Kura Oncology, Inc. (KURA) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to the Kura Oncology EHA Virtual Investor Event. [Operator Instructions] As a reminder, today's program is being recorded. And now I'd like to introduce your host for today's program, Dr. Troy Wilson, President, CEO and Co-Founder. Please go ahead, sir.

Thank you, Jonathan. Good afternoon, everyone, and thank you for joining today's call. Starting here on Slide 1. This is our 2025 EHA Analyst and Investor event. We're delighted to bring this to you now on the back of, first, ASCO in Chicago and then last week, EHA in Milan, Italy. All of our speakers today were in Milan. And so this is an opportunity to get everybody back and now walk through, in particular, the Phase I combination data and help contextualize that for all of you. So if we can go to the next slide, Slide 2. We will be making today forward-looking statements. Those forward-looking statements have risks and uncertainties, and we would refer you either to our website or to the website of the SEC for more information about Kura Oncology. If we turn to Slide #3. Of course, today -- the focus of today's discussion is ziftomenib. As all of you know, ziftomenib is an investigational menin inhibitor currently under review by the FDA for relapsed and refractory NPM1-mutant AML. We were granted PDUFA target action date of November 30 and priority review. And of course, this effort is part of a much larger development and commercialization effort for ziftomenib with our partners at Kyowa Kirin. And importantly, through that partnership, we believe we will have the operational and financial resources to advance this program through to commercialization in these frontline opportunities. And as we've guided in the past, we think the opportunity with intensive chemotherapy may represent the first such opportunity for top line results and potential approval. Turning to Slide #4. This is an agenda today. We're going to -- I'll introduce the speakers in just a moment, the key opinion leaders who are joining us. But we want to just contextualize the unmet need in newly diagnosed AML, walk through the Phase I data for the KOMET-007 IC cohorts that was presented at EHA then to contextualize that in the context of the global development plan, and in particular, the 2 Phase III clinical trials that are -- that comprise KOMET-017. And then finally, a couple of slides on the opportunity now as we -- while we are focused in the near term on our preparations for commercialization in the relapsed and refractory setting, ultimately, we're looking to benefit as many patients as possible. So we'll try to connect with you the clinical data to what we see as the market opportunity. Turning to Slide #5. We're delighted to have with us 2 of the leading investigators in the field, Dr. Harry Erba, who is the Director of the Leukemia Program at the Duke Cancer Institute; and Dr. Gus Issa, who's Associate Professor of Leukemia at The University of Texas MD Anderson Cancer Center. Between the 2 of them, they're going to walk through with you most of the content I just described in the agenda. Turning now to Slide #6 and the unmet need in newly diagnosed AML. I'll ask if Dr. Issa can take us through the next couple of slides. Dr. Issa?

Thank you, Dr. Wilson. So Slide #7. I will discuss with you guys the unmet needs in acute myeloid leukemia and why we're excited for ziftomenib and the addition of menin inhibitor to frontline treatment of AML. So there's an estimated 22,000 new cases of AML each year in the United States. And AML is really a disease of the elderly. The median age is 69. The majority of patients have the diagnosis above age 69 -- or half have the age of diagnosis above 69. And the current approved therapies include 7+3 or HMA, venetoclax for older and unfit patients or the addition of targeted therapies like FLT3 inhibitors, such as midostaurin or quizartinib in the frontline setting. So despite a lot of advances made in treatment of acute myeloid leukemia, the outcomes long term are still not great, especially for older patients. And for younger patients, even what has turned good AML or favorable AML has a chance of survival of 60% to 50% in 5 years of therapy. So this is not -- if you tell a patient favorable, that is not what they want to hear. And I think with the addition of menin inhibitors, we have a chance to improve on that. Next slide, Slide #8. If we focus on acute myeloid leukemia instead of looking at it as a whole, but instead look at it as slices and figure out targeted therapies, up to 50% of patients with acute myeloid leukemia have a signature, a gene signature that indicates potential response to menin inhibitors. So these would be the mutations in NPM1, which is the most common alteration in AML, up to 30%; and KMT2A rearrangements, which are up to 5% to 10%. And then there are other alterations that could have the same gene expression and could also respond to menin inhibitors. So we view this slice of the pie or this slice of the targeted therapy in AML as the largest subset that can be targeted with agents, with targeted agents that are not chemotherapies. So these would be the menin inhibitors. Next slide, Slide #9. So I'll take you through the mechanism of how menin inhibitors work, and I'm sure many of you are familiar with this. So menin inhibitors are small molecules that are designed to disrupt the binding of menin, a key protein that is important for genetic alterations in AML, such as KMT2A or NPM1 to exert their leukemic function. So by taking away the protein from KMT2A, it reverses the abnormal gene expression, and that leads to differentiation. In other words, this is turning leukemia cells back into normal cells, and this is by downregulating critical genes, MEIS1, PBX3 and HOXA9. And through that differentiating mechanism, this allows response and antileukemic effect. And we've demonstrated single-agent activity of these drugs, which is excellent. And in my opinion, an interesting mechanism of action like this single-agent activity and the tolerability of these agents make them ideal candidates for combination therapies. This is what we've seen -- what we've learned from multiple malignancies. And that's why we think that the addition of ziftomenib to standard therapies, such as what we're going to discuss today, 7+3 would be an excellent opportunity to improve outcomes of acute myeloid leukemia. And I'll turn it over to my colleague, Dr. Erba, to take you through the data.

Thanks, Gus, and good afternoon. We should be on Slide 10 now. I'm Harry Erba from Duke University. And on behalf of the KOMET-007 study investigators, I was given the honor to present the Phase Ia/Ib results of ziftomenib plus intensive chemotherapy for newly diagnosed NPM1-mutant and KMT2A-rearranged acute myeloid leukemia at the European Hematology Association meeting in Milan on June 12. Slide 11. In the KOMET-007 combination study, patients with NPM1-mutated or KMT2A-rearranged AML enrolled independently. Phase Ia included dose escalation ziftomenib combined with 7+3 in patients with high-risk AML defined as either KMT2A-rearranged AML or NPM1 mutated with adverse risk cytogenetics, aged 60 years or older and/or treatment-related AML. In the Phase Ib, all intensive chemotherapy eligible AML patients were permitted to enroll in the dose expansion. The primary endpoints included safety, dose-limiting toxicities and complete remission. Key secondary endpoints included composite complete remission, objective response rate and duration of remission. Ziftomenib 600 milligrams once daily beginning on day 8 of 7+3 was selected as the recommended Phase II dose in combination. It should be understood, however, that patients achieving remission could continue with ziftomenib orally with high-dose cytarabine consolidation followed by ziftomenib monotherapy maintenance. Patients were allowed to proceed to allogeneic stem cell transplant per the decision of the treating physician. At this time, 15 patients are receiving maintenance ziftomenib. Here, we're going to present the updated safety and clinical activity of newly diagnosed AML patients across the dose escalation and expansion phases treated with ziftomenib 600 milligrams once daily in combination with 7+3. So we can move on to Slide 12. And as of the data cutoff, March 21, 2025, a total of 82 patients across Phase Ia and Ib were enrolled and treated with ziftomenib 600 milligrams once daily in combination with 7+3. 49 patients were NPM1 mutated and 33 were KMT2A rearranged. Among the 49 NPM1-mutated patients, 44 were evaluable for response. 30 patients were on treatment at the cutoff, and 2 patients had received allo transplant. 14 patients discontinued. 1 patient died of ischemic enteritis during the first 30 days. Among the 33 KMT2A-rearranged patients, 27 were evaluable for response. 19 patients were on treatment at the data cutoff with 6 patients receiving a stem cell transplant, 1 of whom received ziftomenib maintenance therapy. 8 patients have discontinued, and 1 patient died during induction therapy of disseminated mucormycosis. Slide 13, please. The baseline characteristics were generally similar across NPM1-mutated and KMT2A-rearranged patients. In all patients, the median age was 56, although slightly older in the NPM1 cohort. 52% were female and 90% had an ECOG performance status of 0 to 1. FLT3-positive AML patients were only excluded in the NPM1-mutated arm since a true standard of care has not been determined for the KMT2A rearranged. There were 11 FLT3 co-mutated patients, 11 total, 6 in the FLT3 -- I'm sorry, 6 in the NPM1 mutated and 5 in the KMT2A rearranged. At the time of the data cutoff, 93% of patients remain on study with a median duration of follow-up of 18.4 weeks. Slide 14, please. The safety population included the 82 newly diagnosed adult patients with NPM1-mutated or KMT2A-rearranged AML. 94% of patients had treatment-emergent adverse events as expected in AML trials, the most common of which was febrile neutropenia occurring in 60% of patients, again, quite as expected with 7+3. The safety profile observed with ziftomenib in combination with intensive chemotherapy was similar to that reported for newly diagnosed patients treated with 7+3 alone. Slide 15 continues with the safety and tolerability and shows that 87% of patients had Grade 3 or greater treatment-emergent adverse events, again, the most common of which was febrile neutropenia occurring in 55% of patients. 35% of patients had Grade 3 or greater ziftomenib-related adverse events. And the most common, again, were febrile neutropenia, decreased platelet count, anemia and decreased neutrophil count. To me, what's impressive is that all but one of these cytopenias occurred in combination with the chemotherapy and was also attributed by the investigator to the chemotherapy as well as possibly the ziftomenib. There was 1 case of Grade 3 differentiation syndrome in a KMT2A-rearranged patient, which was successfully managed with the mitigating strategies of the protocol, as well as 2 cases of investigator-assessed QTc prolongation, both Grade 3, both in KMT2A-rearranged patients who are receiving other medications associated with QT prolongation. Next slide, please, #16. A total of 71 patients, 44 NPM1 mutated and 27 KMT2A rearranged, were evaluable for response defined as having at least 1 response assessment or had died before that response assessment. Composite complete remission rates were 93% for NPM1 mutated and 89% for KMT2A rearranged, while complete remission rates were 84% for NPM1 and 74% for KMT2A rearranged. Now in the evaluable patients with complete -- composite complete remissions, responders were tested for measurable residual disease by a variety of local assays that could include flow cytometry, NGS, FISH and PCR, including fusion panels. MRD rates were 68% in NPM1-mutated patients with a median time to negativity of 4.7 weeks and 83% in KMT2A-rearranged patients with a median time to MRD negativity of 4.1 weeks. Preliminary central MRD testing is being done by NGS-based approaches and generally shows concordance with the local MRD negative rates. Next slide, 17. For the NPM1-mutated patients, after a median follow-up of 24.9 weeks, the median duration of CR and median overall survival were not reached. 2 NPM1-mutated patients received stem cell transplant. 3 were -- there were 3 discontinuations due to relapse, and 96% of patients remain alive and continued on study. Most impressively to me is if you look at the top of the swimmers plot, many of these patients achieved early remissions and then have remained on study and on ziftomenib without allogeneic transplant with follow-up continuing. Slide 18 shows the duration of treatment outcomes for the KMT2A-rearranged patients Here, the median follow-up is somewhat shorter, 15.7 weeks, and the median duration of CR was 25.6 weeks. But keep in mind that follow-up continues and the median overall survival was not reached. The 6 KMT2A-rearranged patients that received stem cell transplant thus far, 1 patient received ziftomenib maintenance following stem cell transplant, 1 patient discontinued due to an adverse event that disseminated mucormycosis, and 88% of patients remained alive and continued on study. If I could just go back for one second -- you don't have to go back to the slide. But in the NPM1-mutated patients, there were 9 patients who came from the Phase Ia portion. Remember, these were either older patients or those with complex karyotypes, adverse risk karyotypes or therapy-related NPM1-mutated disease. And of those 9, 8 achieved complete remissions. Moving on now to Slide 19. In the evaluable patients with CRc, the median time to absolute neutrophil recovery was 1,000 per microliter or more of -- I'm sorry, to that degree was 32 days, and the median time to platelet recovery of 100,000 per microliter or more was 29 days. Generally, the combination did not delay recovery with time to neutrophil and platelet recovery comparable to that reported for intensive chemotherapy regimens in other clinical trials. These calculations have to be taken with a large grain of salt because the time to neutrophil recovery will depend on co-mutational status, the number of cycles of induction therapy required and again, whether the patient already had therapy-related AML and possibly AML arising out of a kind of beaten-up bone marrow. It should be noted in the KMT2A-rearranged patients where you see time to recovery was slightly longer that more patients require 2 cycles of chemotherapy and more patients had therapy-related disease. So in conclusion, on Slide 20, in the ongoing KOMET-007 study, ziftomenib 600 milligrams once daily combined with 7+3 was well tolerated with a safety profile consistent with previous reports. I want to remind you that ziftomenib was continued through count recovery and starting on and continue through day 1 of the high-dose cytarabine cycles and then continued as a maintenance. There were low rates of ziftomenib-related cytopenias, and no additional myelosuppression were observed with the combination. And ziftomenib 600 milligrams once daily did not delay neutrophil and platelet count recovery. There was 1 case of Grade 3 differentiation syndrome in a KMT2A-rearranged patient, which was successfully managed. And we saw robust clinical activity with deep responses in the newly diagnosed NPM1-mutated and KMT2A-rearranged AML. The CRc rate was 93% for NPM1-mutated and 89% for KMT2A-rearranged patients. And importantly, 68% of the NPM1-mutated patients achieved MRD negativity at a median of 4.7 months. And for the KMT2A CRc patients, 83% achieved MRD negativity with a median time to that -- achieving that of 4.1 months. 96% of NPM1-mutated and 88% of KMT2A-rearranged patients remain alive and continued on study therapy with median follow-ups of 25 and 16 weeks. So we believe, and I definitely believe, that taken together, these data support the Phase III advancement of ziftomenib combination in newly diagnosed NPM1-mutated and KMT2A-rearranged AML patients in the KOMET-017 study. And for that, I will now turn over the presentation to Dr. Mollie Leoni, who is the Chief Medical Officer at Kura Oncology. Mollie?

Thank you so much Dr. Erba. If we could proceed to Slide 22. Together with our partners at Kyowa Kirin, we are truly trying to make sure that all patients that could potentially benefit from zifto, and we think that could be up to 50% of patients with AML, regardless of where they are in their treatment journey, have a potential opportunity to access therapy with this menin inhibitor. On the left-hand side of this slide, you'll see our frontline development strategy where we add ziftomenib to current standards of care regardless of eligibility for transplant. Notably in the front line, our strategy uses company-sponsored studies to support potential registration in both the intensive and nonintensive settings. We were pleased to share data updates with you at EHA as described by Dr. Erba and look forward to sharing additional data with you later this year. We also look forward to initiating these frontline trials within the coming months. On the right-hand side, we are building on the data generated in KOMET-001, our monotherapy registrational trial, to evaluate ziftomenib in various combination regimens in the relapsed/refractory setting. And again, we look forward to providing some data updates later this year. And with that, I will turn it over to Dr. Issa.

Okay. Thank you, Dr. Leoni. So I'll take you through the design of KOMET-017, which is the frontline randomized Phase III study of adding ziftomenib to the high-intensity chemotherapy backbone. Also, we're going to -- as you see on top of the slide, this is Slide 23, there's also the addition of ziftomenib to aza and venetoclax, which is the standard of care for older patients or those who are unable to get high-intensity chemotherapy. So these are 2 independent studies that are registration-enabling. The primary endpoint for the HMA and venetoclax portion of the study or low-intensity portion of the study is CR and overall survival. And for the high-intensity chemotherapy, the primary endpoints are CR-MRD negativity for the NPM1 subgroup, which is the majority of these patients. We expect about 95% of the patients would be NPM1. And the second primary endpoint is based on event-free survival. Patients who are eligible for intensive chemotherapy are those that have NPM1 or KMT2A and their FLT3-ITD/wildtype are a low burden, less than 0.05 because the standard of care for these patients would be a FLT3 inhibitor such as -- those that have high FLT3 would be quizartinib or midostaurin, age 18 and above and a performance status 0 to 2. There are 3 arms of the study that would test the addition of ziftomenib to a backbone of chemotherapy 7+3, so compared to placebo. And there's also an arm that would test the effect of maintenance ziftomenib post transplant or maintenance compared to placebo. So this would allow us to address multiple questions, the question of addition of ziftomenib and the contribution of maintenance. Next slide, Slide 24. And the reason why this study is an important milestone and an exciting design is because of the importance of CR-MRD negativity as an endpoint. So NPM1-mutant AML is a subtype that has excellent MRD marker, measurable residual disease marker. So NPM1 is a founding event in AML. In other words, this is the mutation that causes leukemia. If there's no NPM1, in 95% of the cases, there is no leukemia. Also, this is an endpoint that has patient level data that indicates effect on survival. This is the curve -- the Kaplan-Meier curves that you see are from a large group work in the U.K. showing that patients that attain MRD negativity after 2 cycles following high-intensity chemotherapy no longer need a stem cell transplant or no longer benefit from the addition of a stem cell transplant. So as a surrogate endpoint, MRD negativity at 2 cycles has all the levels of data that we need to inform us about an effect on overall survival. Also if you take all variables in NPM1-mutant AML, attaining MRD negativity is the single most important factor to predict overall survival. So with the addition of menin inhibitors, we hope to improve MRD negativity, and that would allow us to improve chances of survival for patients that have NPM1-mutant AML because we don't want outcomes in 5 years of 60%. We want to improve them for more patients, similar to what's been done in other cancers like, for example, HER2-positive breast cancer or ER-positive breast cancer where the addition of targeted therapy improved outcomes. And I'll turn it over to my colleague for the next slide.

Thank you, Dr. Issa. This is Brian Powl, the Chief Commercial Officer with Kura Oncology. If we can go to Slide 26, please. I'm going to talk a little bit about the market opportunity for the newly diagnosed setting. And our teams were at EHA last week with -- engaging with a variety of the thought leaders that were at the meeting, understanding their perception of the data, understanding their perception of the relapsed/refractory monotherapy data as well. And we want to share a little bit of the feedback and views that we heard from the data that Dr. Erba presented here and at EHA. Just a few points to highlight. As you can see on the slide, I think some of the feedback we heard is that the safety profile differentiates ziftomenib in terms of lack of QTc prolongation, CYP3A4 drug-drug interactions and potentially less myelosuppression with also a very good time to count recovery. We also heard some feedback that, we think this is a new era for menin inhibitors to combine with frontline therapy in newly diagnosed AML, both with the NPM1 mutated -- mutations or KMT2A rearrangements. And I think the discussion around the CR-MRD negativity was very supportive of the data that we -- were presented. And I said that the choice of using that as a primary endpoint for KOMET-017 also gives good promise to be able to get ziftomenib potentially top line results sooner than waiting for EFS or other survival-based endpoints. So some of the feedback overall we hear, we think that ziftomenib is potentially differentiated on the safety, the tolerability, the combinability with intensive chemo, the strong CR rates, MRD negativity and the durability along with the once-daily dosing that offers convenience for patients. If you go to the next slide. As Dr. Issa presented around the market opportunity earlier around the disease area, you could see that there is a high unmet medical need where 70% of patients who achieve CR will relapse within the first 3 years. And at that 5-year survival rate of only about 33% for all ages, there is still significant opportunity to improve on the rates that current therapies offer. Based on the overall population of approximately 22,000 newly diagnosed cases each year, if you do assume that patients may be able to benefit and receive therapy for a menin inhibitor for 12 to 24 months, you ultimately can get to an opportunity using analogs of exceeding $7 billion per year for the AML total addressable market menin class. So we think that the combination of our encouraging activity, both clinical efficacy and safety in a once-daily oral medication, could unlock a large market opportunity as we move into the frontline setting. And with that, I will pass it over to Dr. Wilson again. Troy?

Yes. Thanks, Brian. Just a couple of slides to wrap up and then we'll turn to your questions. If we can turn to Slide 29. Our goal is -- at Kura is to drive better outcomes for patients. That's really what motivates and inspires us. We are looking forward both to regulatory review and the precommercialization planning for ziftomenib in the relapsed/refractory setting. We are eagerly preparing for -- to operate the 2 KOMET-017 Phase III trials that Dr. Issa overviewed. And all of this is done in close collaboration with our partners at Kyowa Kirin. Beyond that, we see an opportunity to drive better outcomes in GIST. That's something we hope to talk more with you about either later this year or early next year using ziftomenib and as well as with our pipeline programs potentially to drive superior outcomes for patients in these large solid tumor indications. What you should take away is we're at a point now where we believe we can deliver meaningful clinical updates on a regular basis at these major medical meetings, including ASCO and EHA. Turning to Slide 30. As we look forward, we just continue to sort of execute. That's what this is all about. And the 2 big updates here for ziftomenib in AML are the start of the 2 Phase III trials for KOMET-017 as well as we hope to be in a position to share data with you of ziftomenib in combination with venetoclax and azacitidine in the fourth quarter at a major medical meeting. And then finally, Slide 31. We do this all from a position of strength. This -- really through the support of Kyowa Kirin as well as our shareholders, we can just focus on execution. And we are really looking forward now to the second half of the year and everything that is to come. So with that, I'll turn it to Slide 32, Jonathan, and I think with that, we're ready to take questions.

[Operator Instructions] Our first question for today comes from the line of Jonathan Chang from Leerink Partners.

For the docs on the call, I have 2 questions. First, how do you think about whether a patient should receive transplant or continue on treatment with ziftomenib? And also, second question, what's your level of confidence in the Phase III KOMET-017 intensive therapy study succeeding given these results?

Great. Thanks, Jonathan. Dr. Erba, maybe I'll start with you and then ask Dr. Issa to comment. But Dr. Erba, maybe we can start with you. Jonathan's first question is how do you think about transplant versus keeping a patient on ziftomenib continuation therapy. Dr. Erba, you may need to go off mute.

You're right. I'm sorry about that. I did go on mute. Thank you. So it's not just how I think about it, it's how patients think about it. The issue is, is that although transplant has the greatest antileukemic effect of any therapy that we have for AML that has achieved a remission through a graft versus leukemia effect, it is a very intensive treatment with significant morbidity and mortality. And there are quite a few barriers even in patients who have very high-risk disease like FLT3-mutated disease or KMT2A rearrangements in some retrospective studies. Only about 40% to 50% of these patients actually get to a transplant. So many are called, but few actually, only a minority get there. And so in my mind, if we can intercede with a treatment that results in deeper remissions that can be maintained without an allo transplant, that will be a benefit for patients. So that's why I would answer that currently, what I am doing for my AML patients, if they -- in my own practice is if they become negative for the NPM1-mutant transcript using a very sensitive RT-PCR assay based on the data retrospective from the United Kingdom, I discuss with them transplant, show the data that Dr. Issa has shown you. And most times, patients will elect not to undergo transplant in first remission. If I could just follow that with one final comment. Having menin inhibitors and seeing the single-agent activity, seeing the data of aza/ven with ziftomenib or my own patients on the trial, I know that I have effective salvage regimens then, too, if a patient doesn't undergo transplant in first remission. So this is going to completely change the dialogue that we have with our patients and hopefully have more patients not need transplant at first remission, elect to continue ziftomenib. And in the setting of relapse, we know we have effective salvage therapies.

Thank you, Dr. Erba. Dr. Issa, would you like to add any comments?

No, I think Dr. Erba summarized it really well. I'm hoping that we would need less transplant with the addition of therapies like menin inhibitors. And the decision can be also guided by MRD negativity. This is what the data is showing us. I think there was another portion to the question about how confident we feel based on those initial results. I think we need to do the randomized study for sure. But for -- and it may be a little too early to tell based on this initial data, but I think we're off to a great start. This is a therapy that is -- can be combined with high-intensity chemo and it's leading to excellent results. So I'm very encouraged by it.

And our next question comes from the line of Roger Song from Jefferies.

Congrats for the data. Maybe one question and one clarification. So the question is, when we see the swimmer plot, pretty clear patient on continuous treatment of ziftomenib for a long time without the dose interruption. Maybe the question for doctors, what do you think is the driver to make zifto on treatment -- patient on treatment for a long time? And how do you compare that to other menin inhibitor seemingly have some dose interruption? And then how meaningful is that for you to select which menin to use if future multiple menin is available to you? And then I have a clarification question later.

Dr. Issa, would you like to start with Roger's questions?

Sure. So the fact that patients continue on ziftomenib indicates that they're tolerating the treatment in addition to high-intensity chemotherapy. The ability to continue on the long term is hopefully going to allow us to prevent relapse. We are trying to address the question in the trial of whether the component of maintenance is going to add to just simply knocking down the disease with chemotherapy and menin inhibitor to start with. And hopefully, we're doing better than chemotherapy alone. Now the second portion about selection between menin inhibitors, I think it's going to be driven by data. The decision of doctors eventually are going to look at the data and try to see where there is primary endpoint that is met. So an MRD negativity that is better than placebo, that's an early surrogate, and ultimately, survival, regardless of what is happening of how the drug is delivered. The more meaningful things for patients is prolonging life and minimizing side effects. We can try to tease out things for now, but it's going to -- we're going to have to wait for the full data.

Dr. Erba, would you like to add -- thank you, Dr. Issa. Would you like to add anything to that?

Yes. I'll add briefly to that. I definitely agree with all of those efficacy endpoints. But another way of distinguishing drugs is by the apparent toxicity profile of all of them. And in this regard, so far, ziftomenib checks all the boxes. From a GI perspective, my patients tolerate this incredibly well. You have to be careful when you look at toxicity data that I showed you with 7+3 that shows nausea, vomiting, diarrhea. It's not a randomized Phase III study. So you're not seeing that, that's probably the incidence that we would see with 7+3 alone. What's more impressive is those patients who get to maintenance, and I have a few of them myself, are taking this medication and tolerating it very well. So GI tolerance is, one, the absence of significant drug-drug interactions, very important in our AML patients who are often at the beginning, getting other drugs that can affect QT that are affecting drugs that affect CYP3A4 and metabolism. So that's very important. And then finally, we didn't see in this study -- plus in the 001 study, we really didn't see a signal for QT prolongation. So I think tolerability on top of all of those things are important. I think how this plays out in the future will be interesting. We don't understand all of the mechanisms of menin inhibitor resistance. We know to some degree, it depends on mutations that occur in the menin inhibitor binding site. But there are apparently other mechanisms of resistance. And so what we need to figure out over time is whether sequencing these or using 1 inhibitor over another in the setting of different mutations will make a difference. But we have really almost no data on that at this point.

Roger, did you have a quick clarification that you wanted to ask about?

Yes. And then a quick clarification question is for the MRD activity, just confirming, is that all from the bone marrow? And then if that's the case, what's the benchmark from the intensive chemo 7+3 in that population we should know?

Mollie, would you like to speak to Roger's clarification question?

Yes, of course. For the vast majority that we presented, you were seeing bone marrow assays that were performed at the same time that we were looking for essentially the clearance of the blasts. But of course, I can't say that they were 100% all from the marrow, but the vast majority were. And if you look at the AML [ 17 ] and [ 19 ] analyses that were done in the [ Austin ] paper, there's a nice little table -- it might be in one of the supplements. But it shows you what the MRD negativity you would expect to see both in blood and bone marrow look like after cycles 1 and 2 of intensive chemotherapy. And essentially, after 1 cycle, which most of these patients were, which is why you'll see potentially MRD evolving over time, you would expect in the bone marrow for 79% of the patients to still have MRD positivity. After course 2, that dropped significantly to 56% of patients would be MRD positive. So obviously, about 44% MRD negative. So that gives you a good basis for seeing the trends that we're watching for in our data. And again, these data will evolve as patients are on for longer periods of time.

And our next question for today comes from the line of Jason Zemansky from Bank of America.

Congrats on the data. Troy, you previously indicated that you should be able to keep patients in the first-line intensive setting on zifto for 18 to 24 months. Look, obviously, the data are still somewhat early. But based on what you've seen from the 2 different swimmers plots, are you still confident you can get there? And then secondarily, I guess, given overall how important this data point is for your assessment of the overall market opportunity, maybe you could discuss some of your assumptions in getting here. For example, does this include patients remaining on zifto if they're moved to transplant?

Sure. Yes, I'll take the first part of your question, Jason, and I'll ask Brian to take the second part. So look, it's obviously early days, relatively limited follow-up, as Dr. Erba indicated. I think we're encouraged by what we're seeing. I think there's reason for optimism. As Dr. Issa presented, we believe, and I think the data -- we'll generate the data over the coming years that up to 50% of patients can benefit from menin therapy, likely in combination. We're looking for sort of a median time on therapy of 18 to 24 months. We will always, of course, have patients who unfortunately don't respond or have shorter periods. But the -- particularly given that the backbone does well, we're really looking to improve upon that. And that's why Mollie's answer, I think, is an important one, right, how deep can we drive that MRD negativity. We will look to give all of you an update on this data probably sometime next year, and we can take another look. As to how did we take that and other factors, Jason, into the market assessment, the market opportunity, let me ask Brian if he can just speak to that very briefly. Brian?

Sure. Thanks, Troy. Yes. And just to maybe kind of walk through that. If you -- the numbers that I shared on the slide that you've seen, if there's about 22,000 patients, about half of those have the potential to benefit from a menin therapy. So let's say about 10,000 patients. If they get 12 months of therapy, if every patient gets 12 months of therapy at the current rates pricing that you see, that comes out to about $5 billion a year for the total market. If you pull out the -- if you look at extending that time to 18 or 24 months, that's where you get to $7.5 billion or up to $10 billion in the market. We think that zifto has an opportunity to get to -- given that there will be multiple menin inhibitors available, we think our profile allows us to get to $3 billion or more of that market as we go forward. I hope that helps to answer that question for you.

And our next question comes from the line of Li Watsek from Cantor Fitzgerald.

A couple here. Just curious, have you observed any differential responses maybe based on co-mutations or any other patient characteristics, for instance, maybe based on the risk factors? And then second, just based on the CR-MRD negativity rate here, have you done any work to predict OS based on the correlated data that you just shared on the call?

Sure. Thanks, Li, for the questions. Dr. Erba, maybe I'll ask you to take the first one as to these questions, have we observed differential responses based on mutation or other criteria?

So a differential response is based on NPM1 versus KMT2A?

The presence of co-mutations or adverse risk, that sorts of factors, yes, sorry.

Yes. Well, we don't have complete data set yet. I did not present mutational data. We had very limited data for FLT3 and IDH in terms of co-mutation. So it's hard to really answer that question at this time. In the KMT2A, if I start there, the work that Gus Issa has done at MD Anderson shows that fewer than 50% of patients have co-mutations. But when they do, they have -- with the KMT2A, they'll have RAS mutations and FLT3 mutations as some of our patients did. With NPM1, it's a little bit different in that we can't see NPM1 developing on the background of CHIP mutations, on the background of MDS-related mutations. And so that's an important question. It's still debated to what degree those co-mutations, MDS-related co-mutations affect prognosis in NPM1-mutated disease. However, we do know that adverse risk karyotype does affect outcome. So to get to your point, I wouldn't be surprised if we saw differential effects based on the biology of the disease, but we just don't have that information yet. I think the most important subset that I will just focus on for you is the FLT3-ITD mutated. As you may know, I was involved in the QuANTUM-First study looking at quizartinib in FLT3-ITD mutated. And in that data set, 50% of patients had an NPM1 mutation. And again, here, we showed you for patients with NPM1 mutation, about 50% often do have a FLT3 mutation. So it goes both ways. I think what's important about hitting this target of NPM1 is, as we showed you in the diagram, the schema of the pathogenesis of NPM1-mutated disease, by inhibiting menin, we may be inhibiting upstream of things like FLT3. I think what's more important than that is we know that FLT3 is a late event in leukemogenesis, later than NPM1. And the important observation is that in all -- I think it was all but 1 of the patients with a FLT3-ITD who received 7+3 with a menin inhibitor. And again, without a FLT3 inhibitor, all but 1 had a complete remission. And we presented data in the relapsed/refractory setting of the same that if you inhibit menin without a FLT3 inhibitor, you can achieve remissions. Now we don't know very much about the durability of those remissions. So we have a lot more to learn. But I think it is important to recognize that by hitting KMT2A, by hitting NPM1 through menin inhibition, we are inhibiting something earlier in leukemogenesis that may abrogate the need for other inhibitors to be used with it.

Thank you, Dr. Erba. And Li, with respect to your question, I'll just take it. It's too early on OS. We haven't done any predictions yet. So I would say stay tuned on that. We'll share more data as we have it.

Dr. Wilson, if I can add one thing.

Please, Dr. Issa, yes, of course.

So it's still small numbers, but I find it very interesting is that the IDH1 co-mutated are benefiting more from menin inhibitors. And this is data from both the ziftomenib presentation that Dr. Wang did in ASCO and the revumenib manuscript in blood. And interestingly, there was a paper, a preclinical paper about 2 weeks ago from Dr. [ Mack ], who's one of the leading scientists in like IDH biology. In an NPM1 IDH1 co-mutated model, mouse model, menin inhibition was the best therapy in that model compared to IDH inhibition or chemotherapy. So I think there may be something there. It's still small numbers, but I'm interesting to see on the long term whether IDH1 or IDH2 confer more sensitivity to menin inhibitors.

Yes. Gus, I agree. We're a long way away from this, but you could imagine based on the biology that we've seen, that preclinical data that menin inhibition may actually take over part of the market that we're seeing with FLT3 inhibitors or IDH inhibitors in the future. But we have a lot of work to do there before we get to that.

That's a great insight. Dr. Issa, thank you for sharing that.

And our next question comes from the line of Phil Nadeau from TD Cowen.

Two from us. First, as the KOMET-017 trial is on the cusp of starting, we're curious whether you'd be willing to disclose the powering of the trial on its primary endpoints. That's first. And then second, to follow up on the question of transplant versus forgoing transplant. It seems like the physician's comments suggest that getting a transplant in second lapse has curative potential just as in first relapse. I guess we've always been taught at least historically that patients -- any patient who can do the transplant should do it as soon as possible because it is the only possibly curative regimen. So I guess I'm curious to get the physicians' take on whether transplant in the second relapse could be as curative as in the first relapse. And what data is there to support that, particularly post-menin therapy where you may be taking away one of the most effective second-line agents?

Dr. Issa, would you like to start with this one and then Dr. Erba can go second? And I'll answer the KOMET-017 question at the end.

Sure. But I'm just going to clarify a few things. So transplant in NPM1, we're going to just dive in on the data on NPM1, is for now most indicated in patients who do not achieve MRD negativity. Those that achieve MRD negativity may not need a stem cell transplant. Now those that are MRD positive after 2 cycles, even before they get the first relapse, may need a stem cell transplant. Now those that are in first relapse, there is still a chance of transplant leading to cure, but the chances are less. We're probably half of that than when you start. And certainly, in a second relapse, it's even worse, but it becomes the only curative option. For KMT2A, regardless of MRD, patients should proceed to transplant before first relapse. And absolutely, if they've relapsed the first time or the second time that they need a transplant. I hope I addressed the question.

You did. Dr. Erba, would you like to add anything to that?

I agree on that assessment. Part of the issue with KMT2A is not only the biology. It's a very aggressive disease. And so yes, we do try to get those patients to transplant. But even there, the relapse rates are very high after transplant. And so we're excited that the 007 study has this maintenance in it that allows reinstitution of ziftomenib post transplant. Without clinical data, if you ask most leukemia doctors, would they just put their patient back on a menin inhibitor if they had a transplant for KMT2A-rearranged disease? I think the answer would be is if you could show it's safe, we're going to do it because we're more worried about the leukemia than looking for Phase III data for these patients. You just can't wait that long for that data to come along. So I agree that we're going to try to get those KMT2A patients to transplant. But again, very few -- only half of them may actually be able to get to transplant. And so it is an issue.

Thank you. And Mollie, do you want to speak to Phil's question about the powering assumptions and the stats for 017?

Sure. We haven't disclosed all those details just yet. But the only person or persons it would hurt for us to underpower it would be ourselves and the patients. So you can rest assured that it is sufficiently powered to be able to detect clinically meaningful differences between the treatment arms. But we haven't specified exactly what that is yet.

And our next question comes from the line of Charles Zhu from LifeSci Capital.

I have 2. One's quick, one, hopefully, also about as quick. First one, I guess, I think you've already kind of mentioned it, but would it be safe to presume that the majority of your KMT2A patients going into transplant will initiate and hopefully stay on prolonged maintenance therapy similar to that top patient in the swim lane? And maybe like a more general second question, would you also be able to perhaps compare and contrast some of your early experience with the menin inhibitors in combination with frontline chemo relative to that of the FLT3 inhibitors? And where I'm coming from with the second question is how might some of these observations that you pointed out throughout this call around MRD maintenance transplant really translate to that $7 billion market opportunity just given what some could point to as an analog in the FLT3 market that has frankly fallen short of $7 billion.

Dr. Erba, would you like to start?

Well, let me start with the question about comparing what we're doing here to using a FLT3 inhibitor with intensive chemotherapy. And I'll tell you, one thing that I've been impressed by is the study that I've been involved in, the QuANTUM-First study, is actually the first study that has shown in a prospective trial with prospectively collected MRD assessments done by a validated NGS-based assay for the FLT3-ITD that regardless of therapy, achieving an MRD negative status or a deep MRD -- a very deep complete remission using a very sensitive MRD assay, regardless of the therapy, was associated with improved survival. And we published that. So we've kind of shown that already. And here, we're trying to replicate that. We already have data that achieving that MRD negativity in NPM1-mutated disease is really, really important. And so the hope is, yes, that we're going to be able to get more patients into an MRD-negative remission because we do believe that's going to translate into an improvement in overall survival. That wasn't shown in the RATIFY trial because they didn't actually collect samples. But there, again, in the RATIFY trial, midostaurin was only a benefit for the patients who actually received an allo transplant. In QuANTUM-First, with a strong FLT3 inhibitor, we saw a benefit -- survival benefit with both transplant and with using quizartinib. And so these were independent variables that led to a remission. So I'm very hopeful that by having a target such as menin early in leukemogenesis that we will be able to replicate that data and in NPM1-mutated disease. And here, it might be even more important because we are hitting the founder mutation as opposed to FLT3, which is a later mutation. It begs the question with a potent FLT3 -- NPM1 or menin inhibitor, will we actually even need FLT3 inhibition. And I think that's a question that's open for some debate.

Then our final question for today comes from the line of Salim Syed from Mizuho.

Just maybe a couple from us. Mollie, when you look at this data set, just -- I mean, some of these numbers are pretty wide in the range, right? Like the time to MRD negativity, the range is like 2 weeks to 17 weeks. And of course, there are some patients who achieve MRD negative status here and some who don't. Can you just maybe like clarify for us -- and it doesn't need to be perfect, could be even perhaps a little theoretical if you want, but what do you think are the greatest drivers there getting to this time, MRD negativity or actually getting to that status? And then how are you using that data to optimize the 017 intensive chemo therapy trial? And then just maybe for the docs because Troy, I know you're not going to comment on the stats. But for the docs on the line, for the panelists, just curious to get your view of clinically meaningful benefit over the benchmark intensive chemo.

Yes. Mollie, do you want to start with Salim's question about MRD negativity?

Sure. So yes, I mean, there are small numbers, wide range of recoveries. But a lot of those longer recovery periods happened earlier on when we were first learning to use the combination appropriately. Sometimes, we weren't sure what to pause or what not to pause for. And we eventually learned to just treat through in order to get these patients onto their next cycle and realized that, that was the easier answer. And as Dr. Erba referred to earlier, there's so many reasons why a patient has an easier time clearing their marrow or having their disease addressed depending on exactly the origination of the disease. So that's why you see the wide range and maybe count recoveries as well. But with regards to the MRD negativity, seeing that the median time to get there is about 4.5 months, that bodes well for the way we've designed our trial. And we have shared previously that the MRD -- the CR-MRD negative endpoint will be measured after the second cycle. And as the physicians on the phone can tell you that, that is the time point at which MRD negativity has been shown to have the most correlation with overall survival, so lower MRD negativity, a longer overall survival. So these data showing us that it's already showing a delta between what we would expect and what we're seeing gives us a lot of reassurance in our study design that we'll be able to pick up on any meaningful differences between arms.

That's what I was going to say. Just one clarification. Mollie said months and she meant about 4 weeks. And then this is really, I think, the last question. Dr. Erba and Dr. Issa, to Salim's question, like what would you look for in terms of a clinically meaningful benefit over 7+3 in this setting? If you can provide any context on that.

Okay, I'll start. So as much as I believe in MRD negativity as a surrogate endpoint for survival with intensive chemotherapy, as you pointed out, there's this wide range that we see. We don't know what's the best time after 2 cycles because that's how the United Kingdom did it or is there another time to achieve it. And so at the end of the day, with intensive chemotherapy for KMT2A and NPM1, it's going to be overall survival. I mean that's going to be the most important endpoint for the study. I'm glad we're looking at NPM1 MRD assessments. But what this study is doing is similar to QuANTUM-First. It's collecting it prospectively and using a very sensitive assay for determining MRD negativity. You might have looked at the KMT2A and NPM1 and said, wow, the MRD negativity was so much higher in KMT2A than in NPM1. That could only be -- that might just be an artifact of the fact that the only way we look for NPM1 with -- for KMT2A is flow cytometry and FISH, which aren't very sensitive. And so it may be that we're seeing a lower MRD negative rate because of the hodgepodge of assays that have been used. So at least we'll have prospective data. I guess the final point I'll make, and it's something that I think we need to learn more about is, yes, we're giving this treatment with intensive chemotherapy. But let's remember, it's a differentiating agent. And so it is conceivable that any signal that we see by RT-PCR in the marrow or the blood, is that internally differentiating cells that will go away? Or is that persistent leukemia? And so we have a lot to learn from this combination. This is the first we're doing it. We're getting away from intensive chemotherapy that is just cytotoxic and now adding in the complexity of a differentiating agent. So at the end of the day, long-winded answer of saying, if fewer of my patients need a transplant to end up with long-term survival, for me, that will be a win.

Thank you, Dr. Erba. Dr. Issa, anything you'd like to add? You get the last word.

Not much. I mean the clinical benefit to me is cure in simpler terms. We want to get a larger fraction of patients to be cured and not need any more treatment beyond what we initially give them. And we have a chance with ziftomenib because we can give it for a longer time, because it acts on the founding event, because it can be tolerated for hopefully duration of maintenance that this would prevent relapse, act on the leukemia. And maybe we will learn someday that patients may not need as many patients would need transplant. So it's a different way of saying exactly what Dr. Erba is saying. We want studies powered for MRD, but ultimately, the overall survival. And that's the view of the FDA, too. Overall survival is what matters.

And let's forget -- remember, I'm sorry to jump back on. But every time you talk about AML, people want to talk about transplant. But that is really the minority of patients who are getting transplanted. And so it's important to remember that the median age of this disease is older, in the 60s. Many patients don't get a transplant. So my patients want to know, hey doc, do you have something that can help me live longer without toxicity? And that's how I see a drug like ziftomenib. And so I'm really -- of course, I'm interested in the 7+3 with zifto, but by the same token, a less intensive approach combining very effective therapy, aza/ven, which is very effective in NPM1-mutated disease, now adding in a menin inhibitor, can I get more patients into a long-term MRD-negative remission and they can be maintained potentially on oral therapy, getting rid of azacitidine? These are things that I look forward to in the future because I know my patients are looking forward to getting on with their lives without seeing a doctor and having these oral agents that target effectively the biology of the disease. I think that's the gold -- the exact spot that we should be aiming for in the majority of our AML patients.

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

Thank you, Jonathan. I hope you found this useful. Our goal was to bring 2 of the leading experts in the field to provide their insights, give you their clinical and medical context. And there's really nothing more I can say than what Dr. Erba and Dr. Issa ended it. We do look forward to sharing our ven/aza combination data with you here at the end of the year. That will be an important update to stand alongside this one. In the meantime, we get a bit of a break from the conference season, but we are available to answer additional questions. I'm sorry, we couldn't get to everyone today. We just -- but this was a robust discussion, and that's what -- that was our goal. So with that, I want to thank Dr. Issa, Dr. Erba, Mollie and Brian, and I want to thank all of you for your attendance and your attention and your very excellent questions. Thanks all.

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