Kura Oncology, Inc. ($KURA)

Good day, everyone. My name is Stephen, and I'll be your conference operator today. At this time, I'd like to welcome you to Kura Oncology's investor call to discuss the long-term results of ziftomenib and 7+3 in newly diagnosed AML. [Operator Instructions] At this time, I'd like to turn the call over to Troy Wilson, President and Chief Executive Officer of Kura Oncology. Please go ahead, Dr. Wilson.

Thank you, Stephen. Good morning, everyone. We're coming to you from Stockholm, Sweden, the European Hematology Association meeting, and we're delighted to share with you the latest update from our frontline results of ziftomenib with 7+3. If we could please go to the next slide. In today's presentation, we're going to be making forward-looking statements. So of course, we'll refer you to our website and the SEC's website for more information about Kura Oncology and the risks and uncertainties of an investment in the company. If you can take us to the next slide, please. It was just a couple of weeks ago that we came to you from ASCO where we brought you an update on our darlifarnib program, we're really at a point now where we're executing across the company. The KOMZIFTI launch is going very well. We have robust new patient starts and early momentum. Today is part of our effort to help provide data and talk about how we think we can advance ziftomenib to achieve our goal of addressing up to 50% of AML patients. And this is the next in a number of important readouts around the program. If we can please go to the next slide. I'm joined this morning by 2 other participants, Dr. Amer Zeidan. Dr. Zeidan is Professor of Medicine at Yale Cancer Center. As well as Dr. Mollie Leoni, who, of course, is the Chief Medical Officer of Kura Oncology. If we can go to the next slide, please. The agenda for today is Mollie is going to spend just a moment or two on results that were published in blood on the combination of ziftomenib and venetoclax azacitidine in the relapsed/refractory NPM1 mutant AML setting. Dr. Zeidan will take us through the presentation at EHA, where he'll discuss the long-term results for ziftomenib and the 7+3 combination in the newly diagnosed NPM1 and KMT2A populations. And then Mollie is going to take over and relate the results from the 007 trial that Dr. Zeidan is discussing to how you should think about our ongoing KOMET-017 study in frontline AML. If we could go to the next slide. And with that, I'll turn it over to Mollie. Mollie?

Thank you, Troy. So now that ziftomenib or KOMZIFTI is approved as a monotherapy, Kura has been dedicated to generating data in the combination setting. To this end, we have a robust development program that has the ability to benefit patients with met independent AML across the treatment continuum. Next slide. In today's presentation, we will be discussing 2 important pieces of the continuum. The combination of ziftomenib with venetoclax and azacitidine in the relapsed/refractory setting and a combination of ziftomenib with 7+3 in the frontline setting. Both of these data sets come out of the KOMET-007 trial. The sample sizes have been robust and able to support and inform the KOMET-017 registrational trial that is evaluating ziftomenib in newly diagnosed patients. While frontline data and their applicability in the KOMET-017 trial are a primary focus of today's presentation, we wanted to begin with an important update in relapsed/refractory setting. If we go to the next slide. The important results of ziftomenib in combination with ven/aza in the relapsed/refractory setting have recently been published in blood. Moving to the next slide. And the results are very important to patients, relapsed/refractory NPM1 mutant AML. This study enrolled patients that were heavily pretreated, many of whom had already received venetoclax-based therapies. In the venetoclax experienced patient population, where we would expect minimal patient benefit, we saw a 48% ORR with 24% achieving a CRC of significant durability. Importantly, we saw in patients that were VED naive and 87% ORR with 70% of patients reaching a CRC with a meaningful duration that appears to have also translated into survival for these patients as the median OS has not been reached. These data are remarkable when we consider the poor ORR and OS expected for these patients. These deep and durable responses, exceeding what one would expect with ven/aza alone in this relapsed/refractory setting with a well-tolerated combination regimen speaks volumes with regards to the importance of menin-inhibition early in the treatment paradigm. And with that, I will pass it over to Dr. Zeidan, who will discuss the data surrounding zifto's use in the frontline setting.

Thank you so much, Dr. Leoni. So I'm going to be talking about the combination in the front line setting with ziftomenib. This is a presentation we will be doing in [indiscernible] meeting this weekend. Next slide, please. So these are my disclosures, including consulting for Kura and [indiscernible]. So as you just heard, ziftomenib is an oral [indiscernible] inhibitor that is given once a day that has been already approved as a potent selective inhibitor in the relapsed refractory setting for patients who have refractory leukemia, acute myeloid leukemia with NPM1 mutations. But at the same time, it has shown a promising preclinical activity in combination with standard of care therapies that we have been using for AML for a long time, including intensive chemotherapy with 7+3. And as you just heard, with aza and ven. So the KOMET-007 has been exploring these combinations in a large ongoing international study that includes dose escalations as well as dose expansions both in the frontline setting as well as in the refractory labs setting for both subsets of leukemias that have been shown to benefit from in inhibition primarily NPM1 and KMT2A arranged leukemia. Next slide, please. So the focus of the presentation in [indiscernible] this year is going to be on the frontline combination with intensive chemo, 7+3, and this is in patients who are deemed to be fit to receive intensive chemotherapy by their physicians. So the way the trial was conducted is that we have 2 separate cohorts, one for NPM1 and one for KMT2A rearranged leukemias. Both of those underwent a dose escalation starting with a 200-milligram, 600 milli -- 400-milligram and then 600-milligram of ziftomenib in combination with 7+3 and the dose escalation phase, that went subsequently into a dose expansion phase using the optimal dose, which was determined to be 600 milligrams of as ziftomenib. And what we are presenting in the meeting is all the patients who have been enrolled on both the dose escalation and the dose expansion part of the study that have received the optimum dose 600-milligram, which I would note is the dose that's also being tested in the randomized the registrational Phase III trial that you will hear about later in this meeting. So here, you can see the patients who are enrolled in terms of their disposition. We are presenting data in 99 patients, which I believe is the largest experience in the frontline setting reported to date [indiscernible] menin inhibitor in combination with intensive chemotherapy. 49 patients had NPM1 mutations and 50 patients had KMT2A translocations. You can see that at the time of this data cutoff, which was April 10, 2026, the median follow-up at that point was 17.6 months for NPM1 and 11 months for KMT translocation. And at the time of the cut of 90% of the patients with NPM1 and 62% of the patients with KMT2A patients were still on study either on treatment phase or in the survival [indiscernible] phase of the study. Next, please. So these are the baseline characteristics. I would note for the NPM1 mutation, and I think this is important as you interpret the results that the dose escalation part of this study required patients who had NPM1 mutation to also have what we call factors that make an adverse risk. So they had to be either older than 60 or they had what we call therapy-related AML or they had adverse cytogenetics. All of these predict worse outcomes. So those were the patients who were treated in the dose escalation part. But once we have gone to the dose expansion part of the NPM1 mutation patients, it was open for all newcomers. And what this resulted in is that the median age of the patients who had the NPM1 mutations in this study was 60 years old, so there were -- half of them were older than 60 basis. While the KMT2A [indiscernible] were slightly younger with the median age of 43. We have slight predominance of females on this. And some of the patients, as you can see here, had communications as expected in the setting, including a small number of patients who had FLT33. The FLT3 patients who had those mutations were generally considered to be too low to receive -- in terms of where [ variable-frequency ] to receive a FLT3 inhibitor or had a FLT3 [indiscernible]. Next, please. So these are the -- an overview of the side effect profile. What you can see here is the treatment-emergent adverse events that occurred in 30% or more of all patients. This does not really add much in terms of the safety beyond what we have seen in previous presentations from the study. Primarily, most patients will experience treatment-emergent adverse events because this is given in combination with intensive chemotherapy and the safety profile is very well recognized in this setting. So I think the primary conclusion from this data set is that it does not seem that the addition of ziftomenib to 7+3 is causing additional toxicities. What we are primarily seeing here is [indiscernible] separation in the form of thrombocytopenia and neutropenia as well as several neutropenias, some GI side effects in the form of the area, some pruritus. However, again, all of these are within what you typically expect with no new or unexpected adverse events with a longer-term follow-up of this patient cohort. Next, please. This slide on the safety front is looking at the severe treatment-emergent adverse stages defined as Grade 3 or higher that occurred in at least 10% of patients. And again, the same focus in being [indiscernible] suppression, which is primarily driven by the intensive chemotherapy that's given to those patient as well as a small incidence of other things such as pruritus and GI side effects. I think what is important to note is that the treatment adverse events of [indiscernible] such as differentiation syndrome and [ PTC ] promotion occurred in a small number of patients. For example, differentiation syndrome occurred only -- has a Grade 3 and 4 patients. There were no Grade 4 or Grade 5. All of these [ DS7 ] completely resolved with protocol mitigated interventions. And 3 of them were actually able to continue on ziftomenib therapy and the same play for QTC prolongation. There were 3 cases that were grade 3 that were assessed by the investigators and there were no grade 4 or higher, and all of them resolved and the patients were able to continue on therapy. Next, please. So I think here, we are seeing, in my opinion, the most impressive data of this presentation in the next 2 slides, focusing on the responses and the survival data. So I'm going to present the data kind of looking at each cohort separately because I think there's important differences between these patients that are important to know. So I will start by the complete response, which is really understood in the context of intensive chemotherapy to be one of the most important endpoints to achieve in this setting. And what you can see in NPM1 mutated patients out of a relatively large sample size for a Phase II trial of 49 patients, we are seeing a stable CR rate of 94%. This number actually over the previous 3 presentations we had of this data set not only has been in this range, but actually went up, indicating the stability of the CR rate, which again is, I think, one of the highest we have ever seen in the context of intensive chemotherapy for any accurate leukemia patient subset. And again, most of those were full CRs, meaning you have complete count recovery. The MRD negativity, which is another indication of the debt of the response was observed using local assessment in the vast majority of patients. For the NPM1 that was observed in 85%. I will be talking about the central MRD negativity, which is we are presenting for the first time in this presentation in the next slide. And I would also observe that the median time to CR MRD negativity was quick at 1.5 months. When you look at the KMT2A, again, those patients generally have a more severe disease. They are generally expected to have worse outcomes in the NPM1 and this is -- reflects what we see. But at the same time, I think those outcomes compare favorably to what we typically expect with 7+3. For example, the complete response rate was 82%, the complete -- the composite CR was 90%. And again, the CR -- MRD-negative CR was the majority of patients at 86%, and it was observed to occur relatively quickly with a median time to MRD-negative CR of 9 months. Next, please. Here is the central molecular MRD negativity, and this is important because MRD negativity locally has been as said by different methods, including close cytometry and genetic studies, but also it was done locally by different centers. So here, the advantages you are using one highly sensitive genetic test that's done in a central lab giving you, I think, a lot of confidence in the findings. And here, what you can see is that the MRD negative composite CR was also quite high, as you can see. And we looked at it at 2 different thresholds using 1.1%, 1 in 1,000, which was observed and 79% of patients. And again, this is only in NPM1 mutated patients where MRD-negative CR has been really, I think, shown to be a surrogate for long-term outcomes, including [indiscernible] OS. For using the threshold of 0.1 -- 0.01% or 1 in 10,000, it was 56% of patients. And again, those MRD negativity results were obtained relatively quickly with a median time of around 2.2 months. So by the second cycle, by the end of consolidation, one, which generally has been considered the most important endpoint time for the MRD negativity, all of those patients who have achieved MRD negativity have already reached by the end of the second cycle of intensive chemo, which is usually the end of the first cycle of consolidation therapy. Next please. And concurrent with the safety profile that I think was impressive and the fact that we think one of the problems of adding drugs to intensive chemotherapy in general has been the concern about additional [ myelosuppresion ] which can translate into adverse events. One of the -- I think one of the most reassuring aspects of this particular combination is that it does not seem to add additional myelosuppression. And this is here reflected by the turn to count recovery with a neutrophil count of more than 1 and a platelet count of more than 100, which constitute the CR. You can see that the time to median time to count recovery for both was around 28 days, which is what we generally see with 7+3 itself. So that suggested that the [indiscernible] suppression is not being worsen by the addition of ziftomenib to intensive chemotherapy. Next, please. So these are some [indiscernible] spots that demonstrate the durability of that response. So it's not only a very high rate of complete responses, but those CRs appear to be durable as you can see in this figure. So with the median follow-up of 17.6 months, the median duration of the CR and this is for the NPM1 mutated patient cohort was not reached. At 12 months, the 80% of patients were still in CR, 10 patients underwent transplant of the NPM1 mutated patients. And most of those patients were able to continue on maintenance, which was allowed on the protocol in which the ziftomenib again was started on day 8 and was continued throughout. And the protocol allow the patients to go into maintenance, either [indiscernible] transplant if their physician elected to go to transplant or after the completion of consolidation chemo. So most patients were able to proceed to the maintenance stages. 31 patients were able to do that. 8 of them were after on study transplant. And only 8 patients discontinued at any point due to relapsed or refractory disease with a very low rate of discontinuation due to adverse events only 4 patients, one of them only was a ziftomenib [indiscernible]. Next, please. In the KMT2A rearrange leukemia, again, we see here the durability of the responses noting again that this patient subset have a higher-risk disease and generally not only they have a lower chance of achieving responses with 7+3, but generally, their durations are lower. So I think when you look at the data in combination with ziftomenib, you can see that these data are exciting. Here with a median follow-up of 11 months, the median duration of CR was 12 months. Most of those patients have undergone transplant, again, reflecting the belief by the physicians that those patients are at high risk of kind of adverse outcomes and relapse. So this is why most of those patients are being [indiscernible] our transplant in general, whenever possible. And many of those patients continued on ziftomenib maintenance primarily after the transplant performance. 10 patients discontinued due to relapse or refractory disease and 7 due to adverse events, only 2 of them were ziftomenib related. Next, please. So I think, in my opinion, this is the most important slide in this presentation. If I was going to show one slide summary of what I think is most exciting. This would be the one. So this is what you can see here is the overall survival care in NPM1 mutated patients. You can see a very nice, almost straight line with the survival. Of course, here after a median follow-up of 17.6 months there median over survival was not reached at 12 months, the overall survival rate was an impressive 94%. And I would add here one of the things that we also monitor when we give patients intensive chemotherapy is what I call induction mortality or early mortality, which is the chance of dying in the first 60 days from complication, this was very low at 2%, which again is extraordinary low. Remembering, again, that this is a large international study. Those patients were treated in many centers. This was not only one highly specialized single center. So I think to see such a low induction mortality is quite impressive. And the other point I would make also is that those patients, as I mentioned at the beginning, those are older and higher risk than your average patient because of the patients who are included in the dose escalation part of the study, in particular, the median age was 60. So when you try to compare historically generally in terms of the CR rates, in terms of the durability of the CR as well as the overall survival rate, I think these numbers compare very favorably. And at the same time, this is combined with good safety where time to count recovery is only 28 days and the risk of adverse events is generally along the lines of what you expect that was 7+3 itself. And as you can see, most of those patients are still alive and continued on study, and we will continue to follow these data until maturity on the longer run. Next, please. So these are similar data for the KMT2A arrange patient subset. Again, the outcomes here look a little bit worse than the NPM1, but this reflects the higher risk nature of this particular entity of acute leukemia, still here with a follow-up of 11 months, median OS was not reached and 60-day mortality was still good at 4% and 62% of those patients were still on study either on the treatment or on the follow-up phase of the study and the 12 months [indiscernible] was 71%. Next, please. So I think in conclusion, in this analysis from the KOMET-001 study, which, as I mentioned in the beginning, I believe to be the largest data set of intensive chemotherapy-treated patients who received it in combination with a menin inhibitor that has been presented to date, the combination was very well tolerated with a safety profile that is consistent with previous reports and also doesn't seem to be significantly different than 7+3 by itself, in particular, when it comes to lack of additional myelosuppresion quick time to count recovery. And I think the adverse events of special interest in particular differentiation syndrome seems to be very largely mitigated. This is one of the advantages of giving a combination of chemotherapy along with them a menin inhibitor not only to enhance the synergistic activity and the efficacy, but also it [indiscernible] for the differentiation syndrome. Beyond the safety, I think the clinical results are extremely exciting, in particular, the NPM1 cohort with a CR rate of 94% and a CR that is very durable. The median duration has not been reached and 80% of those in CR were still in CR at 12 months, but also the median was not reached and OS at 94% for NPM1 patients at 12 months. And similarly, for KMT2A, a high rate of complete remission of 82% with a median CR duration and median OS that were not reached. So I think all of these data support the ongoing registrational Phase III trial, KOMET-017 for the intensive chemo therapy part of it that combines ziftomenib with 7+3 against randomization to 7+3 by itself. With that, I think this is the last slide.

Thank you. Every time I see those data, I get more excited and more confident in our ongoing frontline registrational trial, the KOMET-017 trial. And I want to highlight that the experience with KOMET-007 has been able to inform the development of this important registrational KOMET-017 trial. That -- the basics of KOMET-017, the trial was designed to generate clinically and registrationally relevant data for global markets. The trial contains 2 large independently and conservatively powered Phase III studies which have the ability to detect clinically meaningful benefit for patients. We are enrolling across North America, Europe and Asia Pacific, with the intention of generating a geographically diverse data set pertinent to all major commercial markets. However, our trial sites have a limited focus on markets that potentially have significant differences in their treatment paradigm, thus reducing potential risks to 017 that could manifest via differences in clinical practice or supportive care. This multiregional clinical site footprint will support commercial readiness by building investigator experience and familiarity globally. Our ultimate goal with the design of KOMET-017 was to optimize for speed but just as importantly, for regulatory and scientific credibility, statistical probability of success and commercial relevance. KOMET-007 data are instrumental in facilitating this design. If we can go to the next slide. So first and foremost, the safety and tolerability emerging from the KOMET-007 trial is reassuring for the conduct of KOMET-017. The overall safety profile for ziftomenib in combination with 7+3 is consistent with that seen with the 7+3 backbone. The rate of differentiation syndrome and known risk with administering a differentiating agent like ziftomenib, is considerably decreased compared with monotherapy rates. The events have been readily resolved with supportive treatment. QT prolongation was seen infrequently in the trial. When events were detected, they each had causes likely unrelated to ziftomenib therapy that were resolved so that treatment could continue. The ziftomenib therapy, the concurrent use of zifto with 7+3 does not result in delayed count recoveries for these patients. Neutrophils and platelets return to normal ranges within 28 days of treatment initiation, indicating no additive myelosuppression with 7+3. And finally, the addition of zifto to this backbone regimen does not adversely affect induction-related mortality rates. This totality of data from the KOMET-007 trial supports and recommends the ongoing registrational KOMET-017 trial. Going to the next slide. Even more striking is the efficacy we are seeing that more than recommends continued momentum in the KOMET-017. Here, I'm focusing on the NPM1 mutant solely because they will make up the majority of patients enrolled into the registrational trial. However, as you can see in Dr. Zeidan's presentation, the same apparent benefits and outcome measures are seen with the KMT2A patient population. Starting with the CR rate, we are seeing even our older patients having a 90% to 100% complete response rate. far exceeding the expected benchmarks of 56% to 88% for this patient population. The 7+3 portion of KOMET-017 was designed to have an accelerated approval endpoint of CR MRD negativity in the bone marrow. The reference for this in NPM1 patients is 44%. We saw 56% of our patients achieved this bone marrow MRD negativity, which again supports the design of KOMET-017. And the most important of outcomes is the overall survival. MRD-negative CR is expected to predict an improvement in overall survival. Our median OS has not been reached for NPM1 mutant patients, but at 12 months, 94% of the NPM1 mutant patients are alive in sharp contrast with historical numbers ranging from 45% to 80% in these age groups. Again, this supports and recommends continuance of the KOMET-017 registrational trial as designed. If we go to the next slide. What we have seen with the KOMET-007 trial gives us great confidence and KOMET-017. But with KOMET-017, we have put additional measures in place. Important among them is central MRD testing. Having a central method in place improves reliability and maintains regulatory standards. With local MRD testing, there are multiple laboratories performing different types of tests with the likelihood of creating site-to-site variability and making comparison difficult. With central MRD samples are tested a single lab with the same test allowing uniform assessment in accordance with regulatory requirements. Moving to the next slide. Assessing the MRD in this uniform way allows us to translate these deep molecular responses we have been seeing into an accelerated path towards value creation in frontline NPM1 AML. As a reminder, MRD-negative CR is the co-primary endpoint for accelerated approval in the 017 trial. As data has grown in the field, MRD negativity has consistently emerged as a predictor of long-term outcomes. The bone marrow MRD negativity we are seeing in 007 compares favorably with historical benchmarks. And these data that we believe are predictive of outcomes in 017 are clinically meaningful and appropriate to support FDA accelerated approval. Moving to the next slide. As Dr. Zeidan was referencing, ultimately, it's this slide that tells the story better than any of us actually can. An OS survival curve for AML that extends at this level over a 24-month period, and I don't know what other endpoints could actually matter more than that. The median EFS and OS have not been reached. The 12-month OS is superior to 7+3 alone. These data all tell you that menin inhibition is an important part of the treatment paradigm. And that treating early with the combination appears to have a positive benefit risk balance that we will continue to explore, not only in the relapsed/refractory setting as we showed you in combination with ven/aza, but also for newly diagnosed patients. And with that, I'll pass it back to Troy.

Thank you, Mollie. If we could go to the next slide, please. So this is part of our initiative with the launch underway in the relapsed/refractory NPM1 setting as we've guided, we think that total addressable market opportunity in the U.S. is $350 million to $400 million. As both Dr. Zeidan and Dr. Leoni mentioned, the goal is go earlier go in combination, and you can see that as we work our way up the curve. Ultimately, and I think the data support this, we're optimistic that if the KOMET-017 studies are successful, we could be poised to achieve a much more significant U.S. total addressable market of up to $7 billion. I mean I think you could see why we say that now. The goal is to get these patients into response and then keep them on continuation therapy. Many of those NPM1 patients, in fact, did not go to transplant, they're just remaining on zifto cycle-after cycle. We go to the next slide, please. So where we are today, again, a couple of weeks ago, we talked about darlifarnib. This week, we're talking about ziftomenib, on the left-hand side. The launch is going well. We have robust momentum in gaining market share. And we are firmly focused on continuing to advance ziftomenib through a variety of different combinations to address up to the 50% of AML patients that we think could benefit. The 007 results, although they are Phase Ib results, we think that they support a best-in-class profile among menin inhibitors and that they continue to derisk the ongoing Phase III registrational studies. Both Dr. Zeidan and Dr. Leoni said it well, the survival data sort of speaks for itself. And we're very excited. The enrollment in the 017 studies is going very well. We're hopeful that with this data, it will only accelerate, and we remain committed to transforming the standard of care for patients with acute leukemia. Next slide. And with that, that concludes our prepared remarks, and we'll now go to a question-and-answer session. Stephan?

[Operator Instructions] Our first question will come from Li Watsek with Cantor Fitzgerald.

Very impressive OS data. Can I guess, just give an impressive durability of the response, an OS rate, what is your best estimate for duration of therapy in a frontline study?

Mollie, would you like to -- I don't know if we can answer that question, but we still have to try.

I mean it's certainly still evolving. You'd see that it's going to be at worst, about 24 months is what it looks like at this point. These patients are, in general, very successful on treatment, getting into a response and then staying on treatment with the monotherapy once they're in their response. So we don't have the exact answer yet because, thankfully, for these patients, their treatment is still ongoing, and we're still able to follow them to get additional information.

Great. And let me just clarify, those of you who want to ask a question, if you'd like to ask a question and a follow-up question, please feel free. We're going to limit it to just one question and one follow-up, but you're welcome to get back in the queue. But going forward, one and one is fine. . Stephan, next question.

Our next question will come from Jason Zemansky from Bank of America. Okay. We'll move on from Jason in the meantime. We'll move on to Phil Nadeau from TD Cowen.

Congrats on the data. We have a question on the MRD negativity rates. What level of MRD negativities,correlated with survival? Is it the lowest threshold that you presented or the second threshold? And then kind of as a follow-up to that, how is MRD negativity going to be used to decide on the treatment plan for patients. So which patients will go to transplant, which ones would be more minimal to maintenance therapy without transplant? We're curious to hear your thoughts on that.

Mollie, do you want to start with that?

Yes, sure. So we showed you multiple treatment -- multiple MRD cutoff points because it would allow you to compare it to maybe the local values. And that's why we showed you the less sensitive and the more sensitive values. We ultimately -- obviously, the lower -- the more sensitive you go, the more predictive things generally tend to be. However, more data is going to come out over the next year or so that are going to show you probably even at less sensitive levels, even the MRD negativity is quite predictive of survival in these patients, but I would offer it over to Dr. Zeidan to give his opinion on how this is going to influence treatment in the coming months.

Yes, I agree. So I think the more sensitive the test and kind of the deeper the response, we believe, is correlating with kind of longer-term outcomes. I think when it comes to how people are influenced there has been generally with NPM1 kind of AML, a general practice that if the patient is still MRD-positive beyond the first consolidation cycle or subsequently turns from negative to positive. The standard approach has been in patients who are otherwise a transplant candidate has to consider transplantation. There is a separate question about whether these patients need to receive a treatment that can convert them to negativity to -- before they proceed to transplant, but I think that reflects the field belief and supports the clinical observation that MRD positivity beyond 2 cycles, generally correlates with poor outcomes. And I think, certainly, this is influenced in terms of how we kind of counsel and treat these patients.

And Phil, maybe I'll just add a thought or 2. We wanted to be really clear and break this down because we see a lot of numbers for MRD negativity getting discussed. The treatment decisions are based on the local values, but ultimately, to support an application for accelerated approval, the FDA requires the central testing with that level of rigor that Mollie described. So that's why we're breaking it down for you, both of them look to be quite clinically meaningful. But when one is thinking about are you going to meet the bar for an accelerated approval, you really need to be now talking about the central values. So hopefully, that will provide some clarity as we look at the menin inhibitor field continue to evolve in the frontline.

And I will circle back to Jason Zemansky with Bank of America.

Apologies for the technical difficulties, but congrats on the great progress. I guess this is somewhat theoretical. But given what you've seen from that Kaplan-Meier curve, how much do you think you could realistically [indiscernible] the 1- and 5-year survival rates? And is this sufficient to support widespread use?

Dr. Zeidan, do you want to speak to that?

Yes. So I think we know with acute myeloid leukemia in general is that most patients who relapse generally tend to do so in the first 3 years. And the risk is highest in the first year, it goes down a little bit in the second year and then a little bit lower in the third year. So we have patients who can still relapse after 5 years or after 3 years, but the number goes down significantly. Historically, some people used to use 5 years, but I would say a 3-year is a pretty good indicator if the patient is cured or not. So I think based on how this curve is looking, we showed the 12 months as a 94%, but because of the 17-month median follow-up after the 12 months, there is some degree of censoring. So I think -- but when you look at the curve, it looks still quite good up to 24 months. So my estimation is that if this trend continues and especially those patients are still ongoing ziftomenib maintenance therapy, my expectation is that this continues. And I would add to that, I think Troy touched on this in patients who are older than 60, generally, there has been an ongoing discussion in the field about whether those patients should be transplanted because although they have NPM1 they tend to have worse outcomes. And I think it was quite impressive to me, the very high rate of CR on this trial, 100%. I mean you cannot get any better than that with the menin inhibitor combination was 7+3. But also the favorable, as you could see, the average survival and the CR rate is much lower in those patients with 7+3 by itself. So it's clear to me that the combination is adding benefit in terms of the durability and the overall survival. I think in another year or so will have a much better sense about the durability, but all the early indicators are going in the right direction, in my assessment.

Great. And if I could follow up with a quick one. But to what extent is this data extrapolable to the KOMET-007 of the ven/aza combination?

Mollie, do you want to speak to that?

So as we've discussed in the past, I believe, we will be showing you an update on the KOMET-007 ven/aza frontline as well in the coming months because we think it's important for you to be able to see that translatability as well. But we have just as much confidence in the ven/aza data as we do in the 7+3 data. This just happened to be more mature and available for sharing. But I think you should assume that you're going to see us similarly excited about that data.

Sure. And maybe, Jason, just one more comment for you in the audience. Before we started these studies, we heard from all quarters sort of a desire to move from 7+3 to ven/aza. And what has been interesting is 7+3 enrollment has remained very robust throughout the Phase I and now into the Phase III. And I think Dr. Zeidan spoke to it. This combination of ziftomenib and 7+3 provides a really compelling option for patients, particularly those who may -- you may not need to go to transplant. So that's one of the things that has us excited about running the 2 studies as 1 protocol, in 017 patients and their physicians can elect intensive chemo, they can elect ven/aza. They have the option to do either. And I think we're confident that each of these 2 independent cohorts are going to show meaningful clinical benefit for patients. It's great to give those patients options. So if we can go to the next question.

Our next question will come from Salim Syed with Mizuho.

Can you guys hear me okay?

We can, Salim.

Okay. Okay. Congrats on the data. Just one from us on the safety side. This is for Troy. On the QTC prolongation, I know that was mentioned is unrelated, but just curious how those patients were managed with zifto pause in those cases? And similarly on the differentiates in syndrome for the 4 cases, what exactly was the mitigation protocol that was implemented here?

Mollie or Dr. Zeidan, whichever one of you wants to take that, I'll leave it to you.

I can start and then Dr. Zeidan can fill in. For the QT cases, they were all clearly attributable to other underlying issues such as [indiscernible] medications or electrolyte imbalances. And once those were corrected or dose adjusted, these patients were able to remain on ziftomenib therapy without any additional issues. The differentiation syndrome, we've developed that method of treatment and intervention over many years now. And so it does result in an interruption of therapy, although it probably doesn't need to in the combination setting. And again, these are all just grade 3 easily resolved of supportive care and these patients were able to continue on treatment. But Dr. Zeidan, you...

Yes. So I'll have over my own also personal experience as I have treated quite a number of patients on this protocol. And I think some of that also speaks to the experience of the investigator in terms of like working with these drugs, I think, in some size where there might not necessarily be a lot of familiarity with ziftomenib, sometimes the initial reflex would be to stop the investigational drug [indiscernible] see prolongation. But I think to Mollie's point and has been my own experience is that almost always there are other reasons such as low magnesium, low potassium. So we tend to correct these. We often in the context of intensive chemotherapy, we use a number of other drugs, in particular, antibiotics and antifungals. And all of these -- some of them can have QTC prolongation. So actually, I will always tell my team when we face this situation is that don't stop all drugs at the same time because this is what usually happens that they stop the IP and antibiotics and it becomes tough to exactly what's causing things. So I tend to stop the antibiotic [indiscernible] for 2, 3 days and then see what happens with the QTC. And I can tell you when we did that, generally, the QTC would have normalized without stopping the ziftomenib. But I think sometimes it gets confusing when people stop the drugs at the same time. But my -- again, the -- there were no grade 4s. They were -- everybody was -- for me -- since you are able to restart all the patients back on the drug without QTC prolongation that's also empiric proof that it probably has not been caused by the drug itself.

And without dose adjustment.

Yes.

Our next question will come from Roger Song with Jefferies.

Congrats on this impressive survival data. This is Nabeel on for Roger. Just one from us. So we did see triple therapy at ASCO with [indiscernible] sorry, [ quizartinib ] necessitating dose reductions. How do you compare your menin inhibitor safety profile with regards to [indiscernible]? And then anything else we should keep in mind for combos?

Mollie, do you want to take that?

Sure. But I also am going to then ask Dr. Zeidan to comment because he has some very definite feelings on this topic. I think the data shows you for -- shows you itself that we're not adding any [indiscernible]. So we don't have to sit there and interrupt our therapies to accounts to recover. We don't have to change doses to [indiscernible] to recover. When the patients are solely on the ziftomenib therapy after their consolidation, they don't have to have a dose adjustment. They're not having thrombocytopenia or neutropenia issues. So we do not believe that we are having any additive myelosuppressive effects with this addition of ziftomenib. But again, I really welcome Dr. Zeidan to comment as well.

No, I fully agree with this. And actually, one of the fun things, in my opinion, when you do the randomized Phase III trials is when you don't have a very good sense of which patient is getting what is when because everybody is recovering very quickly. This is always very exciting. But I think in this particular context, as someone who have given 7+3 with [indiscernible] inhibitors all the time because these are approved treatments. You could see that the time to count recovery is generally upwards of 35 days before you get like the ANC and the platelets. So you could easily see that the drug is adding some degree of myelosuppression, which is not the situation with ziftomenib. With ziftomenib, it starts on day 8 and actually continues -- you don't stop it. Like I don't know if you are aware of this, but with the FLT3 inhibitors, most of them, they only are given from day 8 through day 21. We have to hold them because if you keep going with them, the patient count recovery will even take longer. So here, you are able to continue throughout without interruptions and still the patients are recovering within 28 days. So I think, in my opinion, this is the best empiric proof that you have in terms of the current recovery. But I would add one of the functional consequences of a prolonged time to count recovery and a detailed myelosuppression why we hit it is because it leads to infections, bleeding and inpatient induction mortality. And again, on all of these fronts, the combination is doing very well. To have only 2%, 1 patient out of 49 in the NPM1 [indiscernible] within the first 40 -- within the first 60 days. And again, remember, the median age of those patients was 60, half of your patients were older than 60. And to get intensive chemo and only have 1 death out of 49 and no increased significant risk of like severe infections, I think all of this speaks to the lack of additive myelosuppression and the tolerability of the combination.

Our next question will come from Jonathan Chang with Leerink Partners.

Dr. Zeidan can discuss your experience with ziftomenib in the commercial setting. How are you using the drug currently? And how do these recent results potentially impact that?

Yes. So I think the drug certainly has a safety profile that has been very good. Primarily, my use has been in the context of the clinical trial because the drug has just been presently approved. But my own experience has been similar to the clinical trial experience, in particular, in terms of how relatively easy it is to give it as a monotherapy. I would make the point that all of these -- that the patients after going into the intensive chemo, whether it's in induction and consolidation, they are going to monotherapy on this particular trial in the 007 drug and 007 trial. And this is sitting in which you can really see the isolated part of the kind of what is the resulting from the drug itself compared to when you are giving it with 7+3. And in that context, I can tell you, most of the patients are tolerating it quite well, not only lack of severe toxicity, but sometimes we see what I call chronic low-grade toxicities that are not severe, but they are taken at all on the patient life that they have to discontinue. And that's not something we see with ziftomenib patients are able to continue on it. And again, in the setting of maintenance therapy where the chronic use is going to be even much longer than the refractory relapse setting. I think this becomes very important.

Our next question will come from Charles Zhu with LifeSci Capital.

This is Peter on for Charles. Just thinking about the patients who have relapsed on this trial, what therapies are they getting after? Are any of them getting menin now that a couple are approved in these settings? And is there any role for menin inhibitors actually after relapse on frontline menin combinations?

Mollie or Dr. Zeidan, one of you wants to take it?

I can say from the overall study perspective, we are certainly tracking that. And it's something that we have seen even within the 007 trial, where we had both frontline and relapsed refractory patients that patients that may be relapsed after the frontline therapy even in the same trial then went on to our relapsed/refractory ven/aza, which also obviously included the menin inhibitor. But I think Dr. Zeidan's experience with his own patients will probably be more pertinent.

Yes. So I would say, historically, when you had a patient relapsed after 7+3, we historically have used other intensive chemos such as FLT [indiscernible], but with -- once the venetoclax became available, although aza ven is not approved as a refractory lapsed regimen, it has become very widely used as a salvage regimen after intensive chemotherapy in the case of relapse in particular, for patients with NPM1 or IDH, which are thought to be subsets that are quite sensitive to venetoclax. So the practical question became is what do we do with menin inhibitors in that setting? And I think this is where the blood data that Dr. Leoni showed at the very beginning is very relevant because right now, if you have a patient who relapses after 7+3, your question is, do I give him menin inhibitor or do I give aza ven? And you can just give all 3 together where you are getting kind of, I think, encouraging reasons. And you can do that in definitively for patients who are on -- who are candidates for transplant or you can use it as a bridge to get to transplant and then subsequently continue some form of maintenance. Now to the second part of your question, I think, about what do you do if the patient has got a menin inhibitor as part of their frontline treatment? This is going to be primarily a clinical trial question because these drugs are not approved as a combination of frontline-intensive chemo yet. I think we are going to collect data from this trial and other trials and understand the issue of the sequencing and whether there are certain mutations that are predictive of responses to certain drugs. But I think this is something that still needs time to be answered.

Our next question will come from Etzer Darout with Barclays.

Great. Congrats on this data update. Just given a meaningful proportion of patients proceed to transplant, particularly in KMT2A, how should we think about the relative contribution of ziftomenib versus transplant and driving the durability in OS outcomes you're seeing? And then would this be something that the Phase III KOMET-017 would allowed to isolate to get a better understanding of the contributions?

I actually think you've answered your own question. We don't know for sure exactly what the contribution is with the post-transplant maintenance and if it influences the outcomes, we think it does. But that's what the 017 trial is specifically designed to look at. That's why there are 3 arms in the trial so that you can look at the effects of post-consolidation maintenance as well. So you have the one arm of patients who are receiving ziftomenib during induction consolidation and post-consolidation maintenance and that consolidation can be transplant or chemo. You have the patients that are getting zifto through induction consolidation followed by placebo during that post-consolidation maintenance and you're getting patients that are getting placebo throughout. So we really did design it to be able to answer that question. But so far, we think that it's adding to the equation. And really, when you have a drug that's not bringing on additional toxicities even with incremental benefit, it becomes worthwhile to keep the patient on. And Dr. Zeidan would -- could you please also?

Yes. So I'll add my clinical perspective actually not only to the KM2 but also to the NPM1 because I think this is also relevant to some of those patients. So I think it's very important to remember that with KMT2 to arrange leukemia, the vast majority of patients would still relapse post-transplant. So transplant is not something that you do and then you are [indiscernible] most patients are still relapsing and dying from their leukemia. So it's the community and the patients are really in need of something that would improve their survival beyond. Now I think like when you approach these therapies, and I'll tell you, for example, if the trial is positive and the drug is available, and I would tell you many people are already probably using this off label. We are trying to give something post transplant for these patients that has any chance of success because we know that their outcomes are poor even with transplant. So if you have a drug that is easy to take that does not add to the myelo suppression that's once a day, and it's approved in that setting. I think there's going to be out of interest to use it. Now in terms of the NPM1, I wanted to add that part because NPM1 again, sort of has a favorable risk disease, but still a significant number of those patients who are relapsed in particular, among older patients, patients who are older than 60. And there is still controversy in the field in terms of recommending transplant in older patients, some centers still recommend transplant, especially in the lack of -- or in the presence of MRD positivity. But one of the things that patients find extremely, I think, intriguing about this combination as well as the doctors, is the potential to be able to get rid of the need for transplant even for older patients. I think something that Troy alluded to is that we only have 10 patients who want to transplant in the context of NPM1. I can't recall the age difference, but I suspect some of them are older patients because again, this is where we tend to think of transplant have 4 patients. And I think if you have drug that will improve the outcomes by adding it to consolidation induction and maintenance post chemo, I think there will be a lot of interest in moving away from transplant completely.

Our next question will come from David Dai with UBS.

Congrats on the data as well. So you mentioned that the MRD negativity is favorable compared to historical 7+3. Maybe just can you clarify how the baseline characteristics for the patients and transplantation rates in KOMET-007 compares to the historical 7+3 cohorts?

David, I'm sorry, I'm not sure I understand. Can you ask the question again? I'm not sure you're asking how do the baseline characteristics and the transplant rates that we're seeing in 007 relate to historical precedent? Is that the question?

That's right. Yes. Just any thoughts on how the baseline characteristics of your KOMET-007 study compares to the historical 7+3 treatments in the real world?

Yes. And let me -- I think, David, the key slide is the slide that breaks down the CR rates by age. You've heard Dr. Zeidan speak to it. You've heard Mollie speak to it. Typically, you see a disconnect between the younger patients and the older patients. The older patients have much worse outcomes. Here, I mean it's very early days. These are small numbers. But I think that's -- what your inductors have cited is you have a 100% CR rate at patients older than age 60. So that jumps out at you. You're seeing lower rates transplant because we have the ability to keep these patients on continuation therapy. It's difficult. We've really made an effort to try to break down the various components of what all of you should be comparing and to give you appropriate references because we get this question regularly. We can't parse the data too much further. But I think you've heard this consistently. You're seeing a great benefit in both younger and older patients, no additive toxicity possibly the ability to prevent transplant. I mean, everything is sort of going in the right direction. So I hope that answers the question.

Well, this was our last question for today. So I'd now like to turn the call over to Troy Wilson for any closing remarks.

Great. Thank you, Stephan, and thank you all for joining the call today. We're just -- we're absolutely thrilled with this data. It's another step toward our goal of improving outcomes for patients with acute leukemia. I want to thank Dr. Zeidan for being so gracious with his time today. I want to thank my team, and I want to thank all of you for your questions. We're available. Most of our team is at EHA, but we're available if you have additional questions. And so you can reach out to Greg or me. And we hope this was helpful and look forward to the next time. So thanks very much. We'll adjourn the call.