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

Good day, everyone. My name is Abigail, and I will be your conference operator today. At this time, I would like to welcome you to the Kura ASH 2025 Update Call. [Operator Instructions] At this time, I would like to turn the call over to Troy Wilson, President and CEO of Kura Oncology. Dr. Wilson. Please go ahead.

Thank you, Abigail, and good afternoon, everyone. Welcome to our ASH 2025 analyst and investor event. This is -- this has been a big day, and it's been a great conference for menin inhibitors in acute leukemia. If we can go to the next slide. We're going to be making certain forward-looking statements today in the presentation. And I would just refer you either to our website or to the SEC's website for more information about Kura Oncology and about the risks and certain investment in the company. If we can go to Slide 3. Here, you can see the agenda. Today, we're going to be reviewing the data that was actually just presented in the oral session here at ASH. That is ziftomenib combination with azacitidine and venetoclax both in the newly diagnosed NPM1 mutant AML setting as well as in the relapse and refractory NPM1 mutant and KMT2A rearranged AML setting. We're going to aim to have prepared comments approximately half an hour. That should leave us plenty of time for Q&A. So if we can go to the next slide. It's really my pleasure to welcome and to thank the 2 key opinion leaders that we have on today's call. Dr. Wang is the Chief of Leukemia Service as well as Professor of Oncology at Roswell Park, and Dr. Zeidan is the Chief of Hematologic Malignancies and the Director of Hematology and Early Therapeutics Research as well as Associate Professor of Medicine at Yale. Each of them are intimately familiar with ziftomenib and, I think, can really speak to the data that we're going to go through today. We're, of course, thrilled because this is the first ASH where ziftomenib is now approved and the branded name is, of course, KOMZIFTI, available as 200-milligram capsules. For Kura Oncology and our partners at Kyowa Kirin, this has really been a very exciting ASH. The feedback has been extremely positive. Physicians, caregivers, patients, the entire community are thrilled to have another option available for patients. And it's our goal, as you'll see today, to build on this initial approval in the monotherapy setting, and continue to evaluate ziftomenib in combination with various standards of care. If we can go to the next slide. We'll talk about this, but we like to frame the opportunity for KOMZIFTI as one is evaluating this data really around 4 pillars, and they're shown here: efficacy, safety, compatibility and simplicity. We'll touch on each of these in turn in the data, both in the frontline and in the relapsed/refractory setting. We think this combination of these 4 features really provides a compelling option to physicians as they think about how best to treat their patients with AML. And we'll touch on these, I'm sure in the prepared remarks, and in our answers to your questions. So if we can go to the next slide. It's my pleasure to turn it over to Dr. Zeidan, who's going to take us through the ziftomenib and ven/aza data in the newly diagnosed NPM1 mutant population. Dr. Zeidan?

Yes, thank you so much. So it's my pleasure to be here today. So I'm going to preview the data that was actually just presented this morning about the combination of ziftomenib with venetoclax and azacitidine in newly diagnosed NPM1 mutated acute myeloid leukemia from the ongoing Phase Ib trial on behalf of my colleagues. Next slide, please. So this is overall schema of the trial. There was a dose escalation, as many of you are familiar of ziftomenib in combination with ven/aza in the refractory relapse patient population, and we have settled on 600-milligram daily of ziftomenib as a dose to go forward. And this what was tested in the frontline setting in patients who are newly diagnosed with acute myeloid leukemia who were mutated for NPM1. So here, ziftomenib was started on cycle 1 day 8 is -- was given as a standard for 7 days, and venetoclax was given as per the label continuously with interruptions of venetoclax based on the bone marrow clearance by the end of cycle 1, and then adjustment based on the blood count recovery. The primary endpoint of this study was complete response as well as assessment for adverse events, and we observed a number of secondary end points focusing on duration of response, other important clinical responses as well as MRD readings from this trial. This is the first presentation of data in the frontline setting. Next, please. So here, you can see the study flow for the patients who were enrolled. We had a total of 40 patients who are included in this data cutoff as of September 2025. Of those 40 patients, all of them are safety evaluable and 37 were efficacy evaluable. As you can see, the median follow-up on the study was 26 months. And at the time of the data cutoff, 70% were still on study and 55% were still receiving ziftomenib. Of the patients that discontinued 16, you can see are the causes of discontinuation, but the discontinuation due to death on study was only on 4 patients, which aligns with what was seen with aza/ven as without a third agent. 5 patients went to transplant, and subsequently, 3 of them went to maintenance with ziftomenib. Next, please. Here are the baseline characteristics of this patient population, and this is very typical for older unfit patient population. So the median age of this group was 75 years old. We have as old as 93-year old going on this study. 53% of those patients were females primarily white patient population. And there, as common concomitant mutations, including FLT3 and IDH2 as you can see here. Next, please. So these are the most commonly seen adverse events that were seen in 25% or more that, as you can see here, can be categorized by ziftomenib-related as well as all treatment-related adverse events. This is basically very similar to what we would expect with aza/ven doublet. The most common side effects are in the form of GI adverse events such as nausea vomiting, some diarrhea and the blood count suppression, neutropenia, leukopenia and some incidence of liver enzyme abnormalities. However, again, those are very common in patients with AML who undergo aza/ven therapy. And once you look at the 3 ziftomenib-related adverse events as designated by the investigator, again, most of these were in line of the previous experience with ziftomenib. Next, please. Here, we are focusing on the Grade 3 and higher treatment emergent adverse events that occurred in 10% of more. Again, mostly blood count suppression in the form of neutropenia, thrombocytopenia and leukopenia, which are very common in patients with acute myeloid leukemia getting treatment as well as febrile neutropenia and very rarely cases of sepsis. Importantly, differentiation syndrome was very rare, occurred only on one patient out of the 40 and it was Grade 2 and successfully treated and the patient was able to continue on ziftomenib or resume ziftomenib. And there was also one case of QTC prolongation that occurred in the setting of concomitant electrolyte abnormality and other medication. And again, this is a very common situation that we see in patients with acute myeloid leukemia because of the low magnesium, low potassium, other antifungal drugs to see some QTC prolongation. Next, please. In terms of the efficacy, this is an overall view of the efficacy, evaluable patient population, the 37 patients who are efficacy evaluated at the 600-milligram dose. And you can see that the CR rate, which is the most important readout from this trial was very high at 73%. And when you look at CR plus CRH, the total was 78%. And when you look at the overall response rate, it was 89%. The composite CR was 86% and the median term to first CRC in weeks was 3.4 weeks so [Technical Difficulty] the first response. Next, please. Importantly, the MRD in this trial was assisted both centrally as well as locally, using a very sensitive assay to the level of 0.005%. And we looked at 2 thresholds. Both of them, I think, showed very favorable results with the MRD negative rate being 68% when you look at the threshold of 0.1%. And when you look at 0.01%, it was 44%. And you can see very clearly that the patients who were able to stay on treatment had deepening MRD responses where by the fourth cycle, almost all patients, 100% achieved a very deep level of MRD negativity, which we think correlates well with long-term outcomes. Next, please. This is a study that is still ongoing and the data continues to mature. So for that reason, the median follow-up is 26 weeks. The median duration of complete response was the median OS duration or the median overall survival was not reached either. As I mentioned earlier, some patients with this disease will go to transplant, 5 patients did go to transplant, and 3 of them continue to receive subsequent ziftomenib maintenance. And at the time of this cutoff, 68% of patients were alive and still on study. Next, please. Importantly, each time when we add a drug to aza/ven , we think about additional myelosuppression and delayed count recovery because this can cause problems in terms of infection and bleeding. But the good news in this trial is that the addition of ziftomenib to aza and ven did not seem to prolong recovery of neutrophil count and platelet count beyond what has been the historical experience with ven/aza. You can see here by 2 cutoffs that the median time to ANC recovery to more than 500 was 36 days and platelet count more than 50, 24 days. When we look at the higher thresholds of ANC of 1, it was 37 days and more than 100 of platelets, it was 30 days. And again, these are in line of aza/ven doublet therapy. Next, please. So in conclusion, this is the first readout of the frontline NPM1-mutated older patient population on the KOMET-007 receiving the triplet of ziftomenib at 600-milligram daily and combined with aza/ven, and we are seeing high rates of CR. Almost 73% of patients achieving CR, 86% achieving composite CR ,68% achieving molecularly defined MRD negativity, deepening MRD responses over time as the patients continue on trial and the median duration of the complete response and the median overall survival was not reached. Importantly, the addition of ziftomenib to aza and ven did not seem to worsen the safety profile of aza/ven. The myelosuppression was in line with what we typically see with the doublet. The time to count recovery was also in line and adverse events of special interest such as differentiation and investigator-assist QTC, were very limited and generally well managed. So taken together, I think this data speaks very well for advancement of this combination to the registrational approach in the randomized ongoing Phase III trial, KOMET-017 that will this combination against aza/ven and hopefully, will lead to the approval of this combination in the frontline setting. Thank you so much.

Thank you very much. This is Eunice Wang, and I'm pleased to present the results of ziftomenib in combination with venetoclax and azacitidine in the relapsed/refractory NMP1 or KMT rearranged acute myeloid leukemia. This is an updated Phase Ia/b safety and clinical activity results from the KOMET-007 study. So as shown here, this is an ongoing Phase I combination study. We previously presented data with the Phase I dose escalation, which established ziftomenib dose of 600 milligrams as the dose to move into Phase Ib dose expansion and recommended Phase II dosing. For this trial, patients were enrolled on ziftomenib following then aza. Ziftomenib was started on day 8 and administered continuously thereafter. The primary endpoints of the study were similar to the ones described by Dr. Zeidan, primarily CR and adverse events. And secondary endpoints, we're looking at other clinical endpoints of efficacy, including MRD-negative disease and duration of remission. Shown here are the dispositions of the 83 patients who are enrolled and treated with the combination of ziftomenib 600 milligrams and ven/aza. There were 51 patients with NMP1 mutant relapsed/refractory AML and 32 patients with KMT2A rearranged relapsed/refractory AML. There were a couple of patients on the NPM1 cohort who did not have a response assessed at the time of the data cut, so we present data here on response evaluable [indiscernible] patients encompassing 48 NMP1 mutant and 32 KMT rearranged patients. Shown here are the baseline patient characteristics of these relapsed/refractory AML patients. As we would expect in adult patients with AML, the median age of patients enrolled in the study was in the mid-60 range. The ECOG performance status was anywhere from 0 to 2 and about 24% or 29% of our patients had co-mutations in FLT3, again, as would be expected in our NPM1 mutant cohort. Of note, patients had a median of one prior therapy with up to 4 and these included the prior allogeneic stem cell transplantation, almost 20% of patients, the overwhelming majority, 58% of patients had received prior venetoclax-based therapy and 10% of patients had even received prior menin inhibitor therapies. The median follow-up for these patients was 25 weeks or approximately 6 months and there are currently 25% of patients that remain on treatment. The safety and tolerability of ziftomenib combined with venetoclax azacitidine in the relapsed/refractory AML population was very favorable. As you can see here on the right-hand side, zifto-related treatment-emergent adverse events were uncommon. You have nausea, vomiting, diarrhea, which is consistent with any oral chemotherapy administration and you have very low rates of cytopenias, anywhere from 10% to 15% that were attributed to the chemotherapy drug. There was about a 13% or 15% incidence of pruritus, but the majority of these were low grade and easily manageable with supportive medications. Of note, ziftomenib-related adverse events of interest included QTC prolongation and differentiation syndrome. There was no ziftomenib-related QTC prolongation reported with the combination of ziftomenib 600 milligrams combined with venetoclax azacitidine. Only 2 patients discontinued therapy due to zifto-related adverse events of sepsis and stomatitis. And there was only one patient who developed differentiation syndrome. This was an NMP1 mutant patient who developed Grade 3 differentiation syndrome, which was successfully mitigated with protocol-specified interventions. And the patient was subsequently able to resume ziftomenib therapy after this occurrence. You can see here again thrombocytopenia, neutropenia, leukopenia and anemia were under 10%. And the rate of sepsis in these pretreated relapsed/refractory AML patients attributed to ziftomenib was only 5%. The clinical activity of ziftomenib with venetoclax azacitidine in relapsed/refractory AML patients was impressive. In this heavily pretreated patients, the CR rate was 27% in NMP1 mutant patients, 6% in KMT rearranged patients, but in patients who achieved some sort of clinical remission, the numbers were 48% or almost half of NMP1 mutant patients and 28% of patients with KMT rearrangements. You can see here that MRD negativity rates were 60% in the NMP1 mutant patients, 43% in the KMT rearranged patients. And overall, the response rates were 2/3 of NMP1 mutant patients and 41% of KMT rearranged patients. Of note, 58% of these patients treated with this combination had a history of prior venetoclax exposure. So when we took a specific look to examine the activity level in patients with and without prior venetoclax exposure. As you can see here in patients who had received no prior venetoclax therapy, i.e., for example, patients who had received prior 7+3 induction chemotherapy and then relapsed. We noted very high overall response rates and NMP1 patients of 83% and 70% in KMT rearranged patients. CR rates were 44% in NPM1 mutant patients and 20% of KMT to be arranged and MRD negativity in NMP1 patients was over half of patients. Patients who had received prior venetoclax did still have responses, but these responses were less than those who had not received prior BCLA inhibitor therapy. For NMP1 mutant patients follow up of 27.4 weeks, the median duration of a CRC response was 39.9 weeks. Then venetoclax-naive patients had the same response, 39.9 weeks and 14 NPM1 mutant patients were able to undergo allogeneic stem cell transplantation with 5 of these individuals continuing on to ziftomenib maintenance. The median overall survival for NMP1 mutant patients in the relapsed/refractory NMP1 setting was 54.9 weeks. Patients with relapsed/refractory KMT rearranged, acute leukemia also had benefit from this combination. The median duration of CRC in these patients was 12.4 weeks and 2 KMT rearranged patients were able to undergo subsequent allogeneic stem cell transplantation followed by ziftomenib maintenance in both of these individuals. The median overall survival in these relapsed/refractory patients was 21.1 weeks. Similar to the upfront data presented by Dr. Zeidan, we see here that times to neutrophil and platelet recovery with the combination of ziftomenib ven/aza, were comparable to those for ven/aza backbone therapy alone and shown here ranging anywhere from 27 to 36 to 45 days. So in conclusion, in the ongoing KOMET-007 study, ziftomenib 600 milligrams once daily, combined with venetoclax azacitidine was well tolerated in patients with relapsed/refractory NMP1 mutant and KMT rearranged leukemia. There were very low rates of zifto-related myelosuppression. There was no appreciable ziftomenib-related QTC prolongation reported in any patients and only one case of differentiation syndrome in a patient with NMP1 mutant disease was reported and was successfully mitigated with protocol-specific measures. There is evidence of encouraging clinical activity demonstrated in this patient population, particularly in patients with prior venetoclax exposure and more prominently in patients without prior venetoclax exposure. As you can see here, 2/3 of patients with NPM1 mutant disease achieved an overall response with therapy with a median duration of response of 40 weeks. Venetoclax-naive patients had an overall response rate of 83%, 70% of which was CRC, then exposed patients still benefited with 48% overall response rates and 28% CRC. And in the KMT rearranged population, the overall response was still an impressive 41% with the 28% CRC and a median duration of response of over 12 weeks. Taken together, these data support further investigation of ziftomenib-based combination therapies in relapsed/refractory NMP1 mutant and KMT rearranged acute leukemia patients.

At this point, we'll turn it over to Mollie Leoni, our Chief Medical Officer, to give some comments on next steps and conclusions. Mollie?

Yes. Thank you so much. So we are extraordinarily excited to be approved in the relapsed/refractory monotherapy setting, we were able to offer new hope for patients. We now remain committed to developing KOMZIFTI in the combination setting. And as we presented, the combination yields high rates of response and better activity than either the doublet or zifto alone. In fact, there are some evidence of potentially enhanced activity with the backbone in the relapsed/refractory then naive patients. In addition, the combination was well tolerated with no meaningful added toxicity and no increased burden in administration. Combinations have low rates of DS, no additive myelosuppression and no zifto-related QTC prolongation. We have a robust and comprehensive clinical development plan that is producing significant data with other combinations such as quizartinib, gilteritinib, FLAG-IDA and LDAC. We will continue to generate these data and publish potentially paving the way for future NCCN guideline submissions. All of this supports our confidence in our registrational KOMET-017 trial in the newly diagnosed patients, which we are showing here on this slide. As you can see, this trial encompasses 2 different independently powered trials on the left for our non-intensive chemotherapy patients and on the right for intensive chemotherapy patients. On the left, for non-intensive patients will be randomized to either ziftomenib or placebo with the venetoclax-azacitabine backbone and the outcomes we are looking at are complete response is an accelerated approval point and overall survival for full approval. In addition, on the right is our intensive chemotherapy option. And here, we have 3 arms that the patient could be randomized to. One involving the administration of ziftomenib throughout induction and consolidation and into the post consolidation maintenance space, one where we discontinued ziftomenib at the time of the post-consolidation maintenance phase and one where they received placebo throughout. This will allow us to really evaluate the contribution of ziftomenib to the post-consolidation phase. The endpoints under of interest here are CR MRD negativity and EFS that we will be continuing to measure. So the opportunity is significant and meaningful in this frontline where we hope to prevent more patients from becoming relapsed and refractory. And our goal is to be the first approved menin inhibitor in the newly diagnosed setting, and our team is laser-focused on execution. With that, I should turn it back.

Yes. With that, that concludes our prepared remarks, and we're now going to turn to a question-and-answer session. [Operator Instructions] So with that, operator, we are prepared to now move to questions.

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

[Technical Difficulty].

Li, we're not able to hear your question. I don't know if you're dialing in, but your question is breaking up.

Our next question will come from Roger Song with Jefferies.

Can you hear me?

We can hear you, Roger. Thank you.

Excellent. Okay. Congrats for the data. Yes, I will limit my question to one. Troy, maybe the KOL as well. So as we start to see more data in the frontline and then with a different combination, can you help us to further compare the efficacy kind of level particularly for the depth of the efficacy, maybe the durability of the efficacy. Do you start to see some different among all the menin inhibitor? Because we definitely heard the comments saying, "Yes, it's -- we no longer call this a menin party because every menin inhibitor may be different."

Sure, Roger. And I'm actually going to -- I'm actually going to turn it over to Mollie for that. I mean just with the caveat that these are -- it's difficult to do cross-trial comparisons. We're not comparing head-to-head. But that being said, I think what you're asking is if we can look at MRD negativity and durability. So maybe I can ask Mollie, if she can speak to that to get us started.

Sure. So obviously, the backbone alone, especially in the frontline, does provide a good amount of responses for these patients. But it is not curative. And it is how do we judge whether we're making a difference by adding something on an addition. We think our best marker for that is MRD negativity. And that's why we chose to present MRD negativity using a central assay. And as you can see, we did it at 2 different cut points. One, which would be the more traditional point one where you see flow and things like that at the local level come around. And the more conservative cut point of 0.01, which is favored by the FDA. So when we did that, let's say, just looking at the point one, the more conventional site level cut, we see a 68% MRD negativity rate. Now if I look at other trials like Beat AML, we were seeing more like a 31% MRD negativity rate in that -- in a similar cut point. So we do think that there's reason to believe that we are adding significant benefit as our differentiated menin inhibitor, if you will, since we aren't all part of the same menin party anymore. And then again, when we go down to the even more stringent cut point of 0.01, we saw the 44% MRD negativity rate. And realistically, it was more like 60% because there were 4 additional patients who buy 0.001, missed the cutoff. And so obviously, with even running the assay again, probably would have hit that cutoff. So we're very encouraged that we are seeing evidence via MRD that our responses are of greater depth than we've previously seen, which would hopefully translate into longer durability and ultimately better overall survival.

Our next question comes from Jonathan Chang with Leerink Partners.

I'm curious to get your thoughts on the PARADIGM study results presented at ASH and how that impacts your thinking on the development strategy for zifto?

Great. Jonathan, thanks for the question. Again, let me let Mollie lead off with that, and then we can go from there.

I'm so happy for Amir Fathi and his data was beautiful. I don't know that it's necessarily a representative of the patient population we are enrolling as it does tend to include -- well exclude most of the NPM1s as well as include much more of the high-risk patients. So I'd really like to turn it over to our KOLs to hear how they would -- they feel that this data might influence their practice. We could start with Eunice.

Sure. So I think the PARADIGM is an incredibly important study. It was very much anticipated and the results were beautifully presented by Dr. Fathi, however there are some significant caveats with the study. It's a randomized Phase II study, and they screened over 300 patients, but only were able to enroll about 50% of that population onto their studies. So it leads you to a question which patients did not get enrolled upon the study and the reasons why and whether the physicians that were enrolling the patients decided to move forward with one treatment versus another. The other point of contention is that NMP1 mutant patients which is the primary population that we're looking at with ziftomenib were excluded from the trial unless they were 60 years and above. Third, the NMP1 mutant and IDH2 patient population was much enhanced in the patients that received the venetoclax azacitidine with about double the number of NMP1 IDH1 mutant patients treated with ven/aza as opposed to those treated with standard induction chemotherapy. So that, again, introduces a bias because we know that patients with NMP1 and IDH2 mutations tend to have favorable outcomes with a less intensive regimen. And lastly, the patients that have NMP1 tend to be in the intermediate risk category and 76% of the patients enrolled on the PARADIGM study had adverse carrier type. So again, it's not relevant for the patient population that we receive KOMZIFTI. Dr. Zeidan?

Yes, I think I agree with all of this. And again, while this is an important study, I'm not quite sure it changes much in terms of what we were already doing. I think the general practice, if you are treating with aza/ven is to go to transplant if you are trying to go for a cure. So I think the main decision continues about are you trying to cure patient or is a patient potentially curable without transplant? In my opinion, the addition of a third agent to whether intensive chemo was 7+3 or to aza/ven could offer the opportunity to change the natural history of the disease without necessarily going to transplant. And I would also note -- and again, I give the Kura team a lot of credit for this, is that having 2 protocols and under -- or having 2 studies in the same protocol offers the patients to be able to go on the study whether the doctor thought they were intensive chemo candidates or not. So they don't have to go to another study just because they are deemed to be intensive chemo candidate or not. But I do not foresee the PARADIGM study to have like a meaningful impact on our ability to conduct the study.

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

This is Peter Green on for Charles. Congrats on the data. Really great to see the thesis potentially start to play out of, honestly, frankly, really nice safety in combination and potentially even better safety than for monotherapy, if do. So congrats again. Just wondering if these data give you any line of sight or any confidence into a potential frontline label as KOMET-017 begins to read out in the future and whether there's any read-through from the first label in monotherapy relapsed/refractory setting, whether potentially a lot of the language around inclusion criteria and monitoring criteria might stay through or whether if you can show an even safer profile in the combination here, whether that's kind of grounds for negotiation for potentially even a less stringent label.

Thanks, Peter, for the question. and agree with you on your interpretation, particularly around the differentiation syndrome that it gets better in combination, right? As well, it gets better, I think, as the community generally gets experience with these agents. We see that kind of across the board. But let me let Mollie start off by answering your question about maybe how this reads into the ongoing Phase III trials and what that differentiated label might look like, Mollie?

Sure. So the 007 trial has been enormously helpful in how we've designed and planned for the 017 trial. So all of these results continue to support us moving forward. They tell us we've made correct assumptions. They help us understand the likelihood of success. And I think every time we look at the data, we are more excited, but I think your second point is very important. Having a randomized study with a placebo control is going to absolutely be able to impact the safety and the labeling for KOMZIFTI. Ultimately, it's very difficult to interpret a single-arm trial. And thus, the FDA is always going to take a more conservative route and attribute things to the investigational agent even if they might be due to the underlying disease alone or to the concomitantly administered medications. So having a randomized controlled trial with that data to be able to show for example, a lack of QTC prolongation with ziftomenib therapy will be extremely important and will absolutely be useful in amending the label and making it so that patients really do have the ability to make an informed decision about their treatment options.

Our next question comes from the line of Etzer Darout with Barclays.

This is a question that goes back to the earlier presentation. Just curious about the relevance and impact of the updated ELN guidelines on MRD negativity on maybe the field and sort of future plans, particularly again in these first-line AML settings?

Thanks, Etzer, for the question. Mollie, do you want to...

Sure. I mean we're obviously waiting -- they may have been published today. I guess that might be why you're asking firstly. We're waiting to see them come out. We're not sure how generalizable all of that data will be because they -- it was largely PCR, we're focusing on NGS and various time points of when these measurements are taken. So I don't know how much cross read there will be but we will continue to evaluate now that's come out. But I'd absolutely turn it over to Dr. Zeidan to see his thoughts as well.

No, I agree. I think the paper needs to come out so that we kind of clearly discuss this particular aspect. But I personally feel very comfortable with the frontline results both in the intensive and the non-intensive chemo in terms of the CR rate being 73% in terms of the MRD negativity using very sensitive assays being very deep. So I do not have any concerns about how does that translate when you compare it by other techniques, whether it's PCR or flu. One point I just want to highlight quickly kind of Mollie mentioned is that the MRD negativity seems to deepen with time. So by the fourth cycle, for the aza/ven cohort, actually all the patients who got 4 cycles basically became MRD negative. And this is very important because this speaks to the importance of adding a drug where the patients are able to stay on therapy. You don't want to have a drug that causes a lot of myelosuppression that patients fall off the drug and the trial. So I think this, in my opinion, could differentiate ziftomenib from some of the other drugs that are other menin inhibitors that could add additional myelosuppression. So I don't think the issue of the MRD is going to be a problem. Of course, MRD is more relevant in terms of a regulatory front to the intensive chemo front because this is where it's going to be used for accelerated endpoint. But we know that in the non-intensive setting, there is a good correlation between MRD negativity and survival. In the VIALE-A, the MRD negativity was around 30% to 35%. So I do think we are seeing some differentiation in a 40-patient sample size. So clearly, we have to wait for the randomized data, but I think everything looks promising from what has been presented. I don't know if Dr. Wang wants...

No, I completely agree. And the VIALE-A data took 7 cycles or more for the majority of patients to achieve the same amount of MRD negativity that we're starting to see by cycle 4 with the triplet combination.

Next question will come from Hunter Hurley with Guggenheim.

And again, congrats on the data. Again, this is Hunter Hurley on for Brad Canino from Guggenheim. Just wanted to kind of as a segue for this MRD conversation. And I guess, how we're kind of using this in combination. Have you reported anything on reductions for this combination as I didn't really see that in the presentation? And as we're kind of thinking about this with treatment long term for this combination, what are your kind of expectations for the regimen as far as like durability, long-term usage? And then in combination, are you planning on keeping ziftomenib on indefinitely or potentially reducing ven/aza? And how is this kind of combination going to look over time?

Yes. So Hunter, let me just ask -- so you actually asked 3 questions. So we're trying to keep people limited to one. But let me just ask a question back in return. You mentioned reductions. Are you specifically asking about the rate of dose reduction? Is that what you're asking?

That's correct.

Okay. Let me ask Mollie speak to that, and then we can kind of go from there.

Yes. I think one of the best ways to be able to look at that in our data is to look at our swim lanes. We -- well, not necessarily the dose reductions, the dose continuation, which was the second half of your question, where we can see that we started zifto and we continue it from cycle 1, day 8 on, while the backbone might be modified to lesser days or lesser doses depending on covenantly administered medications, the zifto remains. With regards to ziftomenib reductions, we're really not seeing very many at all. I'm hard-pressed to think of more than 1 or 2 that have been seen. And most often, even with our monotherapy, we see a return back to the initial dose even after an initial interruption or reduction. So we're really not seeing a requirement for the ziftomenib to be changed in order for these patients to successfully remain on the treatment regimen. And as we will see, we'll see the data play out in both 007 and then ultimately 017 to see what effect that has on the backbone therapies as well because we know that physicians are trying to modify and make sure that these patients are not overly myelosuppressed and once they -- especially once they've reached response. And so we'll be watching the ven/aza dosing a lot over the coming months. But so far, I would really direct you towards those swim lanes to see how it's being handled currently.

And I think Dr. Zeidan wants to add a few thoughts.

Yes. I just want to add like my own personal experience as someone who has treated many patients on both of the 007 trial as well as 008 trial. And many of those patients are actually able to continue on the drug in my own hands. I don't believe we have reduced anybody in terms of the dose. And I think from discussion with patients, this is one of the easier drugs to give in terms of being -- especially in the maintenance setting, where you are giving it without other drugs. So you have a very good sense of what is actually related to the drug and what is not related to the drug. And it's really very easy for most patients to be on. This is, again, very important because I do believe strongly that patients need to be on the drug especially in the frontline setting for as long as possible to try to minimize the chance of the leukemia relapsing. So I think my own experience kind of goes in line with what Mollie has mentioned in terms of the overall trial.

So I just wanted to mention just if I could throw in that, this is in contrast to what we see with some revumenib HMA and venetoclax combination. So for data presented with the combination of oral decitabine with revumenib and HMA that the SAVE trial that was presented yesterday, they noted that there was a 48% incidence of Grade 4 febrile neutropenia, 24% thrombocytopenia and 19% neutropenia. So they had significantly Grade 3, Grade 4 neutropenias with that triplet combination of revumenib, venetoclax and HMA. Similarly, if you look at the BEAT AML trial in newly diagnosed older unfit patients, they had significant cytopenias with delay of subsequent cycles of that triplet for 40 or 50 days. That neutropenia cytopenia incidence is not present with the combination of zifto. I also want to point out that the QTC prolongation and the need for dose adjustment of revumenib with azoles and concomitant medications may also impact on the ability to give revumenib long term, particularly elderly individuals with concomitant meds, cardiac issues, et cetera. And as we mentioned, the durability and the overall survival of these patients in the newly diagnosed as well as refractory setting is really highly dependent on patients being able to take it in the long term for months or even years.

So Hunter, I limited you to one question, but you got 3 answers. So if you do want to follow up, we're happy to take the next -- your other 2 questions, but I want to make sure we give everyone at least a chance to ask one question. But happy to have you jump back in the queue, and we can speak to, if there's an additional question you have. Let's go on to the next.

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

Congratulations on the data. There's a lot of talk looking at co-mutations like FLT3. Can you talk a little bit about the percentages of NPM1 patients that are FLT3? And can you talk about the importance of zifto being able to combine with some of these FLT3 inhibitors?

Sure. I mean, I can start us, Ren. FLT3, I think, is estimated at 25% to 30% of AML patients, and it's about half of your NPM1 population. So it's a significant population. It's of the same order of magnitude as NPM1. But I'll let Mollie get us started. That's data actually that everyone, I think, as Mollie will say, maybe we can look forward to next year. But Mollie, over to you.

That's exactly right. We'll be presenting our FLT3 data next year. And keep in mind, we're generating data both with gilteritinib, which is known to cost prolonged QTC, as well as quizartinib, which actually has a black box warning for having a different mechanism of QTC prolongation. And so far, we have yet to show the data. But obviously, if we are continuing to escalate and go through with our expansions, it's probably going well. I would draw your attention to the combination of revumenib plus gilteritinib where we saw dose-limiting toxicities at every dose level tested. And I believe the vast majority were QTC prolongations. So obviously, in combination, the safety profiles of these different drugs are going to play out with the ability to use them. And I think that the FLT3 inhibitors, in particular, are going to be difficult for some of our competitors to combine with.

I think -- Yes. I just want to add quickly that I think that the quadruplet frontline combination that's ongoing now with the quizartinib and ziftomenib plus 7 and 3, I think, would be very important because one of the kind of main questions in the field is what do you give these patients? Do you give them a menin inhibitor with 7+3 or do you give them a FLT3 inhibitor? And I think currently, most people are giving FLT3 inhibitors because this is where we have the survival advantage. But having good data with the quadruplet, I clearly will open, hopefully, the ability to use menin inhibitors in the frontline sitting intensive chemo FLT3 positive setting with the communication with NPM1.

And Ren, just to add to that, we often get -- the ziftomenib label is limited to NPM1-mutated relapsed/refractory AML adults. We do -- we're doing many, many trials, evaluating ziftomenib in various combinations. We're promoting specifically on label, but we often get the question of how to use combinations, how to think about sequencing. And as Dr. Wang commented in her presentation with ven/aza, there's interesting data on sort of how you use these agents and in what sequence. We think the same thing will be true in the FLT3 case. What our responsibility is to generate robust data where we're talking about tens of patients, not sort of -- more than single digit, really to give our collaborators, the physician experts, the data that they need to make the determination of how best to use these menin inhibitors. So you're going to -- again, that's 2026 goal and objective, but I think that will be an exciting next chapter.

Our next question -- your next question comes from the line of Salim Syed with Mizuho Security.

This is Erik on for Salim. Congrats on the data. So my question is on the combinations with menin inhibitor, particularly with zifto other than ven/aza or 7+3. Just wondering, assuming -- I'm assuming, and correct me if I'm wrong, that those 2 combinations will likely take up the majority of usage. I'm just wondering if for these other combinations like what portion of the AML population do you think that they would be used? And this is about like [indiscernible] the FLT3s and all of that stuff.

Mollie?

Yes. No, you're correct. At least right now, the 7+3 and the ven/aza are dominating the frontline space and times will change. More therapies will come out and be approved, more targeted therapies. And so it will continue to evolve. A lot of the data that we've been generating that I think you're referring to is in the relapsed/refractory setting. And that is data with FLAG-IDA, that is with gilteritinib, that is with low-dose cytarabine. And it is so that physicians have the optionality because not all patients can handle ven/aza, not all patients can handle 7+3. Unless they're relapsed/refractory, they really need to have multiple options depending on what they've previously seen. So our plan is to obviously generate as much data as we possibly can, robust data. I don't -- we generally don't tend to present our data until we have really good patient pool to be able to make some calls off of. And so that's what we'll continue to do. And like we said earlier, we will be presenting a lot of these data in the 2026 time frame.

So I'm going to just jump in here, Abigail, because Li Watsek, who was up first couldn't ask her question. She e-mailed it to us, so I'm just going to ask it on her behalf. She said, may I ask in the real-world study at ASH, it seems as though doctors like to use menin inhibitors in combination with venetoclax. Can Dr. Wang and Dr. Zeidan talk about potential real-world adoption of zifto and the combinations with the venetoclax based on the safety profile. Dr. Wang, maybe I'll start with you.

So since the approval of ziftomenib, I've received a lot of calls from colleagues and other physicians, clinicians asking about, for example, should they use ziftomenib? Or should they use revumenib, for example, for an NMP1 mutant relapsed/refractory patient? And out call as should we -- is it combinable? Can we use it in the post-transplant setting, which would be preferable? And I feel that for a lot of practical reasons, we are recommending potentially that ziftomenib has certain advantages. It is easily combinable with venetoclax and even azoles because those drugs may have a predisposition to prolong the QTC. There's no dose adjustment with azoles in a patient with baseline neutropenia. There's no concern -- less concern about the risk of significant QTC prolongation in a patient that has concomitant cardiac meds or in the relapse setting maybe on some immunosuppressive meds, again, that can cause interactions. It's a once-a-day dosing. So that also is preferred by patients. And in combination with ven, we have seen actually a decrease in the ven/aza combinations of differentiation syndrome to be concerned about and having it really be 1 or 2 patients among 50. So I think in the real-world setting, as these drugs start to populate out into clinical practice, I think we are going to see greater adoption, ziftomenib particularly in combinations because of those reasons. I think that revumenib has been largely adopted by providers because they had no other option. But moving forward and discussing some of these features with people in the real world, almost all of the colleagues that have asked have said that those are valid concerns. And this is also a drug that my patient may be taking for weeks, months, and those are things that my practice or my providers may not want to be seeing the patient and adjusting the medicines on a daily basis. Dr. Zeidan?

Yes. So I agree with all of this. And just to put this in a kind of practical situation. So when you have a patient with NPM1, your first decision is generally do I give intensive chemo or do I give is aza/ven? And when you have good data in both settings, many doctors tend to be kind of progressive ahead of the formal approvals when there is very good data, especially in terms of the safety and the efficacy. So when you have a drug that's easily combinable doesn't add to the myelosuppression from a logistical point of view, does not cause problems with the other drugs like the antifungals and easy for the patient to take. I think certainly, there would be preference to using this drug. We have similar experience, for example, in the CML setting where some of the TKIs have to be taken twice a day, and they have QTC issues. And I can tell you, most physicians prefer not to use these and go with the drug that's given once a day and does not have issues in terms of drug interaction. But I wanted to emphasize that aza/ven, zifto and the refractory relapse setting because the practical question that we face as physicians right now is that if you have an NPM1 mutated patients who got 7+3 in the frontline setting, what many of us would do is they would give aza/ven in the refractory relapse setting, although it's not approved, but it's very commonly used. We prefer that rather than a second line of intensive chemo. However, with the menin inhibitor evolution, many doctors are asking the question, do I give menin inhibitor, do I give aza/ven? And I think having the data about the triplet with aza/ven, ziftomenib will remove that issue because you can just give all 3 of them because, again, the combination is safe, the durability is better, the survival, as you saw, is 1 year, which on the relapsed/refractory setting is very good. You probably can't bridge many patients to transplant because they are MRD negative. So I think this kind of data, even it does not lead in the refractory setting to a label and it's very unlikely that you can do randomized big Phase III trials in that setting. It's very, very important because we face these decisions all the time in terms of how to combine and which drug to use. So I think the same potentially could apply, hopefully, once we see the data with gilteritinib and ziftomenib in the relapsed/refractory setting because we currently face the same discussion. So I think -- in real life, I think, is probably going to follow the same patterns you are seeing with these clinical trials.

Abigail, maybe we have a few more people in the queue. Let's see if we can -- and try to get -- keep people on schedule.

Your next question comes from Jason Zemansky with BofA Securities.

Congrats on the progress. Maybe to connect some of the dots here regarding the KOL's previous comment, but as the menin inhibitors advance in combination settings, what specifically do you think will be the deciding factors in terms of prescribing decisions? I mean, I think recognizing efficacy is certainly paramount. But thus far, I think it's fair to say that each of the developers at the conference has been quick to highlight some distinct output and discount some minor -- discount some safety issue as minor. But I guess as we're sort of seeing the preliminary evidence data come in, what stands out to you?

Dr. Zeidan, do you want to?

Yes, I think we kind of touched on some of these kind of points. But when -- I'm just going to put it again in a practical context. When you are giving a drug for, let's say, a few months in the refractory/relapsed setting where the patient is coming to the clinic every day or -- sorry, once a week or twice a week and the patient is very easily monitored and you are doing EKGs, you are monitoring their drugs. I think you could do that for a few months, but as the drugs move in the frontline setting where the patient is going to be on the combination for years, it's very unpractical to be doing EKGs continuously and to be worrying about if the primary care doctor is going to give a drug that causes an interaction. So having that logistical component of a very convenient drug to give once a day, I cannot tell you how important it is on the chronic use of medication, the big difference between once a day versus twice a day. And we know this is -- we don't have data in this setting, but I can tell you in CML setting, for example, missing a few days every month can significantly worsen the outcome. So having a drug that is given once a day rather than twice a day could be a huge differentiator. Having a drug that you don't have to worry about other doctors giving a drug that could interact with the drug or cause QTC. These things are very important. So even if you take the viewpoint that there could not be huge differences in the efficacy, which I personally don't think that's the case. I think as the data matures, ziftomenib is probably going to differentiate on that front as well, but I think on the convenience on the myelosuppression in terms of the other adverse events, this is very important in the chronic use of the drug, which eventually, I think, would be the most important value of these menin inhibitors.

So I just wanted to bring up some additional points in addition to those, which we've already mentioned. I think the fact that we do not see any additional toxicity or side effects or adverse events with the addition of ziftomenib to both 7 and 3 and/or ven/aza, I think is pivotal because -- when you look at overall health care costs, you don't want to be having extra days of hospitalizations. You don't want extra transfusion days, extra admissions for febrile neutropenia, what is going to add to the health care costs and the admissions and the clinic visits for the patients. So we look at the financial cost of adding a drug that's adding significant toxicity, and we look at quality of life issues to patients, okay? Patients taking a drug once a day, not having transfusion dependence, not having to go in, not having to have potentially excessive QTC monitoring or have to go into their cardiologist. I mean these are significant other parameters of the success of upfront and a relapsed/refractory regimen that should not be ignored in addition to all the efficacy as well as the interactions with other drugs. But just looking at the overall spectrum of health care costs, visits, quality of life, patient reported outcomes, et cetera.

Your next question comes from Phil Nadeau with TD Cowen.

Congrats on the progress. In the discussion of the KOMET-007 data here at the meeting, one physician asked whether the addition of ven/aza to zifto in ven-experienced patients was really adding any efficacy. The presenter of the abstract suggested maybe not, maybe zifto monotherapy in inexperienced patients is just as good as the triplet. We're curious to get your thoughts on that question. Do you think the triplet is actually guiding efficacy in ven-experienced patients?

Dr. Wang?

Yes. I mean I think it's clear when we look at our response rates in the relapsed/refractory setting, there is more benefit for patients who, for example, got 7+3, plus or minus geo upfront and did not have prior even, but we still see benefit 20% to 40% response rates in patients who've had prior ven exposure. This is in contrast to some of the single-agent data with revumenib that showed significantly less benefit in prior ven-exposed patients. And so when you look at the revumenib data, there really is a significant -- practically no response to revumenib in patients with prior ven. If you look at the monotherapy data with ziftomenib, we retain the same response rate in patients regardless of whether they had prior transplant, regardless of whether they had prior ven. So I do think that this is a distinguishing feature. Prior ven is always considered to be something that predicts for lack of response to targeted therapy. There's data showing that prior ven exposure reduces or eliminates the response to subsequent IDH1, IDH2 and FLT3 inhibitor therapy. The fact that we don't see that same phenomenon with zifto but that we do still see resistance to revumenib could be a distinguishing remark. So I would disagree with that particular commentary based on just the data that's been presented by the 2 trials.

Your next question comes from David Dai with UBS.

I also want to congrats -- add my congratulations on the data here. So just want to follow up on the prior question around the real-world use of zifto plus ven/aza in relapsed/refractory AML. Maybe just help us understand from a physician's point of view, what percentage of relapsed/refractory NPM1 patients do you expect to benefit from this combo use? And I'll just stop here.

I would -- this is Amer Zeidan. I think that the menin inhibitors in general, but in my opinion, ziftomenib would be widely used in this setting because in the frontline setting, either the patient has received 7+3 and then the patient relapsed and the practical question we were having at that time, do I give aza/ven or do I give menin inhibitor. And now we have good data on the combination of the triplet. So that patient would be getting all 3 drugs, which would be what I would recommend if I'm asked about a patient like that. If the patient has gotten aza/ven in the frontline, I think the question would be what Dr. Wang just kind of discussed is do I give menin inhibitor by itself or do I give that triplet? And I think in that setting, you have to consider things like how long was the patient on venetoclax and was it -- did the patient was primary refractory or subsequently relapsed? But in my opinion, in both scenarios that I just outlined, the patient would be getting an inhibitor likely ziftomenib. So I think most of these patients will likely get exposed in the second line. I just want to add like kind of to the earlier question, I think what we are trying to aim in the AML world is really not to be in situations where you have venetoclax resistance or you have -- because these situations are very difficult. And even if you get responses, generally, they are not durable and patients would ultimately in most situations pass from the leukemia. What we are trying to do is hit the leukemia very hard from the very beginning with these combinations. And we have a very nice paradigm, outstanding paradigm in multiple myeloma where all these drugs were good in the second-line setting and third, fourth line. And now the combinations in the frontline are just transforming the field, number of patients who are achieving very deep responses, MRD negativity and do not relapse for many years is outstanding. So I think this is where we are going to go with menin inhibitors. I think they are going to really transform the field in the frontline setting so that hopefully, we don't have to worry as much about the situations like venetoclax failure.

I just want to mention, there's data presented at this ASH meeting that if you don't respond to menin inhibitors that your median overall survival post menin inhibitor single-agent therapy is about 4.4 months. And there are certain features like FLT3 ITD disease that can predict for lack of response to monotherapy. So given that, the data in the relapsed/refractory patient population with a median duration of response of 40 weeks, with the triplet therapy certainly is a reason for people to utilize the ziftomenib plus ven/aza even potentially now with these results to try to improve upon like 4, 5, 6 months with single agent that we're seeing. So I definitely think this data is highly relevant with the approval of ziftomenib right now.

There are no more questions at this time. I'd now like to turn the call over to Troy Wilson for closing remarks.

Thank you, Abigail, and thank you all for the questions. I want to just touch on 2 themes quickly before we conclude. And they relate to what Dr. Zeidan and Dr. Wang were saying. So we are tremendously grateful for the advice, the guidance, the support that we get, not only from the two doctors here, but from our entire group of investigators and key opinion leaders. We were originally planning to just present the frontline ven/aza data, but we were strongly encouraged by the investigators and by our -- sort of our advisory board to present to you the -- or to present at ASH, the relapsed/refractory data as well for, I think, just the reasons that were mentioned. Hopefully, we're providing safety and tolerability data that makes it so that we can provide more and better options to patients. In a similar vein, and we've alluded to it, we're working on the FLT3 zifto combination in the relapsed/refractory setting. We're working on the quad in the frontline setting. We'd like to -- as Dr. Zeidan alluded, we'd like to follow from the lessons in the myeloma and ideally bring quads -- at least quad, let's start with that to these patients to drive deeper and better responses and bring them hope for long-term durable remissions and a cure. We think ziftomenib has an ideal profile to really be able to set up to do that. That's obviously going to take us a number of years and the efforts of many talented people. But that's what we're building on now with this initial approval. This is the first ASH with KOMZIFTI approved, hopefully, the first of many successful ASHs and EHAs and other conferences to come. So I want to thank Dr. Wang and Dr. Zeidan. I want to thank the tremendous efforts of all of the study teams, the investigators and, of course, our team. I want to thank all of you for your questions. And with that, we'll conclude. We wish you all a good rest of the afternoon, and thank you again very much.