Aptose Biosciences, Inc.

Hello, and thank you for standing by, and welcome to Aptos Biosciences reports for the fourth quarter and year-end 2022 conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask the question during the session, you will need to press star 11 on your telephone, and you will then hear an automated message advising your hand is raised. To withdraw your questions, please press star 1-1 again. I would now like to hand the conference over to Susan Peptralo. You may begin.

Thank you, Tawanda. Good afternoon and welcome to the Aptos Biosciences Conference call to discuss financial and operational results for the year-end and fourth quarter ended December 31, 2022. Earlier today, Aptos issued a press release relating to these financial results. The news release as well as related SEC filings are accessible on Aptos' website. Joining me on today's call are Dr. William G. Rice, Chairman, President, and CEO, Dr. Rafael Behar, Senior Vice President, Chief Medical Officer, and Mr. Fletcher Payne, Senior Vice President and Chief Financial 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 Aptos' current expectations regarding future events. They 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 Aptos' most recent annual report on Form 10-K and SEC and CEDAR filings. All forward-looking statements made during this call speak only as of the date they are made. Aptos 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 Aptos Biosciences. Dr. Rice.

Thank you, Susan. I want to welcome everyone to our call for the year end and fourth quarter end of December 31st, 2022. First, I'll provide a very quick overview of 2022. While the biotech market has been extraordinarily challenging, Aptos continued a steady march forward. We extended our cash runway to the end of Q1 2024. We continued building a talented and experienced team. We created and began testing a new formulation for Luxeptinib. And most importantly, we made significant strides in the development of Tospetinib for the treatment of acute myeloid leukemia, or AML. When it comes to tuspetinib, or TUS as we call it, I want to emphasize its highly differentiated profile, having demonstrated the potency to achieve complete remissions in very ill relapsed or refractory AML patients, while also being safe and well-tolerated. It's extraordinary for an antileukemic agent to deliver formal responses in such an aggressive cancer without causing the typical toxicities of other agents. And today, we will unpack both the potency and safety attributes of TUS. It's also important to highlight the AML population that has been treated with Tuspatinib to date in our Phase 1-2 dose escalation and dose exploration trial. These are typically third line, fourth line, or beyond, having failed the best available approved therapies, and in many cases, having failed various investigational drugs or prior hematopoietic stem cell transplants. These are incredibly difficult patients to treat and to reverse the disease progression. What makes these patients even more difficult to treat is the extreme diversity of highly adverse genetic and epigenetic alterations expressed by their disease. If we recall the Admiral trial from just five years ago, during which the commercial dose of giltaritinib, a FLT3 inhibitor, was tested for responses in AML, the patients were second-line, essentially had not seen other FLT3 inhibitors and had not seen venetoclax. In contrast, patients entering our trial are far more treatment-experienced, with half failing prior venetoclax, 60% failing prior treatment with hypomethylating agents, or HMAs, more than a quarter having failed transplants, and half of the FLT3 mutant patients having failed prior therapy with a FLT3 inhibitor. Nevertheless, TUS has delivered responses with convenient once-daily oral dosing of tablets across four dose levels, 160 milligram, 120 milligram, 80 milligram, and 40 milligram, and no DLTs were observed with any of those active dose levels. From a mutation sensitivity perspective, TUS has shown an unprecedented breadth of activity. TUS delivers responses in FLT3 wild-type patients as well as it does in FLT3 mutated patients. We also have seen responses in AML patients having the very difficult-to-treat TP53 mutations as well as patients with NPM1 and FLT3 commutations. and patients having alterations in the DNMT3A, RONC1, IDH1, splicing factors, ASXL1, and MLL genes. But one of the most interesting observations is the activity in relapsed refractory AML patients with RAS mutations. Mutations in the RAS pathway serve as an escape mechanism to generate resistance to many other drugs. However, we've measured a 42% overall response rate in patients with RAS mutations including a 29% CR-CRH response rate. In fact, one patient had a RAS mutation and a mutation in PTPN11, representing a dual mutation in the RAS pathway. We will continue to monitor the response rate in RAS-mutated AML patients this year and determine if RAS-mutated relapsed refractory AML patients may represent a population of high need for future accelerated approval trials. As Dr. Behar will describe in further detail in a few minutes, we wrapped up our highly successful Phase 1-2 dose escalation and dose exploration trial. We've treated over 60 patients to date in that trial. We've assembled a strong safety data package. We selected safe and effective doses for our single-agent and drug combination trials. We demonstrated the ability of TUS to dramatically reduce bone marrow blasts in a high fraction of patients and to achieve formal responses. and we initiated our Aptivate dose expansion study of TUS in a single agent and in combination with venetoclax. In the Aptivate trial this year, we will enrich certain patient populations to receive monotherapy so that we can collect data to guide our conversations with the FDA to request an accelerated approval path for TUS in patients of high and met need. In parallel with the Aptivate monotherapy dosing, we will treat a broad array of AML patients with a combination of TUS plus venetoclax, referred to as the TUS-VEN doublet. This TUS-VEN doublet is being conducted to support doublet combination registrational trials in second-line AML patients and to serve as a bridge to a pilot study of TUS plus VEN plus a hypomethylating agent or the TUS-VEN HMA triplet in frontline AML patients. While TUS clearly can deliver responses as a single agent, the ultimate goal and commercial success of TUS or any drug for AML will be in combination with other drugs. As of this week, we have begun enrollment of AML patients on the TUS-VEN doublet, and we will place additional patients on this doublet throughout 2023. Once we gain experience with the doublet, we plan to initiate the TUS-VEN HMA triplet in frontline patients. The future of AML therapy will also revolve around cocktails of drugs in earlier lines of therapy to take patients into deep remissions. Such AML cocktails will require the blending of drugs that best can serve broad populations of patients, can deliver deep remissions, and can be tolerated without cardiotoxicities, unnecessarily prolonged myelosuppression, and other complicating side effects. And this precisely describes TUS. TUS is positioned to become the ideal partner for addition to the Venn HMA doublet because of its convenience as a once-daily oral agent, its broad activity, and its safety profile. Together, data to date point us toward application as a monotherapy for accelerated approval in relapsed to refractory AML, as doublet therapy for accelerated approval in second-line AML, for use in triplet combination in frontline patients, as well as use in maintenance therapy. and Dr. Behar will provide you with additional color of these activities momentarily. Now let me turn briefly to Luxeptidib. Many of you know it as CG806. Lux, as we typically refer to it, is our secondary pipeline program. Lux is a clinical stage, small molecule, oral, FLT3, and BTK kinase inhibitor. Lux's ability to target kinases operative in certain leukemias and lymphomas led us to develop it in patients with B-cell leukemias and lymphomas and in patients with AML. We already have reported that LUX, administered as our initial first-generation or G1 formulation, delivered a CR in an AML patient and a CR in a DLBCL lymphoma patient, demonstrating LUX is a clinically active agent. You also are aware that we developed a new formulation of LUX, and we call it the G3 formulation because it represents the third-generation formulation. In single-dose administrations during 2022 in AML and B-cell malignancy patients, we determined that G3 formulation achieved up to 18-fold greater absorption than the original G1 formulation. Because the highest dose of the original formulation was set at 900 milligrams, we initiated continuous dosing of G3 at an 18-fold lower dose level of 50 milligrams. We continue to collect PK and safety data with G3 and AML patients, and the preliminary results suggest continuous dosing of 50 milligrams G3 does indeed deliver roughly equivalent plasma exposures as 900 milligrams of the original G1 formulation. That was the target we hoped to achieve with the 50 milligrams of G3. And next, we plan to administer a higher dose of G3 to determine if it can achieve even greater plasma exposure levels. We will keep you posted on our findings, and likely we'll report preliminary data around EHA. I also want to mention that Aptos and collaborators at UCSD, Dr. Manchu Sonowal and Dr. Stephen Howell, just published an article entitled, Luxeptinib Interferes with Lin-Mediated Activation of Sick and Modulates BCR Signaling in Lymphoma, in the online journal PLOS One, in which we describe the ability of LUX to act on the B-cell receptor pathway at the level of the LCK and LYN, or LIN, kinases, and to influence downstream BTK activity. This relates to the role of LUX to act on B-cell cancers, as well as inflammatory and autoimmunity processes. So, please take a look at the article if you get a chance. Finally, we often get asked about potential partnerships for Tuspatinib. In January, during J.P. Morgan Week, We engaged in productive discussions with several big pharma and biotech companies that further helped to define our priorities and to solidify our clinical plans with Tuspatinib. It's clear what we need to accomplish with a drug that has such an extensive commercial opportunity. We were pleased to see that we're on the radar of these companies and interest in our program is growing. The treatment paradigm for AML is shifting toward doublet and triplet therapy. And despite some successes, the current combination therapies are somewhat limited by toxicities, as I mentioned previously. The proven breadth of activity and superior safety profile of Tuspetinib lends itself to combination therapy, potentially as the drug of choice, addressing the most sizable markets in AML and clearly making TUS a prospective big pharma drug. The data we've generated to date have helped us delineate clinical and commercial plans for Tuspetinib in multiple lines of therapy, including its use in doublet and triplet combinations and as maintenance therapy. Our chief medical officer, Dr. Rafael Behar, will speak about our recently initiated APTIVATE clinical trial of Tuspatinib in AML as a single agent and in combination with Venetoclax, as well as our extended clinical plans, which include triplet combination therapy. He also will be available for questions afterwards. I now will turn it over to our resident KOL, our chief medical officer, Dr. Rafael Behar, to talk more about our Tospetinib clinical plans. Raf?

Thanks, Bill. In January, we were thrilled to kick off the 120-milligram dosing of Tospetinib in the monotherapy arm of the Aptivate Phase 1-2 trial. As most of you know, we have successfully completed dose escalation and dose exploration stages of our TUS Phase 1-2 trial, treating approximately 60 relapsed refractory AML patients who were heavily exposed to multiple agents. In fact, as Dr. Rice mentioned, While we were wrapping up the dose exploration part of the study, we took the prudent step of putting additional patients on the lowest 40-milligram treatment group because of the FDA's Project Optimist that emphasizes dose exploration during early development of oncology products. This experience gave us the additional data needed to support our monotherapy dose selection and was not born out of a safety concern. Rather, as higher doses of Dyspedinib have shown an impressive safety profile, since we lost the 40-milligram dose level late last year, we have achieved two clinical responses in that low-dose group. both AML patients with unmutated FLT3, including the most recent harboring a challenging TP53 mutation, one of the most highly adverse somatically mutated genes. Importantly, this is the second TP53 patient that has achieved a clinical response. The first was at the 80 milligram dose who achieved an unqualified CR at their best response. So we look to enroll more of these patients who with such a poor prognosis have a great unmet need in the APTIVATE trial. The APTIVATE expansion trial is designed to confirm monotherapy activity to patient enrichment of specific mutationally defined AML populations, including the TP53 mutant patients, as well as split three mutated patients who had been failed by prior for three inhibitors, as supported by an FDA fast track designation and a clinically significant response rate to date. These patients continue to have great unmet medical need, and we believe that the ability to rescue these patients and perhaps allow them to receive a stem cell transplant, which we have now done with several patients in our study, would allow us a quicker path to registration. In addition to being potential accelerated approval pathways for tispetinib, treating these subgroups will provide critical data to inform our continued development path. I am pleased to say that we have begun treating patients in the monotherapy arm of the Aptivate trial and that a growing network of clinical sites and investigators are engaged in enrollment and that this has been risk. In the Aptivate expansion trial, tispetinib also will be tested in combination with venetoclax. Several sites now have regulatory clearance and both drugs in hand, allowing us to initiate patient enrollment on the TUS-VEN combination earlier this week. Having the TUS-VEN combination arm open is an important advance, as this represents an attractive treatment option for patients and their physicians, leading them to enroll earlier in the course of treatment, increasing the likelihood of achieving a meaningful clinical benefit. So what is our timeline for our clinical trials? Because Aptivate is an open-label trial, we will report data when available at appropriate forums. We will have an update around EHA in June, for example, as we usually do, but because data collection and verification does take time and Aptivate has only been open for a short while, this will be an incremental update. We would expect to have more complete data, particularly for the monotherapy arm, at the European School of Hematology meeting, ESH, at the end of October in Estoril, Portugal. Expect more data, including from the TUSF and combination cohort, to then be updated at ASH in San Diego in December. So, 2023 will be a busy year for us. Having tested tispetinib in specific genetically defined populations, we would expect to have sufficient patient data this year, then segue into Phase II registrational studies to support accelerated approval. As Dr. Rice mentioned, we are including relapsed or refractory AML patients with unusaged FLT3, what we often call wild-type patients, that have other adverse mutations, exploring safety and activity in these patients with tispetinib treatment, both as a single agent and in combination with venetoclax. Identifying meaningful activity in other adverse subgroups could lead to other options for accelerated approval. The paradigm for the treatment of AML is increasingly moving towards combination therapy, and we hope to position despetinib as a preferred agent for combination and used in earlier lines of treatment. It is our hope, and based on our data thus far, it is our expectation that we will move forward with despetinib in a triplet combination and in maintenance settings. Dr. Naval Dauber from MD Anderson, who's been one of the investigators pioneering AML combination therapies with venetoclax, is our lead investigator on Aptivate and is eager, as we are, to see what Suspendip can do in this setting. We'll also highlight a few comments from Dr. Harry Erba of the Duke Cancer Institute during a recent KOL event. He noted that this drug may be better suited for the combinations that we hope to develop than anything we have right now. And he was excited about the apparent lack of myelosuppression noted in our clinical study to date. And he emphasized that a drug like TUS will have a position mostly because it has better toxicity profiles than the drugs we're using now in terms of myelosuppression. Clearly, we agree wholeheartedly with Dr. Urba, and we believe that potency, breadth, and anti-leukemic activity, along with the safety profile, make TUS-BET the ideal drug for combination therapy and scalable commercialization. On our website, you can see our projected timeline for our ongoing and planned clinical trials. I want to thank our clinical team for their hard work and execution in getting both arms of after-date expansion study up and running. We certainly look forward to sharing the data with you. Now, I'd like to turn the call over to our CFO, Fletcher Payne, for an update on our financial status. Fletcher?

Thanks, Raf. And good afternoon, all. Before we start speaking about the financials, I'd like to introduce to you the newest member of our finance team, Brooks Ensign, who is a VP and controller of Aptos. Mr. Ensign has more than 20 years of pharmaceutical industry experience in accounting, finance, corporate development, and he served in this position for multiple public and private companies. Mr. Ensign has a master's and holds an MBA from Harvard Business School and a master's in accountancy. We're pleased to be able to recruit quality people like him, and we're very happy to have him here at Aptos. Let's review the fourth quarter and year-end financials. As most of you know from following Aptos, we take a disciplined approach to cash management and always look to prioritize our clinical activities without sacrificing quality of our programs. These efforts have extended our cash runway into 2024, and our cash management policies and the actions taken have helped us avoid the financial impact of Silicon Valley Bank's fallout. Now let's review our cash position. We ended 2022 with approximately $47 million in cash, cash equivalents, and investments, a decrease of $4.8 million as compared to the previous quarter. During the quarter, the net loss was approximately $10 million, translating into approximately negative 11 cents per share loss, down from $24.3 million loss from the comparable period in 2021. As identified in the income statement, we had no revenues during the fourth quarter of 2022. Research and development expenses were $6.8 million for the quarter, down $20.2 million from the same quarter in 2021. research and development expenses for the full year period ended December 31st, 2022 were $28.1 million as compared to $46 million for the comparative period, a decrease of $18 million. That decrease was due to several factors, including a $12 million licensing fee paid to HANMI in the previous year to acquire global development rights for Tecetanib, which comprised a $5 million cash payment, and a $7 million worth of common shares. Additionally, there were lower costs for the LUX program and 253 program, as well as lower personnel costs. These savings were potentially offset by costs for the Deceptin program that was adopted in 2022. G&A expenses were $3.6 million for the quarter, as compared to $4.1 million for the same quarter of 2021. GNX expenses for the 12-month period ended December 31, 2022 were $14.5 million as compared with $19.5 million for the comparative period, a decrease of approximately $5 million. The decrease was primarily due to a decrease in stock-based compensation expenses offset by higher compensation expenses, travel expenses, and professional fees. As of March 2023, APTOS has 93,005,278 common shares outstanding. More detailed information can be found in our filings on Edgar and Cedar. Now let's turn it back to Dr. Rice.

Thank you, Fletcher. As we open the call for questions, please feel free to pose a question to any of us. Operator, if you could, please introduce the first question.

Thank you. At this time, I would like to remind everyone how to ask the question. To ask the question, please press star 11 on your telephone and then wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster.

Our first question comes from the line of Matthew Beigler with Oppenheimer.

Your line is open.

Okay, guys, thanks for the update. Just two for me. I'm wondering, is it too soon to guide on patient numbers for that October update? Yeah, from the Aptivate trial. And then I'm just curious about some of the comments Raf made about the doublet versus the singlet to Spetniv and Aptivate. I'm just, I'm curious if you're concerned that it might be challenging to enroll the monotherapy arm given that there is a doublet, or kind of how are you approaching that, or how are you thinking of kind of weeding out patients from one to the other? Thanks.

Thanks, Matt. This is Bill. I'll start on that. Your second question is really easy, doublet versus monotherapy. We've had exceptional uptake, rapid uptake, and I think the word that Dr. Behar used was brisk uptake as the monotherapy. We got it up and running first this year. It's been great enrollment pace, and we're just now beginning to enroll the doublet. In terms of the numbers of patients and all, I'm going to turn that back over to Dr. Behar. We'll be careful not to really bracket them too much, but we'll try to give you a sense. Raph?

Yeah. Thanks, Matt. And just to follow up on, Bill, your earlier point about the enrollment to both, the doublet, I think, is going to be more appealing to investigators than the monotherapy in general. But once both arms are open and those options exist, there'll be a random assignment. So we are hoping that not only do we get more patients on because there's more enthusiasm for the study, but the patients may actually come on earlier in the course of therapy because there is this double accommodation option available to them. So we will focus on both through the end of the year, and we'll give you more clarity when we get to that point. In terms of numbers of patients, like I said, it's hard to put an exact number on it, but I would say the enrollment has been very good. There certainly will be, I'm not bragging too much, maybe tens of patients on the myotherapy arm, and hopefully somewhere between 10 and 20 patients on the doublet arm by the time that we read out near the end of the year. All right, great. Thanks.

Thank you.

Please stand by for our next question. Our next question comes from the line of Shumit Roy with Jones Trading.

Your line is open.

Hi, everyone. Thank you for the update. Could you give us a little bit more color on the different dose cohort size you're enrolling currently between 40, 80, 120, and then the 100th patient you mentioned, what split is monotherapy and doublet?

All right. Hey, Shumit. This is Bill Rice. So, yeah, we have completed the dose escalation and dose exploration trial. And so I'll ask Dr. Behar to give you a breakdown on the numbers of patients there, and then he can talk about the Aptivate.

Right. So as of the ASH meeting, when we had not yet opened Aptivate, we had treated 60 patients between the dose escalation and what we call the dose exploration trial. We've since treated additional patients in the dose exploration arm, primarily at the 40 milligram dose level, to further characterize that better. Before Aptivate was opened, we were then dosing patients, ideally exclusively on Aptivate. As studies became online, we were able to do that. The dose level that we started Aptivate at for the monotherapy was 120 milligrams. That may change as we learn more about the PK and the activity of the drug. but we may move to 80 milligrams for the monotherapy dose, seeing the level of activity, although it's not something we have implemented. For the combination study, 80 milligrams will be the starting dose that we've signaled before in combination with venetoclax, and as always, that is also subject to change based on the data that we receive.

Right. So how are you thinking of presenting the data mid-year or later second half also? Are you going to do... with this from the activate trial, like the traditional ORR response rate or CR rate over a number of patients treated? And alongside, you're going to show a long-term, if any, durability data from the dose escalation expansion part of the trial?

Traditionally, we have done that kind of more complete update at major medical meetings like EHA and ASH. And I think that that will definitely hold true for ASH. I do think that EHA will be a more incremental update, so there may not be that much level of detail, just because, to be honest, the cutoff date for data to present at EHA is about now. So we won't necessarily have a lot more to say than we have said earlier this year in that regard. So we will do an incremental update. We'll certainly highlight any activity or issues that arise in the study around EHA, but expect a larger data package with some of the more detail that you just described to happen later in the year. Perfect. Thank you so much.

Just to add to that, we will have certain scientific findings at EHA that we'll be presenting. That's the plan, as well as some of the additional data, as you said, as we follow some of these patients that have been on the dose escalation, dose exploration. We'll be able to provide that. But then, as Dr. Behar said, we just started the Aptivate trial, and we'll present the data that are available. It won't be a huge number of patients by that time, but we'll present what we have.

Thank you, and congratulations on all the progress. Thank you, Shuman.

Thank you. Please stand by for our next question. Our next question comes from the line of Joe Tanguinis with HC Wainwright.

Your line is open.

Hey, guys. Good afternoon. Thanks for taking the question. So, Bill, I was wondering maybe if you could do a little benchmarking for the audience about your regulatory plan for the monotherapy arm in Aptivate. You talked about, you know, since it's mono, you know, potential accelerated approval. So, you know, based on your internal thoughts, regulatory consultants or what have you, can you benchmark how many patients do you think you'll need for the FDA to be happy with? And more importantly, can you benchmark essentially a response rate or a CR rate to beat?

Boy, a number of questions there. So, first of all, I'm not going to go too much out on a limb because soon we are going to be having the FDA, and we've already articulated that to the street. So, we'll be speaking with all the parameters you just mentioned for the monotherapy, as well as the doublet data that are coming out. We want to make sure that as we go to the FDA, by then we will have a number of patients that are already on the monotherapy, the AFTAVATE trial, make sure that we're doing everything that we should. determine if there are additional parameters we need to measure so that when we go to them with the data later in the year we'll have everything that we need and hopefully the data will be supportive of going toward a an accelerated approval whether that's a monotherapy a doublet you know we'll see how those data emerge toward the end of the year and Raph is there anything else that you wanted to add to that in terms of regulatory no I think that's a

That's a good way to put it. I think that we do need to have that meeting with the FDA to really align ourselves. And depending on what features we agree upon, that'll change the scope of the study. But certainly an accelerated approval study would be a much smaller study than you would have to do if you did a randomized multi-armed study. Yeah.

And then also a little bit later in the year, as we collect data on the doublet, we want to be able to go to the FDA, present the data there, and hopefully have the ability to move into the triplet trial. Does that answer your question, Joe?

No, it does. And I guess maybe just a little on the, you know, for the listeners and everyone and investors in general, you know, benchmarking you would look at from an efficacy standpoint. A lot of therapy.

Yeah. So, Raph, do you want to put that in context relative to the Admiral trial? And, Joe, thanks for the question.

Yeah, exactly. I think that that's the way you need to view it is, you know, what population are we treating and what expectations might they have from alternatives if testbed wasn't available? And remember, these are patients who, if they are FLT3 mutated and have seen FLT3 inhibitors, they've likely been through at least two lines of prior therapy, so they're coming to a third line or beyond. In the second-line setting with the Admiral study, at the interim analysis for giltritinib, the CR-CRH rate was 21%. Now, later that matured, especially with the inclusion of patients whose best response was measured after transplant, But at the point of that interim analysis that led to the approval of the drug, that was 21% in the second line in patients largely naive of other therapies. So we would argue that a meaningful number in the third-line setting would be significantly less than that, perhaps as well as half of that or somewhere between half to that range, given that the alternatives for those patients at that point are going to be even less effective than they might have been in the second-line setting, as they were in the Admiral study where the chemotherapy response rate for CR was about 11%. So that's the ballpark that we're working with, and what we come down with with the SCA I think will then shape the scope of the study, the size, and so on, and that's the discussion we're going to have.

Great.

Yeah, I think the bar is fairly low for that patient population, as you said. Many of them will have already failed other FLT3 inhibitors. venetoclax and more and more patients that are coming along now, especially in the U.S., are having much more experience with prior drug therapy. And so, these patients are very difficult to treat. So, we think the bar will not be exceptionally high, but we also believe we can achieve it. Thanks, Joe. Appreciate you coming on.

Thank you.

Please stand by for our next question. Our next question comes from the line of Edward Tenhoff with Piper Sandler.

Your line is open.

Great. Thank you very much, and congrats on all the progress. It's going to be an exciting year. I think most of the questions on 235 or 539 were asked, but I wanted to ask on Locke's sort of higher level how this fits into the treatment or how this treats into your development plan, and specifically, You know, what are our expectations here? Is this a drug that you would consider partnering? Does it ultimately have combinability, maybe even with fibrin? Thanks very much.

Thanks, Ted, for the questions. Yeah, we don't get that many questions on Lux anymore, but we're still excited by the drug. Now that we have our new formulation, and especially as we go up to that next higher dose level, that's the plan now. And we hope we get higher exposure as we go into that. But in terms of what we'd like to do with this molecule, I mean, first of all, I must say that Tospetinib is our top priority among everything. And it has to be because it is delivering. It's more advanced. It's delivering. But Lux, as we move forward, we'd love to see that we're getting the exposure that we want and that the pill burden is also much less. Cost of goods, much less. If we continue to see activity in AML, we have done studies where we put TUS and LUX together, and they are not antagonistic. They also, we know, have different activities against different kinases. So it may turn out to be like some of the other indications where you have multiple kinases that hit different patients with different mutation profiles. But most likely, we likely will move it more toward the B-cell arena and also toward inflammation and autoimmunity because we've been, as you can tell from the publications, we've been digging into that area, understanding it. There's still a need because this drug is different from the other non-covalent BTK inhibitors. It hits a different set of kinases. It has different activities. And we believe that if we're able to combine it, for instance, with with some of these other drugs that are being developed for the B-cell malignancies, like Venetoclax, for instance, then we believe we can see real activity there. So there are paths for it that do not interfere with Tuspatinib. Does that answer your question?

Yes, it does. Very helpful. Thank you.

Yeah. All right. Thank you.

Thank you. Please stand by for our next question. Our next question comes from the line of Lee Watzak with Cattle Textural.

Your line is open.

Hi, everyone. This is Rosemary for Lee. Thanks for taking my questions. Just a couple here. Firstly, are you able to give some color around the early activity that you see from the monotherapy arm and activate? And then on the RAS pathway, can you talk a bit more about where you can go with this finding, if RAS correlates with any other mutations potentially? and whether you see mono or combo therapy potential here?

Thank you. Thanks, Rosemary, for coming on. So I'll start with this, and then maybe Dr. Behar would want to jump in. So in terms of early activity, again, it is very early in the Aptivate trial on the monotherapy. And as we said in our press release, we are beginning to see what we call initial anti-leukemic activity. You'll remember we're very conservative on what we say in terms of what we're seeing in the clinic. So, yes, if you're asking us, we do see some level of blast reductions. We're not going to be talking about how much or what we're seeing or the number of patients. It's just very early. But are we seeing hints of activity beginning? Yes, it's early, but we are. You also asked about the RAS mutations. I find this one very exciting, to tell you the truth, because many of the other drugs out there, one of the major escape pathways for other drugs is the RAS pathways. But we've seen activity, CR, CRHs. I mean, these are real responses in patients that have NRAS, KRAS, and also other mutations within the RAS pathway. So it's a real need that I don't think people have highlighted enough in AML because there hasn't been really a good drug to treat these. But I'm hoping we get more of these patients. I'm hoping that we see activity in these patients. And maybe this will be another indication that we can look toward as an accelerated approval. But the data will have to point us in those directions. I'm going to turn it over to Dr. Behar and see if he has any additional comments.

I think that was well put. I think what is exciting about the activity in RAS mutant patients is that RAS mutations in the relapse setting really mean something different than they do in the frontline setting. Even drugs like venetoclax, you can get responses in patients who have NRAS in that frontline setting. But when patients relapse, it's typically with an expanded NRAS clone or a new NRAS clone or FIT3 clone that activates that signaling network. So the ability to target patients that have NRES mutations is exciting not only to treat potentially refractory patients, but also to treat patients in the front line and prevent the development of resistance through that pathway. So we're hopeful that it has benefits in both patient populations. And Bill, to your point about the activity in the APTIVATE study thus far, I'll just point out that patients began enrolling in APTIVATE in January. It takes a month before their first assessment, bone marrow assessment, takes place, and then another month before the confirmatory biopsy takes place. So we're just about at that point now for the earliest patients enrolled. So all we can really say is that we've observed activity in terms of peripheral blast reductions and looking at early looks at the bone marrow only, but we'll have more data around that as we get further along.

Thank you, Rob. So, Rosemary, did we answer your questions?

Thank you.

All right. Thanks for coming on.

Thank you. As I'm reminded, ladies and gentlemen, that's star 1-1 to ask the questions.

Please stand by for our next question. Our next question comes from the line of Gregory Renza with RBC.

Your line is open.

Hi, guys. It's Anish on for Greg. Congrats on the progress, and thanks for taking my question. Just on TUS, in considering the different AML mutations or subpopulations studied, And with the data to date, in which type are you seeing the most responses? And as a follow-up, in which subtype are you seeing greater response with a 40-milligram dosing regimen versus those that require greater exposure slash higher dose for a response with tests? And how might these findings inform regulatory next steps? Thanks so much.

Good question. But, Raph, do you want to jump in on this one?

I can start. That is a great question. I think that that is something that we're very interested in learning. We're limited by a few things. The first is patient numbers. Even after treating 60-plus patients, you don't necessarily have that many patients in any particular genetic subgroup when you open a study at oil commerce. So we don't have large denominators with which to be highly accurate about our response rate. But we do see activity in these patients that have these mutations that we would like to have activity against, including NRAS. We've, again, seen two patients with TP53 mutations that have activity. These are all patients that are predicted to not do as well because of these adverse mutations that they carry. It could be subsets of populations with great unmet medical need. But to be fair, all relapsed refractory hemo patients are a population of great unmet medical need. As many can't be cured with conventional therapy, they need to go to some sort of stem cell transplant at that point. So the ones of interest, I think I mentioned NRAS, TP53, for three patients that have exhausted for three inhibitors prior. But there may be others, and it may be combinations of mutations that matter, for example, NPM1 and FLIP3 mutations. We've seen a reasonable response rate in that patient population as well. And the Aptivate study, by enrolling additional patients, will really give us the confidence that we understand what those response rates are in the different populations. You had asked about differential activity at the 40 milligram dose level. We've reported that there were two responses at that dose level. So, again, very small numbers, not really enough to discriminate whether, you know, 40 was enough for some patients but not enough for others. I think we'll have to really look at the PK more to define what the optimal dose is there, even though we're thrilled to see activity at the 40-milligram dose level.

Well said. Great. Thank you. All right. Thanks for coming out.

Thank you. Please stand by for our next question. Our next question comes from the line of John Newman with Canaccord.

The line is open.

Hi, guys. Thanks for taking the question. As you move forward with the F2-8 study, in terms of the potential for accelerated approval, would you expect that you'll be focusing on a specific mutational type, or would you be focusing more broadly? Thanks.

Yeah. I'll start, and then Dr. Behar can come in. Thanks, John, for coming on. So as we look at the patients being treated with monotherapy, clearly we want to enrich for certain of these populations. The ones that Dr. Behar had mentioned, those that had failed prior FLT3 inhibitors, those that have TP53 mutations. Now that we've seen some of these data with RAS, we'll ask the investigators if we can try to find patients more like that and hope to get enough of these patients to be able to go to the FDA and say, hey, there's a real signal here. We'd like to move forward for the accelerated approval. But I also want to emphasize the doublet is very important for us. Because showing that your drug works well and is well tolerated in combination with venetoclax, that's what's going to launch us into two different pathways. One is it's going to position us for the triplet and to go toward frontline patients. And that is ultimately where we want to go. And we think our drug is going to be the ideal drug to combine with the HMA VENs because of all the reasons that Dr. Behar articulated. But it also will allow us then to decide how to move forward in doublets. So we're looking at ways to have the VIN-TUS patients for, and hopefully we could design it so that we could have an early look at the data, accelerated approval as we continue to bring patients on for full approval in a doublet trial. And I'm sure Dr. Behar can say it far more eloquently. So would you like to jump in?

Yeah. It won't sound as good as coming from you, Bill, but I will say that the Admiral study is actually a good model for what you might be able to do in a second-mind setting, say, for example, with a test bed and a venetoclax tablet, where you have a study that's powered to eventually read out overall survival, but that includes an incremental and interim analysis that could be compelling enough to seek approval. So that is one option. With the monotherapy study, of course, you don't have anything to compare it to, so we'd just be shooting for a target response rate at that point. Yeah.

But thanks for giving us the opportunity to talk about those a little bit, John.

Thank you. Yeah. Any other questions? John? Oh, no. Thank you. Okay. All right. Thank you.

Thank you. I'm currently showing no further questions in the queue. I would now like to turn the call back over to Dr. Rice for closing remarks.

I want to thank everyone for joining us this afternoon, and thank you for all the interest in Aptos, the drugs, and the data that we're generating. We're gratified as we look in the rearview mirror of 2022, and we see the clinical progress of Tospetinib and the strides we're making with the G3 formulation of LUX. Yet our eyes now are really looking forward to 2023 and beyond. and we're eager to share data with you during the coming year. Again, we talked about being able to present data at the conferences, but also at the earnings calls as well as in banking meetings. So we want to thank our clinical team, our investigators, our patients for their help in this important work. We appreciate the support of our shareholders and analysts, and we look forward to keeping you updated on our progress the rest of the year. Thank you, and have a good evening.

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

Thank you. you you

Hello, and thank you for standing by, and welcome to Aptos Biosciences reports for the fourth quarter and year-end 2022 conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask the question during the session, you will need to press star 1-1 on your telephone, and you will then hear an automated message advising your hand is raised. To withdraw your questions, please press star 1-1 again. I would now like to hand the conference over to Susan Peptralo. You may begin.

Thank you, Tawanda. Good afternoon and welcome to the Aptos Biosciences Conference call to discuss financial and operational results for the year-end and fourth quarter ended December 31, 2022. Earlier today, Aptos issued a press release relating to these financial results. The news release as well as related SEC filings are accessible on Aptos' website. Joining me on today's call are Dr. William G. Rice, Chairman, President, and CEO, Dr. Rafael Behar, Senior Vice President, Chief Medical Officer, and Mr. Fletcher Payne, Senior Vice President and Chief Financial 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 Aptos' current expectations regarding future events. They 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 Aptos' most recent annual report on Form 10-K and SEC and CEDAR filings. All forward-looking statements made during this call speak only as of the date they are made. Aptos 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 Aptos Biosciences. Dr. Rice.

Thank you, Susan. I want to welcome everyone to our call for the year-end and fourth quarter-end of December 31st, 2022. First, I'll provide a very quick overview of 2022. While the biotech market has been extraordinarily challenging, Aptos continued a steady march forward. We extended our cash runway to the end of Q1 2024. We continued building a talented and experienced team. We created and began testing a new formulation for Luxeptinib. And most importantly, we made significant strides in the development of Tospetinib for the treatment of acute myeloid leukemia, or AML. When it comes to tuspetinib, or TUS as we call it, I want to emphasize its highly differentiated profile, having demonstrated the potency to achieve complete remissions in very ill relapsed or refractory AML patients, while also being safe and well-tolerated. It's extraordinary for an antileukemic agent to deliver formal responses in such an aggressive cancer without causing the typical toxicities of other agents. And today, we will unpack both the potency and safety attributes of TUS. It's also important to highlight the AML population that has been treated with Tuspatinib to date in our Phase 1-2 dose escalation and dose exploration trial. These are typically third line, fourth line, or beyond, having failed the best available approved therapies, and in many cases, having failed various investigational drugs or prior hematopoietic stem cell transplants. These are incredibly difficult patients to treat and to reverse the disease progression. What makes these patients even more difficult to treat is the extreme diversity of highly adverse genetic and epigenetic alterations expressed by their disease. If we recall the Admiral trial from just five years ago, during which the commercial dose of giltaritinib, a FLT3 inhibitor, was tested for responses in AML, the patients were second line, essentially had not seen other FLT3 inhibitors and had not seen venetoclax. In contrast, patients entering our trial are far more treatment experienced, with half failing prior venetoclax, 60% failing prior treatment with hypomethylating agents, or HMAs, more than a quarter having failed transplants, and half of the FLT3 mutant patients having failed prior therapy with a FLT3 inhibitor. Nevertheless, TUS has delivered responses with convenient once-daily oral dosing of tablets across four dose levels, 160 milligram, 120 milligram, 80 milligram, and 40 milligram, and no DLTs were observed with any of those active dose levels. From a mutation sensitivity perspective, TUS has shown an unprecedented breadth of activity. TUS delivers responses in FLT3 wild-type patients as well as it does in FLT3 mutated patients. We also have seen responses in AML patients having the very difficult-to-treat TP53 mutations as well as patients with NPM1 and FLT3 commutations. and patients having alterations in the DNMT3A, RUNX1, IDH1, splicing factors, ASXL1, and MLL genes. But one of the most interesting observations is the activity in relapsed refractory AML patients with RAS mutations. Mutations in the RAS pathway serve as an escape mechanism to generate resistance to many other drugs. However, we've measured a 42% overall response rate in patients with RAS mutations including a 29% CR-CRH response rate. In fact, one patient had a RAS mutation and a mutation in PTPN11, representing a dual mutation in the RAS pathway. We will continue to monitor the response rate in RAS-mutated AML patients this year and determine if RAS-mutated relapsed refractory AML patients may represent a population of high need for future accelerated approval trials. As Dr. Behar will describe in further detail in a few minutes, we wrapped up our highly successful phase 1-2 dose escalation and dose exploration trial. We've treated over 60 patients to date in that trial. We've assembled a strong safety data package. We selected safe and effective doses for our single agent and drug combination trials. We demonstrated the ability of TUS to dramatically reduce bone marrow blasts in a high fraction of patients and to achieve formal responses. and we initiated our Aptivate dose expansion study of TUS in a single agent and in combination with venetoclax. In the Aptivate trial this year, we will enrich certain patient populations to receive monotherapy so that we can collect data to guide our conversations with the FDA to request an accelerated approval path for TUS in patients of high and met need. In parallel with the Aptivate monotherapy dosing, we will treat a broad array of AML patients with a combination of TUS plus venetoclax, referred to as the TUS-VEN doublet. This TUS-VEN doublet is being conducted to support doublet combination registrational trials in second-line AML patients and to serve as a bridge to a pilot study of TUS plus VEN plus a hypomethylating agent or the TUS-VEN HMA triplet in frontline AML patients. While TUS clearly can deliver responses as a single agent, the ultimate goal and commercial success of TUS or any drug for AML will be in combination with other drugs. As of this week, we have begun enrollment of AML patients on the TUS-VEN doublet, and we will place additional patients on this doublet throughout 2023. Once we gain experience with the doublet, we plan to initiate the TUS-VEN HMA triplet in frontline patients. The future of AML therapy will also revolve around cocktails of drugs in earlier lines of therapy to take patients into deep remissions. Such AML cocktails will require the blending of drugs that best can serve broad populations of patients, can deliver deep remissions, and can be tolerated without cardiotoxicities, unnecessarily prolonged myelosuppression, and other complicating side effects. And this precisely describes TUS. TUS is positioned to become the ideal partner for addition to the Venn HMA doublet because of its convenience as a once-daily oral agent, its broad activity, and its safety profile. Together, data to date point us toward application as a monotherapy for accelerated approval in relapsed to refractory AML, as doublet therapy for accelerated approval in second-line AML, for use in triplet combination in frontline patients, as well as a use in maintenance therapy. and Dr. Behar will provide you with additional color of these activities momentarily. Now let me turn briefly to Luxeptidib. Many of you know it as CG806. Lux, as we typically refer to it, is our secondary pipeline program. Lux is a clinical stage, small molecule, oral, FLT3 and BTK kinase inhibitor. Lux's ability to target kinases, operative in certain leukemias and lymphomas, led us to develop it in patients with B-cell leukemias and lymphomas, and in patients with AML. We already have reported that LUX, administered as our initial first-generation or G1 formulation, delivered a CR in an AML patient and a CR in a DLBCL lymphoma patient, demonstrating LUX is a clinically active agent. You also are aware that we developed a new formulation of LUX, and we call it the G3 formulation because it represents the third-generation formulation. In single-dose administrations during 2022 in AML and B-cell malignancy patients, we determined the G3 formulation achieved up to 18-fold greater absorption than the original G1 formulation. Because the highest dose of the original formulation was set at 900 milligrams, we initiated continuous dosing of G3 at an 18-fold lower dose level of 50 milligrams. We continue to collect PK and safety data with G3 and AML patients, and the preliminary results suggest continuous dosing of 50 milligrams G3 does indeed deliver roughly equivalent plasma exposures as 900 milligrams of the original G1 formulation. That was the target we hoped to achieve with the 50 milligrams of G3. And next, we plan to administer a higher dose of G3 to determine if it can achieve even greater plasma exposure levels. We will keep you posted on our findings, and likely we'll report preliminary data around EHA. I also want to mention that Aptos and collaborators at UCSD, Dr. Manchu Sonowal and Dr. Stephen Howell, just published an article entitled, Luxeptinib Interferes with Lin-Mediated Activation of Sick and Modulates BCR Signaling in Lymphoma, in the online journal PLOS One, in which we describe the ability of LUX to act on the B-cell receptor pathway at the level of the LCK and LYN, or LIN, kinases, and to influence downstream BTK activity. This relates to the role of LUX to act on B-cell cancers, as well as inflammatory and autoimmunity processes. So, please take a look at the article if you get a chance. Finally, we often get asked about potential partnerships for Tuspatinib. In January, during J.P. Morgan Week, We engaged in productive discussions with several big pharma and biotech companies that further helped to define our priorities and to solidify our clinical plans with Tuspatinib. It's clear what we need to accomplish with a drug that has such an extensive commercial opportunity. We were pleased to see that we're on the radar of these companies and interest in our program is growing. The treatment paradigm for AML is shifting toward doublet and triplet therapy. And despite some successes, the current combination therapies are somewhat limited by toxicities, as I mentioned previously. The proven breadth of activity and superior safety profile of Tospetinib lends itself to combination therapy, potentially as the drug of choice, addressing the most sizable markets in AML and clearly making TUS a prospective big pharma drug. The data we've generated to date have helped us to alleviate clinical and commercial plans for Tospetinib in multiple lines of therapy, including its use in doublet and triplet combinations and as maintenance therapy. Our chief medical officer, Dr. Rafael Behar, will speak about our recently initiated APTIVATE clinical trial of Tuspatinib in AML as a single agent and in combination with Venetoclax, as well as our extended clinical plans, which include triplet combination therapy. He also will be available for questions afterwards. I now will turn it over to our resident KOL, our chief medical officer, Dr. Rafael Behar, to talk more about our Tospetinib clinical plans. Raf?

Thanks, Bill. In January, we were thrilled to kick off the 120-milligram dosing of Tospetinib in the monotherapy arm of the Aptivate Phase 1-2 trial. As most of you know, we have successfully completed dose escalation and dose exploration stages of our TUS Phase 1-2 trial, treating approximately 60 relapsed refractory AML patients who were heavily exposed to multiple agents. In fact, as Dr. Rice mentioned, While we were wrapping up the dose exploration part of the study, we took the prudent step of putting additional patients on the lowest 40-milligram treatment group because of the FDA's Project Optimist that emphasizes dose exploration during early development of oncology products. This experience gave us the additional data needed to support our monotherapy dose selection and was not born out of a safety concern. Rather, as higher doses of Dyspedinib have shown an impressive safety profile, since we lost the 40-milligram dose level late last year, we have achieved two clinical responses in that low-dose group. both AML patients with unmutated FLT3, including the most recent harboring a challenging TP53 mutation, one of the most highly adverse somatically mutated genes. Importantly, this is the second TP53 patient that has achieved a clinical response. The first was at the 80 milligram dose who achieved an unqualified CR at their best response. So we look to enroll more of these patients who with such a poor prognosis have a great unmet need in the APTIVATE trial. The APTIVATE expansion trial is designed to confirm monotherapy activity to patient enrichment of specific mutationally defined AML populations, including the TP53 mutant patients, as well as split three mutated patients who had been failed by prior for three inhibitors, as supported by an FDA fast track designation and a clinically significant response rate to date. These patients continue to have great unmet medical need, and we believe that the ability to rescue these patients and perhaps allow them to receive a stem cell transplant, which we have now done with several patients in our study, would allow us a quicker path to registration. In addition to being potential accelerated approval pathways for tispetinib, treating these subgroups will provide critical data to inform our continued development path. I am pleased to say that we have begun treating patients in the monotherapy arm of the Aptivate trial and that a growing network of clinical sites and investigators are engaged in enrollment and that this has been brisk. In the Aptivate expansion trial, tispetinib also will be tested in combination with venetoclax. Several sites now have regulatory clearance and both drugs in hand, allowing us to initiate patient enrollment on the TUS-VEN combination earlier this week. Having the TUS-VEN combination arm open is an important advance, as this represents an attractive treatment option for patients and their physicians, leading them to enroll earlier in the course of treatment, increasing the likelihood of achieving a meaningful clinical benefit. So what is our timeline for our clinical trials? Because Aptivate is an open-label trial, we will report data when available at appropriate forums. We will have an update around EHA in June, for example, as we usually do, but because data collection and verification does take time and Aptivate has only been open for a short while, this will be an incremental update. We would expect to have more complete data, particularly for the monotherapy arm, at the European School of Hematology meeting, ESH, at the end of October in Estoril, Portugal. Expect more data, including from the TUSF and combination cohort, to then be updated at ASH in San Diego in December. So, 2023 will be a busy year for us. Having tested tispetinib in specific genetically defined populations, we would expect to have sufficient patient data this year, then segue into Phase II registrational studies to support accelerated approval. As Dr. Rice mentioned, we are including relapsed or refractory AML patients with unusaged FLT3, what we often call wild-type patients, that have other adverse mutations, exploring safety and activity in these patients with tispetinib treatment, both as a single agent and in combination with venetoclax. Identifying meaningful activity in other adverse subgroups could lead to other options for accelerated approval. The paradigm for the treatment of AML is increasingly moving towards combination therapy, and we hope to position despetinib as a preferred agent for combination and used in earlier lines of treatment. It is our hope, and based on our data thus far, it is our expectation that we will move forward with despetinib in a triplet combination and in maintenance settings. Dr. Naval Dauber from MD Anderson, who's been one of the investigators pioneering AML combination therapies with venetoclax, is our lead investigator on Aptivate and is eager, as we are, to see what Suspendip can do in this setting. We'll also highlight a few comments from Dr. Harry Erba of the Duke Cancer Institute during a recent KOL event. He noted that this drug may be better suited for the combinations that we hope to develop than anything we have right now. And he was excited about the apparent lack of myelosuppression noted in our clinical study to date. And he emphasized that a drug like TUS will have a position mostly because of its better toxicity profile than the drugs we're using now in terms of myelosuppression. Clearly, we agree wholeheartedly with Dr. Urba, and we believe that potency, breadth, and anti-leukemic activity, along with the safety profile, make TUS-BETNEP the ideal drug for combination therapy and scalable commercialization. On our website, you can see our projected timeline for our ongoing and planned clinical trials. I want to thank our clinical team for their hard work and execution in getting both arms of after-date expansion study up and running. We certainly look forward to sharing the data with you. Now, I'd like to turn the call over to our CFO, Fletcher Payne, for an update on our financial status. Fletcher?

Thanks, Raf. And good afternoon, all. Before we start speaking about the financials, I'd like to introduce to you the newest member of our finance team, Brooks Ensign, who is a VP and controller of Aptos. Mr. Ensign has more than 20 years of pharmaceutical industry experience in accounting, finance, corporate development, and he served in this position for multiple public and private companies. Mr. Ensign has a master's and holds an MBA from Harvard Business School and a master's in accountancy. We're pleased to be able to recruit quality people like him, and we're very happy to have him here at Aptos. Let's review the fourth quarter and year-end financials. As most of you know from following Aptos, we take a disciplined approach to cash management and always look to prioritize our clinical activities without sacrificing quality of our programs. These efforts have extended our cash runway into 2024, and our cash management policies and the actions taken have helped us avoid the financial impact of Silicon Valley Bank's fallout. Now let's review our cash position. We ended 2022 with approximately $47 million in cash, cash equivalents, and investments, a decrease of $4.8 million as compared to the previous quarter. During the quarter, the net loss was approximately $10 million, translating into approximately negative 11 cents per share loss, down from $24.3 million loss from the comparable period in 2021. As identified in the income statement, we had no revenues during the fourth quarter of 2022. Recurrence and development expenses were $6.8 million for the quarter, down $20.2 million from the same quarter in 2021. research and development expenses for the full year period ended December 31st, 2022 were $28.1 million as compared to $46 million for the comparative period, a decrease of $18 million. That decrease was due to several factors, including a $12 million licensing fee paid to HANMI in the previous year to acquire global development rights for Tecetamib, which comprised a $5 million cash payment, and a $7 million worth of common shares. Additionally, there were lower costs for the LUX program and 253 program, as well as lower personnel costs. These savings were potentially offset by costs for the Deceptin program that was adopted in 2022. G&A expenses were $3.6 million for the quarter, as compared to $4.1 million for the same quarter of 2021. GNX expenses for the 12-month period ended December 31, 2022 were $14.5 million as compared with $19.5 million for the comparative period, a decrease of approximately $5 million. The decrease was primarily due to a decrease in stock-based compensation expenses offset by higher compensation expenses, travel expenses, and professional fees. As of March 2023, APTOS has 93,005,278 common shares outstanding. More detailed information can be found in our filings on Edgar and Cedar. Now let's turn it back to Dr. Rice.

Thank you, Fletcher. As we open the call for questions, please feel free to pose a question to any of us. Operator, if you could, please introduce the first question.

Thank you. At this time, I would like to remind everyone how to ask the question. To ask the question, please press star 11 on your telephone and then wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Matthew Beigler with Oppenheimer. Your line is open.

Oh, hey, guys. Thanks for the update. Just two for me. I'm wondering, is it too soon to guide on patient numbers for that October update? Yeah, from the Aptivate trial. And then I'm just curious about some of the comments Raf made about the doublet versus the singlet to Spetniv and Aptivate. I'm curious if you're concerned that it might be challenging to enroll the monotherapy arm given that there is a doublet, or kind of how are you approaching that, or how are you thinking of kind of weeding out patients from one to the other? Thanks.

Thanks, Matt. This is Bill. I'll start on that. Your second question is really easy, doublet versus monotherapy. We've had exceptional uptake, rapid uptake, and I think the word that Dr. Behar used was brisk uptake as the monotherapy. We got it up and running first this year, and it's been great enrollment pace, and we're just now beginning to enroll the doublet. In terms of the numbers of patients and all, I'm going to turn that back over to Dr. Behar. We'll be careful not to really bracket them too much, but we'll try to give you a sense. Raph?

Yeah, thanks, Matt. And just to follow up on, Bill, your earlier point about the enrollment to both, the doublet, I think, is going to be more appealing to investigators in the monotherapy in general. But once both arms are open and those options exist, there'll be a random assignment. So we are hoping that not only do we get more patients on because there's more enthusiasm for the study, but the patients may actually come on earlier in the course of therapy because there is this doublet combination option available to them. So we will focus on both through the end of the year, and we'll give you more clarity when we get to that point. In terms of numbers of patients, like I said, it's hard to put an exact number on it, but I would say the enrollment has been very good. And there certainly will be, I'm not bragging too much, maybe tens of patients on the myotherapy arm, and hopefully somewhere between 10 and 20 patients on the doublet arm by the time that we read out near the end of the year. All right, great, thanks.

Thank you. Please stand by for our next question. Our next question comes from the line of Schumann Roy with Jones Trading. Your line is open.

Hi, everyone. Thank you for the update. Could you give us a little bit more color on the different dose cohort size you're enrolling currently between 40, 80, 120, and then The hundredth patient you mentioned, what split is monotherapy and doublet?

All right. Hey, Schmidt. This is Bill Rice. So, yeah, we have completed the dose escalation and dose exploration trial. And so I'll ask Dr. Behar to give you a breakdown on the numbers of patients there, and then he can talk about the Aptivate.

Right. So as of the ASH meeting, when we had not yet opened Aptivate, we had treated 60 patients between the dose escalation and what we call the dose exploration. We've since treated additional patients in the dose exploration arm, primarily at the 40 milligram dose level, to further characterize that better before Aptivate was opened, where we were then dosing patients ideally exclusively on Aptivate as studies became online and were able to do that. The dose level that we started Aptivate at for the monotherapy was 120 milligrams, That may change as we learn more about the PK and the activity of the drug. We may move to 80 milligrams for the monotherapy dose, seeing the level of activity, although it's not something we have implemented. For the combination study, 80 milligrams will be the starting dose that we've signaled before in combination with venetoclax. And as always, that is also subject to change based on the data that we receive.

All right. So how are you thinking of presenting the data mid-year or later second half also? Are you going to do with this from the activate trial like the traditional ORR response rate or CR rate over number of patients treated and alongside you're going to show a long-term, if any, durability data from the dose escalation expansion part of the trial?

So traditionally we have done that kind of more complete update at major medical meetings like EHA and ASH. And I think that that will definitely hold true for ASH. I do think that EHA will be a more incremental update. So there may not be that much level of detail just because the, to be honest, the cutoff date for data to present at EHA is about now. So we won't necessarily have a lot more to say than we have said earlier this year in that regard. So we will do an incremental update. We'll certainly highlight any activity or issues that arise in the study around EHA, but expect a larger data package with some of the more detail that you just described to happen later in the year. Perfect. Thank you so much.

Just to add to that, we will have certain scientific findings at EHA that we'll be presenting. That's the plan, as well as some of the additional data, as you said, as we follow some of these patients that have been on the dose escalation, dose exploration. We'll be able to provide that. But then, as Dr. Behar said, we just started the Aptivate trial, and we'll present the data that are available. It won't be a huge number of patients by that time, but we'll present what we have.

Thank you, and congratulations on all the progress. Thank you, Shuman.

Thank you. Please stand by for our next question. Our next question comes from the line of Joe Tanguinis with HC Wainwright. Your line is open.

Hey, guys. Good afternoon. Thanks for taking the question. So, Bill, I was wondering maybe if you could do a little benchmarking for the audience about your regulatory plan for the monotherapy arm in Aptivate. You talked about, you know, since it's mono, you know, potential accelerated approval. You know, based on your internal thoughts, regulatory consultants or what have you, can you benchmark how many patients do you think you'll need for the FDA to be happy with? And more importantly, can you benchmark essentially a response rate or a CR rate to beat?

Boy, a number of questions there. So, first of all, I'm not going to go too much out on a limb because soon we are going to be having the FDA, and we've already articulated that to the street. So, we'll be speaking with all the parameters you just mentioned for the monotherapy, as well as the doublet data that are coming out. We want to make sure that as we go to the FDA, by then we will have a number of patients that are already on the monotherapy, the Aptivate trial, make sure that we're doing everything that we should, determine if there are additional parameters we need to measure, so that when we go to them with the data later in the year, we'll have everything that we need, and hopefully the data will be supportive of going toward an accelerated approval. Whether that's a monotherapy, a doublet, we'll see how those data emerge toward the end of the year. And Raph, is there anything else that you wanted to add to that in terms of regulatory?

No, I think that's it. That's a good way to put it. I think that we do need to have that meeting with the FDA to really align ourselves. And depending on what features we agree upon, that'll change the scope of the study. But certainly an accelerated approval study would be a much smaller study than you would have to do if you did a randomized multi-armed study. Yeah.

And then also a little bit later in the year as we collect data on the doublet, we want to be able to go to the FDA, present the data there, and hopefully have the ability to move into the triplet trial. Oh. Does that answer your question, Joe?

No, it does. And I guess maybe just a little on the, you know, for the listeners and everyone and investors in general, you know, benchmarking you would look at from an efficacy standpoint. A lot of therapy.

Yeah. So, Raph, do you want to put that in context relative to the Admiral trial? And, Joe, thanks for the question.

Yeah, exactly. I think that that's the way you need to view it is, you know, what population are we treating and what expectations might they have from alternatives if testbed wasn't available? And remember, these are patients who, if they have FLT3 mutated and have seen FLT3 inhibitors, they've likely been through at least two lines of prior therapy, so they're coming to a third line or beyond. In the second-line setting with the Admiral study, at the interim analysis for giltritinib, the CR-CRH rate was 21%. Now, later that matured, especially with the inclusion of patients whose best response was measured after transplant, But at the point of that interim analysis that led to the approval of the drug, that was 21%. In the second line, patients were largely naive of other therapies. So we would argue that a meaningful number in the third-line setting would be significantly less than that, perhaps as low as half of that or somewhere between half to that range, given that the alternatives for those patients at that point are going to be even less effective than they might have been in the second-line setting, as they were in the Admiral study, where the chemotherapy response rate for CR was about 11%. So that's the ballpark that we're working with, and what we come down with with the FDA I think will then shape the scope of the study, the science, and so on, and that's the discussion we're going to have.

Yeah, I think the bar is fairly low for that patient population, as you said. Many of them will have already failed other FLT3 inhibitors. venetoclax and more and more patients that are coming along now, especially in the U.S., are having much more experience with prior drug therapy. And so, these patients are very difficult to treat. So, we think the bar will not be exceptionally high, but we also believe we can achieve it. Thanks, Joe. Appreciate you coming on.

Thank you.

Please stand by for our next question. Our next question comes from the line of Edward Penhoff with Piper Sandler.

Your line is open.

Great. Thank you very much, and congrats on the progress. It's going to be an exciting year. I think most of the questions on 235 or 539 were asked, but I wanted to ask on Locke's sort of higher level how this fits into the treatment or how this treats into your development plan, and specifically, You know, what are our expectations here? Is this a drug that you would consider partnering? Does it ultimately have combinability, maybe even with 5-3-9? Thanks very much.

Thanks, Ted, for the questions. Yeah, we don't get that many questions on Lux anymore, but we're still excited by the drug. Now that we have our new formulation, and especially as we go up to that next higher dose level, that's the plan now. And we hope we get higher exposure as we go into that. But in terms of what we'd like to do with this molecule, I mean, first of all, I must say that Tospetinib is our top priority among everything. And it has to be because it is delivering. It's more advanced. It's delivering. But Lux, as we move forward, we'd love to see that we're getting the exposure that we want and that the pill burden is also much less. cost of goods much less. If we continue to see activity in AML, we have done studies where we put TUS and LUX together, and they are not antagonistic. They also, we know, have different activities against different kinases. So it may turn out to be like some of the other indications where you have multiple kinases that hit different patients with different mutation profiles. But most likely, we likely will move it more toward the B-cell arena and also toward inflammation and autoimmunity because we've been, as you can tell from the publications, we've been digging into that area, understanding it. There's still a need because this drug is different from the other non-covalent BTK inhibitors. It hits a different set of kinases. It has different activities. And we believe that if we're able to combine it, for instance, with with some of these other drugs that are being developed for the B-cell malignancies, like venetoclax, for instance, then we believe we can see real activity there. So there are paths for it that do not interfere with TUSPADNIP. Does that answer your question?

Yes, it does. Very helpful. Thank you.

Yeah. All right. Thank you.

Thank you. Please stand by for our next question. Our next question comes from Ilana Lee-Whatsack with Caterpix Stural.

Your line is open.

Hi, everyone. This is Rosemary for Lee. Thanks for taking my questions. Just a couple here. Firstly, are you able to give some color around the early activity that you see from the monotherapy arm and Aptivate? And then on the RAS pathway, can you talk a bit more about where you can go with this finding, if RAS correlates with any other mutations potentially? and whether you see mono or combo therapy potential here?

Thank you. Thanks, Rosemary, for coming on. So I'll start with this, and then maybe Dr. Behar would want to jump in. So in terms of early activity, again, it is very early in the Aptivate trial on the monotherapy. And as we said in our press release, we are beginning to see what we call initial antileukemic activity. You'll remember we're very conservative on what we say in terms of what we're seeing in the clinic. So, yes, if you're asking us, we do see some level of blast reductions. We're not going to be talking about how much or what we're seeing or the number of patients. It's just very early. But are we seeing hints of activity beginning? Yes, it's early, but we are. You also asked about the RAS mutations. I find this one very exciting, to tell you the truth, because many of the other drugs out there, one of the major escape pathways for other drugs is the RAS pathways. But we've seen activity, CR, CRHs. I mean, these are real responses in patients that have NRAS, KRAS, and also other mutations within the RAS pathway. So it's a real need that I don't think people have highlighted enough in AML because there hasn't been really a good drug to treat these. But I'm hoping we get more of these patients. I'm hoping that we see activity in these patients. And maybe this will be another indication that we can look toward as an accelerated approval. But the data will have to point us in those directions. I'm going to turn it over to Dr. Behar and see if he has any additional comments.

I think that was well put. I think what is exciting about the activity in RAS mutant patients is that RAS mutations in the relapse setting really mean something different than they do in the frontline setting. Even drugs like venetoclax, you can get responses in patients who have NRAS in that frontline setting. But when patients relapse, it's typically with an expanded NRAS clone or a new NRAS clone, so a three-clone that activates that signaling network. So the ability to target patients that have MRS mutations is exciting not only to treat potentially refractory patients, but also to treat patients in the front line and prevent the development of resistance through that pathway. So we're hopeful that it has benefits in both patient populations. And Bill, to your point about the activity in the Aptivate study thus far, I'll just point out that patients began enrolling in Aptivate in January. It takes a month before their first assessment, bone marrow assessment, takes place, and then another month before the confirmatory biopsy takes place. So we're just about at that point now for the earliest patients enrolled. So all we can really say is that we've observed activity in terms of peripheral blast reductions and looking at early looks at the bone marrow only, but we'll have more data around that as we get further along.

Thank you, Rob. So, Rosemary, did we answer your questions?

Thank you.

All right. Thanks for coming on.

Thank you. As a reminder, ladies and gentlemen, that's star 11 to ask the questions.

Please stand by for our next question. Our next question comes from the line of Gregory Renza with RBC.

Your line is open.

Hi, guys. It's Anish on for Greg. Congrats on the progress, and thanks for taking my question. Just on TUS, in considering the different AML mutations or subpopulations studied, And with the data to date, in which type are you seeing the most responses? And as a follow-up, in which subtype are you seeing greater response with a 40 milligram dosing regimen versus those that require greater exposure slash higher dose for a response with tests? And how might these findings inform regulatory next steps? Thanks so much.

Good question. But, Raph, do you want to jump in on this one?

I can start. That is a great question. I think that that is something that we're very interested in learning. We're limited by a few things. First is patient numbers. Even after treating 60-plus patients, you don't necessarily have that many patients in any particular genetic subgroup when you open a study to all comers. So we don't have large denominators with which to be highly accurate about our response rate. But we do see activity in these patients that have these mutations that we would like to have activity against, including NRAS. We've, again, seen two patients with TP53 mutations that have activity. These are all patients that are predicted to not do as well because of these adverse mutations that they carry. It could be subsets of populations with great unmet medical need. Although, to be fair, all relapsed refractory animal patients are a population of great unmet medical need. As many can't be cured with conventional therapy, they need to go to some sort of stem cell transplant at that point. So the ones of interest, I think I mentioned NRAS, TP53, FLIP3 patients that have exhausted FLIP3 inhibitors prior. But there may be others, and it may be combinations of mutations that matter, for example, NPM1 and FLT3 mutations. We've seen a reasonable response rate in that patient population as well. And the APTIVATE study, by enrolling additional patients, will really give us the confidence that we understand what those response rates are in the different populations. You had asked about differential activity at the 40 milligram dose level. We've reported that there were two responses at that dose level. So, again, very small numbers, not really enough to discriminate whether, you know, 40 was enough for some patients but not enough for others. I think we'll have to really look at the PK more to define what the optimal dose is there, even though we're thrilled to see activity at the 40-milligram dose level.

Well said. Great. Thank you. All right. Thanks for coming out.

Thank you. Please stand by for our next question. Our next question comes from the line of John Newman with Canaccord.

The line is open.

Hi, guys. Thanks for taking the question. As you move forward with the Aptivate study, in terms of the potential for accelerated approval, would you expect that you'll be focusing on a specific mutational type, or would you be focusing more broadly? Thanks.

Yeah. I'll start, and then Dr. Behar can come in. Thanks, John, for coming on. So as we look at the patients being treated with monotherapy, clearly we want to enrich for certain of these populations. The ones that Dr. Behar had mentioned, those that had failed prior FLT3 inhibitors, those that have TP53 mutations. Now that we've seen some of these data with RAS, we'll ask the investigators if we can try to find patients more like that and hope to get enough of these patients to be able to go to the FDA and say, hey, there's a real signal here. We'd like to move forward for the accelerated approval. But I also want to emphasize the doublet is very important for us. Because showing that your drug works well and is well tolerated in combination with venetoclax, that's what's going to launch us into two different pathways. One is it's going to position us for the triplet and to go toward frontline patients. And that is ultimately where we want to go. And we think our drug is going to be the ideal drug to combine with the HMA VENs because of all the reasons that Dr. Behar articulated. But it also will allow us then to decide how to move forward in doublets. So we're looking at ways to have the VENTUS patients for, and hopefully we could design it so that we could have an early look at the data, accelerated approval as we continue to bring patients on for full approval in a doublet trial. And I'm sure Dr. Behar can say it far more eloquently. So would you like to jump in?

Yeah. It won't sound as good as coming from you, Bill, but I will say that the Admiral study is actually a good model for what you might be able to do in a second-line setting, say, for example, with a test bed and a venetoclax tablet, where you have a study that's powered to eventually read out overall survival, but that includes an incremental and interim analysis that could be compelling enough to seek approval. So that is one option. With the monotherapy study, of course, you don't have anything to compare it to, so we'd just be shooting for a target response rate at that point. Yeah.

But thanks for giving us the opportunity to talk about those a little bit, John.

Thank you. Yeah. Any other questions? John? Oh, no. Thank you. Okay. All right. Thank you.

Thank you. I'm currently showing no further questions in the queue. I would now like to turn the call back over to Dr. Rice for closing remarks.

I want to thank everyone for joining us this afternoon, and thank you for all the interest in Aptos, the drugs, and the data that we're generating. We're gratified as we look in the rearview mirror of 2022, and we see the clinical progress of Tospetinib and the strides we're making with the G3 formulation of LUX. Yet our eyes now are really looking forward to 2023 and beyond. and we're eager to share data with you during the coming year. Again, we talked about being able to present data at the conferences, but also at the earnings calls as well as banking meetings. So we want to thank our clinical team, our investigators, our patients for their help in this important work. We appreciate the support of our shareholders and analysts, and we look forward to keeping you updated on our progress the rest of the year. Thank you, and have a good evening.

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