Aptose Biosciences Inc (APTO) 2023 Q4 法說會逐字稿

Good afternoon. My name is Jonathan, and I will be your conference operator today. I would like to welcome everyone to Aptose Biosciences conference call for the fourth quarter and year ended December 31, 2023. (Operator Instructions) As a reminder, this conference call may be recorded. And now I'd like to introduce to your host for today's program Susan Pietropaolo. Please go ahead.

Thank you, Jonathan. Good afternoon and welcome to the Aptose Biosciences conference call to discuss financial and operational results for the fourth quarter and year ended December 31, 2023. Earlier today, Aptose issued a press release relating to the financial results. The news release as well as related SEC filings are accessible on Aptose's website.

Joining me on today's call are Dr. William Rice, Chairman, President, and CEO; Dr. Rafael Bejar, 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 US and Canadian securities laws. Forward-looking statements reflect Aptose's 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 Aptose's most recent annual report on Form 10-K and SEC and SEDAR filings. All forward-looking statements made during this call speak only as of the date they are made. Aptose undertakes no obligation to revise or update the statements to reflect events or circumstances after the date of this call except as required by law. We encourage you to refer today's press release and the 10-K for additional information and disclosures regarding today's announcement. I will now turn the call over to Dr. Rice.

Thank you, Susan. I want to welcome everyone to our call for the fourth quarter and year ended December 31, 2023. Today, we will provide updates on our financial status on the near term and long-term clinical development plan for our lead agent, tuspetinib and quick update on our luxeptinib program.

From a financial perspective, during 2023, we financed corporate activities with cash glean from our ATM facility, from a committed equity facility and through our strategic investment by our partner, Hanmi Pharmaceutical.

Then in January of this year, we closed financing with gross proceeds of $13.7 million, inclusive of a $9.7 million public offering, along with the separate $4 million private placement with Hanmi pharmaceutical. This provided us with more breathing room. And Mr. Fletcher Payne, our CFO, and CBO provide additional financial details in a few minutes. And I want to pivot to our lead program tuspetinib.

So why should you care about tuspetinib? It's because tuspetinib or TUS as we often call it, is convenient, orally administered, once-daily kinase inhibitor with an excellent safety profile and potent anti-leukemic activity that is being developed for the treatment of acute myeloid leukemia or AML.

And we believe a tuspetinib containing triplet regimen can become a new standard of care for the frontline treatment of newly diagnosed AML patients across a broader set of genetic subtypes. This day we'll explain why we believe this, and how we arrived at this point.

First, you're aware that we've been performing studies in relapsed or refractory AML patients with tuspetinib as a single agent and with tuspetinib in combination with venetoclax, which we refer to as the TUS/VEN doublet.

The valuable findings gleaned from these studies have now led us to pursue the development of tuspetinib as a triplet combination therapy for the frontline treatment of newly diagnosed AML patients at the highest priority. The triplet include tuspetinib, the BCL-2 inhibitor venetoclax and a hypomethylating agent such as a [Saturday] collectively referred to as a TUS/VEN/HMA triplets.

In fact, we just heard from a group of KOLs in AML that they had great enthusiasm for the safety and activity of tuspetinib, and they believe this is a real drug with the potential to go all the way. These KOLs and our internal team all agree that the immediate focus of tuspetinib should be primarily on the TUS/VEN/HMA triplets. And that is precisely where we are focusing our resources because this TUS/VEN/HMA triplet has the potential to deliver the greatest patient impact, the greatest commercial impact and the greatest return to our investors.

At the patient level, we believe tuspetinib can have its greatest impact in frontline AML by improving the response rates, the depth of responses, the durability of responses, the quality of life and the long term survival across the diversity of AML patients relative to the current [bin] HMA standard of care in frontline AML patients who are ineligible for intensive chemotherapy.

Plus the commercial aspect, our impact of the TUS/VEN/HMA Triplet and front-line therapy is estimated to exceed $1 billion annually. And we've heard from many potential partners that the application of these TUS/VEM/HMA to the frontline market. There's a primary interest to them. Indeed, the safety, breadth and efficacy profiles of tuspetinib today make us believe that tuspetinib can be the best agent to combine with have been VEN/HMA, which is the current standard of care.

All the goal for the tuspetinib program is to move into frontline AML therapy at the triplet, the path to the frontline tripIet begin with the tuspetinib single agent trial and then transition through the tuspetinib doublet trial to understand activity, safety and contribution of components.

With the tuspetinib single-agent trial, we completed enrollment of 93 patients across 6 dose levels. tuspetinib single agent achieved an excellent safety profile without many of the key liabilities seen in competitor agents, who demonstrated broad activity across AML populations with that first genetic alterations.

We observed a threefold longer median overall survival in responding patients relative to non-responders and 80 milligrams once daily was selected at the recommended Phase 2 dose for single-agent therapy, but the 80 milligram dose level tuspetinib single agent was highly active, achieving high quality responses with high response rate.

We were delighted to see a strong 36% CR/CRh rate among all-comer genotype in patients who had not previously been treated with venetoclax referred to as been naive patients. Notably, at the 80 milligram dose level, few of the patients had failed prior therapy with venetoclax. However, as we dose escalated above the 80 milligram dose level, we saw that [power bin] failure patients are emerging as a new category of relapsed refractory AML at that point in time. And the proportion of prior been patients increased dramatically to greater than 80% and the next dose level of 120 milligram.

Once patients develop venetoclax containing therapy, they're more refractory to all subsequent salvage therapies, including tuspetinib as a single agent. And this led to lower response rates in the 120 milligram dose level and then and the 160 milligram dose level. Fortunately, there is a silver lining to this change in the relapsed refractory AML patient population.

In our past scientific conference presentation, we've described our tuspetinib target venetoclax resistance mechanism and how tuspetinib come to combine synergistically with venetoclax in AML models. Plus we've shown that tuspetinib resistance AML cells are hypersensitive, 2,000 fold more sensitive to venetoclax.

This mechanistic complementarity provided a rationale for us to combine tuspetinib with venetoclax to evaluate the TUS/VEN doublet in the relapsed refractory AML population. In our TUS/VEN doublet trial, we now have completed enrollment with 40 milligram tuspetinib and with 80 milligram tuspetinib combined with 400 milligrams venetoclax in a total of 79 patients.

First, we observed that the excellent safety profile of tuspetinib as a single agent was maintained with the TUS/VEN/ doublet. We observed bone marrow leukemic blast reductions in the majority of patients, including those who failed prior therapies with FLT3 inhibitors or prior venetoclax therapy. And we can see -- continued to see evidence of broad activity across AML patients with a diversity of adverse mutations, including patients that failed prior therapy with venetoclax.

We see great promise for the TUS/VEN doublet, to effectively treat the prior [vent] failure patients and even become a standard of care for those patients. And there remains a potential accelerated approval path for the TUS/VEN doublet in a molecularly defined subpopulation of relapsed refractory AML, especially if we increase the dosage of tuspetinib and the TUS/VEN doublet and demonstrate even greater activity. This has been a source of high interest for KOLs, collaborators and certain potential partners.

And as resources become available, we would like to pursue the TUS/VEN doublet with higher doses of tuspetinib for the relapsed refractory population. However, in the near term, we have chosen to focus our resources on the TUS/VEN HMA triplet and frontline AML therapy.

So our next step to build value as quickly as possible, will be to initiate a tuspetinib plus venetoclax plus [hypomethylating] triplet pilot study in frontline newly diagnosed AML patients and to select the optimal triplet dose -- dosage of tuspetinib, which will be driven by CR/CRh rate, MRD negativity and safety data. After selecting appropriate Phase 2 doses of the triplet, we plan to transition into registrational studies that compare the safety and efficacy of the triplet to the VAN/HMA control for frontline newly diagnosed AML patients.

I also want to mention that our ongoing BD conferences -- conversations with a number of large pharma companies emphasized the need for the AML therapeutic paradigm to focus on creating more effective, more durable, broader active and less toxic front-line cocktails of targeted agents for AML patients.

And they point to the frontline triplet therapy as a cornerstone of a commercial success, it's clear that we can create the greatest value for tuspetinib and the shortest period of time are in the least amount of capital by performing a TUS/VEN/HMA triplet pilot study in frontline AML patients and such data can then support partnerships for later-stage development of tuspetinib.

So this provides you with a framework for our strategic thought process. And Dr. Bejar, our Chief Medical Officer, will provide you with additional clinical insight and perspectives in a few minutes. But first, I also want to mention our other drug luxeptinib. You'll recall that LUX, as we often call, it is an oral highly potent kinase inhibitor that selectively targets defined kinases operative in myeloid and lymphoid hematologic malignancies.

This small molecule has been evaluated in a Phase 1 a/b study for the treatment of patients having relapsed or refractory B-cell leukemias and lymphomas and in a Phase 1 a/b study for the treatment of patients with relapsed or refractory AML.

Enrollment and dosing of patients in the B-cell malignancy trial have now been completed, including 36 patients who were dosed with the original G1 formulation across 5 dose levels, ranging from 150 milligrams to 900 milligrams bid. In this trial, LUX achieved tumor shrinkage among 63% of the evaluable B-cell cancer patients and across dose levels from 450 milligram to 900 milligram.

This also includes a complete response or CR and a DLBCL patient, an impressive tumor reductions and follicular lymphoma patients and an SLL patients. Likewise, enrollment and dosing of patients in the AML trial now has been completed. In this trial AML patients received the original G1 formulation across dose levels, ranging from 450 milligrams to 900 milligrams BID.

Bone marrow blast reductions were observed in 38% of the evaluable FLT3 mutated patients and 50% of the evaluable FLT3 wild type AML patients. In addition, an MRD-negative CR are complete remission response in one relapse refractory AML patient occurred with the 450 milligram BID dosing of the original G1 formulation.

Our clinical demonstration data demonstrate that LUX is active in AML patients and in B-cell cancer patients. But we were not consistently achieving the desired exposure levels to drive consistent responses because absorption of the original G1 formulation hampered the effectiveness of luxeptinib and new generation 3 or G3 formulation was developed.

And now we can report that the clinical evaluation of the G3 formulation also has been completed. First, the G3 formulation was tested in a single dose bioavailability study in 20 patients, including both B-cell cancer and AML patients and across five different dose levels from 10 milligrams to 200 milligrams.

The G3 formulation was then evaluated in relapsed refractory AML patients with continuous dosing using two different dose levels, 50 milligrams bid and 200 milligrams bid and in total of 11 patients.

Recent data show the G3 formulation dosed at 200 milligrams twice daily can achieve two to three micromolar steady-state plasma levels with approximately tenfold better absorption. And interestingly, even better tolerability than the original G1 formulation. This means the G3 formulation achieved our desired plasma exposure benchmarks and that the G3 formulation will be the formulation of choice for future studies with LUX.

Selectively these findings demonstrate LUX is a viable drug with a viable formulation, and LUX has the G3 formulation should be advanced into a focused clinical development program. And we are delighted to see a future for us.

Regarding any next steps with LUX, we are exploring the potential to advance LUX to treat molecularly defined relapsed refractory hematologic malignancy patient populations of high unmet need, and we now are seeking alternative development paths and collaborations to execute that strategy.

I now want to turn the call over to Dr. Bejar, our Chief Medical Officer, and resident KOL for his insights and comments on our data and clinical plans for tuspetinib.

Thanks, Will, and good morning from Japan. As Bill mentioned, combination therapy is becoming more and more common for the treatment of newly diagnosed AML. [Patients] who have been tested as tuspetinib with standard of care backbone venetoclax with a hypomethylating agent in older patients who are ineligible to receive intensive chemotherapy.

There have been promising proof of principle successes in treating patients with triplet therapies that include kinase inhibitors [like this], but in fact, our lead investigator, Dr. [Nabil dumber] and his team at the MD Anderson Cancer Center have seen impressive response rates nearing 100% with this approach in certain AML populations.

However, these types of triplet therapies to date are complicated by increased toxicity that require reducing the dose intensity of each agent and the use of peer for kinase inhibitors that have been limited only to FLT3 mutated AML, which accounts for just 30% of the population. But with this paradigm shift, many companies are expanding their clinical development plans to test their drugs in this type of triplet combination protocol

We've maintained from the start of its development and suspended appears to be an ideal candidate for triple combination therapy. And our experience to date continues to build and support the strategy. As Will mentioned, we've taken a deliberate can tiered clinical approach. First, we successfully demonstrated significant activity of TUS in a single agent dose escalation exploration trial in a broad relapse refractory AML population.

We completed dose escalation exploration and expansion studies with 93 patients treated with TUS dosed once daily for 28 days without interruption. And the leukemic activity that included durable objective. clinical responses was observed 4 active dose levels, all of which were taught well-tolerated with no dose-limiting toxicities in over 70 treated patients.

At the 80 milligram dose in the then naive patient population to spend. It had an excellent CR/CRh rate, 50%, 36%, 25% in FLT3, overall FLT3 wild-type overall and into FLT3 wild-type respectively. Importantly, test demonstrated an excellent safety profile with no instances of drug-related QTc prolongation, differentiation syndrome or muscle damage in any patient or prolonged myelosuppression in responding patients who had clear to leukemia.

As Will mentioned, we observed productivity across AML populations at 4 dose levels. This included patients with adverse genetic alterations and FLT3 graphs, -- DNMT3, AidH genes, NPM1 genes, MLL-PTD and others. Then in conjunction with the FDA, 80 milligrams once daily was selected as the recommended Phase 2 dose for single-agent therapy.

As AML care has shifted toward venetoclax containing combination regimens. We began to find in our single biggest and still challenging to treat relapsed refractory AML population. Those patients who had received and failed venetoclax. This emerging patient population now accounts for a large percentage of relapse refractory patients entering all the AML trials something we all developing these trials need to consider as then failure patients are more resistant to subsidy (technical difficulty)

To treat very ill prior been treated AML population, which led us to conduct after they are tough and doublet study in relapse refractory AML,

We initiated activate doublet study of tests then to explore the ability of tests to treat these then failed patients. We completed TUS exploration with 40 milligrams and 80 milligrams with 79 patients. TUS/VEN doublet treatment was well tolerated with no drug-related deaths and lower rates of febrile neutropenia than observed with other band combination studies.

Response activity, 80 milligrams TUS and 400 milligrams VEN was broad-based and was observed in patients with and without a history of venetoclax treatment and in patients with and without FLT3 mutations. Importantly, we observed a dose response relationship such that patients receiving 40 milligrams of suspended with venetoclax achieved bone marrow blast reductions, but did not achieve formal responses in large numbers.

In contrast, many of the patients who received 80 milligrams tuspetinib with venetoclax did achieve both bone marrow but formal responses. This combined with a clean safety profile, tells us that we should explore even higher to spend at dose levels in combination with venetoclax to achieve even greater response rates and more durable responses in this growing exceedingly difficult to treat patient population.

Overall, tuspetinib tested demonstrated potent activity across diverse with adverse mutations, achieving responses broadly in AML with a variety of adverse genetic mutations and tested and has a favorable safety and tolerability profile. Tuspetinib also is convenient as a once-daily oral tablet and mechanistically targets of venetoclax resistance mechanisms. This makes tuspetinib an even better [triplet] therapy for we're now rapidly heading.

All of these data from the TUS single agent and TUS/VEN doublet studies have led us into tuspetinib and venetoclax is [hypomethylating] in triplet pilot study in front-line newly diagnosed AML patients in eligible for intensive chemotherapy.

With the goal of becoming the standard regulation. After discussions with our scientific advisers and potential partners, we are prioritizing this study and our clinical team is active in planning to begin this study within the first half of this year.

The high level of interest in seeing TUS developed as frontline therapies not only because of its safety and combinability with the fact that it has demonstrated activity in FLT3 mutated and FLT3 wild-type run mutated AML, differentiating it from many of the other compounds being developed by targeting the vast spectrum of AML, not just a narrow target or subset of that group.

Our triplet pilot study is being designed as an all-comers trial and is designed to combine with standard of TUS/VEN/HMA and to select the optimal TUS Triplet dose to enable further randomized double-blinded clinical study. We plan to initiate this pilot in frontline newly diagnosed AML patients during the first half of 2024 and expect to see initial findings by ash 2024.

We plan to follow these patients to assess overall survival. While HMA/VEN demonstrated a median overall survival of about 14.7 months, not all treated patients benefited equally. Patients with growth factor signaling mutations such as those FLT3 ITD, [MRS KRES] had more modest survival. In those FLT3 mutations seem to not benefit from the doublet over [hazel] alone. And based anticipating this mechanism of action, we would hope to see deeper more durable responses compared to patients receiving the current HMA standard of care alone, particularly in a subset of patients with these resistance type mutations.

As standard of care for frontline AML patients unfit for chemotherapy, the potential impact for to spend it is tremendous addressing a market in excess of $1 billion. We expect that the pilot data could support launching test spend HMA registrational programs in 2025.

Meanwhile, as resources allow and at the encouragement of KOLs a second priority is to develop the [spend]. In comics, TUS/VEN doublet for relapse refractory first salvage for FLT3 mutant AML. We saw the greatest response rates to TUS/VEN doublet in the AML population with FLT3 mutations, even if they have been previously treated with FLT3 inhibitor.

We can envision an approach where in relapsing AML patients with FLT3 mutations are treated with a TUS/VEN doublet in compared to those treated with the current approved standard of single-agent venetoclax. This is an avenue that several KOLs would like us to consider as the current standard of care benefits, a minority of treated patients and these patients in need of more likely and more durable responses. This is a study we hope to be able to initiate later this year if resources allow.

Let me now leave you with a quick summary of why we believe tuspetinib the best agents combined with an HMA and Tuspetinib, then the triplet can become the standard of care for frontline newly diagnosed AML patients.

TUS has an excellent safety profile without concerns for drug-related QTc prolongation differentiation syndrome, yet damage or prolonged myelosuppression once patients achieve remission. TUS also has broader activity that includes three mutant and three mutated patients compared with other competitor kinase inhibitors and is active in patients with the diversity of other adverse mutations.

TUS has an extended patent coverage that could well beyond that and TUS us has the potential for premium pricing, filing is looking more unlikely that the kinase inhibitors will enter pivotal frontline studies with an HMA.

TUS/VEN/HMA triple therapy could serve as an off-the-shelf mutation agnostic triplets, allowing for rapid deployment physicians [will not and agnostic stick assays] for delay therapy while they identify target mutation profiles before putting patients on treatment.

So we believe that TUS/VEN/HMA can clearly feel the sizable gaps left by competitors even combined further with future complementary targeted agents.

Now I'd like to turn the call over to our CFO and Chief Business Officer, Mr. Fletcher Payne for an update on our financial steps. Fletcher?

Thanks, Raf, and good afternoon all. I'd like to start by saying in addition to the comments in this call, additional information can today's press release and the 10-K filed with SEC.

During 2023, we continued our disciplined financial management of operation, reducing expenditures on a number of different fronts and prioritize investments in our clinical programs. As always, we continue to evaluate ways to reduce operational expenses.

Also during the year, we used the ATM facility and our 2023 committed equity facility and entered into agreement with Hanmi Pharmaceutical to raise a total of $7.3 million of additional capital. This past January just two months ago, we announced the closing of a $9.7 million public financing, including the full exercise of the over-allotment option and a separate strategic investment of $4 million private placement with Hanmi Pharmaceutical.

The gross proceeds from the public offering and private placement were approximately $13.7 million, excluding underwriters' discounts based on agent commissions and other offering related expenses. The total number of common shares outstanding after the closing of the public offering and the private placement, including the over-allotment, is 15,706,810 and the warrants outstanding are 8,332,163 warrants.

Based on current operations, the company expects the cash on hand plus our ATM and committed export facility will provide the company with sufficient resources to fund planned operations, including research and development through August of 2024.

Now you're probably aware that on February 29, we received a letter from NASDAQ, claiming it in January 2024, private placement of securities to Hanmi violated rule 5635(d) of the NASDAQ listing rules because we did not obtain shareholder approval prior such issuance.

NASDAQ stated that Hanmi's private placement involve the issuance of greater than 20% of our issued and outstanding common shares with the assumption that it closed on the same date as our public offering. We believe the Harmony private placement was completed in accordance with the NASDAQ listing rules as it was a separate issue with different deal terms and closed on a different date.

The deficiency letter has no immediate effect on listing of our common shares. In accordance with NASDAQ listing rules, we are given 45 calendar days or until April 14, 2024 to submit a plan to regain compliance. If NASDAQ accepts the plan, as NASDAQ can grant an extension of 180 calendar days from the date of the deficiency letter of evidence of compliance. We respect NASDAQ query or working with NASDAQ, resolve their concerns and consider available options to regain compliance.

I'd like to direct you to review the company's risk factors and the discussions regarding the NASDAQ letter and our going concern footnote in our 10-K filings.

Now let's review the year end 2023 financials. We ended the fiscal year of 2023 with approximately $9.3 million in cash, cash equivalents and investments, that is a decrease of $27.7 million as compared to December 3, 2022. The $27.7 million decrease in our cash and investments has resumed result of use of funds for the activate study and operating expenses was offset by an increase in cash from certain financing activities.

On a cumulative basis through December 31, 2023, the company had rate raised a total of $7.3 million, $3 million from Harmony subscription, $1.9 million in gross proceeds from the 2022 ATM facility and $2.1 million in gross proceeds from the committed equity facility.

After the gross proceeds from the January 2024 financing a $13.7 million the cash, cash equivalents was $18.6 million that's an audited results.

As seen in the income statement, we had no revenues during 2023. During 2023, the net loss was approximately $51.2 million, translating into approximately $7.58 loss per share compared to $41.8 million loss and $6.80 loss per share from the 2022 annual period.

As of March 26, 2024, Aptose has 15,717,701 common shares outstanding. All references to the loss per share in the shares outstanding effort presented to reflect the 1 for 15 reverse stock split completed on June 6, 2024. Due to our continuous strategic relationship with Hanmi we are now separately reporting related party R&D from our normal R&D expenses.

Related party R&D expenses from the Hanmi relationship were $3.5 million for the year end 2023, compared to $3.6 million for the same period in 2022. Remaining research and development expenses were approximately $33.3 million for the year ended December 31, 2023, compared to $24.5 million during the year ended December of 2022.

Program costs for test substantive were $24.9 million for the 12 months ended December 31, 2023, compared to $10 million for the 12 months ended December 31, 2022. By our program costs for tuspetinib in the current period represents the enrollment of patients in our APTIVATE clinical trial clinical materials and the healthy volunteer and other expenses related to after [the end program].

Program costs Luxeptinib for $3.5 million for the 12 months ended December 31, 2023, and decreased by approximately $4.9 million, compared to the $8.4 million for the 12 months ended December 31, 2022. Primarily due to lower clinical trial costs, lower manufacturing costs as a result of the current G3 reformulation, which requires less API than the prior formulation.

G&A expenses were $15.6 million for the year ended December 31, 2023, compared to $14.5 million for the same period of 2022. The increase was primarily due to increased salary risks, expense, higher professional fees, and partially offset by lower stock-based compensation.

Now let me turn it back to Dr. Rice.

Thank you, Fletcher. Now we'll open up the call for questions and please feel free to pose a question to any of us. Operator, if you could please introduce the question.

(Operator Instructions)

Soumit Roy, Jones Research.

Afternoon, everyone. So as I'm trying to understand the strategic path forward. The -- development of TUS in relapsed refractory AML is on pause. And we are going to see the latest update data at EHA, is that correct?

It is, currently we've been treating patients to relapse refractory patients. We've completed the enrollment of the patients in both single agent and doublet in the relapsed refractory and we don't plan on putting any more patients on their immediately because our top priority is to put all of our cash resources into that triplet trial if additional resources become available. We will move it into the doublet trial in which we increase the dose of tuspetinib in the relapsed refractory patients. And yes, we will be presenting the single-agent and doublet data in relapsed refractory patients at the EHA conference in June. Dr. Bejar do you want to add anything to that?

No, I think it's accurate. The goal will be to dose escalate in the doublet as we had a very clean safety profile at the doses that we tested already. As Will mentioned that will depend on additional resources.

So the strategy to move to put the entire our resources towards the front line because Frontline is going to be a much longer trial has to be randomized. It's a full Phase 3 trial versus we were expecting the relapsed refractory setting could have a potential path for regulatory approval. And do you think it's just the clinical benefit you're seeing and even if you dose escalate, the clinical benefit might not be significant enough to go for the access repair?

Well, I wouldn't view this as a negative by any means. So in the relapsed refractory setting, we do, we saw a dose-dependent effect 40 milligrams. And in combination with venetoclax, we saw activity but not as extensive as we went up to the 80 milligrams much more extensive responses in patients. And the good news is we're able to dose escalate even further we believe with covenants with Tuspetinib, whereas other drugs you tend to have to dose reduced.

So we believe we can get an even higher response rate, greater durability in the relapsed refractory population. And you're right, if we were to move forward there the next step would be in a potential accelerated approval, our development path, and that would be, that also would be in a randomized trial, but we believe the greatest value in the near term is in this pilot triplet study frontline because tuspetinib really differentiated itself, it's very safe when it's combined with the other drugs, it's a very broad activity and this is what's needed in the front-line therapy, the triplet. And we hear that from all potential partners as well as the [kinase] and AML.

Dr. Bejar want to add anything?

No, I think it's exactly accurate. I think that we are excited about the idea of being able to treat these relapse refractory AML patients and to pursue that avenue. So when we think about prioritization, not just like we've had a process but also scope of market potential patient benefit, it is substantially greater in the frontline setting.

And much of that is very much driven by what we're hearing from potential partners as to the data that would drive the major partnership.

In the frontline setting, are you going to put any inclusion criteria or select for FLT3 or TP53 mutant patient, which are a little harder to treat? And that's the mechanism of tuspetinib allow to combined with seven plus three regimen also? Or is it going to be respiratory HMA/VEN only?

Quite a bit. Right now, the focus is on those older individuals that are ineligible for induction chemotherapy. And we would want to include patients with and without FLT3 mutations. But we know that there are other triplet studies that are going to be out in the world. And so we don't want those patients who couldn't qualify for those studies. We want to see the broad range of AML. So we would include patients that have TP53 mutations, but we would limit their fraction to be representative of what we see in AML population, which are about 20% to 25% of those individuals. So we don't do a trial exclusively in that patient population.

And then your question about combining with seven plus three, I think that would be very doable for tests. It would be a great way to go. There's two reasons that we've de-prioritized that at the moment and one of which is, I think, the low-intensity treatment with venetoclax and hypomethylating agents containing regimens is becoming more common even in individuals [who like would that be] patients who you might be able to give chemotherapy to, but you can achieve perhaps similar if not better response rates and duration of response even without giving chemotherapy by giving a low-intensity therapy.

And finally, they are already are approved agents in the kinase inhibitor realm in that chemotherapy combination regimen, [quizartinib] and of course, in my store. And while those states were approved against a non- [myeloid] kinase containing regimen, we would have to pursue a registrational strategy against the kind of containing regimen. So for these reasons, we think that there is greater viability for going after the chemo ineligible population first. But we would certainly love to explore combining chemotherapy as well. as we look into the.

As we look into the future, we will likely will see the triplet combination of targeted agents showing much better or much higher response rates, much greater durability. That's the hope for all of the triplets in the patients who are ineligible for chemotherapy. And then once that is proven, we would expect that those triplets would also move over to the patients who are chemo eligible. So we would expect that these triplets of targeted agents would then go across both the fit and unfit patients for therapy.

Got it. And one last question. So in terms of data readout for from the frontline setting, we expect safety readout only towards the end of this year, and efficacy readout is likely to be the end of 2025, if that's the right assumption?

And I'll jump in on first and Dr. Bejar can come in. So ultimately, you want to see that you have an extended overall survival of these patients, [myeloid] overall survival and would expect that to be much longer with the triplet. So by the end of this year, we won't have a full duration of myeloid overall survival, but we should be able to see the CR/CRh rate during that period of time, the safety profile and possibly MRD negativity because in these patients with the triplet, you tend to see the responses very quickly in these patients and then you want to be able to see that you're also recovering the account. Perhaps Dr. Bejar wants to add to that.

That's exactly right. I think we will have early indications of activity. At other studies that have been done with a combination of HMA/VEN, a kinase inhibitor, for example, the vast majority of responses occurred in the first or second cycle suggesting that even if we had a handful of patients put on in the first portion of the year, that we would have a follow-up data to see what their likely response rates are. Now fortunately, it takes longer to get survival in this patient population because they do live longer, and we would hope to have more of that data in 2025.

And we hope to be able to have multiple dose levels of tuspetinib combined into the triplet. We would hope to start we started out around 80 milligrams if possible. And then if that's safe, we look to move up again with most other drugs when you combine with the VEN/HMA, you may have to do dose reductions, both that molecule as well as the VEN/HMA. We hope we will not have that issue. We expect that we'll be able to dose the 80 milligrams and to maintain the label dosing for the VEN/HMA. So that's the plan.

Thank you again for taking all the questions and congrats on all the progress.

This does conclude the question-and-answer session of today's program. I'd like to hand the program back to Dr. Rice for any further remarks.

All right. We'd like to thank everyone for joining us this afternoon. As I mentioned earlier, our KOLs test bed is a real drug, has demonstrated activity across a breadth of genetic subtypes of AML. It has a surprisingly favorable tolerability profile with no significant safety signals. And these are true differentiators. For a year to initiate this triplet study because Tuspetinib, which we believe can be the ideal candidate for triplet combination therapy and the rapidly shifting AML treatment landscape.

As always, we thank our patients, our investigators and our employees for their important role in this effort. We appreciate our shareholders and analysts who continue to support us. And we look forward to keeping you updated on our progress. Thank you, and have a wonderful day.

Thank you. Ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.