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

Hello, everyone, and welcome to the Kura Oncology ASCO Virtual Investor Event. [Operator Instructions] Please note, this event is being recorded. Now it's my pleasure to turn the call over to the CEO and President of Kura Oncology, Dr. Troy Wilson. The floor is yours.

Thank you, Carmen, and welcome, everyone. We're here at ASCO where we're delighted to have an analyst and investor call to discuss the KOMET-001 monotherapy registrational data and our ziftomenib program. Turning to Slide 2. I want to remind you that we'll be making forward-looking statements during today's presentation, and I would refer you to our website or to the SEC's website for more information about the risks and uncertainties of an investment in Kura Oncology. Turning to Slide #3. I don't think it's an understatement to say that even with oncology research and development, AML has proven to be particularly challenging. Approximately 22,000 people are diagnosed with the disease each year in the U.S. And even with available therapies, their 5-year survival rate remains unacceptably low. There's a desperate need for new therapies, and we believe up to 50% of AML patients may benefit from menin inhibitor therapy. Turning to Slide #4. Today, we will be reviewing the clinical data from the KOMET-001 trial, which evaluated ziftomenib as a monotherapy for patients with relapsed and refractory AML bearing NPM1 mutations. Yesterday, we were thrilled to announce FDA has accepted our new drug application based on positive results from the KOMET-001 trial. The agency granted priority review and assigned a Prescription Drug User Fee Act or PDUFA target action date of November 30, 2025. Along with our partners at Kyowa Kirin, we're pursuing an aggressive development and commercialization strategy for ziftomenib, and we anticipate the partnership will fully fund Kura's efforts through the frontline commercialization in the U.S. Turning to Slide 5 and the agenda. We'll start with a review of the KOMET-001 registrational data that was just presented by Dr. Wang in an oral session here at ASCO, which just ended. Dr. Mollie Leoni will briefly discuss how the KOMET-001 trial and results fit within our broader development plan. Then Brian Powl will briefly summarize the market opportunity for ziftomenib in relapsed/refractory NPM1 mutant AML and some of the highlights from our pre-commercial activities. And finally, we hope to have plenty of time for Q&A. We're honored to be joined by 2 esteemed key opinion leaders. Dr. Eunice Wang serves as the Chair of Leukemia Service, Roswell Park Comprehensive Cancer Center in Buffalo, New York and Professor of Oncology in the Department of Medicine at Roswell Park. She presented the KOMET-001 data in the oral session at ASCO. We are also delighted to be joined by Dr. Amer Zeidan, who currently serves as Chief Division of Hematologic Malignancies, Director of Hematology Early Therapeutics Research at the Yale Cancer Center and Professor of Medicine, Hematology at Yale University. Dr. Zeidan is the principal investigator on the KOMET-007 study, which will be the focus of our presentation at EHA 2025 in a couple of weeks. We're honored to have Dr. Wang walk through the clinical data and then the 2 of them will be available to take your questions. With that, it's my pleasure to turn the presentation over to Dr. Wang to discuss the KOMET-001 data. Dr. Wang?

Thank you. So next slide. On behalf of my co-authors, I'm honored to present our abstract ziftomenib in relapsed/refractory NMP1 mutant AML Phase Ib/II clinical activity and safety results from the pivotal KOMET-001 study. Next slide. As you can see here, the KOMET-001 is a pivotal trial of ziftomenib monotherapy in relapsed and refractory NMP1 mutant AML. As you can see, early study phases in the dose escalation and validation cohorts established the recommended phase dose of ziftomenib of 600 milligrams once daily in relapsed and refractory NMP1 mutant and KMP rearranged leukemias. The Phase Ib expansion study, which was completed, continued to validate the safety and efficacy of the 600-milligram daily dosing in patients with relapsed and refractory NMP1 mutant disease. And shown here are the results presented today on the pivotal Phase II portion of this study. This is a registration-enabling study in relapsed/refractory NMP1 mutant patients, which further evaluated the efficacy and toxicity of ziftomenib. Specifically, the primary endpoint of this Phase II registration-enabling study was to determine whether the CR/CRh rate or complete remission with and without hematologic recovery rate achieved with ziftomenib in these patients was statistically superior to a historic 12% CR/CRh rate in the same patient population treated with conventional standard salvage chemotherapy. Key secondary endpoints of the study included duration of CR/CRh, MRD negativity by molecular analysis, transfusion independence and adverse events. Next slide. On this slide, we see the baseline characteristics of the relapsed/refractory NMP1 mutant patients treated on this study. As you can see, the median age of these patients was 69 years with an age range from 22 to 86 years. This is reflective of the real-world experience of newly diagnosed AML patients in the general patient population. Similar to this, we see that the majority of these patients, 63% were greater than or equal to 65 years of age. Again, a largely older cohort of patients that represent what we see in our clinical practice in this day and age. ECOG performance status was between 0 and 2. You also see indicative of other larger studies that there were several co-mutations identified in these patients. 53% of patients had co-mutations in FLT3, 13% IDH1 and 23% IDH2. This was a heavily pretreated patient population with a median of 2 prior lines of therapy and some patients having received up to 7 prior therapeutic interventions. You can see that 1/4 of these patients had prior hematopoietic stem cell transplantation, 60% had prior venetoclax therapy. On the next page, we see here the response data, and you can see here that in the pooled Phase Ib/II patient population that the overall response rate in patients was 35% with a CR/CRh rate of 25%. Of note, 2/3 of these patients or 65% achieved MRD negativity by central molecular testing. In the Phase II patients of 92 listed here, the CR/CRh rate of 23% was significantly superior by a p-value of 0.0058 to the historic 12% CR/CRh rate reported with conventional chemotherapy. You can see that for these Phase II patients, after a median follow-up of 4.1 months, the median time to achieve a CR/CRh was 2.8 months and the median time to achieve an overall response rate was 1.9 months. Next slide. This study also included prespecified subgroup analysis in responding patients. And as you can see across the board that there was no difference in response rates in patients depending on age, performance status and importantly, based on prior therapy. Again, these patients were heavily pretreated and the fact that some patients had greater than 3 prior chemotherapy agents and lines of therapy did not impact on the response rate achieved in this patient population. Similarly, prior allogeneic stem cell transplantation and prior exposure to venetoclax therapy in previous lines of therapy did not negatively impact the overall benefit achieved by these patients in terms of response, neither did the presence of FLT3 mutations or IDH1, IDH2 mutations. Response rates across the board were similar in all of these patient groups. Moreover, next slide, there were other signs of clinical benefit. As you can see here, 21% of patients were converted from being transfusion-dependent for red cells and platelets at baseline to becoming transfusion independent after ziftomenib therapy. 24% of patients who are dependent on red cells became independent transfusion-wise for red cells and 17% of patients who are dependent on platelet transfusions became independent of transfusion of platelets after receiving ziftomenib therapy. Patients who -- about 20% of patients who are already transfusion independent also maintained their transfusion independence throughout ziftomenib therapy, supporting the fact that this therapy is not, in fact, severely myelotoxic. Next slide. The median overall survival of all patients, 112 patients in the POL Ib/II study is shown here and was 6.1 months. 24 patients remain alive on study with 9 patients remaining on ziftomenib therapy at the time of data cutoff. Among those patients who achieved a response, meaning they achieved a CR, a CRh, a partial remission or morphologic leukemic-free survival clearance, you can see the median overall survival of these responding patients was 16.4 months as opposed to 3.5 months in the nonresponding patients in these relapsed/refractory NMP1 patients. Next slide. Encouragingly, ziftomenib was also extremely well tolerated. And you can see here that there were very low rates of zifto-related myelosuppression, as mentioned previously. While 20% to 22% of patients developed anemia, febrile neutropenia and thrombocytopenia, I would argue that these rates of myelosuppression are much lower than we see with similar drugs in the relapsed/refractory setting. Of note, there was no clinically significant QTc prolongation with 3 out of 112 patients developing what investigators thought was a possible QTc prolongation due to drug. Among these 3 patients, 1 had a Grade 2 QTc prolongation, 2 had a Grade 3 QTc prolongation. But of note, all 3 of these patients were on concomitant medications were known to prolong QTc and 2 patients had electrolyte abnormalities that could have contributed to these QTc prolongation. None of the investigators deemed any of these QTc prolongations to be significant, and none of the patients ended therapy because of QTc prolongation effects. On the next slide, we see ziftomenib related adverse events occurring in greater than or equal to 5% of all patients. As you can see here, differentiation syndrome occurred at any grade in 23% of patients and 15 of these 112 patients had Grade 3 differentiation syndrome. However, of note, there were no grade 4 or 5 events. There were no deaths associated with the differentiation syndrome. And with the institution of protocol-defined mitigation strategies, the majority of these CS events were successfully resolved with the majority of these patients resuming drug after management of this complication. Only 3% of patients discontinued ziftomenib due to any adverse events. You can see though there were instances of nausea, vomiting, pruritus and decreased appetite and ALTs, none of these were considered significant or ended up with serious adverse events. Next slide. So in conclusion, the pivotal KOMET-001 Phase II study met its primary endpoint, demonstrating that ziftomenib therapy resulted in statistically significantly improved CR/CRh rates over historical control of patients treated with salvage chemotherapy. Of note, these responding patients achieved an overall survival of 16.4 months. 2/3 of these responses were MRD negative by molecular testing and 20% of patients achieved transfusion independence supportive of the clinical benefit of this agent in these individual patients. In these heavily pretreated patients who had received a median of 2 prior lines of therapy, there was similar response rates regardless of the number of prior therapies, prior allogeneic stem cell transplantation and prior venetoclax therapy. In addition, ziftomenib was well tolerated in these patients with low rates of zifto-related myelosuppression and only 3% of patients discontinuing therapy because of zifto-related adverse events. There was no clinically significant QTc prolongation. And although Grade 3 and lower differentiation syndrome was observed with the implementation of protocol-specified mitigation strategies, there were no grade 4 events, and there were no DS-related deaths. The majority of patients continued to perceive ziftomenib after resolution of differentiation syndrome. Based on these data, a new drug application, as mentioned by Troy Wilson, was accepted by the FDA for consideration of zifto-monotherapy as a new treatment option for adult patients with relapsed and refractory NMP1. And based on the very favorable safety profile, ziftomenib appears to be a very attractive agent for combinatory studies together with intensive and nonintensive chemotherapy backbones in the frontline setting.

Thank you, Dr. Wang. Turning to Slide 17. We'll ask Dr. Mollie Leoni if she can give an overview -- a quick overview of the ziftomenib global development plan to help contextualize the results from KOMET-001 that Dr. Wang just presented. Mollie?

Thank you, Troy, and on to the next slide. So together with our partners at Kyowa Kirin, we are investigating ziftomenib across the AML continuum in up to 50% of patients for whom we believe the menin KMT2A pathway could be a driver of disease. On the left hand of this slide, we have a comprehensive development strategy to address patients in the frontline setting, whether or not they are eligible for transplant, treating along the continuum of their therapeutic intent. On the right-hand side, we are building on the data generated by the KOMET-001 monotherapy study to evaluate ziftomenib in other various combination regimens in the relapsed/refractory setting. This comprehensive strategy uses both company-sponsored studies as well as investigator-initiated studies to provide the greatest number of options and therefore, benefit for patients. Moving to the next slide. Previously at ASH 2024, we presented Phase Ia dose escalation data for the combination of ziftomenib with intensive chemotherapy or 7+3, ziftomenib was generally well tolerated in combination with standards of care at all dose levels studied. Moreover, the interim analysis from the Phase Ia portion of the dose escalation study showed high CR rates in both the NPM1 and the KMT2A rearranged adverse risk frontline populations. At EHA, we are excited to share an update on the KOMET-007 study, where we will see updated results, including data from the Phase Ib expansion cohort of ziftomenib at the RP2D of 600 milligrams plus intensive chemotherapy. It will represent a more mature data cut of the evolving clinical data. As it is a combination of the dose escalation and subsequent expansion, the median time for patients on study is approximately 20 weeks with some patients from the Phase Ia now having been on study for up to 47 weeks. As we have discussed, the challenge in the frontline setting is to maintain patients in a durable response, and we look forward to sharing data on the benefit of a targeted agent such as ziftomenib being on board with a focus on these expansion cohorts. Moving to the next slide. We are pleased to have unveiled our strategy to evaluate ziftomenib in combination with standards of care in the frontline AML population with significant leadership roles. [Technical Difficulty]

We can hear you now. Thank you so much. We can hear you.

Okay. We're going to -- apologies for that. We had a technical glitch. We're going to go back to Slide 20 and just pick it up from Slide 20. Apologies to all of you in the audience. Mollie, do you want to go ahead, Slide 20.

Sure. [indiscernible] with significant leadership roles being played by Dr. Zeidan and Wang for which we thank them greatly and with options for both accelerated approval and survival-based full approval endpoints. We are making good progress in study startup and the KOMET-017 trial remains on track to start in the second half of 2025. And turning to the next slide. With that, I will turn it over to Brian to talk about the market opportunity in the relapsed/refractory NPM1 mutant AML patient population.

Thanks, Mollie. Turning to the next slide, Slide 22. Along with our regulatory efforts towards the ziftomenib NDA, we have been conducting pre-commercialization activities and market research. Specifically, we've sought feedback from both academic and community physicians and investigators on some of the differentiating features of ziftomenib. The feedback we're getting has been very positive, and some of the key highlights are summarized here. Starting in the upper left, in addition to the 23% CR/CRh rate, we're hearing from physicians and KOLs, they are impressed with the overall survival amongst responders, which is longer than many of them would have expected in this population. Turning to the middle. We also hear consistently that physicians are impressed by the combinability and convenience of ziftomenib. Patients can take it once per day. They don't have to worry about drug-drug interactions, and there is no need for weekly cardiac monitoring. Finally, if you look in the upper right panel, another highlight of ziftomenib is the low rate of myelosuppression. This allows patients to recover counts more quickly, and they are less prone to infection. Next slide. Turning now to Slide 23. We see that physicians highlight the presence of MRD-negative responses among patients with or without prior venetoclax, which is seen as an advantage in this patient population. Moving to the middle, the overall safety and tolerability profile was viewed as compelling, particularly the absence of ziftomenib-associated myelosuppression and the lack of a need for cardiac monitoring. Finally, the combinability and convenience are highlighted as key advantages, which will be relevant for both the initial population as well as the ongoing development work in combination. Next slide. We're very happy that the FDA has accepted our NDA submission for ziftomenib and assigned a PDUFA date of November 30, 2025. We see an attractive opportunity in the relapsed/refractory AML population. There continues to be a very high unmet medical need. Among patients, 20% are primary refractory and 50% will relapse within 1 year. We see significant potential for ziftomenib as an active, safe and well-tolerated targeted therapy to support sustained treatment. With an anticipated 6 months of duration of treatment in the relapsed/refractory setting, we believe ziftomenib is well positioned to achieve significant share with the combination of clinical activity, best-in-class safety and tolerability with a once-daily dosing regimen. And with that, I'll pass it to Troy for concluding remarks.

Great. Thanks, Brian. If we can turn to Slide 26. [indiscernible]

Please get closer to the microphone, doctor. We cannot hear you.

As you know, this is just the first step of our strategy to treat up to 50% of AML -- of all AML patients. With the PDUFA action date of November 30, we're squarely focused on supporting the FDA in its review as well as preparing for a potential approval and launch in the fourth quarter. We believe ziftomenib represents potentially best-in-class menin inhibitor for AML, and we think this will be reinforced by the clinical data we'll share at EHA in 2 weeks as well as additional data we look to share in the fourth quarter. Beyond AML, we're looking to create value for patients with menin inhibitors in solid tumors as well as diabetes. And finally, we look forward to sharing data with you from our FTI programs in the second half of the year. Turning to Slide 27. Given our focus today on AML, I'll just highlight for you that we intend to present preliminary clinical data from the 007 Phase Ib trial in frontline intensive AML at EHA in Milan, Italy in about 10 days. We expect to initiate the KOMET-017 Phase III registration-enabling trials in frontline NPM1 and KMT2A-r intensive and non-intensive AML in the second half of this year, and we expect to present preliminary clinical data from the Phase Ib expansion cohorts of KOMET-007 in frontline non-intensive AML in the fourth quarter, potentially at ASH. Turning to Slide 28. Finally, we're doing all of this from a position of financial strength. We had more than $700 million on the balance sheet as of the end of the first quarter. And with the progress we continue to make on the ziftomenib program, we continue to feel confident about our ability to earn up to an additional $375 million in near-term milestones. This should allow us to invest appropriately in the research, development and commercialization of ziftomenib. That concludes our prepared remarks, Carmen, and we're happy to take questions.

[Operator Instructions] And it comes from the line of Li Watsek with Cantor.

congrats on the data. 2 from me. I guess, first is just given such a prolonged OS benefit in the responders versus nonresponders, can you talk a little bit about if there is any good ways to predict which patients might be more likely to respond to zifto versus not? And then similarly, I know there are some patients in the trial had pseudoprogression. So I guess just based on your clinical experience, are there any good indicators for that versus true progression?

Thanks, Li. Let me ask Dr. Wang if she could -- we'll take your 2 questions separately. So starting with the question around the OS. Is there a way that we know of to predict the responders?

I don't know that we know. That's the one million dollar question is that we'd love to be able to tell which patients are likely to respond versus not. I think that we don't, at this point, know when we look at our prespecified subgroups, even patients who've gotten 3 or more lines of therapy do respond and patients that have gotten prior venetoclax and other prior lines of therapy respond. So that's a little counterintuitive because some of our other agents in the market, the more pretreatment you have or if you have prior venetoclax, that tends to build resistance. So I think at this point, I feel that we don't have a clear signal as to which patients are going to respond. That being said, patients who are responding to ziftomenib also do very, very well. We've had a number of patients. I believe, there were a number of patients that went on to subsequent allogeneic stem cell transplantation, 5 patients from the KOMET-001 study, and I believe we have 2 or 3 of them still on ziftomenib maintenance. So I feel that ziftomenib provides long-term benefit to these individuals and can control their disease with very few side effects. And so I think we're going to be continuing to explore which of these patients might be predictive. We did see a small signal in that the patients that had co-mutations in IDH1 apparently did very, very well with overall response rates in the -- a little bit better than the 23% and the 40%. So that might be a subgroup of patients worthy of further investigation.

And Mollie, maybe I'll ask you on the question of, Li termed it pseudoprogression. Can you maybe talk to our strategies as we look across the trials to mitigate the risks of pseudoprogression?

So one of the things, Li [indiscernible] is the response rates, albeit not statistically significant between the U.S. and the ex-U.S. regions or the North America and ex-North America regions. where this drug was used, somewhat lower of a response rate in the EU, for example, than in the North American regions. And in part, we think this is because these sites came on later. They didn't have the experience of the Phase Ia/Ib and learning what kind of a pseudoprogression looks like in the -- with use of a menin inhibitor. I think we've learned a lot since then. I think we -- investigators and KOLs and treaters in general have learned a lot that there's more to it in the menin inhibitor setting than there is in potentially other even differentiating agents. And I think that...

So, Carmen, can we go on to the next question?

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

This is Yen-Der Li on for Jonathan Chang. Congrats on the positive data and also the priority review decision. So my question is, can you share your plan in preparation of the commercial launch of ziftomenib potentially later this year? And what are the key lessons from revumenib launch that might help inform your strategy?

[indiscernible]

Please, can you get closer to the microphone while you give the answers?

Yes. I'll ask Brian, Yen-Der, to speak to your question.

Yes. Thank you, Yen-Der, for the question. So we -- as you know, now that we are -- have been granted the PDUFA date, we are preparing ourselves for commercialization. We have been building out our capabilities to ensure that product will be available to patients upon approval. And this is supportive across our marketing commercial teams as well as our market access and medical affairs groups to begin the build-out of the commercial team and engage with the appropriate customers at the right time. So we feel that we've -- because we've been following the market, and as you mentioned, revumenib has been on the market for at least one full quarter now. We've been trying to track their progress, and we're glad to see that there is a market for menin inhibitors, and we're looking forward to taking learnings from their approach to educating around the role of menin inhibition for their particular indication in KMT2A rearranged as we move into the NPM1 population.

One moment for our next question. Comes from the line of Roger Song with Jefferies.

Congrats for the data at ASCO and then the priority review for your first NDA. So the question is really interesting related to the mechanism, potential mechanistic hypothesis, why ziftomenib seems to having consistent response for the experience versus the naive patients. And also for the hem tox, it seems you are significantly lower than other menin inhibitor. seems the ziftomenib have some inherent differentiation, which we may not know so far. So if you can give us some color, that would be helpful.

Yes. Thank you, Roger. So Roger's question is in 2 parts. One is, do we have any mechanistic understanding of why we see activity in post venetoclax? And then why do we see less hem tox? Is there any mechanistic explanation? Dr. Wang, do you have thoughts?

I think [indiscernible] told me the drug isn't very well tolerated in terms of GI side effects and because of the dose reductions and the twice-a-day dosing. I think ziftomenib based on its unique properties is a different drug. Just like we have different BCR-ABL inhibitors, different BTK inhibitors, these are different agents. And what we see with ziftomenib, we see an excellent tissue distribution, which allows it to be given once a day. We do not see the QTc prolongation. We don't see the azole effects. And in terms of mechanistically, we have consistently seen through all of the KOMET-001 data consistent activity and efficacy in the NMP1 mutant patient population, which I think is maybe a little bit different than what we see with revumenib. Whether it's mechanistic or not, I think in preclinical studies, the mechanism by which it works is similar to the other menin inhibitors, but I just think these are different agents. I hope that answers your question.

Thank you, Dr. Wang. Dr. Zeidan, is there anything you'd like to add to Dr. Wang's comments?

Yes. I think I largely agree with what was said. I think the fact that also what we have seen in the combination study so far does support the idea that the drug does not exert additional myelosuppression. When we look at the time to recovery after intensive chemotherapy when it's combined with ziftomenib, we are seeing numbers that not only close to what we actually see with 7+3, but there's a suggestion that it could be even a little bit sooner in terms of count recovery, which probably goes with the differentiating effect of ziftomenib. Now how does that compare to other menin inhibitors? I think it remains to be seen, but it's my strong belief based on all the data that we have seen so far that this drug is, in my opinion, the best-in-class agent for menin inhibitors. I would also emphasize that monotherapy is only the starting point of kind of seeing the advantage of these drugs. We have a very good paradigm, for example, with FLT3 inhibitors where in the second line or in the relapsed refractory setting, you see responses in the range of 20% to 25% and some transfusion dependence. But once those drugs have been combined in the frontline setting with intensive chemotherapy, there has been overall survival prolongation and the patients will stay on these drugs for many years. So I think overall, having a drug that is easy to combine that does not cause myelosuppression, does not have cardiac toxicity is very important for chronic use.

I just want to make one additional point about the QTc prolongation. So you must remember that on the Phase I revumenib studies, the dose-limiting toxicity of that agent was QTc prolongation. It was not myelosuppression, and it was not differentiation therapy. We, in the Phase I dose escalation of ziftomenib went all the way up to 1,000 milligrams a day of ziftomenib, and we did not see any QTc prolongation. And when you look across the other menin inhibitors in development, I have not seen to date any other menin inhibitors that have that QTc prolonging signal. So that QTc prolongation seems to be unique to the revumenib drug. It is the only menin inhibitor who has listed as of now dose-limiting toxicity due to QTc prolongation. So I think it's not that zifto is different. I think that it's specifically revumenib that has that particular side effect.

Roger, I hope that answers your question. Carmen, maybe we can go to the next question.

Our next question comes from Alexandre Bouilloux or Peter Lawson from Barclays.

This is Peter Lawson from Barclays. Troy, I just had a question around ahead of the PDUFA date. Are there any kind of further regulatory hurdles? Is there a potential of an AdCom? And then as you think beyond that, kind of the go-to-market strategy you're thinking.

Yes. So Peter, I'll address your PDUFA question and then Brian can address -- sort of build on your go-to-market strategy. And we don't expect an AdCom at this point based on the feedback we've received from the agency as part of their acceptance of the NDA and their assignment of a PDUFA action date. We wouldn't expect an AdCom. Now the agency, of course, can change its mind, but we wouldn't expect that. With respect to the go-to-market strategy, Peter, I'll let Brian speak to that.

Thanks for the question, Peter. Yes. In terms of our go-to-market strategy, we are -- have been building our kind of launch strategy based on feedback from both investigators, KOLs and community physicians that we've been working to better understand the profile of our drug relative to other options that are available on the market. And we're putting together our go-to-market strategy that will really help to support a potential best-in-class agent in the relapsed/refractory monotherapy setting. And all of our teams are working towards building that key communication, but also the ability to get the product available to market as soon as we get approval. So we've been working from an access to distribution strategy as well to ensure that we will make ziftomenib available for patients as soon as possible after a potential approval.

And then just on the Grade 3 differentiation syndrome, if I can squeeze in another question just on how physicians are managing that prophylactically? And where do you think that incidence rate can potentially go with that management?

Did you hear Peter's question, Dr. Wang? I'll just restate his question. How are physicians managing differentiation syndrome? And Peter, I'm going to restate your question, can we do even better, right? Are we happy with where things are? Or can we do better?

I think that as Mollie alluded to, over the course of the study, the more experienced investigators like Dr. Zeidan and myself really were experienced enough to utilize mitigation strategies early on, early recognition of potential differentiation syndrome and keeping patients on study to allow them to get sufficient drug so that they would achieve a clinical response. As she mentioned, the median time to response could was 2.7 months. There are some patients that required 3.7 months to stay on therapy, but there was a learning curve. The European colleagues that enrolled on the study, when we looked at when they first enrolled, the time that they left their patients on study was relatively brief as compared to more experienced colleagues. So I thought that over the time of the study and familiarity with the differentiation syndrome led to more comfort and to more consistent institution of these mitigation strategies. As you know, the IDH inhibitors also have a black box warning for differentiation syndrome, but they are widely used in the market now that we have all become familiar with it. Acute promyelocytic leukemia, again, has been associated with life-threatening differentiation syndrome, and that is actually a success story with over 90% of patients going into remission or 95% over time. So I think it's a learning curve, but I think that it is something that we are familiar with. And with the very specific protocol guided therapeutic algorithm, which I have to tell you is extremely detailed and with even initiation of cytoreductive therapies and early initiation of steroids, we've not seen the differentiation syndrome in the more experienced hands has been a barrier to giving therapy and achieving the clinical responses. And I think Dr. Zeidan can speak on to that because I think on the combination studies, which were brought out to larger sites and more investigators, again, there was a learning curve that improved over time.

Yes. And I also fully agree with this. And I would actually point just to follow-on. I think we have to think about differentiation versus differentiation syndrome because differentiation is on target activity of ziftomenib and seeing differentiation is actually something that is expected within the use of these drugs. So the question in my mind really is about the physicians learning how to mitigate it. And I think this has been already clearly achieved in the monotherapy setting. In the combination setting, as I mentioned earlier, this is, I think, where the full potential of menin inhibitors in general, but particularly, I think ziftomenib will be fully revealed would entail combining it with intensive chemotherapy or aza-ven, which will by itself mitigate the risk of differentiation syndrome because it acts both as a synergistic activity, but also it reduces the risk of differentiation. So I do agree that on the longer run, I think differentiation syndrome, people will gain expertise. There will be very clear guidance on how to mitigate that. And we -- as Dr. Wang mentioned, we already have done this with APL, with IDH inhibitors and some FLT3 inhibitors. So it's not -- I don't expect any difference here.

Great. Carmen maybe we can go to the next question.

Our next question is from Jason Zemansky with Bank of America.

Congratulations on the data. Maybe a question for Dr. Wang and Zeidan. When you think about the relapsed/refractory setting, in particular, I appreciate it's a smaller piece of the overall pie here. But in your mind, what's going to differentiate the 2 different products? Is the convenience enough for zifto or are prescribers going to look for something more?

Yes. No, I think there are many things that will differentiate. I think in my opinion, convenience and safety is a very important aspect. When you have multiple drugs that have potentially comparable efficacy, and we already see this, for example, in the CML world where we have a number of TKIs. And the way we choose between them is largely based on the side effect profile and the convenience as well as the comorbidities of the patients. So to have a drug that you can take once a day. And I can tell you, for patients, if you are giving a drug for a short term, maybe a few months, maybe doing an EKG every week and taking it twice a day and all of that might not be a big hassle for the physician and the patient. But once you are talking about administering a drug for years and having to worry about the QTc and having to worry about, is the patient taking the drug twice a day? Are they forgetting taking the drug? Is someone else giving them an antibiotic that might interact with the drug, all of these aspects become very important. So I think you can call it convenience, but I think this is very tied into efficacy because being compliant with the drug, taking it on time, potentially in combination-based strategies, I think all of that will ultimately affect efficacy in addition to the safety. So when you look at all the other inhibitors, I think ziftomenib clearly has an advantage here.

Dr. Wang, would you like to add anything?

Yes, I completely concur. For example, with revumenib, there's a requirement that patients not only have a good baseline EKG, but they also need to come every single week for repeat EKG monitoring, and they have to have all of their drug medications reviewed for potential interactions with a 40% dose reduction. And it's very myelosuppressive. So patients will need to come in as well for weekly count checks for transfusion support. Now this is a mostly older age population. So patients in their 60s and 70s, mostly men over women, they're going to have a lot of cardiac comorbidities, cardiac co-medications that are going to preclude them from being able to get revumenib. And even if they do get revumenib, they have to come in every single week to get EKGs monitoring to get platelet count check. And there is the issue of safety about them having QTc prolongation, cytopenias, transfusion support, infections, neutropenic fevers. So I think it's not just a matter, as Dr. Zeidan pointed out of convenience, it's safety and long-term durability of this drug. And I think that those are for the community physician to start a patient on ziftomenib once a day and then not have to see them back and to be assured that they were safely tolerating their drug is, I think, a game changer. And these are elderly individuals that are not going to want to come in every single week and are not going to want to be able to have to go to their cardiologists and have all of their medications adjusted for these types of drugs. So I think these are not just convenience issues. These are safety, durability, tolerability and long-term maintenance drugs. So I think those are the things that drive the selection of drugs for patients in the community that are prescribing these.

The next question comes from Philip Nadeau with TD Cowen.

Let us add our congratulations on the PDUFA date and the ASCO presentation. 2 from us. First, on the average duration of therapy, I think in the prepared remarks, you said you expect approximately 6 months. We're curious what's the math behind that? So what duration of therapy is assumed for responders and what duration you assumed for nonresponders? That's the first question. And then the second is on the FLT3 ITD patients. There was one discussant who called out that response rate during the session today. Just curious to get the physician's opinion of use in the FLT3-ITD patients and any theories as to why that group may have a slightly lower response rate than the other groups?

Doctor we cannot hear your answer.

Sorry. Let me ask Mollie if she can speak to your question, Phil, around duration of therapy, and then we'll turn to the FLT3 question from the physicians.

So our understanding of how this drug will be used, as you've seen from the data is that these patients need at least 2 to 3 months -- 2 to 3 cycles on therapy in order to achieve a response, which is an unexpected with an epigenetic modifying agent that takes time to kind of reprogram the cell and get it to work properly. With regards to how we get to that 6-month estimate, well, then while they're in their response, we expect them to have at least a median of 3.7 months if they've hit a CR/CRh. Now the more interesting number would be to look at the ORR median duration of response because these are still clinically meaningful responses where patients may just have an incomplete recovery of their platelets, for example, and that goes up to a 4.7 response rate for a median. And that's not even discussing the restricted mean analysis that we've performed. So there's where you get to your 6 to 7-plus months of patient remaining on therapy. But I think as the learning evolves, we'll be able to treat through even any pseudoprogression and even keep patients on longer periods of time. And of course, aiming towards the combination trials, the combinations of these drugs, we'll see a completely different usage pattern.

Thank you so much for the question about the FLT3 mutant ITD patients. So when you look at the subgroup analysis, it is true that there appears to be a trend for a lower CR/CRh rate of 13% in patients with FLT3-ITD co-mutated with NMP1 as opposed to, for example, FLT3 TKD patients that have an overall response of about 33%. Now it's hard to parse that data. We do know that these patients were heavily pretreated. So I imagine that the patients that were FLT3-ITD mutant had probably failed multiple lines of FLT3 inhibitor therapies as well as in the upfront setting, allogeneic stem cell transplantation and possibly intensive or non-intensive chemotherapy. So I think that, that particular patient population is very difficult to treat. We know that somebody has failed 2 or 3 FLT3 inhibitors, their disease tends to be very resistant. The also concern I have is that the more co-mutations and the more prior therapies, for example, FLT3 inhibitor therapies, you build up multiple other mutations and signaling pathways that make it very difficult to treat those individual patients. So based on this -- in part, based on this data, as I mentioned, we actually have initiated on the KOMET-008 study, an arm for relapsed and refractory patients who co-express both NMP1 and FLT3-ITD to treat them with the combination of a FLT3 inhibitor and ziftomenib. Now my personal experience is that if that patient is caught early, they have not received prior gilteritinib and they are receiving gilteritinib and a menin inhibitor, they've done very, very well. The patients who've received prior FLT3 inhibitor therapy don't do quite as well. And I'm going to turn it over to Dr. Zeidan to ask his opinion as well.

Yes. And again, I fully agree with this. But to kind of again, plug it in into the combination front, which I think all these subtypes of acute myeloid leukemia that are very challenging to treat such as the FLT3-ITD mutated disease. When the patient has both mutations, as Dr. Wang mentioned, there is an opportunity to combine in the relapsed/refractory setting, but also we have within the context of the 007 study, have initiated a quadruplet trial where we are giving a FLT3 inhibitor in addition to ziftomenib with intensive chemotherapy. And I think this is a paradigm that we have seen repeatedly on oncology, where your best value for the drug is as you move in the frontline setting. This is where you get, I think, the most significant suppression of these clones. And with that, you make the issue of the emergence of resistance is of a concern because I think your best time to kick these mutations is probably from the front line.

Our next question comes from Charles Zhu with LifeSci Capital.

This is Peter Green on for Charles Zhu. Congrats on the data and especially congrats on the FDA acceptance and PDUFA date assignment. Just wondering on MRD negativity, does the central molecular testing method you see here in KOMET-001 reflect the accepted endpoint for KOMET-017 MRD testing? Is there any kind of read-through here to that frontline intensive combination? And any comment on how MRD-negative responses relate to overall survival or duration of response have observed so far?

Yes. I mean I would hope that there's a read-through from our monotherapy experience into the combination setting. What we've seen is with even intensive induction regimens in the front line, you see in the bone marrow about 40% MRD negativity rate. So obviously, seeing higher in the 60s in the 001 study with just a monotherapy is extraordinarily encouraging. And we will be using similar methods to detect MRD as we move into our 017 trial.

Just wanted to mention on the KOMET-001 study, we did see a difference in overall survival based on MRD status. Patients who achieved MRD-negative responses had an overall survival, I believe, over 12 months as opposed to patients that remained MRD positive who had an overall survival of only 9 months. So I think that -- and the importance of achieving an NMP1 negative response has been highlighted by Hoffman and all our colleagues at the U.K. And they recently published that regardless of whether a patient had NMP1 with or without a co-mutation in FLT3, that patients who achieved an NMP1 negative response after 2 cycles of intensive chemotherapy had -- did not necessarily have to undergo an allogeneic stem cell transplantation for best survival. So as Dr. Zeidan highlighted, by moving ziftomenib into the upfront setting and rendering some of these patients MRD negative with upfront therapy, there is the possibility that we could forgo stem cell transplantation in some of these patients. So achieving MRD negativity is key, we know for NMP1 mutant patients in the upfront as well as the relapsed/refractory setting.

And adding to what Dr. Wang has mentioned, NPM1 AML is actually one of the disease subsets where the correlation between MRD negativity by sensitive assays and the long-term outcomes has been shown to be the most significant out of different AML subsets. And I actually want to give the Kura team a lot of credit because during the discussion of the 017 development, the idea of using MRD-negative CR as a primary endpoint or a co-primary endpoint for intensive chemotherapy was accepted and was discussed with the regulators. And I think this is a very innovative way of doing trials in intensive chemotherapy treated patients because it could allow the patients to access the drug at an earlier stage through accelerated approval rather than just waiting for even free survival and overall survival as the traditional endpoints.

It comes from the line of Salim Syed with Mizuho.

Congratulations on the data, guys. Maybe 3 from us, if that's okay. The first 2 for maybe Troy, Mollie and then the last one for Dr. Wang and Zeidan. So Troy, Mollie, just curious on this line in the press release where you talked about the restricted mean duration of response being 4.3 months. To my knowledge, this is the first time you guys have used this sort of language using the mean duration of response rather than the median duration, which has always been the guidance of 4 to 6 months, and this came in a little bit lighter at 3.7. So just curious, what was the rationale of including the mean duration of response? Is this an important number you think for the FDA or how clinicians view this particular metric? And then second, just quickly on the -- just a quick clarification question on the defining transfusion independence, how many days to be deemed transfusion independent? And then I'll follow up with the doctors on the third question.

All right. So the reason -- a very simple fashion. The reason we used the restricted mean is in part because it is recommended by FDA and other statistical experts. When you have a small number of events, the duration of response per Kaplan-Meier calculations can be "unstable" which means just a couple of days in either direction completely changes the outcome of the analysis. And so FDA as well as other statistical experts do recommend use of this restricted mean, which gives a more cohesive understanding of what these patients are doing, how much time they're spending on trial. It essentially looks at the area under the curve for these patients and takes away the outliers. So the patients that are spending a very little piece of time in their response and the patients that are taking -- spending a very long time in their response. So thus, it's essentially a way of looking more cohesively at the contribution of all patients to the time on therapy. I know it's not the easiest answer, but that's the essence of what the restricted mean provides. And if you were -- your second question, I believe, was about what defines transfusion independence. And again, per FDA guidance, that's 56 days. So to be considered transfusion dependent, they would have had to have had a transfusion within 56 days prior to starting therapy. And then to be transfusion independent, they would have to have a stretch of 56 days without a transfusion after starting therapy.

Okay. Super helpful. Just for the doctors. Doctors you mentioned some language regarding game changer, best-in-class menin. Would you guys be willing to quantify what percentage of your practice you think you would actually put on zifto versus revumenib for relapsed/refractory NPM1.

All right. So this is Dr. Wang. So I have to be a little bit biased in that I have not put any patients on revumenib because we have been involved with the development of the ziftomenib from the onset. And given the very favorable side effects as well as efficacy that we've seen in monotherapy and now in combination therapy, I don't see any need for me to treat my patients with revumenib in the -- just because of the concern I have with my patients being more elderly, the need for the EKG monitoring, the transfusion support, there's issues with nausea and vomiting, myelosuppression. And so I have preferred to use ziftomenib. It's a well-tolerated drug in the outpatient setting. And once patients achieve a response, I don't have to see them for quite some period of time. So I do have that bias. I would turn it over to Dr. Zeidan if he's had different experiences. I do believe that ziftomenib right now is, I think, superior in my hands and my clinical experience to what I'm seeing and hearing from my colleagues with revumenib.

Yes. And I fully agree with that. Again, my own kind of review of the literature and being very attentive to all of the other menin inhibitors as well as my own personal experience with the drug. It's one of the easiest drugs to give in my experience. Again, we have a number of oral targeted agents that we use in the clinic and each one of it comes with its own set of either low level toxicity or need for monitoring, et cetera. But in my experience, it has been one of the easiest drugs to give. Patients rarely complain about any significant side effects. So I don't think there is any specific reason in my mind why I would use revumenib for an NPM1 mutated patients in the refractory relapse setting or in the frontline setting. And we are actually very excited to open the frontline Phase III as well soon so that we treat all of our new patients with the combination with ziftomenib as well.

And so I just wanted to mention that right now, revumenib is not approved for the treatment of patients with NMP1 mutant disease. It's only approved for its use in KMT rearranged disease. So I think my preference and the PDUFA and the indication for ziftomenib and NMP1 mutant disease, I think, is appropriate. I think the data is superior. The tolerability is superior. I think there's an opportunity given the number of patients, as you know, NMP1 mutation is much more common, more frequent, and we're seeing more patients -- significantly more patients with NMP1 mutant disease than with KMT rearrangements. Revumenib does not have that indication at this time. And I think this is an opportunity to capture a larger market share, a safer drug, a better drug for this mutational subset.

Thank you. And this is all the time we have for questions. I will pass it back to Dr. Wilson for closing remarks.

Thank you, Carmen. I want to thank Dr. Wang and Dr. Zeidan for sharing their experience and their wisdom with all of us as well as my colleagues, Mollie and Brian. I want to thank all of you for your attention. We will see some of you at EHA here in about 10 days. We'll also be at Jefferies, as well as at the Goldman Conference and look forward to seeing some of you there. If you have any questions, please feel free to reach out. We didn't have a chance to get to every question today. We're sorry for that, but we wanted to keep everyone on time. But we thank you for your time and your attention. And with that, we'll adjourn. Thank you all so much.

Thank you. And this concludes our program, and you may now disconnect.