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

Thank you for standing by. My name is John, and I will be your conference operator today. At this time, I would like to welcome everyone to the Kura Oncology ASH Virtual Investor Event. [Operator Instructions] I would now like to turn the call over to Troy Wilson, President and Chief Executive Officer. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to our ASH Investor Event. I'd like to start by turning to Slide 2. Today, we're going to be making a number of forward-looking statements, and we would refer you both to our website and to the SEC's website for more information about Kura Oncology and the risks and uncertainties of an investment in the company. Turning to the next slide, Slide 3. We're very fortunate to have with us today 2 of the investigators on the KOMET-007 study, Dr. Amir Fathi, who is the Program Director of the Center for Leukemia at Mass General as well as Associate Professor of Medicine at Harvard Medical School; as well as Amer Zeidan, who's the Chief Division of Hematologic Malignancies, Director for Hematology and Early Therapeutics Research at Yale, as well as an Associate Professor of Medicine at Yale University. I'm also joined here by 2 members of Kura's senior leadership team: Dr. Mollie Leoni, who is our Executive Vice President of Clinical Development and the clinical lead for our menin program; as well as Brian Powl, who's our Chief Commercial Officer. The 2 doctors are going to go through some slides related to the data, then Mollie will take you through a couple of slides as to how that data we'll roll out into our forward development plan, and then we'll end with a slide or two on the commercial opportunity that's beginning to come into focus for the menin inhibitors in acute leukemia. With that, if we could turn to Slide 4. I will turn it over to Dr. Fathi.

Thank you so much, Troy, for the kind introduction, and I'm happy to be here and appreciate speaking with you all this very early morning. So ziftomenib, it's a key inhibitor of the menin pathway foundational target in AML, and 35% to 40% of AML patients in leukemogenesis is driven by either NPM1 mutations or KMT2A alterations. These are upstream regulators of key genes critical for AML progression, including HOXA9 and MEIS1. KMT2A, also known as MLL, and NPM1, sit upstream of major AML targets, which also happened to be promoters, key promoters of leukemogenesis and development of AML in patients. Therefore, inhibiting the menin KMT2A complex down regulates HOXA9/MEIS1, leading to differentiation of leukemic blasts into more mature myeloid cells and ultimately, a response. Ziftomenib is a potent highly selective investigational menin inhibitor, as I mentioned, an inhibitor of the menin KMT2A complex and has shown clinical activity as monotherapy in adults with relapsed or refractory NPM1 mutated AML. Next slide. As a way of background, KOMET-001 was a Phase I/II study of ziftomenib and relapsed/refractory AML. There was multiple phases to this study. The Phase Ia was a dose escalation, which explored multiple dose levels of the drug given once daily to assess the safety and tolerability, pharmacokinetics, and get an early sense of the antitumor activity of the agent. That followed according to the guidelines for the Project Optimus from the FDA to explore specific cohorts in this case, a cohort of 200 milligrams daily and another of 600 milligrams daily to further explore to safety, pharmacokinetics and clinical activity and to pick the right dose, ultimately for expansion, which was explored in a Phase Ib expansion cohort of 600 milligrams daily with those found to be most optimal in terms of pharmacokinetics and activity. Following that, the Phase II portion of the study ensued, which looked at 600 milligrams daily with the primary endpoint of composite remission, CR, and CRH as well as multiple important secondary end points, including duration of remission, transfusional independents, MRD assessments and also safety, tolerability and adverse event profile. Now to move on to the data that we presented last evening, the KOMET-007. And my focus especially will be on the Phase I combination of study in ziftomenib plus venetoclax/azacitidine in relapsed or refractory patients. Dr. Zeidan will speak about the upfront study in combination with intensive therapy. So specifically in regards to the combination of ziftomenib, venetoclax and azacitidine, this was among patients, adult AML patients with either NPM1 mutated or KMT2A rearranged AML to a relapsed or refractory to prior lines of treatment. There was a dose escalation that looked at multiple dose levels. There was also a dose de-escalation level, which we didn't get to because we did not need to dose de-escalate. There was dose level 1 at 200 milligrams, dose level 2 at 400 and dose level 3 at 600 of ziftomenib combination with azacitidine and venetoclax followed thereafter with what we're planning on doing, which is a dose expansion looking at the select -- ultimately, the selected dose, which, in this case, was 600 milligrams daily amount, both relapsed and refractory as well as newly diagnosed AML patients with the primary endpoint of assessing for DLT's adverse events and other key secondary endpoints of response. Ziftomenib was started on day 8 of cycle 1 and was thereafter administered continuously daily. Venetoclax was administered as per the label in 28-day cycle, but there were multiple guidance statements within the protocol to help with dosing and adjustments to optimize patient safety. Azacitidine was also administered for label cycles from Phase I through VII of each. Next slide, please. So this slide provides you the baseline patient characteristics for this cohort of patients, which as I mentioned, included both NPM1 mutated as well as KMT2A rearranged patients. Both of these groups are provided here, 26 patients with NPM1 mutations and 28 with KMT2A rearrangements. The median age for all patients as well as those within the individual groups are provided here. And I think they break down relatively as would be expected within each mutational subject. I'd like to perhaps focus your attention on a few of the roads here that I think are relevant. One is the median number of prior therapies. As you can see, there's a wide range of multiple prior therapies among these patients. And I think this is important. When we do studies among relapsed and refractory patients, oftentimes we don't get as a uniform patient population, in fact, far from it than we would in newly diagnosed cohorts of patients, where patients in this situation ultimately receive multiple different lines of treatment with varying degrees of intensity and depending on the study also potentially include transplant, it oftentimes can make interpretation of data across studies quite difficult, but there was a range of prior therapies among these patients. As you can see, some of these columns have -- all patients that was anywhere between 1 to 8 lines of prior treatment. And those prior therapies included, as I mentioned, stem cell transplant, venetoclax as well as prior menin inhibitors, up to 20% across all patients received the prior menin inhibitor therapy. And that's an important consideration as you look at this stage. Next slide. Safety and tolerability of ziftomenib described here in the form of treatment-emergent adverse events that occurred in 20% or more of all patients. And I would just say, this is a busy slide, and you're welcome, obviously, to look through it. But there was not, I don't think, any significant trend that would make this any substantially different than what you would expect from azacitidine and venetoclax alone in such a relapsed or refractory patient population. What we generally see with this combination was also seen here with the triplet, which included cytopenias that occur during repeated cycles of treatment. Now we've divided up this table according to all of the information, including any grade toxicities, including non-hematologic events and have focused more clearly on hematologic events that occurred at Grade 3 or higher in the final 3 rows. Next slide. Now the key adverse events for menin inhibitors in general, a class effect is differentiation syndrome. This was seen in 4 patients, 3 of the 4 were KMT2A rearranged patients. The events that occurred were Grade 2 and Grade 3, and all of them were manageable with standard approaches to the differentiation syndrome. As has been previously said by various investigators, including myself and Dr. Zeidan, differentiation syndrome probably would end up being a more prominent occurrence in monotherapy studies or monotherapy scenarios as opposed to combination scenarios, mainly because we think that the limiting or decreasing the bulk of the disease probably has an effect on decreasing the incidence of differentiation syndrome, the less leukemia, you have to differentiate, the less likely you would think that you would have differentiation syndrome. And as I think, we are starting to see that here in studies, particularly in the upfront setting where treatment tends to be -- traditional treatment tends to be more effective. Among these patients, there was no ziftomenib associated QTc prolongation and no dose-limiting toxicities were noted at the dose levels tested. Next slide. Here is the clinical activity in response evaluable patients, and these would be defined as patients who have one or more response assessments or who are alive. And the composite remission information is provided at the top row for both NPM1-mutated patients as well as KMT2A rearranged patients. In total, 50% of patients achieved a composite remission, 68% achieved an overall response, which included CR, CRH, CRI or MLFS. This was higher in NPM1-mutated patients than it was in KMT2A rearranged patients in whom composite remission and overall response were lower, but nevertheless occurred in about the overall response in 1/3 of patients that were treated. We also -- on the poster that we presented yesterday, provided information for both prior venetoclax exposure as well as prior menin inhibitor exposure. This is a table that provides the venetoclax, as you can see, a sizable proportion of patients had prior venetoclax exposure. Most people, let's say, all experts in the leukemia field know that once a patient has been exposed to a definitive round of venetoclax containing therapy, oftentimes what follows has to have a substantially reduced likelihood of response. In this case, among patients who received prior venetoclax, actually in NPM1-mutated patients, more than 1/3 actually achieved a composite remission, which I think is remarkable, I would say. And 15% of patients with KMT2A rearrangements also achieved a response. We've had more limited data for patients with menin, prior menin inhibitor exposure, but 2 patients did have an overall response among prior exposed patients. Next slide. We provided this table just to provide a sense of sort of count recovery because I think that's an important consideration for patients who received the combination of HMA and venetoclax combinations and now triplets. As you can see here, based to neutrophilic and platelet recovery ranged from lower to higher numbers, but in general, did not differ substantially, I would say, from what you would expect in patients in the relapsed/refractory setting receiving azacitidine and venetoclax with the majority of patients achieving count recovery as would be expected by the end of each cycle. Next slide. Conclusions. So in the ongoing KOMET-007 study, ziftomenib, a potent and selective menin inhibitor combined with venetoclax and azacitidine was deemed to be well tolerated, which was the main objective here. at all dose levels tested and continue to demonstrate promising clinical activity in this relapsed/refractory NPM1-mutated and KMT2A rearranged AML population. The ziftomenib combination therapy was well tolerated in the sense that no dose-limiting toxicities nor any ziftomenib induced QTC prolongation were reported. Differentiation syndrome occurred in 4 of 53 patients receiving ziftomenib, all were Grade 3 or less, including in 3 KMT2A rearranged patients and 1 NPM1-mutated patients. All patients had resolution of differentiation syndrome with appropriate standard management. Clinical activity was demonstrated in the treated patients, including in prior unexperienced patients in the NPM1-mutated group. Among the response evaluable patients, the overall response rate was 68% and the composite remission rate was 50%. And in the same population of patients with prior ven exposure, the overall response rate was 50% and composite remission was 36%. We also saw that 1/3 of patients with KMT2A rearrangements also responded including those with prior venetoclax exposure. So based on these encouraging initial results, a dose expansion phase is currently moving forward, evaluating this combination of both relapsed/refractory in newly diagnosed patients. Thank you so much for your attention. And I'm going to hand the floor over to Dr. Zeidan.

Thank you so much, Amir. It's a true pleasure to be here talking about, I think, a very excited level from this ongoing trials. So Dr. Fathi covered very well the rationale for combining ziftomenib with various forms of standard of care, hemotherapy, [indiscernible] setting. But here, I think the combination with intensive chemo is also very important. And I wanted to highlight a couple of things that are in general oncology development as most of the drug will be developed in the relapse/refractory phase where they show safety and efficacy and then they would be moved upfront in combination with other standard of care agents where there is non-overlapping toxicities and synergistic activity where we can have the best chance of making a very significant impact on the patient's of survival. And this paradigm has been followed in multiple hematologic malignancies, including acute myeloid leukemia. When we look at the experience, for example, less inhibitors to see responses in the range of 20% to 30% in the relapse/refractory setting. And then once we go to the front line setting in profession and since the chemo, some of those agents have become part of the standard approach of treating patients. And this is, I think, a very good part of why we designed this combination in the frontline setting, part of the study in combination with 7+3. So patients who are being set for intensive chemotherapy who received 7+3. And here in this Phase I study, we had the dose escalation, which was Phase Ia, which used the same doses that Dr. Fathi mentioned, 200 400, 600, as you can see in the hem slide. And patients who are enrolled in independent cohorts of NPM1 or KMT2A rearranged basis. And what you can see also clearly here is that while those patients had NPM1, those patients were considered to have high risk. Why is that? Because we know what NPM1 generally indicates a larger prognosis in the frontline setting. Once we look at patients who are older than 60 and patients who have therapy-related disease and patients who have poor cytogenetics, those patients actually have poor outcomes, relapse is very common. And many times, they would be recommended for one more transplantation. So this was an ideal patient population to go initially to look at the safety and get us in about the premium efficacy. So the primary interest in that part of the study was looking at description of safeties in DLT and adverse events and then secondary endpoints looking at efficacy focusing on CR and CRc. So the [indiscernible] event cohort were given continuously. It started on day 8 and was given during induction, during consolidation and subsequently, were given on the maintenance cohort. The maintenance was allowed to be driven after chemotherapy or after going transplantation. And what I'm going to present today is the level of the dose escalation part of the study, the Phase Ia. But I would note here that there's already an ongoing Phase Ib, looking at expanding the results for expanding the trial to understand on a bigger scale how the combination performs. So on the next slide, you can see the baseline characteristics of the 51 patients that are going to be described in this presentation. You can see the breakdown between NPM1-mutated patients, who are 24, versus the KMT2A rearranged patients, which were 27. Please quickly note that patients with NPM1 who were a little bit older, the median age of 66 because, again, this is by design that those patients were required to be either older than 60 or have therapy related disease of cytogenetics. And again that reflects their poor prognosis. And you can see the distribution of the commutation, which again is very similar to what you would expect in this type of patient population. I would note that patients on study, and I think this is -- you can quickly see, this is relatively a short-term follow-up. But you can see that many patients are still on therapy, 45 patients out of 51 are still on study. So in the next slide, when we look at the safety, and I think here, anybody who was treated patients with acute myeloid leukemia can quickly tell by looking at this slide that these are the side effects, while they are very common, but it is extremely common to have everybody essentially on intensive chemotherapy will have Grade 3 and greatly and AE adverse events in general. And the reason for that is the intensive chemo will need to calm suppression. There is often some GI side effects. So when you look at this in terms of the combination, and although there was no control arm in this particular study, indirectly, when you compare data from other studies that look at 7+3, you can see that the treatment emergent adverse events are in line with what you see with 7+3. So we are specifically describing the treatment emergent adverse events that occurred in 30% or more of patients. You can see that the category basically fall into the blood count suppression, which is, again, very common with intensive chemotherapy as well as febrile neutropenia and some GI side effects. And this is, I would note, are adverse events regardless of attribution and of all grades. And I think a very important note that or observation that we made that on the dose escalation and did not see the rate of the treat-emergent adverse event is correlated with the dose, which allows us to escalate to the highest dose, 600 milligrams. In the next slide, we are describing the safety and tolerability, but looking at the treatment emergent adverse events that were Grade 3 or higher that occurred in 10% or more of patients. Again, this is regardless of attribution and the same observation that we made earlier stands here that most of those studies which are what you typically see in patients who have acute myeloid leukemia who have undergone intensive chemotherapy. I would note here that we could see that the GI side effects are not seen because most of them are mostly Grade 1 and Grade 2. What you are seeing is the febrile neutropenia and the count suppression, which is very typical with intensive chemotherapy along with a low number of infectious complications. But importantly, we did not observe any dose limiting toxicity at any dose level, we did not observe any ziftomenib-associated QTc prolongation. And to support the idea that the combination is not only important from a synergistic point of view but also to mitigate the rest of the differentiation syndrome, you can see here that there was only one case out of the 51 patients or the patient who deal with differentiation syndrome, which was Grade 3 and NPM1-mutated cohort was at the 600-milligram dose. But this patient was actually successfully managed and was able to remain on treatment. So next slide. I think this is clearly the most exciting slide, and I think generated huge interest during the presentation and subsequent to the presentation. In my opinion, extremely impressive clinical data. It's still relatively a small number of patients and limited follow-up, but when you look at the number of responses that were observed in both cohorts, but in particular in the NPM1 cohort. So out of the 23 patients who are treatment evaluable, 100% of the patients responded in the complete remission. And I would note here that this is not composite CR or CRh. This is 100% full CR, which is something that you do not often see with these therapies. And when you look at the MRD, which is the disappearance of the measurable residual disease, which we think correlates with long-term outcomes in the context of intensive chemotherapy, around 3/4 of those patients achieved MRD negativity, although this [indiscernible] was local based on local results, I think, again, this is very encouraging. When you look at the KMT2A rearranged patients, I think you are seeing similar to that. I would note this is a much more difficult treatment patient population to treat, but still out of the 23 patients that were efficacy evaluable, 83% of them achieved complete responses. So when you add to this the NPM1-mutated patients who were, as I mentioned earlier, were the higher risk patients who are older or have therapy-related disease, I think these results speak for themselves. And in the next slide, you can see I think a very important observation that we have been making across the study in terms of how these new therapies can lead to novel approaches in the management of patients with acute myeloid leukemia. So this is actually 60 year old patient within the NPM1-mutated cohort who was treated with 7+3 and ziftomenib. And you can see here in the bone marrow, which is the first column and the diagnosis, you can see some pictures. For those of you who are familiar with this kind of picture, this represents stain from the bone marrow using [indiscernible] CD34 and NPM1. And what you can see, this NPM1 is actually a very nice thing that we use in our institution, other institutions that says that cytoplasmic localization of the mutation to give you a quick idea about having a patient with NPM1-mutation. This is important because you can relatively, using this, diagnose the patients faster than waiting for the results of the next-gen sequencing. So we quickly knew that this patient was a candidate for the trial. We put the patient on the trial. And then subsequently, on day 21, what you can see is that on the top picture, our pathologists, when we did the bone marrow, and the reason why we do a bone marrow in the middle of the treatment is sometimes, we get additional chemotherapy to make sure that the patient will go into remission if there was a significant amount of leukemia. However, the pathologist was concerned that there was residual leukemia. They actually accounted what they called 30% blood. However, what we observed that the patient actually was doing well, and the platelet count was already recovering, over the next few [indiscernible], the platelet count went from 20 to the 70, 80 range. And then subsequently, when we looked at the days, we could see a change from the baseline immunophenotype as well as the NPM1 PCR came back much, much lower than it was at the beginning. It was at the beginning, 38%, and at that time, at day 21, it was 0.08, like less than 1 in 1,000. So based on this, we decided to not treat the patient with the intensive chemotherapy and waited on the patient. And 2 weeks later, we repeated the bone marrow. The patient actually had full count recovery. You can see that the [indiscernible] completely disappeared. The NPM1 [indiscernible] completely disappeared, and the PCR became very minimally minimalistic and subsequently disappeared after the first consolidation. So I think this case highlights that it's very important in the context of adding differentiating therapies to intensive the chemotherapy that there should be a judgment given about whether we get additional chemo. I would argue that we have seen similar pattern to some of the other differentiating therapies that we determine and have differentiation and doses of blood. And I think if this holds up, especially the very high CR rate, I think we probably can get rid of the day 21 bone marrow altogether. But of course, we need to see additional follow-up. Now in the next slide, you can see the duration of treatment and preliminary clinical outcomes in patients in the NPM1-mutated core. So here, there are sort of -- sorry, the follow-up is relatively short as 31 weeks. But you can see that essentially all patients are alive. So basically, there was no treatment related death during the induction, which again, is something that is a risk of leukemia. We can see here that the median duration of CR was not reached. The median survival was not reached. And patients were able to proceed to transplant, 5 patients went to transplant in this cohort and 2 of them were allowed to go into the maintenance after the acquisition and discuss with them as they choose to do that. But importantly, there were no discontinuations due to adverse events or relapse. Similarly, in the next slide, you can see a similar observations for the KMT2A rearranged patients. Here, the shorter -- the follow-up was a little bit shorter at 19 weeks in the median. But still, the observations that most of the patients were alive, 96% at the time of this data cut, the median duration there was not reached. The median overall survival was not reached. And more of those patients went to transplant, reflecting the very aggressive nature of this top part of leukemia. And this is what I think most physicians and patients will still try to go for transplant. Next slide is an analysis similar to the one that Dr. Fathi described for azM. We try to look at the count recovery. Why is that important? Because one of the concerns when you add any agent to combination therapies, including intensive chemo, is prolonging the period of myelosuppression, and that can lead to infectious complications and other things. And actually, this derail the development of several agents, which we found is promising. And once you combine it with intensive chemo, you get prolonged myelosuppression, which could be appropriate. Here, we observed very nicely that when you add [indiscernible], that the time to count recovery, which is generally assisted by DNMT of more than 500 or 1,000 or platelet more than 50,000 or 100,000, that the median time to count recovery does not appear different than what you would expect with 7+3. And also importantly, does not seem to vary across different dose levels or by the cohort. And I think you could even make the argument that a median time to cover might be a little bit shorter as we go up on the doors. But I think this remains to be seen, but this is extremely encouraging in my opinion, because this is one of the issues we have seen historically with other drugs when they added to intensive chemotherapy. So on the next slide, you can see our conclusion from the ongoing KOMET-007 study, that when ziftomenib is combined with intensive chemotherapy, that treatment was very well tolerated in all the dose levels in patients who have newly diagnosed as [indiscernible] NPM1-mutated disease of KMT2A-r AML. We did not observe any dose in toxicities. We did not observe any ziftomenib-associated QTc prolongation. The occurrence of on-target differentiation syndrome was only in one patient, which was 2% Grade 3 successfully managed and the patient was able to remain on therapy. And importantly, as I mentioned, the ziftomenib did not seem to interfere with count recovery and the dose is not seen -- the higher dose, 600 milligram, which was chosen for expansion does not seem to particularly, again, something to impact time to count recovery. Very exciting for us and clearly to our patients is that we observe very high CR rate. And again, I would say, this is CR, not CRC, with CR 100% in the NPM1-mutated patients, 83% in the KMT2A rearranged patients. And 3/4 of those patients achieved MRD negativity at some point during their treatment using local assays. And at the time of the data cut, the vast majority of patients, 50 out of the 51. That's a lot. So taken together, I think it's clearly supportive of further development of ziftomenib in combination with intensive chemo, and actually, the subsequent expansion cohorts on this study are looking at all patients with NPM1 regardless of the age, regardless of previous treatment as well as patients with KMT2A rearranged disease. And I think we look forward to make a better understanding of the durability of the responses as well as the tolerability of the treatment, and have a better sense about how this treatment is going to fit in the future management of frontline as we treat patients with acute myeloid leukemia.

Perfect. Thank you, Dr. Zeidan and Dr. Fathi. We can go to the next slide. Now I'm going to turn it over to Mollie to take us through how these results are now incorporated into our forward development plan for ziftomenib.

Thank you, Troy, and on to Slide 26. So our goal has always been to get zifto to the broadest population that could potentially benefit. And in order to do that, we have been executing a broad zifto development plan to generate a large amount of pertinent data. And now in that top red box, this is what we are executing in collaboration with our partners at Kyowa Kirin. So the top line shows you our monotherapy registration-directed trial, where you should expect to hear top line data in early 2025. In that trial, we're also evaluating ALL patients and non-NPM1 and non-KMT2A rearranged patients. And all of those cohorts are now dosing. As KOMET-007 has been described today on the call, we are successfully through the dose escalation portion and into the dose expansion or dose validation portion for all cohorts being enrolled. KOMET-008 is our relapse/refractory combination trial, where you're combining with agents such as gilteritinib, FLAG-IDA and low-dose CRc, and both of -- all of those cohorts are also enrolling during the dose escalation portion of this trial right now. And if we go on to the next slide, the information that we generated and that was presented this weekend at ASH is now truly our focus as we turn to the frontline and the frontline pivotal trial. And that frontline pivotal trial called KOMET-017, and I will remind you, it is fully funded now through to the end results and is expected to start in mid-2025. Within the study, there's 2 independently powered Phase III randomized double-blind studies. And the population will enroll adult frontline AML with either KMT2A or NPM1-mutations. And depending on their status, they will enroll into the non-intensive therapy, which would be ziftomenib plus venetoclax plus azacitidine versus placebo or the intensive therapy study, which would be the ziftomenib versus plus 7+3 versus placebo. We expect about 150 sites in 20 countries. This will be a very broad development project that we are undertaking.

Thank you, Mollie. And just to give a few comments now about how particularly these frontline results are reflected in the commercial opportunity, Brian is going to take us through a couple of slides here at the end.

Thank you, Troy. Next slide, please. Slide 29. Just summarizing where the development plan that Mollie outlined. We are building a strategy to support development in up to -- up to 50% of AML patients where the menin KMT2A pathway is a driver of disease. We see that across both NPM1, KMT2A rearranged as well as other mutations. We have, of course, with our earlier stage development in the KOMET-007, KOMET-008 a number of combinations in the frontline setting. We'll have KOMET-007 with ven/aza 7+3, and we're also initiating -- we'll be initiating next year quizartinib combination as well here. With this broad development plan, we see a potential to reach a large number of patients, as I mentioned, up to 50% of the patients. If you go to the next slide, please. Where we see is this -- overall, this market potential, I wanted to just give an outline as to where we see this potentially reaching is up to exceeding up to $7 billion potentially per year. When you look at the breakdown of patients on the left side, where we see there are potentially up to 50% of AML patients that may benefit from the menin inhibitors, we realized that there are -- while there are a lot of options for patients right now, there are still a very high unmet need in AML. This includes patients who are considered to have both poor and favorable prognosis. According to the epidemiology, we think that there's an opportunity to treat up to 10,000 patients per year in the U.S., both through the intensive and nonintensive chemotherapy populations. We think that the data that was discussed today leads us to support the potential combinations in both 7+3 and ven/aza in the frontline setting. We believe that the ability for patients to remain on therapy allows for a potential sustained treatment between 12 to 24 months of treatment or more. And with analog pricing of other currently available therapies in the AML space, we believe that this leads to an anticipated market potential exceeding $7 billion a year for the menin inhibitors in the first-line setting alone. Given ziftomenib has the opportunity to reach this market, we think that there is a peak sales potential above the $3 billion per year in the United States.

Great. Thank you, Brian. We can turn to the next slide and actually just the one after that. This will be the last slide before we wrap up and take questions. So we were very pleased to have the presentation of the results from the dose escalation portion of the KOMET-007 study. Looking forward to next year, we anticipate releasing top line results for our KOMET-001 registration-enabling study in NPM1 mutant relapsed/refractory AML in early next year. We are looking forward, plan to give you updates from the KOMET-007 study, both further updates on the dose escalation portion as well as insights into the dose expansion cohorts for both the intensive and nonintensive treatment regimens as has been mentioned. We are looking forward to commencing the KOMET-015 study, which is a combination of ziftomenib and imatinib in patients with advanced gastrointestinal stromal tumors who have progressed on prior imatinib therapy. In another application of menin inhibitors, we intend to nominate a next-generation menin inhibitor development candidate. And of course, as Mollie mentioned, we are moving very aggressively now to initiate the KOMET-017 registration-directed trial in combination with both venetoclax and azacitidine and 7+3. Looking at the pipeline, there were a number of other key milestones that we're looking forward to sharing with you throughout the year. And as was mentioned, we're in a very strong position now, both with the cash we have on hand and our recently signed partnership with Kyowa Kirin, our 017 study is fully funded, and we are currently looking forward to planning either a FLT3 frontline study and/or a post-transplant maintenance study. To Brian's point, really, now we have both the financial and the operational resources to maximize the value of ziftomenib for patients. So with that, just to summarize, where we are now looking across hematologic malignancies, solid tumors, which we'll talk more about in diabetes, we think we can create a lot of value for patients and our shareholders. With our partners at Kyowa Kirin, we are intending to compete aggressively in that frontline patient population. That is really the blockbuster potential. We are hopeful that not only ziftomenib, but the other menin inhibitors will help to transform the standard of care for patients with AML. And if that happens, then as Brian indicated, we expect to transform the market. As part of that partnership, I'll just remind you that we retained some key strategic rights, including commercial control, global development and the ability to book sales in the U.S. Those were key rights to maintain the investment thesis for Kura. We are fully funded at this point with our collaboration and our cash on hand all the way through to commercialization in that front line. That puts us in a very strong position. We are seeing a number of players in the menin space, and things are going to start to go quickly. And so we're happy now to have both the financial and the operational resources. And then again, on to our pipeline, a number of exciting updates early next year. With that, operator, we'll conclude the formal presentation, and we're happy to take -- all of us are happy to take questions from those on the call.

[Operator Instructions] Your first question comes from the line of Li Watsek with Cantor.

Congrats on the data. Troy, can you talk a little bit about your confidence in frontline aza/ven combination? And how should we think about the reads through from the aza/ven combo data that you just shared in the salvage setting?

Sure, Li. I mean I'll just make I think the overarching comment and then maybe I'd ask Dr. Zeidan to add his thoughts. The most important takeaway from that relapsed/refractory data is the safety and tolerability in combination with venetoclax, and the fact that we were able to cleanly declare 600 milligrams as the going-forward dose. The safety and tolerability profile and in particular, the lack of AEs, I think, sets us up very nicely now to be able to move forward into the frontline combination. But I am not the expert. Let me let the expert actually comment on if there are any other key takeaways.

No, I fully agree with this. I think the data clearly demonstrate the safety and tolerability. But also I think the clinical activity in the relapse/refractory setting, which we generally know, especially after previous venetoclax exposure and previous [indiscernible] exposure, those patients generally do not respond very well. So to see the activity that we have seen in the refractory/relapse setting, I think this is going to translate into I think a very impressive activity in the frontline setting. So I don't think I have any concerns about movement at the frontline.

Okay. And I guess for both doctors, can you share your thoughts on the potential of using MRD activity as a potential target endpoint in frontline? And what is your view on using flow versus PCR-based methods to measure MRD?

So I guess I'll start. This is Amir Fathi. So there isn't a substantial amount of precedent when it comes to MRD assessment as a primary endpoint in clinical trials. But there is some limited amount. So I think the regulatory agencies, from what I understand, are increasingly interested in looking at MRD as a potential surrogate endpoint, and that might be a way to potentially get to an earlier understanding of the promise of these agents in combination in larger placebo-controlled studies. And I think this -- and I don't want to speak for anybody, but I think just broadly speaking, such a study might be a good opportunity to potentially pursue that here. As far as NPM1 MRD or flow MRD, I'll let Dr. Zeidan speak for himself. But for NPM1-mutated patients, generally speaking, the standard approach that we use is an NPM1 specific PCR test to inform us regarding decision-making following induction and consolidation chemotherapy, specifically regarding the decision to pursue transplants versus not because historically, not all NPM1-mutated patients require a transplant. So if you are able to demonstrate MRD negativity after 2 cycles generally of intensive therapy, you may not need to pursue transplant at the modality for pursuing cure. As far as flow, flow is increasingly used now in academic centers as an assessment for MRD. But in terms of making decisions regarding choice of treatment, it is more limited in scope. So I would say that in the clinical setting and what we do day-to-day, NPM1-mutated patients, specifically NPM1 PCR [indiscernible].

Yes. I think I agree with all of this note that my sense, again, having discussed this in various settings with different stakeholders in the field that MRD negativity certainly is, I think, gaining increasing acceptance as an endpoint, especially in the setting of intensive chemotherapy, where I think it has been consolidated very well to correlate with long-term outlook. Historically, the guidance on clinical track development in AML for MRD focused on flow cytometry, but I think there has been a lot of data in the last few years, looking specifically at NPM1 negativity by genetic assays, and I agree with Amir that PCR, high-sensitivity PCR is the way to go. And I think while we don't have currently an approval so far using MRD negativity in AML, I'm very hopeful that this will be the first study to do that. I think that besides from the regulators certainly there, and I think the correlation data is certainly there. So it is a bit -- I think the data is not as mature in terms of the correlation between the MRD negativity and the long term outcome, but the body of evidence certainly is increasing. So I have high confidence that this could be, I thin,k, an approval of business.

Just to add to that, Li , we've guided -- for everyone on the call. We will be meeting with the regulators, both in the U.S. and in Europe early next year and intend on giving -- providing feedback to you -- their feedback to you as part of more details around the KOMET-017 study. Our base case is that there is not an accelerated path, but as has been discussed, there are some good arguments that we're going to put forward to the regulators, and we'll do our very best to argue for an accelerated end point, particularly in the context of intensive chemo. So look forward to early next year for us to give more color on those discussions.

Your next question comes from the line of Jonathan Chang with Leerink Partners.

For the docs on the call, given the totality of the data sets across the menin space, what do you see as the key differences on the safety profile between the menin inhibitors in development? And how could that impact, if any, the opportunity in frontline combinations?

So I can -- it's Amer Zeidan, I can start. So I think based on not only the clinical trial data, but my own experience have increased in many patients with this agent. It's definitely one of the easiest agents to get. And many of the drugs that we use in leukemia and oncology will have some -- a certain load of side effects, which might not be severe, but the patient might feel they might not discontinue because of them, but we will tell you about it. In the context of this particular drug, my own personal experience, I have not had a patient who mentioned any kind of side effect that was significant in anyway. And when you look at the data, I think it's clear that the addition to intensive chemo is not worsening the most concerning kind of side effects, especially the count suppression. But I would add, when you compare the space, having a drug that's given once a day is, I think, a huge advantage because drugs that have given twice a day, I think, especially in all the patient population can be challenging to take on the long run. We use a lot of drugs that interact with some of the novel agents such as azoles and QTc drugs, and this certainly has been a pain. If you work in any of our clinics, this can take a significant amount of time to make sure those drugs don't interact. So I think just having the option of having a drug that does not have major interactions with antifungals, which you often use, and not having any issues relating to the [indiscernible] and needing to do frequent [ KKGs, ] not in the context of combination, the risk of differentiation also becomes much lower. So I think I might be biased here, but I think my own opinion is this is a best-in-class agent. But clearly, I think on the efficacy front, I think this, to my eye looks better, but I think all of the current studies are relatively smaller and good limited duration. But I think all the right signals are currently there with this one.

So I've had a relatively limited experience in terms of -- and I think most of us have. I mean we kind of have our own experience with the menin inhibitors that have been open in clinical trials at our sites. So I've had substantial experience with ziftomenib, and I agree with Dr. Zeidan that it has been a good experience. I would say that I, as a leukemia doctor, I'm very pleased with the fact that we now have this kinds of drug. And that multiple companies are pursuing them is good for us and good for our patients. Does it matter if a drug does not interact with other agents? Of course, it does. You have to worry about things like antibiotics, antifungals, other agents, that anti-nausea agents you may have to use at leukemia patients. That's an important consideration. Those QT interval prolongation matter. It can in certain scenarios, although I would also say that there are a variety of agents that we use that prolong QT and AML, and we manage those as well. But in certain scenarios, it can be impactful. Does the incidence of differentiation syndrome have an impact in what -- in our consideration? It does. This is perhaps the biggest aspect of care with menin inhibitors because it's a class effect and it's a potentially lethal class effect. So I think increasing the amount of information and knowledge and experience among physicians that are using menin inhibitors is exceptionally important. And my own personal opinion is this is specifically more relevant to the KMT2A we arranged through in whom we have seen perhaps slightly, although maybe not statistically significant difference, but perhaps a slightly higher occurrence in a more substantially severe occurrence. So I think all of these considerations are important in terms of looking at these agents.

Your next question comes from the line of Jason Zemansky with Bank of America.

Congratulations on your conference updates, and I wanted to circle back on the relapsed/refractory data, and maybe this is one for your KOLs. But can you speak to what we're seeing and the responses between the ven experienced and naive patients in the KMT2A population? Why do you think we're seeing these trends appreciating that the data are still somewhat early?

So if I understand the question correctly, and correct me if I'm not, the question is related to prior event exposure and prior menin inhibitor exposure in patients that were treated in the relapsed/refractory group of patients. I think this is an important consideration -- an important consideration. And we've had a series of conversations over the course of the last few days around that. I think all of us in the leukemia field, I suspect, Amer included, have long -- have for long struggled with interpretation of results for relapsed/refractory clinical trials of AML. And I think what ends up happening when you do not have head-to-head data is a variety of clinical trials that are done in varying patient populations with a varying number of prior exposures to therapeutic agents that range from anything you can imagine, from combinations of chemotherapeutic agents to, in more recent years, IDH inhibitors, FLT3 inhibitors, menin inhibitors, transplants and perhaps most relevant, venetoclax. So depending on the proportion of these patients treated on these relatively small patient populations that range from, I don't know, the teens all the way up to 80 patients. you're going to have varying degrees of results in patients who are treated. And whether that's a relapsed/refractory cohort of patients receiving chemotherapy or targeted agents. So I think it is very difficult for us who are experts in the field to interpret this data in the greater context and I think, unfortunately, for you guys who are outside of this round to sort of make that comparison. But unfortunately, in my view, it's just fact. It's just the feature of where we are, where we -- it's very difficult in relapsed/refractory settings to compare data in that fashion because the patient populations are different. And adding to that, some patient populations are single center experiences, some are multiple different patient populations from sometimes national or global group. So I think it is difficult to make those interpretations. Now going, I guess, specifically to your questions. Does prior venetoclax and prior menin inhibitor closure in the proportion of patients who have had that in clinical trials in relapse/refractory matter? Of course, I mean, historically, I mean I'll let Amer speak to this as well. I kind of consider venetoclax so far, as unfortunately, the grade closer, like it either works for you for a while or it doesn't, but after that, unfortunately, nothing else seems to accomplish what you want to accomplish, mainly because the therapeutic resistance that emerges those pathways that are underneath that resistance to venetoclax oftentimes overlap with resistance profiles to other agents that we have available. So whatever you end up giving a patient following venetoclax, not in every instance, but in most instances, ends up being ineffective. So in a scenario like that, when you -- even with that, you get something like, I don't know, 36% it looks like in the NPM1-mutated patients, but still respond to menin inhibitors in combination. I think that's promising. I think that tells you, albeit in a small cohort of patients, again, with all the correlates that I've just mentioned, that is promising and that's something worth pursuing. Also 20% of these patients have prior menin exposure. That's nothing to be laughed at. Do we expect less exposure to a menin inhibitor in patients who have been previously progressed on a menin? Of course. So I think all of these things have to be taken in context, and I think it's important for us to consider it both.

Yes. So I agree with everything Dr. Fathi mentioned. I would add like from a different angle and in a broader context. When you look at -- we had like 13 drugs approved now but in the last 7 years. And when you look at most of these, they were [indiscernible] in their relapse/refractory setting, take an example like FLT3 inhabitors, the response rate generally in a single agent in the relapse setting is generally in the range of 20% and the median duration is generally in the 6 months range. So this is a very difficult patient population. I think the biggest value of all these agents particularly translate once you move them earlier in the treatment and the combination with [indiscernible]. Why is that? Because the goal is to prevent the patient from getting to the relapse/refractory state. Once you are in the relapse/refractory state, it's really very tough. The leukemia may face all the damage, develop resistance to different drugs. So the goal is to have the leukemia as hard as possible from the get go with the best drugs you have so you don't have to deal with that situation. And I think if you can achieve that with an upfront treatment that combines several drugs and then for the patient to stay on one pill, I would tell you the vast majority of patients will not mind to be on pill for the rest of their life. I always tell my patients, if I can treat leukemia, I'll treat everything so hypertension and you are taking a pill and you are doing very well and you are alive, this is something that most patients will choose. So I think the data in the refractory/relapse setting is promising, but this is as Dr. Fathi has described, a very difficult patient population to give that kind of -- overwhelming as I think in my mind, the major takeaway is this is a drug that's very easy to give. Patients can stay on it for years and years, it might be and probably without having significant side effect and it seems to be very synergistic initially with the chemo at least to very early responses, which I'm hoping will translate into long-term survival and not even having to deal with this in the relapse/refractory setting.

Your next question comes from the line of Roger Song with Jefferies.

Great. Congrats for the data update in ASH. Two from us. One is multipart question related to the transplant and post-transplant maintenance. So just curious for doctors, following zifto treatment, how you make a decision you will move the patient into transplant and how you're going to make decision, put them back on zifto post-transplant. Specifically, the difference between the NPM1 and KMT2A patient? And then if you have any experience with under menin inhibitor, how do you see the difference between zifto versus other menin inhibitor in terms of the decision for transplant and the post-transplant maintenance? And then I have a follow-up question.

Yes. So this is Amer Zeidan, I can take this question. It's a little bit kind of complicated like the decision about bone marrow transplant is a tough decision. I can tell you that if you have any patient, nobody wants to go for bone marrow transplant. This is a procedure that's toxic. Many -- some patients will die initially, some patients will develop lifelong complications, including things that affect their quality of life and the current infection such as graft versus host disease. So the reason we recommended is the risk of relapse generally in certain subsets of leukemia, including clearly KMT2A rearranged patients, for some success of NPM1 mutated AML like those that were enrolled in the dose escalation part of the study, especially the older patients, the patients who have therapy-related disease there is a substantial risk of relapse. And this is why transplant is often discussed with those patients. And some of them will choose to go with it. However, I can tell you most patients will probably -- if they can have an alternative, they will probably not want to go to transplant. So this was at the discretion of the physician in discussion with their patient. And I'm sure every one of us want the best for our patients. So every one of us discuss with their patients. What I can tell you in my own personal experience is many patients, after you have this involved discussion within the NPM1 cohort, for example, those patients were not enthusiastic to have transplant. And when they heard that there is an option of staying on one pill post-treatment for years and years, and potentially still have a second life, if you want to put it this way, should relapse you can still go to transplant. So I think several of my patients who are older than 60 chose not to go to transplant. But I think in terms of one of the nice aspects of this study, and again, I have to get treated to the study team and making the study very patient centric, that even if the patient decides to go to bone marrow transplant, we still have the option to restart the drug after transplant as long as the patient meet certain conditions, which are having a reasonable count recovery and not having graft versus host disease. Compared to some of the other agents that are used in the post-transplant setting, the same considerations we mentioned earlier, if you have a drug that is very myelosuppressive, it's very difficult to get post-transplant. If you have a drug interacts with QTc or prolonged QTc or interactos with some of the agents we use for graft versus host disease, it's difficult to give post-transplant. Here, with ziftomenib, it was relatively easy to start patients. And I think this is what we can see reflected in the trial is that 4 patients in the KMT2A rearranged cohort went into transplant because those are the patients who I still will recommend go to transplant in general with a post-maintenance approach. I think on the NPM1, in my opinion, one of the biggest wins that we could have out of this study is actually to avoid transplant in the vast majority of NPM1-mutated patients by going through the combination and just staying on [indiscernible].

I don't have much to add, and I don't want to upset my transplant colleagues because I work with them. But yes, the less transplant overall, the better, I think. But as Amer just mentioned, there is probably a difference in NPM1 and most subtypes of KMT2A in terms of how we proceed with potentially curative paradigms. NPM1 historically has a nontransplant path to cure. But the goal here is to get more people on that path, right, because many people can't get on that path, they don't achieve a sufficiently deep response sufficiently MRD negative response. So if you're able to increase that, and hopefully, this data is pointing in that direction, we will increase the number of patients that are going to be cured and may not be transplant to get there. With KMT2A, maybe it's another discussion. Maybe it's that we are able to get more people on the path to transplant to give them a chance of cure because among -- and we were again talking about this at the poster session yesterday, among the most difficult, hardest group of patients that I treat is this KMT2A rearranged patient. Over the course of the last 15 years, I've had so many tragic cases. These patients present aggressively. Many of them have had prior exposure to chemotherapy and have developed therapy-related disease. There's a lot of emotional turmoil. There's a lot of extra medullary manifestations. So it's a tough disease to treat oftentimes resistance treatment, particularly in the relapsed/refractory setting. So I think if we're able to get responses and get patients to transplant, that would be great.

I just -- I fully agree with Amir. I mean, actually, I wanted to highlight one particular patient I enrolled on this study because this is exactly what Amir mentioned. This is a patient who had history of breast cancer who have received multiple lines of treatment and she presented to our institution with a very high white cell count. And we really wanted to put her on the trial because we know that patients with KMT2A rearranged disease have a significant chance of relapse, and without transplant generally, the chance of cure is low. But we struggled with patients who are older than 60, who have previous chemo exposure, cancer exposure. And we actually have some doubt even whether she can tolerate the intensive chemotherapy. But after discussion with the patient, we decided to go ahead with the brand, and she got 7+3 with ziftomenib, and she actually was able to achieve a remission. She was able to go to transplant, and she is currently on both transplant maintenance and ziftomenib. And I think, again, this is along the lines of what Dr. Fathi just mentioned, it's potentially a way to hopefully achieve cure for some patients who otherwise I think have an extremely low chance of cure even with transplant. So I think the treatment here complements both aspects of trying to present some patients from needing to go to transplant, but if you do need to transplant to maximize the chance of the cure so that the disease will not relapse.

Roger, did you have a follow-up question?

Yes. So my next question is related to the R&R, the relapsed/refractory population. So given this, the most updated of the ven/aza zifto combination data, what is the read through from this trial to the ongoing pivotal monotherapy for zifto? If you can comment on the patient baseline, the prior therapy and then maybe to companies, how confident you are around the guidance or the expectation you have been giving us in terms of 20% to 30% CR, CRH for zifto monotherapy in the R&R population?

Yes, Roger, let me take that actually. So we haven't said anything at this point about the patient demographics for the pivotal other than it's largely consistent with the 1b. And we keep reiterating the goal for that study is 20% to 30% CR/CRH, Nothing's really changed. I wouldn't take any sort of read-through from the 007 data into 001. That 001 guidance remains intact.

Your next question comes from the line of Peter Lawson with Barclays.

Great. I have a bit of a couple of questions for the KOLs in the call. Firstly would be when a patient discontinues, when you're thinking about the frontline from your experience with relapse/refractory, would you typically discontinue the patient for the chemo component or do the menin component or both? And then just the idea of delaying transplant in the frontline setting. Do you think that's becoming more accepted by your colleagues of when patient hits MRD negative? So If you kind of talk through that.

Yes. So I can start with it. This is Amer Zeidan. I can start with the second part of the question, about the idea of delaying or not even going to transplant. I think there's actually an increasing literature that suggests that patients who convert into MRD negativity in the NPM1-mutated cohorts, including older patients, which, again, is the group of patients we generally thought of as needing transplant, if you convert into MRD negativity using a very high sensitive assays, it's unlikely that you would relapse even without transplant. And I think there has been an increasing use of this assay in the clinic. So I think as a matter of acceptance, I think the acceptance is already there. But clearly, we would prefer to have highly randomized data to support that decision. So I think by extension, if you have therapies that can increase the chance of the patient being MRD negative, as Dr. Fathi mentioned, I think most of us accepted within 1 to 2 cycles of consolidation, then I think that is going to translate into less number of patients going to transplant, but I think most of us will probably choose to keep the patient on a maintenance approach in that situation potentially with the maintenance. Now to your first question about the discontinuation. So the way it works with acute leukemia intensive chemo treatment is that the intensive chemo part of the treatment is actually done. So you don't keep going with intensive chemo. The chemo is given with 7+3, and then you give high-dose [indiscernible] therapy around 6 months, and that's in combination with ziftomenib. And then you are done and then you just continue with the ziftomenib by itself if you and the patient so choose. So I think there is a discontinuation was really low here, clearly. And again, my personal experience, this is one of the easiest drugs to deal with. I have [indiscernible] with many oral drugs for leukemia, almost all have some kind of side effects here. I can tell you most of the patients really never complained about any specific side effect. And in the bigger picture, the menin issue is actually [indiscernible].

I don't have anything to add to that. I think that Dr. Zeidan summarized that pretty well.

Your next question comes from the line of Reni Benjamin with Citizens JMP.

Congratulations on the data. I may have missed this, but can you talk a little bit about the MRD negativity rates in the zifto, ven/aza combo in the relapsed/refractory setting? And I guess as we think about the frontline opportunity, what kind of degree of improvement would you like to be seeing in the frontline opportunity versus just ven/aza alone? And we're seeing some competitive data in the landscape coming out where you're seeing like 95% CRC rate for menin with ven/aza in the frontline. I kind of feel like there's not much more improvement that we can see. So you think in the frontline setting, this largely becomes a competition from a safety perspective as opposed to efficacy? And then I have a quick follow-up.

Do you want to take that question on the MRD negativity?

Sure. For the ven/aza data that you saw presented because we had a scarcity samples that were tested at the local level, we actually have collected them rather routinely for central testing, and we will be doing the centralized testing and sharing that data with you at a later time.

And then, Reni, what was the second part of your question around ven/aza in the frontline? I want to make sure I understand what that question is.

Sure. So I guess I'm looking for -- from the KOLs, maybe what degree of improvement, right, might you see over ven/aza by itself when you add something like zifto? There's been some competitive data, right, that's come out showing a menin inhibitor in combination with ven/aza in the front line, showing like a 95% CRC rate, right? And I kind of feel like there's not much more in terms of improvement that other agents might be able to bring. So in the frontline setting, if you get similar sort of efficacy, which I'm going to assume that across the class, you might see similar efficacy, does it just become a competitive -- just a competitive landscape ultimately focus primarily on safety in the frontline issue, and that's what drives the incorporation of the drug?

I can make one [indiscernible], and Dr. Fathi can make an opinion on this. And I think when you look at any kind of data, when you got response rate, it's very important to look at what is the patient in which the response rate is being quoted. So there are several components to this. It's the early look as to how many patients actually fall off because they have toxicity and they never make it to the response assessment endpoint. So I do think when you look at any study, including some of the ones you mentioned, important to look at the denominator of that response rate. The reason I mentioned that is, again, I want to highlight that the combination with intensive chemo and relatively, all the patient population, the patient who got on several -- on our study had a median age of 66 in that NPM1 cohort. And when you look at the 24 patients, basically, every single of them was alive. 23 out of the 24 related to that efficacy endpoint, and that is in combination with the intensive chemo. So my assumption is in combination with aza/ven, still a very significant number of patients who make it to that efficacy point. Why is that important is because, again, there are other combinations that I think might have more toxicity and that those patients might not necessarily make it to the efficacy endpoint. So I do think I would not take all the data at their face value, and I think it's very important to take into those kind of details of numbers. But I would say, I think in terms of how you can improve above that is the level of the MRD negativity, for example, I think that could be a differentiator. And of course, alternately, with all of these treatments, being able to continue on treatment long term, the tolerability long term is going to be vital. So we could have like short-term responses, but you cannot stay on treatment long term because of the side effects that you have with some of the other drugs. So I think you have to look at most of it, it's not only just one.

So if I understand, I think the -- and correct me if I'm wrong, but I think the spirit of the question is, if ultimately, the menin inhibitor class is so good that we get to sort of this maximal effect across all menin inhibitors, in that scenario, what are we doing? And if -- listen, if we get there, great, but I'm not sure if we're necessarily going to get there. I mean, I think, so right now, the bar is what we have with [indiscernible], which is a composite remission rate that hovers in the mid-60% range. So I think if we improve upon that in a statistically significant, clinically relevant fashion, we've succeeded. And many of these menin inhibitors that are out there now, and again, I'm speaking for myself, are effective, are good drugs. And when these types of scenarios happen in oncology, and I've been at this now unfortunately for a long time. Yes. I mean I think that the distinguishing factors are the group that is conducting the studies, the study design the patient population, the sites that are involved, ultimately, the tolerability of the agents that are a part of it. All of those are going to be differentiating factors in terms of the ultimate success of an agent. So it's not necessarily for us the drugs that we want to succeed when there are many drugs that are good, ultimately, those factors have a substantial effect on the success of an agent. And for us, the ultimate utility of those patients for -- the utility of those drugs for the patients that potentially can benefit from them. So I think it is important to keep those things in mind. But I do agree with Dr. Zeidan. Right now, the amount of data that's out there is limited. So I think coming up with an idea that almost 100% of patients are going to respond, it's hard for us to sort of know that [indiscernible].

Got it. And maybe just a quick follow-up. In the ven/aza combo, I believe about some -- around 40% of the NPM1 patients had 3 co-mutations as well. I'm kind of curious, was there any insights or read-through that you saw from this data that you might employ in KOMET-008?

I don't think we've looked at that yet. I think probably folks are going to look at it and probably later iterations and publications were going to have it. I could point you to the data from the monotherapy experience. There wasn't a substantial difference among patients who overall and those who have FLT3 or IDH mutations in terms of response. I don't know what this is going to look like, but I wouldn't be surprised if it's similar.

Your next question comes from the line of Charles Zhu with LifeSci Capital.

This is Peter on for Charles. Congrats on the data. Just a quick kind of follow-up to the last question. In the frontline, how would you think about count recoveries versus MRD negativity? For example, is it more important to get the blood counts to recover quickly or to get to that MRD negative status just in terms of thinking about which treatments you would use?

Yes. So this is Amer Zeidan. This is a good question, but I don't think that 2 things kind of contradict each other. You could still achieve a reasonable count recovery while you are eliminating MRD, and this is kind of the ideal situation. And what we are seeing from early days that from what we presented is we seem to achieve both of those aspect of not having prolonged count recovery that generally, if you have very low neutrophil count, for example, for, let's say, 2 months, that there is a higher chance of getting infections, other programs. So we want to have your count recovery within a meaningful or relatively shorter period, generally, we think of that as further to less than 42 days. while at the same time, time to achieve MRD negativity. I would highlight here that MRD negativity does not have necessarily to happen after induction. It's ideal, but I think after consolidation, the first one or the second one. So I think it's a combination of factors. One, you are trying -- when you add a treatment, you are trying not to increase the induction mortality. We did not talk about this because it does not even come in a significant way, but you lose intensive chemo, Generally, there is a number of patients who die during the first month because of complications. And when you add additional drugs, this is one of your immediate safety concerns. We did not see any concern for that here in terms of increasing the early [indiscernible] in any substantial fashion and then having the count recovery at the right time. And then looking at the MRD negativity either after induction or after first consolidation. But the 2 things are not contradictory, if I understood your question correctly.

In fact, I would say in my own personal experience, I don't know if this has been definitely proven in those patients who have robust neutrophilic count recovery. It's, in my opinion, more likely that they're going to have a deeper response, including MRD negativity. So sometimes it's not even the fact it's mutually exclusive, but they oftentimes go hand in hand. So that's the good part of this. And I agree. I mean I think it's too early, but you're getting the sense of -- especially in these NPM1-mutated patients that they tend to get their neutrophils up faster. You always love to see that because you don't have to worry about prolonged count suppression and infections and complications and that you get into a nice remission sooner. So that's -- if we demonstrate that in a larger patient population, that's extremely welcome news.

Got it. And just quick follow-up for management. Any plans in the future to release subgroup analyses looking at MRD negativity in terms of response and potentially durability over time?

As we gather additional data, we'll definitely be doing these subgroup analyses. We just need to have enough patients to make it a meaningful data set to interpret. But yes, I would anticipate being able to discuss that data further next year.

Your next question comes from the line of Phil Nadeau with TD Cowen.

Just 2 from us. I guess, first, on the data presented in the relapse refractory population, there did seem to be pretty meaningful difference in efficacy between the KMT2A population and NPM1 population. So we're curious to get your thoughts on why that might be, particularly given that it looked like differentiation syndrome was manageable in both populations? That's the first question. And then second question for management. Could you discuss a little bit more about how the 600-milligram dose was chosen? I guess to our eye, we don't see a lot of difference in the data between the doses. So was the 600-milligram really the default and was going to be chosen as long as there's no safety issues preventing it?

So I'll take the first. This is Amir Fathi. I'll take the first part, and I'll open it to Mollie to discuss the choice of dose. So I'd love to hear what Dr. Zeidan has to say about this. I'm not surprised at all that patients with KMT2A rearrangements to worsen, particularly in the relapsed/refractory setting. These patients, in general, have more resistant disease. We have to keep in mind, again, as I mentioned earlier, that a good number of these patients, including, I think, a proportion of patients in the KMT2A group had prior menin exposure, I think it was 20%. So multiple lines of prior treatment already highly challenging refractory subtype of AML. So having a low proportion of -- relatively lower proportion of response is not surprising in the least as far as I'm concerned, especially compared to group of patients such as NPM1-mutated, which traditionally have a higher likelihood of response. So I think that comparison is of my own personal view, a bit of a false errant. I think in the context of some of the data -- other data that's presented recently, again, I reiterate that in the relapsed/refractory setting, patient population and what makes up that patient population matters a lot. So if it's a single-center experience versus a multicenter experience, that matters. If you've had lower number of prior menin exposure or a higher proportion of prior menin exposure it matters. The difference in prior venetoclax or transplant exposure matters. The difference in the range of prior treatment matters. And you simply can't control for those things. And we, in the leukemia field struggle, forget about menin inhibitors. For years, we've been trying to decide which reinduction regimen is best for AML. Is it Hem, is it FLAG-IDA, we don't know because every single study that's been done, has been done in different patient populations and we cannot get a sense of what is better. So as a result, every cancer center, every academic leukemia program does what they want, and they sort of point to their own studies. So this is not a dissimilar situation. So I fully realize that people want to sort of get a sense of what is better, and you have to in some scenarios. But for me, as a leukemia doctor, it's impossible at this setting to sort of distinguish what is what. And to be honest, the percentages that I'm seeing in terms of response are not that different from another. And and you have to kind of look at this and hope for a better estimate of ultimately what we're going to see in terms of tolerability, safety and activity as we look at larger patient populations. That will ultimately tell us where we're headed.

Yes. No, I think I fully agree with that. In my opinion, like major differences in the refractory/relapse setting in terms of responses across studies are very, very difficult to compare. And I fully agree the patient composition, you have to always look at this data in terms of how were your patients treated previously, how many of them have seen venetoclax. As I said, in my view, my main take on the refractory/relapse combination data is that if given straight, clearly evidence of synergy, some activity that combination continue as to demonstrate to take this to the front line, and it demonstrates that when you take this combination to the frontline, that there some that can be taken for a long period. It does not seem to potentiate the venetoclax-mediated myelosuppression, which is a huge headache with several other agents and certainly could, I think, become a major player. But I agree, I think with all these caveats, I think focusing in the relapse/refractory setting combination studies, when you have different kind of patient cohort to get into your studies, I think it's tough to compare across that.

I would just add 1 quick thing is this is not a patient population that ultimately we're going to try to figure things out in, right? So I think we're trying to get to a patient population that's much more likely to have responsiveness and much more homogenous so -- and that's the newly diagnose -- the newly diagnosed patients, hopefully, have not had prior transplants, prior menin, prior ven, so in that sense, they're more uniform. So I think that's ultimately, I think, I guess the main probably preamble to this is, does what we see in this relapsed/refractory setting tell us a lot about what we're going to ultimately see in newly diagnosed setting? Unfortunately, I don't think it's going to be a clear correlate. It just -- it has not been and it probably won't be.

So with regards to how we selected a 600-milligram dose to carry forward into the expansion, obviously, extremely multifactorial. We had both an independent data monitoring committee and study participants safety monitoring committee that really evaluate all of the data that we had in order to help decide about dose escalation and dose expansion. So we're looking at things in addition to exposure. We're looking at obviously, the response rate, the MRD negativity rate but also safety, as you referred to. And as we escalate, most people are looking to make sure that safety doesn't get worse at increasing doses. We had the good fortune of seeing safety actually improve at increasing doses and increasing exposure. And that supported very heavily our decision to carry through the 600-milligram dose. But all else being equal, if you can get to the highest dose, best exposure for patients without additive safety issues, that is the one that we will try to optimize for patient use.

Ladies and gentlemen, that concludes the question-and-answer session. I would like to turn the call back over to Troy for closing remarks.

Thank you, operator, and thank you, everyone, for joining our call today. We really appreciate Dr. Zeidan and Dr. Fathi spending their time, and they've been very generous with their opinions and their expertise. Appreciate all of your questions, and if you have any questions, please reach out. Otherwise, we wish you happy holidays and a happy new year. Thanks so much.

This concludes our conference call. Thank you for your participation. You may now disconnect.