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spk03: Good afternoon. My name is Josh and I will be your conference operator today. I would like to welcome everyone to the Aptos Biosciences conference call for the first quarter ended March 31st, 2024. At this time, all participants are in a listen-only mode. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand to raise. If you would like to withdraw your question, please press star 1-1 again. Thank you. As a reminder, this conference call may be recorded. I would like to introduce Ms. Susan Pietropalo. Please go ahead.
spk08: Thank you, Josh.
spk09: Good afternoon and welcome to the Aptos Biosciences conference call to discuss financial and operational results for the first quarter ended March 31, 2024. 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 Rice, Chairman, President, and CEO, Dr. Rafael Behar, Senior Vice President, Chief Medical Officer, and Mr. Fletcher Payne, Senior Vice President, Chief Financial Officer, and Chief Business 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 achievement 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 quarterly report on Form 10Q, 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. We encourage you to refer to today's press release and the 10-Q for additional information and disclosures regarding today's announcements. I will now turn the call over to Dr. Wright.
spk11: Thank you, Susan. I want to welcome everyone to our call. the first quarter ended March 31st, 2024.
spk10: Our last call was only about a month and a half ago, so we've decided to switch up our conference call format today to include a selection of slides that can provide you with a better understanding of our clinical strategy to focus the development of TUSPETNIB as a triple drug combination or triplet frontline therapy to treat newly diagnosed AML patients. TUSPETNIB, or TUS as we refer to it, is Aptos' lead clinical asset, TUS is being combined with venetoclax, or VEN, and a hypomethylating agent, or HMA. This forms the TUS-VEN-HMA triplet drug combination that is being developed for frontline therapy to treat newly diagnosed AML patients. VEN-HMA is currently the standard of care therapy for newly diagnosed AML patients, and TUS is being bolted on the VEN-HMA standard of care to boost the activity and to do so safely. And importantly, we expect to report clinical data with the TUS-BEN HMA triplet and the newly diagnosed AML patients during the second half of this year. We all know AML is a highly aggressive cancer of the blood and bone marrow, and that unmet need still exists for the relapsed or refractory patient population and for the newly diagnosed population. I'll remind you, when we began clinical trials with TUS as a single agent and with the TUS-BEN doublet, in the relapsed or refractory AML population, as is the case with many other new cancer drugs. Yet, we've always planned to move TUS-Betinib into frontline therapy for newly diagnosed AML patients. Our trials with TUS single agent and with the TUS-Bin doublet in relapsed or refractory patients are now completed. The single agent and the doublet demonstrated excellent safety profiles and distinguished TUS-Betinib from other agents. Just as important, we observed responses in patients with wild-type FLT3, patients with mutated FLT3, patients with mutated TP53 and RAS genes, patients who failed prior therapies with venetoclax, hypomethylating agents, FLT3 inhibitors, and chemotherapy, and those who had failed prior stem cell transplants, illustrating cuspetinib-achieved responses across a remarkable diversity of AML populations. During Q1 of this year, we presented our clinical findings to the FDA as part of a protocol amendment to allow for evaluation of the TUS-DEN-HMA triple drug combination for the frontline therapy of newly diagnosed AML patients. That protocol for the triplet in frontline therapy is now open, and our clinical team is engaging clinical sites and preparing to initiate dosing of patients on this study. I want to explain why we've accelerated our strategy to focus on the frontline triplet in newly diagnosed AML patients. As we began to share safety and efficacy data from the TUS and TUS-N trials and relapse to refractory AML patients with our KOLs and pharma, it became clear that the greatest unmet medical need and greatest opportunity in AML is the development of a superior frontline therapy for the treatment of newly diagnosed AML patients. It also became clear that the unique safety and broad efficacy properties of test metinib fit the desired profile of a third agent to add to the ven plus HMA standard of care backbone and assemble a superior triplet for the frontline therapy. Before we go further, let's first recognize that progress has been made with the introduction of venetoclax to the ven HMA doublet. And this was a major advancement in the treatment of AML. However, the complete remission response rates are still too low and survival is still too short in frontline therapy. And we all want to see a more effective frontline. But there was another important factor leading our KOLs, pharma, and our internal team to focus on frontline therapy. While venetoclax treatment has resulted in more responses in frontline therapy, there is a double-edged sword with venetoclax. It turns out that relapsed or refractory patients who have failed prior venetoclax treatment respond poorly to salvage therapies, and even if they achieve a response, their survival timeline is grim, on the order of a few months. This tells us we need a new frontline strategy that may be able to help avoid rapid failure of venetoclax-based therapies. So what we need is an exceptional third agent that can boost response rates of ven plus HMA, prolong the duration of responses and survival, improve quality of life, treat a broad spectrum of AML genetic subpopulations, and minimize the likelihood of patients becoming resistant to venetoclax. This is the tall order, and other potential third agents in development may only address specific genetic subpopulations, while other agents bring their own complicating toxicities to the triplet. This has opened the door for Tospetinib to address the greatest single opportunity in AML, which is the development of a superior frontline therapy to treat newly diagnosed AML. Tospetinib is a natural third agent for addition to venetoclax and HMAs. Tospetinib has an excellent safety profile as a single agent and in combination with venetoclax and HMAs and with other drugs. Tospetinib enhances antileukemic activity when combined with venetoclax and HMAs. Tospetinib has a very broad scope of activity across genetic subgroups of AML, even those who have high-risk mutations in the TP53 and RAS genes. And Tospetinib targets known venetoclax resistance mechanisms and may help minimize the rapid onset of drug resistance. Because of this unique safety, activity, and mechanistic profile of TUS-Fetnib, we're developing the TUS-BEN HMA triplet to become a new standard of care therapy to address the safety, scope, and survival needs of newly diagnosed AML patients. I now want to present just one more slide because it's important to understand how TUS-Fetnib works and how TUS plus BEN show mechanistic complementarity and may minimize drug resistance. And I'll illustrate these mechanistic interactions with a cartoon on the right side of the slide. As you can see, AML cells upregulate key oxygenic signal transduction pathways to drive excessive proliferation and cell division. At the same time, AML cells avoid cell death by modifying the expression of anti-apoptotic proteins such as MCL1 and BCL2. Often in AML, the BCL2 protein is upregulated. Venetoclax is administered to patients to target the BCL2 and enable the AML cells to die more readily. However, Venetoclax alone has minimal efficacy in AML. That's why Venetoclax is combined with the hoppomethylating agents to achieve clinical remissions. Unfortunately, over time, the cells can modify a number of key pathways to generate resistance to Venetoclax. Multiple mutations can occur simultaneously in the FLT3 receptor kinases, in the JAK kinases of the JAK-STAT pathway, and in the RASMAP kinase pathway, all leading to upregulation of the MCL1 anti-hepatotic protein. Collectively, these alterations allow AML cells to drive cell division and avoid cell death even in the presence of venetoclax. Now let's look at the effects of TUSPETINib. TUSPETINib directly inhibits the FLT3 kinase, the mutant form of KIT, the SICK and JAK kinases in the JAK-STAT pathway, and the RSK2 kinase downstream in the RAS-MAP kinase pathway, and indirectly reduces MCL1 expression. It's this mechanistic complementarity that can make Tuspetinib and Venetoclax such a powerful combination tool against AML. And Dr. Behar will describe how we plan to use these agents together more effectively to treat AML. With that, I'll now turn it over to Dr. Behar, Aptos' chief medical officer and resident KOL, for his insights into the AML patient journey and to take you through our clinical plan that is already well in place. Raf?
spk06: Thanks, Bill. So, to follow on what you just said, I'd like to describe a little bit about the context in which we're developing TUSPEDDED, namely the AML landscape today and how it is that patients are treated. So, a newly diagnosed AML patient, would likely receive some form of therapy. On rare occasions, patients who have too many comorbidities may elect for palliative care, but the majority of patients receive some sort of therapy in first line. The younger individuals, generally patients younger than age 70, will receive a form of intensive chemotherapy if they are fit enough to tolerate this kind of therapy. This has the potential for curing a subset of patients and has a very high complete remission rate. However, The average age of patients with AML is about 68, meaning that the majority of patients may not be great candidates for high-intensity chemotherapy and instead would receive lower-intensity therapy in the front line, consisting of venetoclax plus a hypomethylating agent, which has become the standard of care in the past few years. This has a complete remission rate of about 37% and a composite complete remission rate that includes a complete count recovery of about 66%, namely two-thirds of patients achieving some form of complete remission. and median overall survival to this therapy in the frontline setting is about 15 months. Now, what can happen to individuals after they achieve complete remission? Ideally, a candidate who might be able to receive an allogeneic stem cell transplant would do so as that is potentially curative therapy, and they may receive maintenance therapy after that kind of treatment. Alternatively, a patient who achieves complete remission and is not a candidate for stem cell transplant may receive maintenance therapy alone or no therapy, as they are hopefully in a deep remission. However, patients may be primarily refractory to initial treatment, meaning they never achieve a complete remission and are immediately considered therapeutically refractory, or they may achieve a remission and even undergo transplant in some cases and yet still relapse and have what we would consider therapeutic failure. And outcomes in patients who have refractory or relapse disease is quite dismal, and therefore, it is really important to try to prevent this outcome. In other words, try to improve the likelihood that patients remain in remission for longer with frontline therapy because the best way to treat relapsed refractory disease is to make sure that it doesn't happen in the first place. So why do I say that we still can improve upon HMA-VEN as it has become the new standard for the treatment of older individuals unfit for intensive induction chemotherapy? Well, from the VIALI-A trial that led to the approval of HMA plus venetoclax as the frontline standard for older unfit individuals, we can break down the benefit in different subpopulations. Those individuals that have a more favorable genetic profile, namely they did not have mutations in TP53, FLT3, or NRAS or KRAS, they had the greatest benefit from this kind of therapy. In fact, the median overall survival was over two years. However, there were some patients that do have some high-risk mutations. They might be in the intermediate benefit category, namely those individuals with FLT3 ITD mutations or mutations downstream of FLT3 ITD in KRAS or NRAS, and their benefit wasn't even half as good. Their median overall survival was only about 12 months. And then there was about a quarter of patients who have a TP53 mutation. Those patients had the worst outcomes. Their median overall survival was less than six months and apparently had little benefit with the addition of venetoclax over NHMA alone. So there was substantial room for improvement, particularly in these patients that have these proliferative signaling mutations in SLID3 and NRAS and KRAS to improve upon the outcomes that they see with NHMA or venetoclax. And that is where I think we have a prime opportunity for it to spend it. So let's talk about that. What are the opportunities for the drug? We know that in AML, is a disease that has about 21,000 cases annually in the US, and with more than half the patients succumbing to the disorder each year. As I mentioned, the median age is 68, meaning that the majority of patients are close to that age, where induction chemotherapy is not a common option, and survival is still relatively poor, especially for those older individuals, where five-year overall survival rates are estimated to be less than 10%. Now, frontline therapies have made improvements in the last few years, as Dr. Rice mentioned, I mentioned that the combination of NHMA have about a two-thirds overall response rate for CR and CRI and a 15-month median overall survival, but there are the subset of patients that have inferior outcomes. We have seen several studies that are combining three agents, the Metaclax, HMA, and a novel agent, to try to improve outcomes in those frontline patients, and we have seen successes there. In particular, trials with kinase inhibitors have shown composite complete remission rates of 80 or even 90% in the frontline setting, which is very promising. Unfortunately, they do have their own liabilities. In part, they tend to be more toxic when combined in that triplet agent, requiring dose reductions, not just of the third novel agent, but of the standard of care backbone of the hypomethylene agent and the venetoclax, meaning that the combined therapy falls short of the standard of care where you'd give a placebo instead of the third agent. And of course, many of these trials have used targeted agents, meaning that they are not applicable to the broader range of AML patients, only a subset defined by either a genetic or other biomarker. So there is an urgent need for a safe and more effective first-line triplet to improve outcomes for AML patients of all genetic subtypes. So how does that fit into the model we derived before? Tispetinib as an ideal third agent with a very favorable safety profile could be combined both with intensive chemotherapy in the frontline setting, as other kinase inhibitors have done and have been approved, or it could be combined as a third agent with venetoclax and HMA in that low-intensity treatment option. This, I think, provides a broad frontline opportunity for tispetinib. And we have chosen, as our first steps in the frontline setting, to focus on those low-intensity therapy patients where there are no other drugs currently approved as an applicable triplet for this patient population. Doing so allows us to potentially increase the complete remission rates and survival of patients with split-three mutations in such a way that doesn't require the reduction of the standard of care. This would permit, for example, a randomized clinical study, placebo-controlled, It would give standard of care to both arms without having to dose reduce them in the treatment arm. As far as we are aware, this is the only agent being developed in combination with NHMA that includes FLT3 wild-type patients or generally patients without a mutational biomarker, which represents the majority of AML patients, of course. And it's the only agent that broadly includes patients with TP53, MRAS, and KRAS mutations in this frontline triplet paradigm. We hope that based on a safety profile to date that the Dispetinib-Vanetoclax-HMA combination will be a safer therapy for unfit patients than other triplets that might bring additional toxicities to the table. So, having expressed the landscape of AML and the rationale for a third agent, I want to talk about why Dispetinib is an ideal third agent. As we mentioned, drugs like giltaritinib have been combined with venetoclax and HMA, and they've boosted the complete remission rate substantially in the flithium mutant population. So the proof of principle is there that this class of drug can make important advances. But we have seen those limitations that I mentioned that required the dose reductions. Now, tispetinib, I think, has an ideal profile as a third agent that might make it superior to these other agents in that frontline setting. And we've learned this from the extensive clinical data we've generated to date with the drugs. We've done extensive testing, both with tispetinib as a monotherapy and with tispetinib in combination with venetoclax. It tells us that tispetinib does not have several of the side effects that could impair its further clinical development, including no QTC prolongation related to drug, differentiation syndrome, evidence of muscle damage, or even prolonged myelosuppression in patients who achieve remission, where patients in remission continue to take the drug disruption and maintain their blood counts. By combining it with venetoclax in the relapsed refractory setting in a large number of patients, we now understand that there aren't significant drug interactions that would require dramatic dose changes of either agent or see developing them at their established doses. And importantly, we have favorable comparisons in direct, of course, with other agents out there. We believe that we can see, we have demonstrated we can see responses in patients with that prior for the three inhibitors. that we don't need to inhibit the pathway as substantially as other agents do, perhaps because of the multi-kinase activity of the drug, and that we have seen responses in a large proportion of FLT3 unmutated patients, which really differentiates testatinib from other agents like giltaritinib. Importantly, we have that superior safety profile where we are targeting the ven resistance mechanisms that may potentially help prevent ven resistance or potentially even resensitize them based on preclinical studies, And by suppressing more oncogenic pathways, may be able to alleviate other potential mechanisms of resistance from arising. Therefore, we believe there's a strong rationale for combining Tospedinib with venetoclax in the frontline setting, particularly where patients are like the naive to all agents. So what have we done to get there? We've completed the single-agent dose exploration, where we treated a large number of patients, as I'll show you. We've demonstrated the activity of the drug in a single agent in select populations, both with and without FLT3 mutations, and we've demonstrated a superior safety profile of the drug in that context. In the doublet study, we've learned about the safety of Tespetinib plus Venetoclax, how it could safely be given without substantial dose modification, and we've characterized the PK of both agents. This has now put us in a position to submit a triplet protocol to the FDA, where we've also achieved orphan drug designation and fast track status for patients with three mutations in this drug. So the triplet pilot study has already been implemented and clinical sites are now being prepared to enroll our first patients later this year. And we hope to select the optimal dose of Dyspetinib that will allow us to maintain the standard of care dosing of the other agents, which would then enable a randomized placebo-controlled registrational study. We will learn about how best to give these drug combinations safely and mitigate myelosuppression, And we'll characterize the activity in those difficult to treat or less likely to benefit subgroups of patients that have P53 mutations, NRAS, KRAS mutations, as well as several kinds of SWIT3 mutations. We'll further characterize the BK and establish the safety and the efficacy profile. And finally, look at what impact we might be having on overall survival before we take our next steps. I want to spend a little bit of time just sharing how we are actually going to be giving these three drugs together and how this compares to other agent mixes that are out there. For the pilot study, our first triplet in the frontline setting, we're proposing to treat about 20 to 36 patients total. These are patients that are going to be older, ineligible for induction chemotherapy, either because of age over 75 or because of comorbidities that would prevent that kind of more intensive therapy. We'll shoot for 50% of the patients having a FLT3 mutation, so we have an understanding about activity both in the FLT3 mutant and in the FLT3 wild-type group. And we'll look at all those other factors that I just described earlier. The way we're going to give the drugs together is by giving the Ven and AZA together as a standard of care doublet with the addition of daily Tospetinib as shown in the top graph here. You can see that at day 18, we'll perform a bone marrow biopsy, and if patients have achieved remission, we will hold the Venetoclax starting on day 22, and this is consistent with the Venetoclax label. It suggests that should begin for 21 to 28 days per cycle. We then will allow patients to recover their counts and monitor how long it takes to do so, making adjustments along the way if necessary. Of course, if a patient has not achieved a remission, then they would continue to take the venetoclax along with the tispetin through day 28 when a second blood marrow biopsy will be performed to see if they've achieved a remission, and if they have, then allow additional time for their blood count recovery to occur before they move on to their second cycle. The dosing in the second cycle will be adjusted based on the patient's experience with the first. Patients who have no significant myelosuppression would go on to receive the same type of cycle as the second cycle. Those that do will have adjustments to their drugs made according to the van azoleza. So, now let's talk about milestones and when we are likely to have data. So, coming up very shortly will be the EHA meeting in Madrid. There we will present the summary of our single agent and doublet data, really, providing an update to what we presented at ASH earlier along these lines in our oral presentation given by Dr. Novel-Dauber. Shortly after that meeting, we expect to have our first patient enrollment in our frontline triplet study. This will begin the treatment in this frontline patient population. We've continued accrual and hopefully the presentation of several patients' worth of data at the annual Society for Hematology meeting here in San Diego near the end of Q4. The trial will continue, of course, and we hope to have a more mature summary at next year's EHA meeting in 2025 as we meet with the FDA and prepare for the regulatory steps with multiple milestones for adding additional data along the way. So, I'll briefly go into some of the frontline, some of that monotherapy data and sublet data that gave us the understanding about how to proceed in the frontline. So to summarize, tespitinib as a single agent has now been given to over 91 patients as a monotherapy, and it has had very clean safety profile with, again, no drug-related mild suppression in patients who achieve remission, no QTC prolongation or CPK elevation that would be evidence of muscle damage, and in fact, in the single agent, no drug-related discontinuations or deaths. Here you can see the percentages of patients with adverse events related to tespitinib, and the most frequent were relatively mild nausea and fatigue, with very few grade three or larger related adverse events. Similar profile occurs when we combine to spend it with venetoclax in the doublet with no new or unexpected safety signals arising and very similar rates of adverse events. Higher rates of neutropenia and other mild suppressive markers as would be expected with the addition of venetoclax is very much in line with what we would expect for venetoclax containing regimens. In fact, lower rates of febrile neutropenia than expected. And here is the evidence of that single agent activity. This graph here shows evidence of bone marrow blast reductions in patients treated with the SpetNib as a single agent. You can see that more than half the patients choose some degree of bone marrow blast reduction. And you can see that this occurred in a variety of different dose levels as shown by the different colors. The other thing I would point out is that patients that had a prior FLT3 inhibitor are marked with a red triangle. And you can see that patients with prior FLT3 inhibitors were just as likely, if not more likely, to show a bone marrow blast reduction. However, patients with prior venetoclax, shown by the black triangles, are less represented in the far right of the graph, consistent with our knowledge that then-resistant patients are less likely to respond to practically any other therapy as a monotherapy. For that reason, we performed the doublet study of patients with relapsed refractory disease, receiving caspative and venetoclax, and again saw blast reductions in more than half of the patients. And in contrast to the figure on the left, we now see many more of those black triangles on the far right of the graph. showing that even then, pretreated patients can have significant blast reductions when treated with a combination of venetoclax and tispetanib in the relapsed or factory setting. And once more, multiple red triangles on the right indicating that patients with prior FLT3 inhibitor are still more likely to respond than patients who don't, likely because of their prior FLT3 mutation status. So now I'll pass on He talks to Dr. Fletcher Payne, who will talk more about the investment thesis and some of the near-term milestones for the drug. Fletcher?
spk07: Thanks, Raf. Good afternoon, all. There are three key points to the TUS investment thesis. First, there's a very high unmet medical need in frontline AML, as has been discussed before, to increase survival across all genetic subtypes. Two, the KOLs support TUS as the ideal third agent for triple study in the frontline patients. Three, TESS is emerging as an ideal agent to combine with then-HMA. This is due to the safety profile, the broad activity across FLT3 mutated and FLT3 wild-type patients, as well as activity against the difficulty to treat mutated TP53 and the RAS gene subtypes. The design of the triplet study and the data readouts line up well to generate several near-term value-creating milestones. The first milestone will be at EHA in June 2024, where we will report single agent and double agent activity, which supports our contention to move into the frontline in the triplet study. The second milestone will be in the summer of 2024, where we will start dosing newly diagnosed patients in our triplet study. The third milestone at ASH 2024, we will report complete responses MRD negativity, and safety data from the triplet study. During the first half of 2025, we expect a complete enrollment of the study. The fourth milestone will be at EHA in the summer of 2025, where we will report data readout from the triplet study. So, as you can see, the triplet study provides for a number of value-creating inflection points over the coming year. Before I cover the first quarter financial highlights, I would like to start by saying that being on our comments in this call, additional information may be found in today's press release and the 10Q filed with the SEC. During the first quarter of 2024, we continued our disciplined financial management of operations. We reduced spending on several fronts and prioritized our investments in our clinical programs. we continue to evaluate ways to reduce operating expenses. The total outstanding share count as of today, May 14th, is 16,393,393 shares. Based on current operations, the company expects the cash on hand plus our ATM will provide sufficient resources to fund planned operations, including research and development activities through August of 2024. Last quarter, we informed you that a 2024 deficiency letter from NASDAQ regarding the private placement with HANME was announced, which was announced in January. Aptos has submitted a plan to NASDAQ to regain compliance. On April 25 of this year, the company received a letter from NASDAQ listing qualifications department notifying the company that the company had regained compliance with the NASDAQ listing rules. 5635D and determined that the matter is now closed. Under the company's plan to regain compliance on April 26, 2024, the company announced that it had amended the warrant agreement with HOMI to prohibit the exercise of HOMI warrants in excess of the NASDAQ 19.99% limitation unless shareholder approval is first obtained. On April 2, 2024, we received a second notification from the NASDAQ stating that the company was not in compliance with the NASDAQ listing rules because our stockholders' equity as of December 31, 2023, was below the minimum $2.5 million. We intend to submit a compliance plan on or before May 17, 2024, Monitor our stockholders' equity, and if appropriate, consider further available options to evidence compliance with the stockholder equity requirement. I would like to direct you to review the company's risk factors and discussions regarding the NASDAQ ladder and the ongoing concern footnote in our 10-Q and our 10-K filings. Now let's review the first quarter financials. We ended the first quarter of 2024 with approximately $9.3 million in cash, cash equivalents, investments approximately equal to December 31, 2023. The $11.8 million in net financing proceeds in January 2024 was offset by $11.8 million used to fund our operations for the quarter, including our active aid clinical study for disappointment. As seen in the income statement, we had no revenues during 2024 or in the first quarter During the first quarter of 2024, the net loss was approximately $9.6 million, translating into $0.73 loss per share, compared to $13.7 million loss, or $2.22 loss per share from the first quarter of 2023. As of May 14, 2024, Aptos had $16.3 million All references to losses per share and shares outstanding had been presented to reflect the 15 for 1 reverse split completed on June 6, 2023. Research and development expenses were approximately $6.4 million for the quarter ended March 31, 2024, compared to $8.8 million for the first quarter of 2023. Program costs for Teseptinib were $3.9 million for the first quarter of 2024, compared to $4.8 million for the first quarter of 2023. Lower program costs for Teseptinib in the current period represented the completion of patient enrollment with a test, then doublet program, and reduced manufacturing costs. Program costs for Luxeptinib were $208,000 for the first quarter and decreased by approximately $1.1 million compared to $1.3 million in the first quarter of 2023, primarily due to lower clinical trial costs and lower manufacturing costs. G&A expenses were $3.3 million for the first quarter of 2024 and decreased by $2 million compared to $5.3 million for the corresponding period of 2023. The decrease was primarily due to lower professional fees or stock-based compensation in the current period. Now let me turn back to Dr. Rice.
spk11: Thank you, Fletcher. Now we'll open the call for questions, and please feel free to pose a question to any of us. Operator, if you could, please introduce the questions.
spk03: Thank you. As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again.
spk14: One moment for questions. Our first question comes from Joe Pangenis with H.U.
spk03: Enright. You may proceed.
spk15: Good afternoon, gentlemen. Thanks for taking the questions. I'll start with two, if you don't mind. So first, on slide number 10, when you presented the trial design for the triplet combination, I'm just curious if there was, what level of before and after was there? So you met with the FDA in the first quarter, as you said. How much does slide 10 align with what you originally wanted with them?
spk11: So, Rat, perhaps Dr. Behar, perhaps you can answer that one and put it in context. Sure.
spk06: Yeah, of course. So, this was developed in conjunction with experts in the field, including our lead PI, Dr. Naval Dauber, who's done several of these frontline triplet studies, and it really reflects both his experience and the Venn-Aza label. It isn't really a consequence of a back and forth with the FDA on this. We did submit a protocol amendment to our existing study that includes this protocol more than, I think, 45 to 50 days ago now. But this is really a function of our discussions with our experts, not a consequence of discussions with the FDA.
spk15: Nope, that makes sense. Thanks. And then I guess as we look to the triplet study now, everyone's going to be Highly looking forward to the year end data. So I guess internally, what do you view as the benchmark for success to be able to move beyond the pilot?
spk06: I can take that too, Bill. I think there's a couple of opportunities, I think, to show benefit here. The expectations are based on prior data that the frontline triplet with a kinase inhibitor like tispetinib can substantially increase the response rate. Of course, I think the metric that really matters is overall survival, and that is not data that we expect to have in the short term. But the expectation with the VLAA study is that you see about two-thirds of the patients responding. I think if we would see something closer to 75%, I think we'd be comfortable that we are at least meeting that if not exceeding it. And given the number of patients we expected, Ash, I wouldn't expect to see a robust value there. But by the time this study is complete and we've treated enough patients, I think we'll have a very good understanding based on the response metrics about what we're doing.
spk10: Yeah, perhaps I can add a little bit to that because it also relates back to the trial design. What we hope to see and we expect to see by year-end is the complete remissions in these patients. We expect to see the robust safety, which we've continued to see all the way through, even in the doublet of TUSPETNES plus venetoclax. And we hope then that that allows us to maintain the standard of care dosing that Dr. Behar had mentioned, because it's really important to be able to maintain the expected levels of venetoclax, as well as the hypomethylating agents, according to the label of the drug. FDA wants to see that. We want to see that. And that's been a real problem with many of the other drugs out there. Perhaps Dr. Behar wants to add to that.
spk12: That's exactly right, Bill. Thank you.
spk02: Okay. Thanks, guys. Appreciate it.
spk03: Thank you, Joe. Thank you. And as a reminder, if you would like to ask a question, please press star 1-1 on your telephone.
spk14: One moment for questions. And I'm currently showing no further questions.
spk03: I would now like to turn the call back over to Dr. Rice for closing remarks.
spk11: All right.
spk03: Well, thank you, everyone, for joining us this afternoon.
spk10: We're genuinely excited to take Tuspetinib into the frontline triplet therapy for newly diagnosed AML patients. And we hope that we've relayed how Tuspetinib is distinguished from other AML compounds in development, not only because of its safety profile, but because it has shown activity across a broad set of mutations. even in wild-type AML, potentially addressing the largest markets in AML, not just a subset. As always, we thank our patients, investigators, and employees for their important role in this effort. Our clinical team has been keen in developing our pilot triplet study to getting it prepared, and I want to recognize them for their execution. We appreciate our shareholders and analysts who continue to support us, and we look forward to keeping you updated on our progress today, and we really do appreciate the questions that came to us today. I want to thank you and have a good evening.
spk03: Thank you, ladies and gentlemen. That concludes today's conference. You may all disconnect and have a wonderful day.
spk01: Thank you. Hello. Thank you. Thank you. Thank you. music music
spk03: Good afternoon. My name is Josh and I will be your conference operator today. I would like to welcome everyone to the Aptos Biosciences conference call for the first quarter ended March 31st, 2024. At this time, all participants are in a listen-only mode. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. If you would like to withdraw your question, please press star 1-1 again. Thank you. As a reminder, this conference call may be recorded. I would like to introduce Ms. Susan Pietropalo. Please go ahead.
spk08: Thank you, Josh.
spk09: Good afternoon, and welcome to the Aptos Biosciences conference call to discuss financial and operational results for the first quarter ended March 31, 2024. 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 Rice, Chairman, President, and CEO, Dr. Rafael Behar, Senior Vice President, Chief Medical Officer, and Mr. Fletcher Payne, Senior Vice President, Chief Financial Officer, and Chief Business 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 achievement 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 quarterly report on Form 10-Q, 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. We encourage you to refer to today's press release and attend queue for additional information and disclosures regarding today's announcements. I will now turn the call over to Dr. Wright.
spk11: Thank you, Susan. I want to welcome everyone to our call. the first quarter ended March 31st, 2024.
spk10: Our last call was only about a month and a half ago, so we've decided to switch up our conference call format today to include a selection of slides that can provide you with a better understanding of our clinical strategy to focus the development of TUSPETNIB as a triple drug combination or triplet frontline therapy to treat newly diagnosed AML patients. TUSPETNIB, or TUS as we refer to it, is Aptos' lead clinical asset, TUS is being combined with venetoclax, or VEN, and a hypomethylating agent, or HMA. This forms the TUS-VEN-HMA triplet drug combination that is being developed for frontline therapy to treat newly diagnosed AML patients. VEN-HMA is currently the standard of care therapy for newly diagnosed AML patients, and TUS is being bolted on the VEN-HMA standard of care to boost the activity and to do so safely. And importantly, we expect to report clinical data with the TUS-BEN HMA triplet and the newly diagnosed AML patients during the second half of this year. We all know AML is a highly aggressive cancer of the blood and bone marrow, and that unmet need still exists for the relapsed or refractory patient population and for the newly diagnosed population. I'll remind you, when we began clinical trials with TUS as a single agent and with the TUS-BEN doublet, in the relapsed or refractory AML population, as is the case with many other new cancer drugs. Yet, we've always planned to move TUS-Betanib into frontline therapy for newly diagnosed AML patients. Our trials with TUS single agent and with the TUS-Bend doublet in relapsed or refractory patients are now completed. The single agent and the doublet demonstrated excellent safety profiles and distinguished TUS-Betanib from other agents. Just as important, we observed responses in patients with wild-type FLT3, patients with mutated FLT3, patients with mutated TP53 and RAS genes, patients who failed prior therapies with venetoclax, hypomethylating agents, FLT3 inhibitors, and chemotherapy, and those who had failed prior stem cell transplants, illustrating TUSFETINib achieves responses across a remarkable diversity of AML populations. During Q1 of this year, we presented our clinical findings to the FDA as part of a protocol amendment to allow for evaluation of the TUS-DEN-HMA triple drug combination for the frontline therapy of newly diagnosed AML patients. That protocol for the triplet in frontline therapy is now open, and our clinical team is engaging clinical sites and preparing to initiate dosing of patients on the study. I want to explain why we've accelerated our strategy to focus on the frontline triplet in newly diagnosed AML patients. As we began to share safety and efficacy data from the TUS and TUS-N trials and relapse to refractory AML patients with our KOLs and pharma, it became clear that the greatest unmet medical need and greatest opportunity in AML is the development of a superior frontline therapy for the treatment of newly diagnosed AML patients. It also became clear that the unique safety and broad efficacy properties of test metinib fit the desired profile of a third agent to add to the ven plus HMA standard of care backbone and assemble a superior triplet for the frontline therapy. Before we go further, let's first recognize that progress has been made with the introduction of venetoclax to the ven HMA doublet. And this was a major advancement in the treatment of AML. However, the complete remission response rates are still too low and survival is still too short in frontline therapy. And we all want to see a more effective frontline But there was another important factor leading our KOLs, pharma, and our internal team to focus on frontline therapy. While venetoclax treatment has resulted in more responses in frontline therapy, there is a double-edged sword with venetoclax. It turns out that relapsed or refractory patients who have failed prior venetoclax treatment respond poorly to salvage therapies, and even if they achieve a response, their survival timeline is grim, on the order of a few months. This tells us we need a new frontline strategy that may be able to help avoid rapid failure of venetoclax-based therapies. So what we need is an exceptional third agent that can boost response rates of VEN plus HMA, prolong the duration of responses and survival, improve quality of life, treat a broad spectrum of AML genetic subpopulations, and minimize the likelihood of patients becoming resistant to venetoclax. This is the tall order, and other potential third agents in development may only address specific genetic subpopulations, while other agents bring their own complicating toxicities to the triplet. This has opened the door for Tospetinib to address the greatest single opportunity in AML, which is the development of a superior frontline therapy to treat newly diagnosed AML. Tospetinib is a natural third agent for addition to venetoclax and HMAs. Tospetinib has an excellent safety profile as a single agent and in combination with venetoclax and HMAs and with other drugs. Tospetinib enhances antiloquemic activity when combined with venetoclax and HMAs. Tospetinib has a very broad scope of activity across genetic subgroups of AML, even those who have high-risk mutations in the TP53 and RAS genes. And Tospetinib targets known venetoclax resistance mechanisms and may help minimize the rapid onset of drug resistance. Because of this unique safety, activity, and mechanistic profile of TUS-Fetnib, we're developing the TUS-VIN HMA triplet to become a new standard of care therapy to address the safety, scope, and survival needs of newly diagnosed AML patients. I now want to present just one more slide because it's important to understand how TUS-Fetnib works and how TUS plus VIN show mechanistic complementarity and may minimize drug resistance. And I'll illustrate these mechanistic interactions with a cartoon on the right side of the slide. As you can see, AML cells upregulate key oxygenic signal transduction pathways to drive excessive proliferation and cell division. At the same time, AML cells avoid cell death by modifying the expression of anti-apoptotic proteins such as MCL1 and BCL2. Often in AML, the BCL2 protein is upregulated. Venetoclax is administered to patients to target the BCL2 and enable the AML cells to die more readily. However, Venetoclax alone has minimal efficacy in AML. That's why Venetoclax is combined with the hypomethylating agents to achieve clinical remissions. Unfortunately, over time, the cells can modify a number of key pathways to generate resistance to venetoclax. Multiple mutations can occur simultaneously in the FLT3 receptor kinases, in the JAK kinases of the JAK-STAT pathway, and in the RASMAP kinase pathway, all leading to upregulation of the MCL1 anti-hepatotic protein. Collectively, these alterations allow AML cells to drive cell division and avoid cell death, even in the presence of venetoclax. Now let's look at the effects of tespetinib. Tuspetinib directly inhibits the FLT3 kinase, the mutant form of KIT, the SICK and JAK kinases in the JAK-STAT pathway, and the RSK2 kinase downstream in the RAS-MAP kinase pathway, and indirectly reduces MCL1 expression. It's this mechanistic complementarity that can make tuspetinib and venetoclax such a powerful combination tool against AML. And Dr. Behar will describe how we plan to use these agents together more effectively to treat AML. With that, I'll now turn it over to Dr. Behar, Aptos' chief medical officer and resident KOL, for his insights into the AML patient journey and to take you through our clinical plan that is already well in place. Raf?
spk06: Thanks, Bill. So, to follow on what you just said, I'd like to describe a little bit about the context in which we're developing TUSPEDDED, namely the AML landscape today and how it is the patients are treated. So, a newly diagnosed AML patient, would likely receive some form of therapy. On rare occasions, patients who have too many comorbidities may elect for palliative care, but the majority of patients receive some sort of therapy in first line. The younger individuals, generally patients younger than age 70, will receive a form of intensive chemotherapy if they are fit enough to tolerate this kind of therapy. This has the potential for curing a subset of patients and has a very high complete remission rate. However, The average age of patients with AML is about 68, meaning that the majority of patients may not be great candidates for high-intensity chemotherapy and instead would receive lower-intensity therapy in the front line, consisting of venetoclax plus a hypomethylating agent, which has become the standard of care in the past few years. This has a complete remission rate of about 37% and a composite complete remission rate that includes incomplete count recovery of about 66%, namely two-thirds of patients achieving some form of complete remission. and median overall survival to this therapy in the frontline setting is about 15 months. Now, what can happen to individuals after they achieve complete remission? Ideally, a candidate who might be able to receive an allogeneic stem cell transplant would do so as that is potentially curative therapy, and they may receive maintenance therapy after that kind of treatment. Alternatively, a patient who achieves complete remission and is not a candidate for stem cell transplant may receive maintenance therapy alone or no therapy, as they are hopefully in a deep remission. However, patients may be primarily refractory to initial treatment, meaning they never achieve a complete remission and are immediately considered therapeutically refractory, or they may achieve a remission and even undergo transplant in some cases and yet still relapse and have what we would consider therapeutic failure. And outcomes in patients who have refractory or relapse disease is quite dismal, and therefore, it is really important to try to prevent this outcome. In other words, try to improve the likelihood that patients remain in remission for longer with frontline therapy because the best way to treat relapsed refractory disease is to make sure that it doesn't happen in the first place. So why do I say that we still can improve upon HMA-VEN as it has become the new standard for the treatment of older individuals unfit for intensive induction chemotherapy? Well, from the VIALI-A trial that led to the approval of HMA plus venetoclax as the frontline standard for older unfit individuals, we can break down the benefit in different subpopulations. Those individuals that have a more favorable genetic profile, namely they did not have mutations in TP53, FLT3, or NRAS or KRAS, they had the greatest benefit from this kind of therapy. In fact, their median overall survival was over two years. However, there were some patients that do have some high-risk mutations. They might be in the intermediate benefit category, namely those individuals with FLT3 ITD mutations or mutations downstream of FLT3 ITD in KRAS or NRAS, and their benefit wasn't even half as good. Their median overall survival was only about 12 months. And then there was about a quarter of patients who have a TP53 mutation. Those patients had the worst outcomes. Their median overall survival was less than six months and apparently had little benefit with the addition of venetoclax over NHMA alone. So there was substantial room for improvement, particularly in these patients that have these proliferative signaling mutations in SID3 and NRAS and KRAS to improve upon the outcomes that they see with NHMA or venetoclax. And that is where I think we have a prime opportunity for dysbendinib. So let's talk about that. What are the opportunities for the drug? We know that in AML, It's a disease that has about 21,000 cases annually in the U.S., and with more than half the patients succumbing to the disorder each year. As I mentioned, the median age is 68, meaning that the majority of patients are close to that age where induction chemotherapy is not a common option, and survival is still relatively poor, especially for those older individuals, where five-year overall survival rates are estimated to be less than 10%. Now, frontline therapies have made improvements in the last few years, as Dr. Rice mentioned. I mentioned that the combination of NHMA have about a two-thirds overall response rate for CR and CRI and a 15-month median overall survival, but there are the subset of patients that have inferior outcomes. We have seen several studies that are combining three agents, the Metaclax, HMA, and a novel agent, to try to improve outcomes in those frontline patients, and we have seen successes there. In particular, trials with kinase inhibitors have shown composite complete remission rates of 80 or even 90% in the frontline setting, which is very promising. Unfortunately, they do have their own liabilities. In part, they tend to be more toxic when combined in that triplet agent, requiring dose reductions, not just of the third novel agent, but of the standard of care backbone of the hypomethetin agent and the venetoclax, meaning that the combined therapy falls short of the standard of care where you'd give a placebo instead of the third agent. And of course, many of these trials have used targeted agents, meaning that they are not applicable to the broader range of AML patients, only a subset defined by either a genetic or other biomarker. So there is an urgent need for a safe and more effective first-line triplet to improve outcomes for AML patients of all genetic subtypes. So how does that fit into the model we derived before? Tispetinib as an ideal third agent with a very favorable safety profile could be combined both with intensive chemotherapy in the frontline setting, as other kinase inhibitors have done and have been approved, or it could be combined as a third agent with venetoclax and HMA in that low-intensity treatment option. This, I think, provides a broad frontline opportunity for tispetinib. And we have chosen, as our first steps in the frontline setting, to focus on those low-intensity therapy patients where there are no other drugs currently approved as an applicable triplet for this patient population. Doing so allows us to potentially increase the complete remission rates and survival of patients with split-3 mutations in such a way that doesn't require the reduction of the standard of care. This would permit, for example, a randomized clinical study, placebo-controlled, It would give standard of care to both arms without having to dose reduce them in the treatment arm. As far as we are aware, this is the only agent being developed in combination with NHMA that includes FLT3 wild-type patients or generally patients without a mutational biomarker, which represents the majority of AML patients, of course. And it's the only agent that broadly includes patients with TP53, MRAS, and KRAS mutations in this frontline triplet paradigm. We hope that based on its safety profile to date, that the Dispetinib-Vineticox HMA combination will be a safer therapy for unfit patients than other triplets that might bring additional toxicities to the table. So, having expressed the landscape of AML and the rationale for a third agent, I want to talk about why Dispetinib is an ideal third agent. As we mentioned, drugs like giltaritinib have been combined with venetoclax and HMA, and they've boosted the complete remission rate substantially in the flithium mutant population. So the proof of principle is there that this class of drug can make important advances. But we have seen those limitations that I mentioned that required the dose reductions. Now, tispetinib, I think, has an ideal profile as a third agent that might make it superior to these other agents in that frontline setting. And we've learned this from the extensive clinical data we've generated to date with the drug. We've done extensive testing, both with tispetinib as a monotherapy and with tispetinib in combination with venetoclax. It tells us that tispetinib does not have several of the side effects that could impair its further clinical development, including no QTC prolongation related to drug, differentiation syndrome, evidence of muscle damage, or even prolonged myelosuppression in patients who achieve remission, where patients in remission continue to take the drug, corruption, and maintain their blood counts. By combining it with venetoclax in the relapsed refractory setting in a large number of patients, we now understand that there aren't significant drug interactions that would require dramatic dose changes of either agent or see developing them at their established doses. And importantly, we have favorable comparisons, indirect of course, with other agents out there. We believe that we can see, we have demonstrated we can see responses in patients that prior for the three inhibitors. that we don't need to inhibit the pathway as substantially as other agents do, perhaps because of the multi-kinase activity of the drug, and that we have seen responses in a large proportion of FLT3 unmutated patients, which really differentiates Tospetinib from other agents like Giltritinib. Importantly, we have that superior safety profile where we are targeting the ven resistance mechanisms that may potentially help prevent ven resistance or potentially even resensitize them based on preclinical studies, And by suppressing more oncogenic pathways, may be able to alleviate other potential mechanisms of resistance from arising. Therefore, we believe there's a strong rationale for combining Tospetinib with Venetoclax in the frontline setting, particularly where patients are like Venetoclax to all agents. So what have we done to get there? We've completed the single-agent dose exploration, where we treated a large number of patients, as I'll show you. We've demonstrated the activity of the drug in a single agent in select populations, both with and without FLT3 mutations, and we've demonstrated a superior safety profile of the drug in that context. In the doublet study, we've learned about the safety of tespitinib plus venetoclax, how it could safely be given without substantial dose modification, and we've characterized the PK of both agents. This has now put us in a position to submit a triplet protocol to the FDA, where we've also achieved orphan drug designation and fast track status for patients with three mutations in this drug. So the TRIPIP pilot study has already been implemented and clinical studies are now being prepared to enroll our first patients later this year. And we hope to select the optimal dose of Dispetinib that will allow us to maintain the standard of care dosing of the other agents, which would then enable a randomized placebo controlled registrational study. We will learn about how best to give these drug combinations safely and mitigate myelosuppression And we'll characterize the activity in those difficult to treat or less likely to benefit subgroups of patients that have P53 mutations, NRAS, KRAS mutations, as well as several kinds of SWIT3 mutations. We'll further characterize the PK and establish the safety and the efficacy profile. And finally, look at what impact we might be having on overall survival before we take our next steps. I want to spend a little bit of time just sharing how we are actually going to be giving these three drugs together and how this compares to other agent mixes that are out there. For the pilot study, our first triplet in the frontline setting, we're proposing to treat about 20 to 36 patients total. These are patients that are going to be older, ineligible for induction chemotherapy, either because of age over 75 or because of comorbidities that would prevent that kind of more intensive therapy. We'll shoot for 50% of the patients having a FLT3 mutation, so we have an understanding about activity both in the FLT3 mutant and in the FLT3 wild-type group. And we'll look at all those other factors that I just described earlier. The way we're going to give the drugs together is by giving the Ven and AZA together as a standard of care doublet with the addition of daily Tospetinib as shown in the top graph here. You can see that at day 18, we'll perform a bone marrow biopsy. And if patients have achieved remission, we will hold the Venetoclax starting on day 22. And this is consistent with the Venetoclax label. It suggests that should begin for 21 to 28 days per cycle. We then will allow patients to recover their counts and monitor how long it takes to do so, making adjustments along the way if necessary. Of course, if a patient has not achieved a remission, then they would continue to take the venetoclax along with the tispetin through day 28 when a second blood marrow biopsy will be performed to see if they've achieved a remission, and if they have, then allow additional time for their blood count recovery to occur before they move on to their second cycle. The dosing in the second cycle will be adjusted based on the patient's experience with the first. Patients who have no significant mild suppression would go on to receive the same type of cycle as the second cycle. Those that do will have adjustments to their drugs made according to the van aza label. So now let's talk about milestones and when we are likely to have data. So coming up very shortly will be the EHA meeting in Madrid. There we will present the summary of our single agent and doublet data, really providing an update to what we presented at ASH earlier along these lines in our oral presentation given by Dr. Novel-Dauber. Shortly after that meeting, we expect to have our first patient enrollment in our frontline triplet study. This will begin the treatment in this frontline patient population. We've continued accrual and hopefully the presentation of several patients' worth of data at the annual Society for Hematology meeting here in San Diego near the end of Q4. The trial will continue, of course, and we hope to have a more mature summary at next year's EHA meeting in 2025 as we meet with the FDA and prepare for the regulatory steps with multiple milestones for adding additional data along the way. So, I'll briefly go into some of the frontline, some of that monotherapy data and sublet data that gave us the understanding about how to proceed in the frontline. So to summarize, Tospetinib as a single agent has now been given to over 91 patients as a monotherapy, and it has had very clean safety profile with, again, no drug-related mild suppression in patients who have achieved remission, no QTC prolongation or CPK elevation that would be evidence of muscle damage, and in fact, in the single agent, no drug-related discontinuations or deaths. Here you can see the percentages of patients with adverse events related to Tospetinib, and the most frequent were relatively mild nausea and fatigue, with very few grade three or larger related adverse events. Similar profile occurs when we combine cuspidinib with venetoclax in the doublet, with no new or unexpected safety signals arising, and very similar rates of adverse events. Higher rates of neutropenia and other mild suppressive markers, as would be expected with the addition of venetoclax, is very much in line with what we would expect for venetoclax containing regimens. In fact, lower rates of febrile neutropenia than expected. And here is the evidence of that single agent activity. This graph here shows evidence of bone marrow blast reductions in patients treated with despenib as a single agent. You can see that more than half the patients achieved some degree of bone marrow blast reduction. And you can see that this occurred in a variety of different dose levels as shown by the different colors. The other thing I would point out is that patients that had a prior FLT3 inhibitor are marked with a red triangle. And you can see that patients with prior FLT3 inhibitors were just as likely, if not more likely, to show a bone marrow blast reduction. However, patients with prior venetoclax, shown by the black triangles, are less represented in the far right of the graph, consistent with our knowledge that then-resistant patients are less likely to respond to practically any other therapy as a monotherapy. For that reason, we performed the doublet study of patients with relapsed refractory disease, receiving caspetid and venetoclax, and again saw blast reductions in more than half of the patients. And in contrast to the figure on the left, we now see many more of those black triangles on the far right of the graph. showing that even then pre-treated patients can have significant blast reductions when treated with a combination of venetoclax and tispetanib in the relapsed refractory setting. And once more, multiple red triangles on the right indicating patients with prior FLT3 inhibitor are still more likely to respond than patients who don't, likely because of their prior FLT3 mutation status. So now I'll pass on It talks to Dr. Fletcher Payne, who will talk more about the investment thesis and some of the near-term milestones for the drug. Fletcher?
spk07: Thanks, Raf. Good afternoon, all. There are three key points to the TUS investment thesis. First, there's a very high unmet medical need in frontline AML, as has been discussed before, to increase survival across all genetic subtypes. Two, the KOLs support TUS as the ideal third agent for triple study in the frontline patients. Three, TESS is emerging as an ideal agent to combine with then-HMA. This is due to the safety profile, the broad activity across FLT3 mutated and FLT3 wild-type patients, as well as activity against the difficulty to treat mutated TP53 and the RAS gene subtypes. The design of the triplet study and the data readouts line up well to generate several near-term value-creating milestones. The first milestone will be at EHA in June 2024, where we will report single agent and double agent activity, which supports our contention to move into the frontline in the triplet study. The second milestone will be in the summer of 2024, where we will start dosing newly diagnosed patients in our triplet study. The third milestone at ASH 2024, we will report complete responses MRD negativity and safety data from the triplet study. During the first half of 2025, we expect a complete enrollment of the study. The fourth milestone will be at EHA in the summer of 2025, where we will report data readout from the triplet study. So, as you can see, the triplet study provides for a number of value-creating inflection points over the coming year. Before I cover the first quarter financial highlights, I would like to start by saying that being on our comments in this call, additional information may be found in today's press release and the 10Q filed with the SEC. During the first quarter of 2024, we continued our disciplined financial management of operations. We reduced spending on several fronts and prioritized our investments in our clinical programs. we continue to evaluate ways to reduce operating expenses. The total outstanding share count as of today, May 14th, is 16,393,393 shares. Based on current operations, the company expects the cash on hand plus our ATM will provide sufficient resources to fund planned operations, including research and development activities through August of 2024. Last quarter, we informed you that a 2024 deficiency letter from NASDAQ regarding the private placement with Hanme was announced, which was announced in January. Aptos has submitted a plan to NASDAQ to regain compliance. On April 25 of this year, the company received a letter from NASDAQ listing qualifications department notifying the company that the company had regained compliance with the NASDAQ listing rules. 5635D and determined that the matter is now closed. Under the company's plan to regain compliance on April 26, 2024, the company announced that it had amended the warrant agreement with HOMI to prohibit the exercise of HOMI warrants in excess of the NASDAQ 19.99% limitation unless shareholder approval is first obtained. On April 2, 2024, we received a second notification from the NASDAQ stating that the company was not in compliance with the NASDAQ listing rules because our stockholders' equity as of December 31, 2023, was below the minimum 2.5 million. We intend to submit a compliance plan on or before May 17, 2024, Monitor our stockholders' equity, and if appropriate, consider further available options to evidence compliance with the stockholder equity requirement. I would like to direct you to review the company's risk factors and discussions regarding the NASDAQ ladder and the ongoing concern footnote in our 10Q and our 10K filings. Now let's review the first quarter financials. We ended the first quarter of 2024 with approximately $9.3 million in cash, cash equivalents, investments, approximately equal to December 31, 2023. The $11.8 million in net financing proceeds in January 2024 was offset by $11.8 million used to fund our operations for the quarter, including our Aptivate clinical study for to supplement. As seen in the income statement, we had no revenues during 2024 or in the first quarter of 2023. During the first quarter of 2024, the net loss was approximately $9.6 million, translating into $0.73 loss per share, compared to $13.7 million loss, or $2.22 loss per share from the first quarter of 2023. As of May 14, 2024, Aptos had $16.3 million All references to losses per share and shares outstanding had been presented to reflect the 15 for 1 reverse split completed on June 6, 2023. Research and development expenses were approximately $6.4 million for the quarter ended March 31, 2024, compared to $8.8 million for the first quarter of 2023. Program costs for Lecseptinib were $3.9 million for the first quarter of 2024, compared to $4.8 million for the first quarter of 2023. Lower program costs for Lecseptinib in the current period represented the completion of patient enrollment, window test, then doublet program, and reduced manufacturing costs. Program costs for Lecseptinib were $208,000 for the first quarter and decreased by approximately $1.1 million compared to $1.3 million in the first quarter of 2023, primarily due to lower clinical trial costs and lower manufacturing costs. G&A expenses were $3.3 million for the first quarter of 2024 and decreased by $2 million compared to $5.3 million for the corresponding period of 2023. The decrease was primarily due to lower professional fees or stock-based compensation in the current period. Now let me turn back to Dr. Rice.
spk11: Thank you, Fletcher. Now we'll open the call for questions, and please feel free to pose a question to any of us. Operator, if you could, please introduce the questions.
spk03: Thank you. As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again.
spk14: One moment for questions. Our first question comes from Joe Pangenis with H.U.
spk03: Enright. You may proceed.
spk15: Good afternoon, gentlemen. Thanks for taking the questions. I'll start with two, if you don't mind. So first, on slide number 10, when you presented the trial design for the triplet combination, I'm just curious if there was, what level of before and after was there? So you met with the FDA in the first quarter, as you said. How much does slide 10 align with what you originally wanted with them?
spk11: So, Rat, perhaps, Dr. Behar, perhaps you can answer that one and put it in context. Sure.
spk06: Yeah, of course. So, this was developed in conjunction with experts in the field, including our lead PI, Dr. Naval Dauber, who's done several of these frontline triplet studies, and it really reflects both his experience and the Venn-Aza label. It isn't really a consequence of a back and forth with the FDA on this. We did submit a protocol amendment to our existing study that includes this protocol more than, I think, 45 to 50 days ago now. But this is really a function of our discussions with our experts, not a consequence of discussions with the FDA.
spk15: Nope, that makes sense. Thanks. And then I guess as we look to the triplet study now, everyone's going to be Highly looking forward to the year-end data. So I guess internally, what do you view as the benchmark for success to be able to move beyond the pilot?
spk06: I can take that too, Bill. I think there's a couple of opportunities, I think, to show benefit here. The expectations are based on prior data that the frontline triplet with a kinase inhibitor like tispetinib can substantially increase the response rate. Of course, I think the metric that really matters is overall survival, and that is not data that we expect to have in the short term. But the expectation with the VLA-A study is that you see about two-thirds of the patients responding. I think if we would see something closer to 75%, I think we'd be comfortable that we are at least meeting that if not exceeding it. And given the number of patients we expected, Ash, I wouldn't expect to see a robust value there. But by the time this study is complete and we've treated enough patients, I think we'll have a very good understanding based on the response metrics about how well we're doing.
spk10: Yeah, perhaps I can add a little bit to that because it also relates back to the trial designs. What we hope to see and we expect to see by year-end is the complete remissions in these patients. We expect to see the robust safety, which we've continued to see all the way through, even in the doublet of TUSPETNES plus venetoclax. And we hope then that that allows us to maintain the standard of care dosing that Dr. Behar had mentioned, because it's really important to be able to maintain the expected levels of venetoclax, as well as the hypomethylating agents, that according to the label of the drug, FDA wants to see that. We want to see that. And that's been a real problem with many of the other drugs out there. Perhaps Dr. Behar wants to add to that.
spk12: That's exactly right, Bill. Thank you.
spk02: Okay. Thanks, guys. Appreciate it.
spk03: Thank you, John. Thank you. And as a reminder, if you would like to ask a question, please press star 1-1 on your telephone.
spk14: One moment for questions. And I'm currently showing no further questions.
spk03: I would now like to turn the call back over to Dr. Rice for closing remarks.
spk11: All right.
spk03: Well, thank you, everyone, for joining us this afternoon.
spk10: We're genuinely excited to take Tuspetinib into the frontline triplet therapy for newly diagnosed AML patients. And we hope that we've relayed how Tuspetinib is distinguished from other AML compounds in development, not only because of its safety profile, but because it has shown activity across a broad set of mutations. even in wild-type AML, potentially addressing the largest markets in AML, not just a subset. As always, we thank our patients, investigators, and employees for their important role in this effort. Our clinical team has been keen in developing our pilot triplet study to getting it prepared, and want to recognize them for their execution. We appreciate our shareholders and analysts who continue to support us, and we look forward to keeping you updated on our progress today, and we really do appreciate the questions that came to us today. I want to thank you and have a good evening.
spk03: Thank you, ladies and gentlemen. That concludes today's conference. You may all disconnect and have a wonderful day.
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