Aptose Biosciences Inc (APTO) 2019 Q4 法說會逐字稿

Good afternoon. My name is Gigi, and I will be your conference operator today. I would like to welcome everyone to the Aptose Biosciences Conference Call for the Fourth Quarter and Year Ended December 31, 2019. (Operator Instructions)

As a reminder, this conference call may be recorded.

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

Thank you, Gigi.

Good afternoon, and welcome to the Aptose Biosciences Conference Call to discuss financial and operational results for the fourth quarter and year ended December 31, 2019.

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 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 fourth quarter and year ended December 31, 2019. We're happy to have many new shareholders joining us on the call today as well as those of you who have been with us on this journey through more challenging times. I'm truly privileged to lead this company while we painstakingly constructed the foundation for our 2 hematology compounds, CG-806 and APTO-253, and now have moved these highly differentiated targeted agents into the clinic. We, along with a stellar group of research collaborators, generated a wealth of preclinical data that supported the advancement of these compounds to the clinic, and by July of 2019, we had 2 active clinical trials. We expect 2020 to be one of continued execution as we treat more patients and continue to generate meaningful clinical data. Let me begin today's call with a quick recap of highlights from 2019, followed by a discussion of the progress of our clinical candidates.

During the year, we presented a wealth of preclinical data at the annual meetings of AACR, EHA and ASH. All of those presentations and the full names of these conferences and the acronyms are available on our website. Preclinical highlights, particularly with CG-806, included data presented by Dr. Brian Druker's team at OHSU, demonstrating that CG-806, our first-in-class FLT3/BTK inhibitor is more potent than other such inhibitors, including midostaurin, sorafenib, sunitinib, dovitinib, quizartinib, crenolanib and gilteritinib against acute myeloid leukemia, or AML, primary patient samples.

Compelling preclinical combination studies with venetoclax in patient samples demonstrated enhanced cell killing, which suggest a potential future combination strategy. Another exciting preclinical study highlighted the exceptional in vivo antileukemic efficacy of CG-806 in a xenograft mouse model. CG-806 suppressed leukemia growth at all doses tested throughout the 28-day period of dosing. After dosing was halted, tumors treated with the lower doses resumed growth, as was seen with other group -- other agents. However, in the mice treated with a higher dose of 100 mg per kg, 5 of 11 mice were cured through day 120. And in the 300 mg per kg group, 10 of 11 or 91% of the mice were cured. Retreatment of the uncured mice in these 2 dose groups for an additional 28 days, beginning on day 88, after the tumors were allowed to grow, led to a rapid antitumor response resulting in cures of all retreated mice through day 120. In the retreated mice, no drug resistance and no toxicities were observed. Collectively, these studies laid the groundwork for delivering CG-806 to AML patients that have failed other FLT3 inhibitors, venetoclax, hypomethylated agents and cytotoxins as well as patients having AML with mutations in p53, RAS and IDH that are less responsive to other therapies.

As a reminder, in spite of our extensive efforts to induce toxicity in animal models, CG-806 demonstrated a desirable safety profile in all of our preclinical studies to date. Most recently, at ASH in December of 2019, researchers from the MD Anderson Cancer Center presented 2 posters elucidating CG-806's mechanism of action in targeting chronic lymphocytic leukemia, or CLL cells, and its inhibitory effect on ibrutinib-resistant mantle cell lymphoma, or MCL cells. Data showed CG-806 to be more potent than ibrutinib, the current standard of care, in primary patient cells of CLL. CG-806 also demonstrated superior anti-lymphoma effects compared with ibrutinib, exerting potent cell inhibitory effects on ibrutinib-resistant MCL cells. Collectively, these data from multiple labs demonstrated 806 has potent activity against CLL and various non-Hodgkin's lymphoma cells, including those resistant to ibrutinib, thereby positioning us for our clinical trial in these B-cell cancer patients.

Clearly, the highlight of the year for us was the much anticipated initiation of our CG-806 clinical program midyear. I'll bring you up-to-date on that clinical program as well as the APTO-253 clinical trial momentarily. Also, during 2019, we considerably strengthened our management team. We've introduced you previously to Dr. Jotin Marango, who joined us mid-year as Senior Vice President and Chief Business Officer. In December, we announced the appointment of Dr. Rafael Bejar, an internationally recognized physician scientist with extensive research and clinical experience in hematology to position of Senior Vice President and Chief Medical Officer. Importantly, in November, we also announced the recruitment of Mr. Victor Montalvo-Lugo as our Vice President of Clinical Operations. In addition to their outstanding credentials, Mr. -- Dr. Marango, Dr. Bejar and Mr. Montalvo have already proven to be an integral part of our collaborative culture. We've been very fortunate to attract the interest of such high-caliber individuals in our field to join the executive team.

As a result of the progress we made throughout 2019, we also were able to appreciably strengthen our financial position and closed on 2 offerings during the year. Our CFO, Mr. Greg Chow will discuss this further momentarily.

Now I want to provide a clinical update and let's begin with CG-806, our oral, highly potent, noncovalent inhibitor of the BTK and FLT3 driver kinases. CG-806, or just 806, is like no other drug commercialized or under development. It is much more than a typical FLT3 or BTK inhibitor, as it not only inhibits all wild-type and mutant forms of BTK and FLT3 but potently and simultaneously suppresses multiple oncogenic signaling pathways upon which cancer cells rely for survival and drug resistance. We consider 806 to be a mutation-agnostic agent that selectively targets clusters of related kinases and suppresses the mutations that occur in AML and CLL cells that render such cells resistant to other agents. A question we sometimes get asked is, wouldn't a multicluster kinase inhibitor be a dirty kinase inhibitor? And the answer is no. 806 has been shown to target the primary drivers of B-cell malignancies in AML, including BTK and FLT3, yet with a precision that avoids known targets such as TEC, T-E-C; eGFR; and ErbB2, that are often associated with toxicity. This selectivity is what sets 806 apart from other hematology drugs on the market or in development and what has contributed to much of the excitement surrounding the compound.

Regarding the lack of toxicity noted thus far, our new Chief Medical Officer, Dr. Rafael Bejar, recently commented that this is one of the most highly rigorously tested preclinical compounds he has ever seen. And it is one thing to say, we have not observed toxicity but it's also important to highlight that we've rigorously tested for toxicity. In July of 2019, we initiated dosing of 806 in our Phase I A/B multi-center, open-label, dose-escalation clinical trial in patients with B-cell cancers. To remind you, the trial is designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamic responses and preliminary efficacy of 806 and established a recommended Phase II dose. Because of the favorable preclinical safety profile, the trial protocol allowed for an accelerated dose escalation schedule, but only 1 patient is required at each of the first 2 dose levels, 150 milligrams and 300 milligrams BID, unless unexpected side effects necessitated additional testing at those levels. As we reported last quarter, one heavily pretreated patient with CLL was treated successfully with the dose level 1 of 150 milligrams BID and another relapsed refractory CLL patient was treated successfully with dose level 2 of 300 milligrams BID. The first 2 cohorts are now complete. Oral 806 at these doses was well tolerated with no drug-related toxicities, including no myelosuppression.

And at the second dose level, there were early indications of pharmacologic activity. To demonstrate pharmacologic activity, we performed a plasma inhibitory assay, or PIA assay, in which we collect plasma from the patients at various times throughout the 28-day cycles. We bring the plasma back to the lab and place it on indicator cells for 6 hours. And then we assess the activation state of key oncogenic pathways by immunoblotting. In these studies, we observed complete inhibition of Phospho-BTK, Phospho-ERK and Phospho-SYK once the patient reached steady-state levels of drug exposures, demonstrating the trough plasma exposure levels are sufficient to potently and sustainably inhibit our key targets and pathways. In addition, in the CLL patient at the second dose level, we observed a robust increase in peripheral blood lymphocytes or lymphocytosis, classically described as a response to envision of BTK. These first 2 dose levels proved that we had a pharmacologically active agent at these safe dose levels.

In these first 2 patients, we were pleased to observe dose-related pharmacokinetic properties, such the steady state was reached by the end of the first week of dosing. And in the CLL patient at the second dose level, we observed the steady state or trough levels to be in the near micromolar concentration range. We were thrilled to see that 806 was absorbed and that the second dose level could approach plasma levels that we believe should deliver benefit to patients. So of course, we were eager to progress to the next dosing cohort.

Since our last call, we have enrolled and have been treating 3 patients at dose level 3, which is 450 milligrams BID. Per the protocol, we will need to successfully complete a 28-day dosing of 3 patients at the 450-milligram BID dose before we continue to the next dose. I'm happy to report that we expect to finish the 450-milligram cohort with 3 patients by hump day of this week, middle of this week. We hope to see well-behaved, steady state PK parameters with acceptable variability among patients and see serum exposures hovering around the 1 micromolar range from the 450-milligram BID dose. I can tell you that no drug-related toxicities have emerged to date. Once collected, we will deliver all safety, PK and PD data to the cohort safety committee who will be advising us on next steps.

With all going well, 3 patients at 450 milligrams will be followed by ascending cohort, with 3 patients each at 600, 750 and 900 milligrams BID, with the intent to select a recommended Phase II dose for patients with B-cell cancers, including those with relapsed and refractory CLL and non-Hodgkin's lymphoma. Once an MTD or safe and biologically active dose has been selected as our recommended Phase II dose, up to 100 patients may be enrolled for treatment in the expansion phase at that dose. As of today, we have 18 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.

Now let's discuss our proposed AML study with CG-806. And remind you that 806 is the only BTK inhibitor that also possesses strong FLT3 inhibitory activity and is applicable, therefore, to both lymphoid and myeloid malignancies. Based on our extensive preclinical work, some of which we mentioned previously, it has always been our intent to treat AML patients with 806 in addition to B-cell malignancy patients. The biomarker analysis of the patients in the current B-cell study are guiding our preparation for the protocol for the AML study. As we've discussed in prior calls, we plan to seek allowance from the FDA to move 806 into patient populations that include relapsed or refractory AML. As a reminder, relapsed or refractory AML patients are acutely ill and we did not wish to dose this patient population with a subtherapeutic dose that likely would not provide clinical benefit. Therefore, we chose to initiate the first clinical trial in patients with B-cell malignancies and collect the safety, PK and PK data. From such data, we should be able to identify a dose that we believe have the likelihood to deliver therapeutic benefit immediately to AML patients.

Based on the exposure levels we're observing in the clinical trial with CLL patients compared to the exposure levels that we observed to eradicate the tumors in mice, we believe that we are close to identifying a starting therapeutic dose for AML patients. We need to review the collective safety, PK and PD data set from dose level 3, again, which is 450 milligrams BID, before we can make a final determination if dose level 3 can be recommended to the FDA as our starting dose. We are well underway with our clinical protocol preparation for this new trial, and we expect to be in a position to submit the appropriate documents to the FDA during the first half of this year. Our clinical team has identified and is working closely with top-tier academic sites to initiate the new AML trial. For the intended trial in AML patients, we plan to focus initially on the relapsed and refractory AML population with high unmet medical needs, in other words, all AML patients that are not receiving benefit from current treatments.

While the current targeted therapies may initially show clinical benefit, a significant number of patients rapidly relapse or become refractory to such treatments. Those of you who tuned into our KOL symposium focused on AML, held last month, also available on our webcast -- website, appreciated the enthusiasm of our guest panelists about the potential of 806 in AML.

I will now turn it over to Dr. Marango to briefly recap the key takeaways from the KOL event. Joti?

Thank you, Bill.

We were very pleased with the outcome of the KOL event and humbled, both by the key opinion leaders who presented on behalf of CG-806 and those of you who attended in person and via webcast. Our guest KOL emphasized the unmet need in AML. FLT3 is the most common mutation in AML and the current FLT3 inhibitors are not curative. They all have limitations that lead to resistance and ultimately disease progression. In the last 2 years, AML treatment has advanced with approval of 2 FLT3 inhibitors: midostaurin, in combination with chemotherapy in untreated AML; and gilteritinib as monotherapy in relapsed or refractory AML. However, as our guest KOLs highlighted, the collective experience with this drug in trials and in the real-world so far suggests that there is still ample room for improvement. In the ratified Phase III study in treatment-naive AML, midostaurin, which is a broad multi-kinase inhibitor but weak FLT3 inhibitor, in combination with chemotherapy, extended 4-year survival from 44% to 51% compared to chemo alone, an important, however, very modest improvement. Further, studies of midostaurin in patients with relapsed or refractory disease did not observe any meaningful clinical responses.

Meanwhile, looking at gilteritinib, which is a more potent and more selective inhibitor of FLT3 in the ADMIRAL Phase III study in relapsed or refractory disease, the 12-month survival rate for gilteritinib versus salvage chemo were 37% versus 17%, respectively. Yet, all gilteritinib responders eventually relapsed and survival rates in both arms equalized by 25 months, at which time, approximately 90% of the patients had succumbed to this terrible disease and died. Strikingly, patients who fail current FLT3 inhibitors do so under certain recurrent and diverse mechanisms of resistance, including mutations in FLT3, RAS, p53 and others. These observations highlight the urgent clinical need for the development of newer generations of kinase inhibitors in AML, ideally combining the strength of the older agents while overcoming their weaknesses.

Our guest KOLs as well as top AML investigators, with whom we'll continue to interact, are all eager to treat the resistant or refractory patients with CG-806. They are enthusiastic about the agent's preclinical and clinical safety and tolerability profile to date, which suggests an encouraging therapeutic window and combinatorial optionality, both of these are important considerations in relapsed or refractory AML. At the same time, the agent's picomolar to nanomolar FLT3 potency in tandem with its coverage of other key oncogenic pathways suggest that it may represent a biologically optimal intervention for the complex cytogenetics of relapsed or resistant AML.

Overall, our data to date support the potential of 806 to benefit patients that have failed other FLT3 inhibitors, venetoclax, azacitidine and even chemo and to treat patients with any wild-type or mutant forms of FLT3 or with mutations in TP53, NRAS, IDH, NPM1 or MYC dysregulation.

If any of you have questions about how 806 might fit in the AML treatment paradigm, you may want to listen to this informative presentation, again, available on our website.

With that, I will turn it back to Bill.

Thank you, Joti.

To wrap up on 806, the compound is now on the radar screen of many in the hematology community as well as many new investors. We look forward to reporting our progress on the ongoing Phase I A/B study in patients with CLL and other B-cell malignancies as well as the prospective AML trial throughout the remainder of this year.

So now just a quick update on the APTO-253, our second clinical candidate and first-in-class MYC inhibitor, currently in a Phase Ib trial, for patients with AML and MDS. As many of you know, the MYC oncogene is a major driver of cancer cell proliferation. In fact, its expression is estimated to be elevated or dysregulated in up to 70% of human cancers, including AML and MDS as well as solid tumors. As we've mentioned previously, targeting of MYC has been the goal of many researchers over the years. But because the MYC protein has been an elusive and challenging target, MYC has been deemed undruggable. However, 253 does not target the MYC protein. Rather, it targets the regulatory multi and the promoter of the MYC gene and suppresses expression of the MYC protein and leads to the depletion of the protein levels in cancer cells. During the ASH meeting in December 2019, preclinical data for 203 confirmed its activity as a MYC inhibitor and further defined the drug's mechanism of action.

Some quick background. In preclinical studies using 80 AML patient cell samples, 54% were responsive to the 253 with an IC50 below 1 micromolar. In addition, in a prior Phase I trial in patients with advanced solid tumors, 253 was found to be well tolerated, importantly with no myelosuppression and showed signs of antitumor activity. Per our Phase I clinical protocol, 253 is being administered once-weekly over a 28-day cycle of 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.

I'm happy to report that we are now in the fourth dose cohort in this trial. Thus far, we have completed the 28-day dosing and the first 3 dose cohorts, the last being 3 patients on the 66 mg per meter square dose. We now have completed the 28-day cycle, with 1 patient at dose level 4, who received the 100 mg per meter squared 253 drug product, and we now are screening for additional patients in that cohort. The good news is that 253 continues to be well tolerated, with no observed myelosuppression. We continue to observe MYC inhibition at all dose levels to date, and we plan to continue dose escalation to higher dose levels that we hope will deliver responses for AML and MDS patients.

We also wish to note that no one truly knows what to expect clinically from a MYC inhibitor. It may be that we observe robust single-agent activity at an appropriate dose or it may be more like venetoclax in AML patients, such its effect is modest as a single agent but highly effective in combinations for AML because it hits a pathway distinct from other agents.

We are eager to learn how best to use 253, and we thank all of the patients that have received 253 and all the physicians participating in our clinical trials.

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

Thank you, Bill, and good afternoon, everyone.

We ended the quarter with approximately $97.6 million in cash, cash equivalents and investments compared to $15.7 million at December 31, 2019, and $30.2 million at September 30, 2019. This increase in cash is primarily due to the recent $74.2 million confidentially marketed public offering that we completed in mid-December. During the quarter, we utilized approximately $6.3 million of cash in operating activities, which were attributable to increased activities surrounding 806 and 253, and also for general and administrative purposes.

Moving on to the income statement. We had no revenues for the fourth quarter of the -- for the year ended December 31, 2019. Research and development expenses were $5.3 million for the quarter and $16.8 million for the year. G&A expenses were -- for the quarter were $2.6 million for the quarter and $10 million for the year. Our net loss was $7.7 million for the quarter and $26.3 million or $0.52 per share for the year.

One last item to note during the quarter includes the filing of a $200 million shelf registration statement in late December that was subsequently declared effective in early January. This shelf replaces the previous one that was exhausted for the recent confidentially marketed public offering. More detailed information can be found in our filings on EDGAR and SEDAR.

Before I turn the call back to Bill and open up for Q&A, we want to mention a few things about how COVID-19 may affect our progress in our operations. With regards to manufacturing of our drug candidates and learning from our past experiences, we have multiple suppliers that source the building blocks to manufacture both the API and a clinical drug product of 806 and 253. At this point, we do not see any delays or -- and are in consistent communication with our manufacturing partners and suppliers.

With regards to the clinical trials, our team is in constant contact with each of the physicians and clinical sites. Unfortunately, for the patient population that we are addressing, these treatments are not elective, and thus, we do not foresee any delays in the treatment of the patients currently on study or the enrollment of patients moving forward.

I will now turn the call back over to you, Dr. Rice.

Thank you, Greg.

I would now like to open the call for questions. Operator, if you could, please introduce the first question.

(Operator Instructions) Your first question comes from the line of Tyler Van Buren from Piper Sandler.

Congratulations on all the progress during the quarter. I guess, my first question is related to the second patient at the 300 mg BID dose cohort that you guys reported on at ASH. I was hoping you could provide an update regarding the 2 observations, the increase in lymphocytosis. Has anything changed there? Have you seen lymphocyte counts come back down? I understand that everyone behaves differently, so maybe that didn't occur.

And then the second part is, they also had bulkier nodal disease, and you mentioned that there's potential signs of decrease in 8 out of the 9 lesions or that there were signs of decrease. So has there been any more decrease observed there?

Tyler, this is Bill. So I'll first answer, and then I'll open it up to Dr. Bejar if he also wants to add anything to it.

So we had mentioned, I guess, it was in January that that second patient, the one at 300 milligrams BID, we actually took them off study. This patient came on with extensive bone marrow involvement. When we put them on the drug, they immediately had lymphocytosis which was caused by inhibition of BTK, indicating that it's pharmacologically active. This patient also, when they entered the trial, they had platelets -- well, they had neutropenia as well as thrombocytopenia. Their platelets were literally right at a grade 4 when they entered the trial.

So as we continued to dose them over time, we did not see any worsening of the platelets but we also didn't see any benefit over time. But what we did see is the patient tolerated the drug very well. The lymphocytosis continued but since it was only the second dose level and we assumed that was not an optimal dose level, we decided to take the patient off of our drug and allowed them to go on a full dose of a currently approved therapy in hopes that they might actually do better. Anecdotally, now what we can say is they have been placed on another drug that is an approved drug at the full dose level, and effectively, what they're seeing is the exact same thing in the patient that we saw on our drug at what we assumed was an early dose level.

So the good news is, our drug was working in that patient but we were trying to be very cautious because that's a sick patient and we were just hoping that when they went on to another drug, they might be able to get additional benefit but it looks like it was just as good as -- that ours was just as good as the full dose of the currently approved drug. So do you want to add anything to that, Dr. Bejar?

No, that's very concise. I think we learned that the drug is well tolerated. It's very important that despite having a highly compromised bone marrow, we didn't see any additional myelotoxicity.

Yes. So we also might add that -- remember in that one -- in that patient, we collected the plasma level -- plasma from the patient and performed that PIA assay. And once we reached steady state, which was by the end of the first week, we had completely inhibited Phospho-BTK, Phospho-SYK that's Phospho-S-Y-K and Phospho-ERK. So we know we're at a pharmacologically active dose. But we assumed that since it was actually one of our lower doses that, that patient might actually get additional benefit from a full dose of another drug. But apparently, that's not the case, and they actually did quite well on ours. So I hope that answered your questions. Anything else, Tyler?

Great. Yes, that's helpful. Yes, just the final -- the second question, with respect to the imminent cohort safety review. I guess, clearly, safety is a major focus. But is there anything specifically that needs to be seen on PK/PD to be able to move forward other than just clean safety? And have you guys already screened patients for the next cohort? The most recent cohort was, obviously, enrolled very quickly.

All right. Again, I'll begin here. So what we want to measure in these patients, first of all, is safety. We've watched carefully for safety. We've seen no signals of any drug-related adverse events in the -- in any of these patients to date.

Secondly, pharmacokinetics. In all of the prior dose cohorts, cohort 1 and cohort 2, there's only 1 patient in each. And so you don't know how well behaved your pharmacokinetics will be. In this third cohort, we actually have 3 patients with full worth of data out through at least 28 days. And what we want to see is that the pharmacokinetics are well behaved, that the coefficient of variability is minimal, so that we can actually predict what the patients are going to get. We're starting to get some of the PK data, but we actually don't have all of these samples from all of the patients yet. So that -- the second part is the PK. We want to see it in, I'll call it, the circa 1 micromolar range and also see that it's minimal variability.

Also, in these patients, we absolutely want to see the pharmacodynamic markers are active -- are responding to the drug. Again, we take the plasma from all of these patients and bring it back to the lab, and we want to look and see, are we inhibiting the Phospho-BTK, the -SYK, the -ERK and the major pathways. It's also important not only to show that it's active in these patients with CLL and various lymphomas, we want to see that we're also inhibiting FLT3 in those patients. So we have an indicator cell line that we'll be looking at inhibition of FLT3 and that will tell us whether or not we have sufficient drug levels to inhibit FLT3, and that will also guide us as to whether or not we have a dose that we believe we can recommend to the FDA.

So dose cohort 3 is a very important dose level to us. Safe, yes; pharmacokinetics, this is the first time we've got 3 patients, and we want to hopefully see minimal variability; and then pharmacodynamics that shows active in the B-cell cancer patients; and also, hopefully, it will show us that we can direct it toward the AML study soon. Anything else you wanted to add?

Just to answer the last part of your question, we are directing sites to start screening patients, assuming that we won't see any issues at the March 27 meeting.

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

Congratulations on all the progress.

Guys, I just wanted to return a bit to the commentary on COVID-19. I appreciate the prepared remarks. But just curious if you had any additional thought or detail on the situation involving with respect certainly to the clinical trials but also with potential regulatory interfacing that you foresee coming up and how you're monitoring those potential interactions as well as just general stakeholder interactions as you convene the key stakeholders in order to move this and the AML trial forward?

All right. Greg, thanks for the questions.

So we've been monitoring this very closely, as has every company out there. The first thing we wanted to assure everyone is that we don't see any effects of this on the manufacturing of our molecules. We've been very careful not to be dependent on any particular site around the planet. Our manufacturing to date has all been performed in the U.S., our starting materials are available through multiple suppliers. And so at least right now, we do not see any risk to the manufacture of the API or the drug products. So that's the first concern that we always have. Because many companies will be dependent upon, especially China for manufacture of some of the starting materials. I think we're in really good shape there. So we don't -- we're not seeing any near-term impact on the manufacturing.

In terms of the clinical trials, regulatory interface, I'll let Dr. Bejar address that in just a second, but you also mentioned the interface with investors. So we also already know that a number of conferences have either been canceled or delayed. We know that many of the investment firms who are around the country and the world are not necessarily welcoming people into their office. And so we're having to take a bit of a different tactic here and have many more of the virtual interactions, but we do plan on providing updates. Even if some of these major conferences are delayed, canceled, we plan on getting the data out one way or another to you as well as the various investors out there. So Raf, do you want to address the clinical and registrational?

I'll say that to date, we haven't seen any direct impacts on our clinical operations. However, I think that will likely change in the near future. We know that many academic institutions are restricting both travel out of those institutions and restricting the number of visitors that can come in. Several of them have recommended a remote monitoring strategy, for example, and we're very flexible and able to accommodate that if needed, so we can continue to carry out the clinical trial at those sites with good oversight.

Other things that are less predictable in the near future are whether institutions are going to redirect resources for tackling COVID-19 if an outbreak becomes relatively large, and there may be less resources available for clinical trials, and whether patients might have restricted mobility and inability to come in. We'll handle those things as they happen, but we are -- it's something that we're monitoring very closely. So far, as I mentioned, none of our sites have been directly affected.

And just one more, if I may. That's all very helpful. Just turning to the -- to tapping the full potential of 806, and you've certainly spoken about and are really establishing the dual opportunity with CLL and AML or B-cell in AML. I'm just curious, to what extent should we think about your appetite for leaning into the AML side of 806's potential and certainly respecting the sequencing and the thoughtfulness that you're taking with the trials as they're laid out. But as these mature, how do you think about both opportunities and certainly leaning into the AML side of the equation?

It's actually a great question. So clearly, we were aggressive on the CLL, the B-cell malignancies. We went there first. We're going to continue there. We want to demonstrate that this drug is active in those patients. But I also want to indicate we are being very aggressive in going toward the AML. We want to get there as soon as possible but we also want to be thoughtful. We don't want to make any unforced errors and be certain that we execute appropriately. We need to demonstrate that we're selecting the right dose to go into those patients, such that we hope we see activity benefiting the patients immediately at the first dose level that we go into. We can't say that absolutely will happen, but that's our hope once we go into those patients.

We, clearly, want to go into the patients and the data support, going into the patients who have failed the other drugs. Raf can speak about this. We -- at our KOL event, we mentioned that there are a number of mutations that occur in response to treatment of patients with venetoclax, with gilteritinib, a variety of other molecules, patients who have p53 mutations, various FLT3 mutations, RAS mutations, and 806 maintains activity against those various mutant forms of the virus. So we hope that we're able to treat the patients who have failed many of the other drugs. But yes, we see a tremendous opportunity in AML. And I think the -- that was echoed by all the investigators that are looking at the drug. Raf, did you want to add to that?

I'd just reemphasize the idea that we see preclinical activity, not just in FLT3 in AML and that there is a good rationale for actually including relapsed/refractory patients that don't carry the FLT3 mutation, in part, because we see activity against other mutations that are relevant in AML, including NRAP and even patients with TP53 mutation. So we are excited to offer this opportunity for those individuals to see what kind of activity we might have.

And at some point, we do hope we have activity also in the MDS population there, too. And Raf has a background in MDS. We hope to be able to take advantage of that. Did that answer your question, Greg?

Yes, sir.

Your next question comes from the line of John Newman from Canaccord.

Bill, I just wondered if you could talk a little bit about the way that responses tend to evolve in CLL. The reason I'm asking the question is because I think that sometimes investors will look at other companies' studies for different agents in CLL or they will just sort of question when they should start to see responses. And I just wondered if you could walk through the way that these responses in CLL have tended to develop, and also just the type of imaging that has to be used in order to confirm them.

All right, John, thanks for the question.

So as it says, CLL is -- it's a chronic disease. So it's very different from AML, which is an acute disease. And we also have to break it into 2 different populations. Patients who are early failures or patients who have just recent diagnosis versus the patients who are deep relapsed/refractory patients. So I think experience has taught us, especially with the ArQule compound, that over time they did develop responses. Once you get to the higher dose levels of the drugs -- if you have a multi-targeting kinase inhibitor, once you get to the higher dose levels and you're actually hitting multiple kinase, multiple pathways, then you begin to see responses in those deep relapsed/refractory patients. But it takes time, and it takes longer than the patients who are just recently diagnosed.

So again, looking back at the example, ArQule showed some of the -- during the EHA conference last year in the middle of 2019, they showed a number of responses that were earlier on, and they said they were expecting throughout the rest of the year or the remainder of 2019 that once the patients were on the higher dose levels that those responses would deepen and they would get additional responses over time, and that is exactly what happened. But again, everyone had to sit and wait and watch to give the CLL and B-cell malignancy patients, especially the relapsed refractory, time to respond. We all wish they would respond quickly but they don't. I don't know of any relapsed/refractory patient also that has seen a complete response. They're all partial response, and they take time.

How do you measure that response? Well, of course, you can look at lymphocytosis in some CLL patients but you don't see that in all of them, especially if it's more of an SLL patient rather than a CLL. So you have to perform the imaging. And you're looking at the various lymph nodes, spleen, the indicator lesions but you only evaluate those every 2 cycles, so you only take the measurement every 2 months. And typically, you don't expect to see much in the first several months, and so you don't see any type of responses early on. And it's much -- takes much longer. I think ArQule also noted that they had a follicular lymphoma patient that it took approximately a year to see a partial response.

So that's what you tend to expect, and that's why we're providing guidance toward later in the year with our drug this year. Once we get into our higher dose levels, we have the second half of the year for the patients to be on the drugs and give them more time to respond. That's why we're not expecting to be able to present responses midyear, but look for it, hopefully, towards the end of the year.

AML is a different story. It's an acute disease. Once we get into an effective dose and that might be the first, second, third dose that we're into there. In the second half of the year, you would expect to start seeing responses there.

Raf, again, would you like to add to that?

I think that's spot on. Just to emphasize the variability between patients, even with the same diagnosis, that some of them are eligible for response in blood counts, for example, or others may not be. Then they already have attacked blood count. Some of them have primarily, lymphocytosis; others maybe -- or splenomegaly. So there are criteria that we follow, but the timing of that is just, as Bill said, that it is not immediate. It can take months. And even in our study, we're really only looking after every other cycle.

Yes. And every patient is almost a freestanding experiment. They're all so different, and it's on a patient-by-patient basis. What else, John?

Yes, just one additional question, which is, I know that yourself as well as investors are sort of eager for 806 to move into AML, but obviously, it takes time to secure the IND and get the study up and running and those types of things. Could you remind us again what types of things you are looking for, in order to determine that you have a dose in the B-cell malignancy study that you feel would be active or close to active in AML?

It's a good question. So we're looking at the totality of the data related to safety, pharmacokinetics and pharmacodynamic responses. So in terms of the safety, we want to be able to show that it's a clean dose level. And so far, cohort 3 has been completely clean, and we hope that the additional ones into the future will be, too.

In terms of pharmacokinetics, we say that we want it to be, and we call it circa 1 micromolar, around that dose level, our exposure level. Why do we say that? Well, it's because if you look at the animal studies in which we have seen complete tumor elimination, cures in animals without any toxicity, we see that range of anywhere from 0.2 to, say, 0.9 micromolar in the animal studies and that gives us complete responses in the animals. So once we're getting into that range in humans, we think that should be a therapeutically active range. And so we're getting into that range. We're even beginning to get into that range with dose level 2. And we hope dose level 3 also is maintained in that circa 1 micromolar. It doesn't have to be over, but in that range.

And then the third one is the PD. I would suspect that the FDA would expect us to demonstrate that the exposure levels in the patients can inhibit FLT3 activity. So how do we do that? Again, we collect the plasma from the patients over the 28-day cycles, take it back from the lab and we put it on the indicator cells. So the indicator cells that I've been talking about thus far, it's one particular cell line. And we've been showing you data with BTK and SYK and ERK. Well, that same cell line, we measure FLT3. We have not disclosed what we've seen in FLT3 in patient dose levels 1 and 2, but we are going to be showing that in dose level 3. Hopefully, that will be at EHA, we'll have that. But we'll also have to present such data to the FDA. And if we hit all of those criteria, then that gives us confidence we should be able to go into the AML or recommend that we go into the AML patients. Then the FDA has to look at our proposal, has to agree to it. Well, we hope they agree to it; they don't have to. And then for AML, we also have orphan drug designation, so it should be a 30-day turnaround. And so that's why we're hoping to get into the patients as quickly as we can, but we have to have that totality of data.

Anything else anyone wants to add? No? I think that covered most of it.

Your next question comes from the line of Matthew Cross from JonesTrading.

Thanks for the update and taking a couple of questions from me here. So you recently presented findings showing that the CG-806 appears to have better activity against NRAS than other FLT3 inhibitors. And that certainly appears significant as a means of addressing this path of resistance to FLT3 inhibition. But because CG-806 inhibits a number of upstream targets that feed into RAS, I was wondering if CG-806's indirect control of RAS extended into other forms of RAS as well as other kinases. Obviously, you wanted to not talk about that lately. It would explain why you see down-regulation of ERK in that play, and maybe what that may mean from a safety or applicability standpoint as we kind of gauge the scope of the market for a kinase inhibitor with this profile?

All right. Well, Matt, you decided to nerd down on that one, so I guess I'll just jump in with you. So when we look at the KINOMEscan and the kinases that we inhibit, the various clusters of kinases, we've always talked about the FLT3 cluster as well as the PDGFR-alpha and CSF1R that are also in the FLT3. We've talked about the track kinases, the BTK, Src kinases. We also have pointed over to the right side, that's kind of the MAP kinase cluster. There are some kinases that are over in that -- what are called the STE cluster that are inhibited. They're a little bit higher in concentration sometimes, but those are meaningful. So any time you have a patient who has the RAS mutations, you want to be able to hit some of the kinases, both upstream as well as downstream.

So upstream of the RAS would be FLT3, CSF1R, PDGFR-alpha as well as BTK. SYK, LCK, Src, we hit all those. And then downstream of the RAS, you also have the MAP kinases, and we hit some of those. So we believe that's why we maintain activity even in the presence of the RAS mutations. Now our drug does not directly inhibit RAS, but we retain activity even in the presence of RAS mutations. The same is true for p53. We've been able to maintain activity even in the presence of p53 mutations and some of the others.

So Raf, how about anything to add?

No, that's exactly spot on.

Okay. All right.

Great. No, that's very helpful, and thanks for indulging me, nerding out of it.

And then the second one I had was just about the trajectory for 253. It sounds like meaningful data could come from the CG-806 program at EHA and then maybe more so at ASH. But 253 enrollment in AML and MDS also appears to be proceeding pretty well in parallel. And I was hoping to get the latest number you would expect to present initial results from this trial in conjunction with those for 806 at EHA and ASH, or if the patient for this may divert a bit based on the designed parameters or other factors.

Yes. So the guidance that we're providing regarding 253 is, as we begin to get up into these higher dose levels, get more patients on, and hopefully, be able to treat them for longer term throughout the second half of the year, we hope to begin to see responses in those patients. So we hope to see something by ASH and to be able to present the data there.

Again, we don't know what to expect from a well-tolerated MYC inhibitor. We don't know if we're going to get single-agent activity or if it's better for combination, more like venetoclax in AML. We mentioned that earlier. But at least we have the drug product, we have the patients, we've completed 1 patient on dose level 4. We've now -- we're evaluating 2 more patients to bring on now. Hopefully, we'll get those on soon and continue to dose-escalate.

And we've always said that we hope to get proof-of-concept with this drug as an IV agent. And then hopefully, in the future, if we can get an orally delivered form of this drug, we're still continuing on that path. And the fact that we were able to raise sufficient levels of capital in December, it's really allowed us to accelerate some of those oral discovery studies.

Great. Well, obviously looking forward to just seeing how that MYC inhibition actually plays out in the clinic longer term, and then looking forward to hopefully see some of that at ASH.

Your next question comes from the line of Jason McCarthy from Maxim Group.

This is Naureen on for Jason. So I just want to piggyback on the NRAS question that was asked earlier. I was just wondering, could you remind us about the incidence of NRAS mutations in AML? And aside from the cell work that you've demonstrated with 806, its activity in NRAS patient samples, have you done any animal model work as well to sort of solidify what you've seen?

All right. In terms of the incidence, the incidence of NRAS has not been really highlighted in the past. It's more emerging now that patients are being treated with a variety of different molecules, of venetoclax, some of the FLT3 inhibitors, some of the others. So it's beginning to emerge, gilteritinib, some of the FLT, some of the patients there developing NRAS mutations. So it's -- again, what we're doing is -- or not we, but collectively, the field, as we begin to dose patients with different drugs, new types of drugs, different targeted agents, we're actually driving the tumors toward different mutations. And in this case, with a variety of other molecules, NRAS mutations are beginning to emerge. So I don't think it's a high incidence at this point. And perhaps Raf will know the number. But those are emerging, and it's clear that the investigators are identifying those patients. They're identifying them as clear failures.

In terms of our work, how did we look at this, we actually took samples from over 200 AML patients. This was Brian Druker's work. So its primary isolates, AML patients treated with our drug, 806, and got an IC50 for cell killing. And our drug was very effective there. But we also had the entire genetic profile of those patient samples as well as gene expression profile. And we were able to go back and look at wild type versus RAS-mutant patients. And effectively, there was a slight increase in IC50 in the RAS-mutated cells, but just slightly higher. And it looks like those exposure levels required to kill the RAS-mutant cells, it looks like we're -- at least, we hope we can achieve that in patients. And so we should be able to treat those RAS-mutant patients. Whereas, when we look at the same thing with other drugs, it doesn't look like they can achieve levels that can inhibit the RAS mutants.

So Raf -- not RAS, Raf, would you like to add to that?

So NRAS is found in de novo AML. It's often actually in favorable risk, but it's about 5% to 10% of patients within communities with AML at base levels. But as Bill pointed out, the really big impact of NRAS is that it emerged after therapy. So they're often mechanisms of resistance to drugs like FLT3 inhibitor and venetoclax. So these are mutations that are selected for -- or that are -- weren't able to expand in the setting of therapy and, are therefore -- tended to have activity against in the relapsed/refractory setting as well as in the upfront setting.

Yes, and it may be that these patients, after being treated with multiple types of therapy, they have a background, not only with RAS, but they have other mutations that are occurring, and then RAS, on top of that. And then the other drugs just can't handle that constellation of mutations.

Would you like to add anything to this?

Yes. So thank you for the question. Just as Raf pointed out, the RAS in the frontline setting is in a relatively low percentage of incidence. However, the real problem with RAS is in the relapsed, first, so patients who failed treatment, for example, FLT3 inhibitors or venetoclax. Now the data there is very preliminary because we're just starting to see a real-world experience and selecting small cohorts. But from those small cohorts of patients who have relapsed following FLT3 therapy, for example, we have seen that the rate of RAS mutant is about 1/4 to 1/3. So that is a fairly high incidence. Again, these are very small studies.

What it shows further is that some of these RAS mutants were there to begin with, so they were original mutations, and then some of them are de novo mutations. So the cell is finding ways to get around a FLT3 therapy. And so that becomes exceptionally important in the -- looking at CG-806 and the potential for treating all of these mutations that are arising after the failure of FLT3 therapies.

That's a good point.

So at baseline, in de novo AML, when an NRAS mutation is present, typically, a FLT3 mutation does not tend to be exclusive at first presentation. But in the FLT3-mutant patients, when they develop resistant disease, then you have a clone of both the FLT3 mutant and the NRAS mutant at the same time. And that's the evidence that its mechanism is really good.

So one or two last notes here. So we want to be able to test 806 with oxygenic cells that have wild type and just the only other change has been RAS. We're looking to do those studies with Dr. Druker, hopefully, into the near future. And we're trying to identify the cells that are oxygenic for such changes.

In terms of an animal model, we have not tested that in an animal model. We do not have such an animal model available. We can look for them. But hopefully, we'll actually have human data later on this year, and that will be much more impactful.

Did that answer your question, Naureen?

Yes, more than that. That was very, very helpful. Thank you. No, no, that was great.

And just one more follow-up, in terms of 806 opportunity in AML. Joti mentioned the combinatorial optionality with the drug, and you've shown pretty impressive preclinical work with 806 and venetoclax in AML patient samples. So with regard to the program, we know that venetoclax got conditional approval in AML in combination with HMA or LDAC back in 2018. But I guess, a few days ago, you probably read that the drug technically failed one of the confirmatory studies which could potentially jeopardize its position in AML -- in venetoclax that is. So are you considering other strategies outside of potential combination with venetoclax? And have you done studies with 806 with other, say, chemo agents?

Yes, there are a couple of answers there. First of all, in terms of our studies with venetoclax, the data were very impressive, whether it was with AML -- and we did all of our combination studies with patient samples, patient-derived samples. AML, CLL, MDS, ALL, so we saw very nice activity, combination activity, in all of those cell types.

Venetoclax is an impressive molecule. But in AML, particularly as single agent, it did not have impressive activity. But in combination, it does have activity. And there's a move to move that more towards frontline and that likely will happen into the future. But it's not going to be perfect in every patient population. But venetoclax is going to be used in AML, I think, broadly, and we want to be able to show that we have activity there.

The other reason we want to look at venetoclax is because it's also used in the B-cell malignancy. And so our drug, much like venetoclax, is active across both myeloid and lymphoid. So that's another reason to look at combinations with venetoclax.

But yes, we have tested in combination with a variety of other molecules. Hypomethylating agents, we actually tried those. And in patient samples, the hypomethylating agents, such as azacitidine, have no effect as a single agent. And so we couldn't get an answer as to whether or not we have a good combinant -- combinability data with the hypomethylating agent in patient samples. But we have tested with a variety of other agents, and it performs very well in combination with other types of agents.

Does anyone want to add anything to that?

I would say that one of the advantages of having a drug that has close to no toxicity that you're able to combine with other agents more readily than you might if you add toxicity to that combination. If you look at the treatment paradigm that's evolved in multiple myeloma, where we've gone from single-agent activity to now combinatorial therapies upfront, I think that is the future of AML. That's where we're headed going forward. Through combinations with venetoclax, hypomethylating agents, these are low-hanging fruits or the obvious ones to go after. But there are many other combinations that are going to be very intriguing, including combinations with biologic agents.

Yes. Targeted agents into the future rather than [cyto-]. Hopefully that answers your question.

(Operator Instructions) Your next question comes from the line of Matt Biegler from Oppenheimer.

First, quickly, just wondering if you could tell us if any of the 3 patients enrolled in the 450 mg cohort were non-CLL patients, because I appreciate the protocol does allow other NHL subtypes.

First of all, thanks for squeezing us in. We know it's been a busy day for you, too. What I can tell you is, yes, we have had patients other than CLL. We do want to look at those patients, especially as we begin to get into the higher dose levels here. So some CLL and not some non-CLL. We have not disclosed what they are, but we're thrilled to get some of those other patient types in there also.

You remember at the lower 2 doses, we really wanted to get CLL patients so we could see if there's a pharmacodynamic effect and pharmacologic effect, particularly when you look at the lymphocytosis as well as the -- collecting the cells in the peripheral blood and looking for the changes. But now that we're getting into some of the higher doses, even if it's our third dose level, still, we believe we're getting to higher doses, we want to begin looking at the patients that have these other diseases, too.

Got it. Got it. And then maybe a broader question on positioning in CLL. It kind of sounds like right now, you're thinking of 806 as a panacea for, like, really, all relapsed and refractory patients. So I'm just curious if you're still planning on expansion cohorts targeting like maybe more targeted populations like C481S or Richter transformation? Or is the strategy now really centered on kind of an all-comers approach?

Well, the study is designed to allow us to look at a variety of different types of subpopulations of CLL as well as the other lymphomas. And particularly patients who are relapsed or refractory who have failed a variety of other molecules, we think that, that could be our sweet spot, which we could show activity where other drugs might not show activity and still be well tolerated. If we see a particular patient population, such as -- you mentioned Richter's, for example, or a DLBCL or an aggressive follicular lymphoma, if we see activity in those patients, we definitely would want to go after an expansion in such patients. If you look at follicular lymphoma, there's really no good standard of therapy there, and so that's a low-hanging population that we'd want to go after.

But ultimately, if we are able to hit multiple kinases, much like one of our competitor drugs does, but we also are very well tolerated, we hope, over time, we'd began to move up toward the first line more, toward the earlier lines. Because in that way, you're still hitting BTK, the wild type and the mutant forms of BTK, you'd be able to hit multiple pathways and then still be well tolerated. So yes, initially, we're going after the relapsed/refractory patients, in particular, and hopefully, some of these other very difficult-to-treat populations, and then over time, moving up towards the front line.

Would you like -- gentlemen, would like to add anything?

Yes, Matt, thank you for the question. We -- the CLL landscape, and we have discussed this together in the past, is in constant flux. Now more than ever, in fact, the therapies are shifting around. However, we are pretty confident that there is still plenty of clinical and commercial opportunity in CLL, within CLL, and without even getting into other B-cell malignancies or AML yet. So we continue to receive very encouraging feedback and enthusiasm from some of the top CLL academic trialists out there which are all interested to join our study. And in the end, in terms of development path or where the agent would fit in the treatment period time, we will just follow the data that we'll see later this year. So we have been and we'll stay pragmatic about the path.

Now that said, we are very confident in the value of this agent, even at this stage where we are at right now. Because if we just take a step back here and look at it very impartially, we are developing an agent with a clean safety record to date, with indications that have unmet clinical need, and then importantly, with validated targets. And I cannot stress enough how important and differentiating this last point is in hematology today, engaging multiple validated targets. So thanks for the question.

Yes. And just to emphasize that just a bit more, we are bullish on this molecule, both in the B-cell malignancies and the AML. We're thrilled with where we are in the clinical trials. But what our focus now is we have cash in the bank, we have our drug in the clinic. We need to just perform -- to execute well and not make any unforced errors. And hopefully, then the responses will emerge as we go into the higher dose levels.

Great. Makes sense. Congrats, guys, on the progress.

Thanks, Matt.

Your next question comes from the line of Joseph Pantginis from H.C. Wainwright.

This is Pasquale Sansone from the line of Joe. A few questions on my end. So the first one, do you expect that therapeutic doses to inhibit BTK levels with 806 would simultaneously eat potential rescue pathways? And the second one, is a consequence, would you anticipate that within the same patient, potential doses adjustment may be required in order to achieve a broad kinase inhibition?

All right. I'm trying to determine how best to answer that. We already know that even at our second dose level, we're able to inhibit multiple kinases. So we're able to inhibit BTK, and we saw complete inhibition. So when we take the plasma from the patients, put it on the cells, we can completely inhibit Phospho-BTK. We also saw complete inhibition of Phospho-SYK, again, that's S-Y-K; ERK; and I believe also PDGFRalpha, we also have the data on that. We just haven't spoken about FLT3 yet. We've done studies there, and we're doing -- going to be doing them in dose cohort 3. But yes, we believe that even at the doses we're already at, we're able to inhibit multiple kinase pathways, both the driver kinase as well as many of these rescue pathways that we've described.

But again, the higher we can go in dose levels and higher levels of exposure that we can get in safely, we're going to be able to hit more and more of these kinases in these pathways, and we'll have better activity in patients. That's why we want to continue to dose escalate as long as we're getting more and more drug in, but doing so safely, in as many of those oncogenic pathways as we can. That gives us greater applicability to a broader group of cancers as well as, hopefully, deeper activity in patients and also preventing rapid emergence of drug resistance.

Did that answer it? Or I'm not sure if I actually answered the second part.

Yes. The second part was like what if you need more like doses adjustments in order to achieve broad kinase inhibition?

You mean a different dose level in a CLL patient versus an AML patient?

Correct, or within the same patient during like the evolution of the disease?

Interesting question. Typically, you will try to take your drug to the highest dose level that you can get into patients safely, and you would treat patients with that. Typically, you don't try to dose at a lower dose level and then increase later because that just allows for the selection of drug resistance. So you want to hit a cancer patient or even in infectious disease as hard as you can initially, try to kill the cells without giving it a pathway to escape.

I see. I see. And my last question. So for APTO-253, how many sites are currently screening, and how many additional ones are about to open?

Let's see, is it 8 or 9? I'm looking. So it's 8 clinical sites that are currently screening. And was that your question?

Yes, but are you going to have, like, more sites in 2020?

Yes.

Yes, so more additional sites?

Yes, there are additional sites pending. We're just making sure that we have everything in place. But early on, you don't have that many patients to put on a study, and so you want to make sure you don't have too many sites because then people get frustrated they're not getting patients on. So now that we're getting in -- begin to getting into the higher dose levels, we hope to be able to put on more patients and get more sites. Good question.

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

Okay. Well, thank you for joining us this afternoon.

I'm exceptionally proud of our organization, the employees, the top-notch investigators, and importantly, the patients who have participated in advancing our important work.

After a year of solid performance, we have 2 well-tolerated hematology compounds in the clinic. We greatly appreciate the support of our new and past shareholders and research analysts, and we look forward to keeping you apprised of our progress.

Thank you, and have a wonderful evening. Bye-bye.

Thank you, ladies and gentlemen. That concludes today's conference. You may all disconnect. Have a wonderful day.