are very heavily pretreated, many of them having received prior chemotherapy as well as other targeted agents and immunotherapies. The mass majority of the patients have received a prior BTK inhibitor for some duration and either have been refractory or tolerant of that drug, but -- as well as many other therapies. So it's not just (inaudible).

Yes. I think the remarkable part is these patients are so relapsed/refractory, they failed so many different lines of therapy. It means the cells, they do depend upon BTK for activity, but they also depend on all these other kinase-driven pathways. So that's why it's so important for these deep relapsed/refractory patients to receive a drug that can inhibit multiple pathways. Because we don't believe that merely inhibiting BTK is going to be sufficient in these deep relapsed/refractory patients. I think we've seen that from some of the other drugs out there. And so we're hopeful that in these patients, as we get to the higher doses, and we're seeing these multiple pathways affected, we're hoping we're going to see responses in them because they desperately need a drug like this. Hope that answers your question.

And I'm currently showing no further questions. I will now turn the call back over to Dr. Rice for closing remarks.

All right. Well, I want to thank everyone for joining us today. It's indeed an exciting time for us with our 2 key assets in the clinic, 806 and 253, progressing now into the higher dose levels. And we remain to -- remain committed to delivering for our patients and our shareholders. I want to especially thank our clinical development team, our investigators, our clinical operations teams, the patients for helping us in this mission. And we appreciate your support, and we look forward to keeping you updated on our progress, in particular, later this year at ASH. Hopefully, we'll be able to give a very detailed update, and we want to say thank you, and have a wonderful evening. Bye-bye.

Thank you. Ladies and gentlemen, that concludes today's conference. You may all disconnect and have a wonderful day.