Kyowa Kirin Co., Ltd. (KURA) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Kura Oncology Virtual Investor Event. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your host today, Patti Bank, Investor Relations. Please go ahead.

Thank you, Elizabeth. Good afternoon, and welcome to Kura Oncology's February 5, 2025, Corporate Update Conference Call. Joining me on the call are Dr. Troy Wilson, President and Chief Executive Officer; Dr. Mollie Leoni, Chief Medical Officer; Brian Powl, Chief Commercial Officer; and Tom Doyle, Senior Vice President of Finance and Accounting. Before I turn the call over to Dr. Wilson, I'd like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company. With that, I'll turn the call over to Troy.

Thank you, Patti, and good afternoon and good evening, everyone. At Kura, we are advancing a robust pipeline of product candidates, including menin inhibitors for AML, menin inhibitors for solid tumors and diabetes as well as farnesyl transferase inhibitors for large solid tumor indications. Today's discussion will be primarily focused on key development and regulatory updates relating to our ziftomenib program in AML, including significant progress and updates in both the relapsed/refractory and frontline AML settings. Under our strategic partnership with Kyowa Kirin, we're well capitalized and resourced to prepare for an NDA submission for ziftomenib, to continue our preparation for commercialization and to expand and accelerate the ziftomenib development program into those critical frontline indications. Although our development and regulatory progress for ziftomenib in AML is the focus of today's discussion, we look forward to sharing important clinical updates across our pipeline throughout this year. In summary, as we progress towards potential commercialization of ziftomenib and advance our robust pipeline of product candidates, we believe 2025 will be a transformational year for patients and for Kura Oncology. So with that, let's dive into the agenda for today's call. If we could turn to Slide 4. Today, we'll provide top line results from our positive KOMET-001 registration-enabling study as well as guidance on the timing for presentation of top line data as well as an NDA submission for ziftomenib in relapsed/refractory NPM1-mutated AML. We'll provide a summary of our recent end-of-Phase I meetings with FDA, where we gained alignment on the design and endpoints of our 2 Phase III registrational frontline trials included under a single KOMET-017 trial protocol. The meetings with the FDA were very collegial, and we were encouraged by agency feedback on our trial designs to support broad utility across the frontline population. Finally, we'll review upcoming milestones for both our ziftomenib AML program as well as our broader product pipeline to help guide you on what to look for from us in 2025. Turning to Slide 5. AML is characterized by significant genetic heterogeneity due to driver mutations, including NPM1, FLT3 and KMT2A-r, and we believe up to half of all AML cases may be menin-dependent. When we look across the intensive and the non-intensive settings as well as the FLT3-mutant AML frontline population, we believe a potential best-in-class safety and efficacy profile and optimal pharmaceutical properties could enable ziftomenib to become a cornerstone of therapy for patients with acute leukemias. Ultimately, our mission is to develop ziftomenib across the continuum of care for all eligible patients with acute leukemias whose disease is driven by the menin pathway. A critical first step toward that mission is establishing ziftomenib as a potential best-in-class menin inhibitor in patients with relapsed and refractory NPM1-mutant AML. With that, I'll turn it over to Mollie to discuss the top line results for KOMET-001.

Thank you, Troy. And if we could turn to Slide 7. We are very pleased to report positive top line results from our KOMET-001 study, evaluating the safety, tolerability and clinical activity of ziftomenib in relapsed and/or refractory NPM1-mutant AML patients. The Phase II registrational trial in relapsed/refractory NPM1-mutant AML patients achieved its primary endpoint of CR/CRh rate. The benefit-risk profile of ziftomenib is highly encouraging, and the safety profile was consistent with prior reports. As a reminder, ziftomenib is the first and only investigational therapy to be granted Breakthrough Therapy Designation or BTD for the treatment of relapsed/refractory NPM1-mutant AML. Facilitated by that BTD status of ziftomenib, we recently completed our pre-NDA meeting with the FDA, and we are pleased to report that we gained alignment on key aspects of the submission, including CMC, clinical pharmacology, companion diagnostics and clinical data needed for the submission. We anticipate submitting an NDA for ziftomenib next quarter, and we look forward to working with the agency to complete its review. We have also submitted the top line data for presentation at a major upcoming medical meeting also in Q2 2025. Turning to Slide 8. I'll ask Brian to reinforce the unmet medical need in patients with relapsed/refractory NPM1-mutant AML.

Thanks, Mollie. Relapsed/refractory NPM1-mutated AML represents a disease of significant unmet need for which there's no approved targeted therapy. 20% of patients are primary refractory to their first treatment, and 50% of patients who achieve a CR will eventually relapse. Unfortunately, even with recently approved therapies, fewer than 10% of all patients with relapsed/refractory NPM1-mutated AML are alive at 5 years. In light of this devastating prognosis, we're committed to developing ziftomenib as a treatment for patients with this disease. Given its consistent safety and tolerability, we believe ziftomenib offers the potential for sustained therapy. This is a market primed for innovative new therapies, with a concentrated base of prescribing physicians making for an efficient market entry. And if we use analog pricing, including a recently approved product, we believe the relapsed/refractory NPM1-mutant AML market represents an attractive opportunity, with total estimated sales for the class of between $350 million and $400 million per year in the United States. In parallel with our efforts to complete the NDA submission, we will be working with our partners at Kyowa Kirin to prepare for commercialization and we look forward to providing more details on those efforts as we are closer to a potential approval and launch. With that, Mollie, I'll turn it back to you to walk through the next updates.

Thank you, Brian. Now turning to Slide 10. We'll start with a summary of the 2 end-of-Phase I meetings held recently with the FDA. The meetings were intended to serve as the key regulatory interaction with the FDA ahead of initiating the KOMET-017 protocol, and our objectives for the meeting were to confirm the breadth of the ziftomenib frontline AML development program was adequate in scope and we were aligned with the FDA on key aspects of the 2 pivotal Phase III trials. In the meeting with the FDA, we confirm that our CMC, nonclinical and clinical pharmacology plans as well as our companion diagnostic plans are acceptable. Additionally, we reached alignment with the FDA on key aspects of the studies, including endpoints which provide pathways for both accelerated and full approval in the U.S. for both the intensive and non-intensive trials. We'll review these endpoints and other key aspects of the 2 Phase III clinical trials over the next several slides. It is worth noting, we continue to work with global health authorities to gain alignment on the KOMET-017 protocol, and we will continue to provide updates on these efforts as appropriate. On the back of these successful end-of-Phase I meetings with the FDA, we are currently in study start-up for both the intensive and non-intensive chemotherapy Phase III trials. Both trials are expected to initiate in the second half of 2025, and we and our colleagues at Kyowa Kirin are focused on expediting study start-up time lines. Now if we turn to Slide 11. We see the KOMET-017 global protocol encompasses 2 independent randomized placebo-controlled Phase III trials. By combining 2 trials under a single protocol, we intend to facilitate study start-up and execution, and we believe the protocol is more attractive to clinical sites because it provides treatment options to the broadest patient profile pool. On the left side of the slide, the KOMET-017-NIC trial or non-intensive chemotherapy trial will evaluate ziftomenib with venetoclax and azacitidine in newly diagnosed NPM1-mutant patients unfit to receive intensive chemotherapy. The trial will assess complete response and overall survival as dual primary endpoints to support potential U.S. accelerated approval and full approval, respectively. Moving to the right side. The KOMET-017-IC trial or intensive chemotherapy trial will evaluate ziftomenib with intensive chemotherapy, 7+3, in newly diagnosed NTM1-mutant and KMT2A-rearranged AML patients. The trial will assess MRD-negative complete response and event-free survival as dual primary endpoints to support potential U.S. accelerated approval and full approval, respectively. Even with approved therapies, up to 70% of patients who achieve a first remission will see their AML return within 3 years, and the 5-year survival rate for AML is at best 31.9% and as low as 11.2% for patients older than 65. Given this urgent need, we are pleased with the outcome of these FDA interactions and look forward to initiating our Phase III trials to establish the benefit-risk profile of ziftomenib in both the intensive and non-intensive chemotherapy combination settings. We are particularly pleased by the FDA's willingness to allow the trials to use MRD-negative CR and CR, respectively, as primary endpoints for accelerated approval of the 2 populations. In doing so, the KOMET-017 protocol is breaking new ground, which may help deliver ziftomenib more quickly to patients living with this devastating disease. Now turning to Slide 12. The KOMET-017-NIC trial will enroll frontline AML patients whose disease harbors an NPM1 mutation. Patients will be randomized to receive ziftomenib or placebo along with venetoclax and azacitidine. Patients will either be required to be aged 75 or older or those patients with medical comorbidities precluding treatment with an intensive chemotherapy regimen. Our decision to pursue development of NPM1-mutant AML only in this trial reflects the reality that most frontline KMT2A-rearranged patients elect treatment with intensive chemotherapy followed by transplant. The use of venetoclax and azacitidine among the KMT2A-rearranged patients is more common among the relapsed and refractory patients who have progressed on initial therapy. Although we continue to enroll KMT2A patients in the frontline setting with ven/aza with an eye toward publishing the data and making it available as an option for patients via our KOMET-007 trial, our registrational focus on frontline KMT2A-rearranged patients will be for ziftomenib and intensive chemotherapy. Turning now to Slide 13. One of the challenges encountered in conducting clinical trials with venetoclax and azacitidine has been the known myelosuppression frequently experienced by patients at the label dose for venetoclax. Clinical practice among AML physicians has moved towards minimizing venetoclax exposure once the patient experiences a response. However, it has not been clear that FDA would accept such a modified venetoclax dosing regimen in the context of a registrational trial. Based on long-term follow-up exposure data from the VIALE-A trial as well as real-world evidence published by Othman et al., we proposed to FDA to use a modified dosing regimen for venetoclax to incorporate real-world practice. We were very pleased to reach alignment with the FDA to modify the dosing, as shown at the bottom of Slide 12. Notably, venetoclax will be used per label in the first 2 cycles at which point physicians may reduce venetoclax dosing to 21 days or even further to manage venetoclax-associated toxicities. It is our hope that this modification will help to create a more consistent use of venetoclax in our KOMET-017-NIC trial and will ultimately help patients to achieve better clinical outcomes. On Slide 14, we have a schematic for the KOMET-017-IC trial, which will evaluate ziftomenib with intensive chemotherapy 7+3 in newly diagnosed NPM1-mutant and KMT2A-rearranged AML patients. The trial will assess MRD-negative complete response and event-free survival as dual primary endpoints to support a potential U.S. accelerated approval and full approval, respectively. Patients will be randomized to receive ziftomenib or placebo along with standard induction and consolidation chemotherapy. Two aspects of the KOMET-017-IC trial are particularly noteworthy. First, the trial incorporates the 3-arm design intended to capture the maintenance indication. Second, the trial uses a novel endpoint of measurable residual disease, or MRD, negative complete response as a potential accelerated approval endpoint for the study and event-free survival, or EFS, as a potential endpoint for full approval. We were very encouraged by FDA's willingness to allow the trial to use MRD-negative CR for accelerated approval in the frontline intensive chemotherapy setting. As I said earlier, the KOMET-017 protocol is breaking new ground, which may help deliver ziftomenib more quickly to patients living with this devastating disease. Now turning to Slide 15. We discussed the importance of this MRD-negative CR endpoint. MRD is a term describing small numbers of leukemic cells, which are still detectable during or after treatment even when a patient has achieved a complete response by standard criteria. Remaining leukemic cells in the body can become active and start to multiply, resulting in a relapse of the disease, which may, of course, be fatal for patients. Achieving MRD negativity, which may be associated with longer remissions and improved survival, means that the treatment has reduced the number of leukemic cells to below the limit of detection by the most sensitive analytical method. There's a growing body of published data, which suggests CR-MRD negativity may better correlate to long-term survival than morphologic CR alone. Additionally, as one can see from the survival curves on the right side of Slide 15, there is a significant impact of NPM1 MRD negativity on long-term survival and the implication on consolidation therapy choices. Higher rates of CR MRD negativity have potential to diminish the need for allogeneic stem cell transplantation. MRD has been used as a surrogate endpoint for approvals in other forms of leukemia but not for AML in part due to the requirement for a unique marker that can be used to track rare residual leukemic cells. In the case of NPM1-mutated AML, the mutated gene itself provides that unique marker. We believe the best opportunity to achieve long-lasting remission and extend survival is to achieve MRD negativity with the first attempted treatment. And by utilizing this endpoint in KOMET-017-IC, we are paving the way in the field to establish this new surrogate endpoint. With that, I'll turn it back over to Brian to discuss the commercial opportunity in the frontline setting.

Thanks, Mollie. Although our focus initially will be on the commercial launch of ziftomenib in the relapsed or refractory NPM1-mutated AML setting, there is considerable interest among physicians and patients to see menin inhibitors used in combination in earlier lines of therapy. Despite approved therapies, there remains a significant unmet need in the frontline AML setting. Although response rates are high, 70% of patients who experience a CR will relapse within 3 years, and the 5-year survival statistics among patients aged 65 or older remain a dismal 11%. In the U.S., more than 20,000 patients are diagnosed each year with AML, and based upon the emerging clinical profile we are seeing in our KOMET-007 clinical trial, we believe the safety, tolerability and clinical activity of ziftomenib could support sustained treatment for patients between 12 and 24 months. Based upon analog pricing, including a recently approved product, we believe the total market opportunity for menin inhibitors in the U.S. to be more than $7 billion per year, and we estimate that ziftomenib could reach peak sales of up to $3 billion in the U.S. And with that, I'll turn it back over to Troy.

Thanks, Brian. This is potentially a transformational year for Kura Oncology. With the release of our top line results for KOMET-001 and key regulatory interactions with FDA completed for both the monotherapy relapsed/refractory setting as well as the frontline combinations, we look forward to the following milestones: submission of an NDA for ziftomenib in relapsed/refractory NPM1-mutant AML in Q2 2025, submission of top line data for KOMET-001 for presentation at a major medical upcoming medical meeting in Q2 2025, presentation of preliminary clinical data from the KOMET-007 Phase Ib expansion cohort evaluating ziftomenib with intensive chemotherapy at a major medical meeting in Q2 2025. Initiation of the KOMET-015 trial evaluating ziftomenib and imatinib in patients with GIST in first half 2025, initiation of 2 independent Phase III registration-enabling trials in frontline intensive and non-intensive AML in the second half of 2025, presentation of preliminary clinical data from the KOMET-007 Phase Ib expansion cohort evaluating ziftomenib with venetoclax and azacitidine at a medical meeting in the second half of 2025 and nomination of a next-generation menin development candidate for use in diabetes in the first half of 2025. While our ziftomenib program has deservedly been the focus of today's discussion, our team has been hard at work also on our farnesyl transferase programs. We're making good progress in the FIT-001 trial, evaluating our next-generation FTI 2806 both as monotherapy and in combination, and we expect the following milestones: initiation of one or more expansion cohorts of 2806 and cabozantinib in patients with advanced renal cell carcinoma in first half 2025, presentation of data from the Phase I monotherapy dose escalation of KO-2806 in patients with RAS mutations in the second half of '25, presentation of data from the Phase I trial evaluating 2806 and cabozantinib in patients with renal cell carcinoma in the second half of '25 and, finally, presentation of data from the current HN trial evaluating tipifarnib and alpelisib in PIK3CA-mutant head and neck squamous cell carcinoma in second half 2025. As we work toward providing clinical updates across our pipeline at every major medical meeting this year, our team continues to execute well across the board, and we look forward to providing updates throughout the year. Turning to Slide 19. We started this presentation by highlighting that we have a robust pipeline of product candidates, we're well financed and well resourced to maximize the value of ziftomenib as well as our robust pipeline. With $785.3 million in pro forma cash as of September 30, 2024, and significant near-term milestones, including payment upon NDA submission and launch of ziftomenib in the monotherapy relapsed/refractory setting, we believe we are well funded and resourced through a potential commercial launch of ziftomenib in the frontline in newly diagnosed AML. We appreciate the commitment and dedication from our team, our investigators and study teams as well as our partners at Kyowa Kirin. We believe this achievement for our KOMET-001 trial positions us to deliver on our path to commercialization of ziftomenib beginning with our potential first NDA submission in relapsed/refractory NPM1-mutated AML next quarter. Furthermore, we believe the positive FDA interactions for the KOMET-017 protocol, including the opportunity for accelerated approval in both trials, paved the way for us to position ziftomenib as a potential frontline therapy to address up to half of patients with AML. And having gained alignment from FDA on potential pathways and endpoints for accelerated approval in both the intensive and non-intensive frontline settings, we believe we're fully financed through the potential commercialization of ziftomenib in those large frontline populations. With that, we'll conclude our prepared remarks. And Elizabeth, we're happy to take any questions.

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

Congrats on the top line data and the regulatory update. I guess just at the top line level, I'm wondering if you can just comment on what you're seeing from your pivotal study relative to the data from the Phase Ib trial. And then just given the profile you've seen, can you talk about your confidence on the best-in-class profile of zifto and how that might translate into the market traction?

Sure, Li. Thank you for the congratulations and for the questions. So I think every time I've been asked this question, I've answered it in the same way. We designed the trial to deliver a CR/CRh rate between 20% and 30%. The trial is statistically powered to hit that endpoint and, in fact, hit that endpoint. As Mollie indicated, the data is largely in line with what we've seen before. We can't get -- be more specific because as many on the call appreciate, we want to present the data at a major medical meeting to the health care community. We think that's the best way to position ziftomenib for a productive launch. The embargo rules are such that we have to be very careful. We've seen this with other companies recently. So Li, at this point, we can't be more specific. We will say that we think the benefit-risk of ziftomenib compares favorably with the competition. And we acknowledge that we will likely be working to get every patient, but we think we have a very attractive positioning out there in the market. And of course, as we get closer to the top line data, which we expect in the middle of this year, we'll be able to say more.

Okay. I wonder if you can also provide more color on the frontline trial size and powering assumptions and what the time line will look like for AA and full approval.

Sure. So we're currently still obviously refining our trials. And as we wait for additional input from rest of world, FDA was certainly helpful and very positive in allowing us to have the accelerated approval and full approval endpoints agreed to within the negotiations. So now we'll just be refining to make sure that this protocol overall would support a global approval in these patient populations. We will be clarifying more as the year goes on as we complete all of these different interactions and discussions.

Our next question comes from Yen-Der Li with Leerink Partners.

So this is Yen-Der on for Jonathan Chang. So congratulation on the positive result and also on the positive FDA feedback. So we have one question about the upcoming 007 data that is going to be presented in 2Q. Could you help us set some expectation on what we are going to see? For example, like are we going to know about durability or other profile? And also, there is another like non-intensive chemotherapy combination. Will we also get update on that this year?

Yes. Yen-Der, thanks for the question. I'll take a first cut at it, and then Mollie can add her thoughts. So on the data -- so the 007 data is the trial where -- it's the data that's leading into the 017 protocols. So the update that we envision in midyear will be from the escalation and the expansion in the frontline 7+3 or the intensive population. To date, all of you have seen the escalation data in, recall, the adverse risk population. Now we are enrolling the expansion cohort in all-comers, and we'll show you that data. So you will get a look at -- it will be a significantly larger number of patients. You're going to get a look at safety, tolerability, activity and durability. And basically, we'll show you all the patients on there as of whatever the data cutoff is. But that 007 data even in the escalation set a pretty high bar and, as Mollie indicated, we think sets us up well to be able to move into a -- into the 017 intensive trial, the IC trial. The data update in the second half of the year is directed toward the combination of ziftomenib plus venetoclax and azacitidine again in the frontline population. Here, you haven't seen any data yet. You've seen -- we did the dose escalation, recall, in the relapsed/refractory setting. This data will now be in the frontline population. And of course, this is the data that we used and are using to help guide us on the 017 non-intensive trial. So that will be a first update. Obviously, based on what we, Kyowa Kirin and, of course, the health authorities are seeing, we feel like that trial is designed to demonstrate -- the 017 trial, excuse me, is designed to demonstrate a clinically meaningful benefit. But that's how you should think about the 2 updates, intensive midyear, non-intensive end of the year. And that's really driven by enrollment and us waiting to give you enough data that we can actually say something meaningful. Is there anything you'd add?

Just so there will obviously be updates on durability at that time. You'll see the complete course of these patients at the time of that data cut. So I do think that it will be a very fulsome update for you, and you'll also be able to see the speed with which these patients have enrolled, which is also a very, very encouraging sign.

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

Appreciate the regulatory and developmental updates. We were hoping you might be able to provide some color about what a positive result for 001 means in terms of capturing that $350 million to $400 million market opportunity, again, recognizing that you may not be able to disclose the number itself.

It's a clever way to ask the question, Jason. We can't tell you the data. What do we think the data means in terms of commercial potential? Brian, would you like to -- I don't know that you can go a lot beyond what we've said, Brian, but do you want to comment on that?

Sure, Jason. I'm happy to try to answer that without answering all the details. I think that what we've done so far as evaluating the potential for ziftomenib is we've been evaluating through TPP studies an opportunity to kind of look at the range that Troy has outlined many times before of CR/CRh rate between that. And I can just say that based on the range that we've tested, I think that we will have a competitive profile relative to the competition, and we look forward to being able to further describe that as we have -- as we're able to share the data more clearly.

Got it. And then maybe, Mollie, regarding the MRD-negative CR endpoint for 017-IC, what do you think the community, be it prescribers or regulators need to see here to be encouraged?

Well, I think first off, we're very excited that the FDA agreed with us about what a clinically meaningful improvement might mean in this patient population. We will be looking at the bone marrow MRD negativity in this patient population. So we will be doing it in a different way than is regularly published, where you're usually seeing it in the blood. The bone marrow we expect to see in these patients may be a 40% MRD negativity rate. So we plan to have some form of clinically meaningful improvement over that. Again, we continue to refine the statistical assumptions. So I don't want to give you an exact number, but obviously, percentage improvement in that should give these patients the ability to -- a greater majority of patients the ability to skip the stem cell transplant and just maintain on ziftomenib monotherapy treatment regimen.

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

Congrats on both monotherapy pivotal data and then the combo pivotal plan. So a couple of questions from us. The first one is related to the pivotal monotherapy data. So it seems you are hitting the statistical hurdle. I know you may not be not ready to share with us the hurdle, but just curious that the data you will present at the medical meeting, it will be the data cut when you hit that typical hurdle or you will keep following them to the time you will submit the -- present data with a later data cut.

That's a really good question. It will actually be a slightly later data cut than what we are using for the submission for the reasons you state, just simply that we have the additional data, then it makes more sense to present to you a little bit more updated data at that time.

Great. Maybe just a quick follow-up. In terms of the regulatory submission, it will be the -- which data cut will be used or reviewed by the FDA?

I don't think we've released the date of our data cuts just yet, but just it will be earlier than the one we presented at the meeting.

Yes. I mean, Roger, the -- so obviously, we've shared enough data to get through the pre-NDA meeting, have those discussions. There are opportunities, as you may know, to update the data as you go along, both from a safety perspective and an activity perspective. As Mollie indicated, you'll see a slightly later data cut, we think, than the data cut that will go into the agency. You can imagine if we're aiming at a Q2 submission, we're well along the path at this point to preparing the NDA. And then it will all sort of get tied out there in the end. So I wouldn't worry too much about exactly what the data cut is. But because you asked the question, you're getting -- the presentation will be a slightly later data cut than the initial one that went to the FDA, we have a chance, of course, to update that data again with FDA, and we'll do so.

Got it. Yes, really helpful. Maybe on the combination, since you're trying to design the study to skip the transplant. So how should we think about those patients if physicians or patients decided to go to the transplant? Will be censored or how we account for those potential transplant in the trial?

Roger, let me just be clear. I think what you mean to say, so we'll get the maintenance label, but that's the continuation label. What you're describing is something slightly different, I believe, but let me let Mollie answer the question.

So what the study will be designed to capture is the post-consolidation maintenance space. Now consolidation can either be a chemotherapy consolidation, where they do a couple more cycles of high-dose chemotherapy or it can be transplant. And we will be designing it to capture the phase after that consolidation, whether it is the chemo or the transplant.

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

Just a few from us. So first, in terms of the top line data, from 001. Can you talk about your rationale a little more about why you're not disclosing numbers this morning. Is that simply the embargo policy at the medical meetings or just Kyowa Kirin typically not disclose data outside of the context of a medical meeting.

Yes. I mean, a little bit of both, Phil. It's a good question. You might have seen Cullinan and Taiho, they did the same thing. We are targeting a U.S. medical meeting because we want -- obviously, this is going to be a U.S. launch. And if we wait until the end of the year for ASH, that's a long time to wait for the data. And that medical conference, as you may know, has a pretty strict embargo policy. So if we put data out and start -- we put at risk -- and obviously, at this point, we don't know is it a poster? Or is it an oral? We'd like to give it the best opportunity to get the broadest audience, but we also have to respect the fact that they have a very well-articulated embargo policy. It's certainly not a reflection at all in the data. Yes, if there are conspiracy theories about the data, this is sort of, from our perspective, best practice, and that goes to the second part of your question. We are now -- we have a very strong partnership with Kyowa Kirin. This is best practice. It may leave everyone wanting for several months, and we appreciate that, but it is pretty typical and we think also best practice. Our goal is to do what is best for patients, whether that is trial execution, trial design with the frontline or data presentation. We want to get out to the very best broadest audience. And we felt it's important to give all of you the update that it is a positive study. It exactly hit its endpoint. We're quite excited by it on top of all of these -- the combination updates and, of course, the pipeline. So hopefully, that gives you and the folks that asked the previous questions a little bit more color.

Got it. That makes sense. Then a clarifying question on the design of the intensive chemotherapy trial given that there's 2 zifto arms versus 1 placebo arm. How are the primary end points going to be calculated? So for CRD, MRD negativity, will both zifto arms be combined compared to placebo? And then similarly for EFS, how will the maintenance versus nonmaintenance be contemplated in calculating that endpoint?

Yes. I mean you're picking up on how complicated it gets. And we are continuing to refine our assumptions, as I said. But, yes, we will be using both zifto arms in order to determine the CR, MRD negativity. And then to varying degrees of powering, we'll be using both zifto arms to determining the significance of maintenance therapy.

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

I guess, we'll just wait until the second quarter for those top line figures. But in the meantime, I was kind of wondering, it sounded like you want to stress the importance and correct me if I'm wrong on this -- the FDA agreement to allow modified dosing of the venetoclax. Could you expand on that a little bit, how might these modifications, for example, impact control arm or experimental arm performance relative to what we saw in the VIALE-A trial.

Well, what's interesting is we're going to do it for both arms, obviously. It's a blinded study. So it will be a homogenized patient population, where we're prescribing the amount of venetoclax that's taken in the first 2 cycles and then cycle 3 and beyond. So it should really not have any differential effect on the 2 arms. The longer VIALE-A data that has recently been released and Othman et al have both shown that in the real world and in real use of venetoclax, the dose is most often decreased and the exposure is less than what is currently labeled to. And what we expect that to do is to allow patients to recover their accounts more quickly and to maintain them more consistently and thereby avoid a lot of the side effects that can result in even going off drug. So we expect to see hopefully improve CR rates overall and count maintenance.

Our next question comes from the line of Brad Canino with Stifel.

The potential to use MRD negativity in AML is really encouraging. But I guess everything the FDA has written in the past 5 years for AML has expressed a lot of concern, the lack of assay and quantification level standardization, false negatives due to disease clonality. And I think they talked about the absence of convincing meta-analysis data to validate as a surrogate. So how did you address these elements? And do you expect an ODAC meeting to talk about this for AML like we saw for multiple myeloma last year?

At the current time, we obviously don't expect an ODAC to cover these. But as you say, the FDA has a pretty prescriptive list of things that they want to see in order to justify a new surrogate endpoint. And we have been working for the past several years with others at large pharma in order to satisfy these requirements. And we will have the pieces that are required in order to confirm CR MRD negativity as a surrogate endpoint well before the time of reaching that accelerated endpoint within the context of our trial. So it's a group effort, but we are planning to be able to address all of those elements that FDA has consistently said they needed to see in order to accept the end point.

And Brad, just to jump on that, I mean you're right, but much of that analysis, as Mollie indicates, exists, particularly for NPM1. The Othman work and the analysis that folks have done of VIALE-A, the -- I have to say, I mean, we were very encouraged by the agency's willingness to consider that end point. It's -- I don't know if people appreciate what a huge lift that is. And if we get to market in the frontline, that's likely to be the first population, right, the first endpoint to get hit. We haven't given specific timing on it because we're still working through the details. But we were very gratified. The FDA has done a tremendous amount of work, and we were very encouraged by their partnership to agree to that -- to agree to the accelerated designs for both trials.

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

Just going back to the data that we're going to see in 2Q, were there any new side effects that emerged from the data set? Or as we think about efficacy, did it kind of fall within the normal bounds that we've seen in the past? Or has anything kind of emerged from in that data set? Anything you can say would be great.

Yes. There's nothing shocking, Peter. There's nothing -- the safety and tolerability is in line. We've touted and continue to tell. I think one of the advantages of ziftomenib is its drug -- its tissue penetrants and its safety and tolerability. That continues to be the case. That's part of why these combinations have gone so quickly because it's so well tolerated. As for the efficacy data, which everybody kind of keeps trying to get under the edge of, we'll show it to you. It's in line. We're looking forward to sharing it with you. There's obviously a lot there. It's -- it will be a good update, I think, around the middle of the year.

Okay. And then just on the venetoclax kind of dosing, is there anything we should read into that, on the negative? Is there kind of any worries that we should be thinking about for drug-drug interactions?

No, you should be reading positively into it and that physicians will be more apt to keep their patients on trial because they will have less exposure and therefore, less myelosuppression and adverse events due to venetoclax is due to the venetoclax alone, nothing with the drug interaction with zifto, but the actual real-world usage of ven/aza.

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

Congratulations on the data. I guess, our question is primarily around the use of MRD negativity for the intensive combo and then just using CR for non-intensive combo. Can you talk a little bit about why MRD negativity wasn't used for both trial sets? And then also, I guess, related to that, I think it was mentioned on the call that you'll be using bone marrow. Can you remind us of the CR MRD negativity rate from 007? And was that bone marrow or peripheral blood?

Sure, I'll start with the last question first. What we presented thus far for MRD negativity from 007 has been site level data. And so in general, it has been peripheral blood. So we will look forward to getting some of our samples essentially and hopefully sharing those soon when we're able to share the broader data set as well. With regards to why MRD negativity for the CR endpoint with 7+3, is really to give us a place to improve. Currently, these patients see an 80% to 90% complete response rate from 7+3, and it's very hard to improve significantly over that, although we do realize that these patients still have a significant unmet need because they're relapsing and -- by 3 years, 70% of them are going to have their AML return by year 3. So the best way to do that is looking at a more targeted endpoint for this particular patient group. And that targeted endpoint will be the MRD negativity, which we actually now know correlates so well with survival based upon data that continues to go out. The reason not to do it in van/aza somewhat to keep it simple. We do have room for improvement there. You expect to see a 40% to 60% CR rate. So there is definite room for improvement over that with addition of a targeted agent. And there's also less data present in the MRD negativity space for venetoclax-azacitidine usage. So we tried to limit the amount of uncertainties when we were designing the trial. And this was the best way forward for us that gave us 2 solid accelerated approval endpoints to use in both of these trials.

And then maybe just as a quick follow-up. Should we expect like maybe some diminution of activity when we -- as we go from kind of this is what we got using peripheral blood. And this is the kind of MRD negativity we're seeing from bone marrow. Would you expect to see some sort of a decrease? Or will it be pretty much in line?

No. There's a documented difference between looking at the peripheral blood and looking at the bone marrow peripheral blood, you see about 70% to 80% MRD negativity in some published studies. And as I said, in those same patients in the bone marrow, you would see about a 40% to 45% MRD negativity. So it's much more sensitive to look at the bone marrow.

Our next question comes from the line of Erik Lavington with Mizuho.

Congratulations, again. I am on for Salim here. So I'm just wondering if we could -- if you could share anything else -- share anything about the secondary endpoints. And as I'm looking at the data readout time lines. It looks like current HN got pushed out a little bit. Just wondering what the puts and takes on that are?

Yes. Thanks for the question. Pleased that you actually read that far down into the release or listened to the call. The timing of that is really -- we had guided on current HN to middle of the year. Honestly, we're just sitting on that data until we show the top line data from 001, the KOMET-001 study and the combination data. I'm not sure anyone from Wall Street wants to see the current HN data. So that's us being -- trying to be judicious on the timing of data. That's number one. Number two is we're guiding toward Phase I data for 2806, both as monotherapy and in combination with cabozantinib. We will do it probably some time in the second half of the year at Investor Day, where we walk through what is the mechanism of farnesyl transferase in these indications? How do you think about these tissue types? How do you think about the baseline activity? What's the clinically meaningful data set? What are you actually looking for? But we deliberately put the monotherapy for 2806, the RCC combo for 2806 and the current data altogether. And the point is, we actually think we have something pretty interesting with 2806, but let's save that to the second half. We have lots to talk about prior to that, again, with the ziftomenib monotherapy data, the ziftomenib combination data. So that's really the rationale. It has nothing to do with the data and us wanting to kind of time data releases so that we can tell a more coherent story.

All right. And can you comment on any of the secondary endpoints on the 001?

On 001, yes. So we'll be looking at the duration of response, of course, transfusion independence and overall safety as well as other ones further down the line like progression-free survival, but just very traditionally, what would support approval, but the main ones being duration of response and transfusion independence.

Our next question comes from the line of George Farmer with Scotiabank.

This is on Chloe on for George. Two from us. First, related to MRD negativity. So I know you can't share too much here. But on timing and time lines, to what extent do you think having MRD as the accelerated approval endpoint will be able to shave off time as opposed to if you have the more traditional [indiscernible] OS time point. Did you get a sense of what it would be shaping up a couple of months or maybe a year or 2 would be great to get your impressions on this. And then on diabetes, we were wondering for your plans to nominate a candidate in, I guess, later this year. Would you be doing that at a company event or a medical meeting? And if at a medical meeting could we expect more preclinical data as well?

Yes, good question. So, Chloe, On the timing of MRD negativity, the difference is meaningful. I mean, we haven't given specifics yet because we're still running the numbers. A lot of it relates to enrollment. In order to get to the end points, you have to get enrollment. And we're still running through what that looks like as well as gaining global regulatory alignment. We don't want to give a date and then start moving that date around based on our own sort of internal discussions or discussions with health authorities. But it's a meaningful -- that's why it's accelerated approval. It's called accelerated for a reason. It's a meaningful difference off of the survival endpoint, EFS in this case. As for the menin development candidate, we are on track to nominate it. I don't think we'll have clinical -- sorry, I don't think we'll have preclinical data on it. We showed a lot of data relating to ziftomenib in the different assays. At some point, we'll likely show it, but I doubt it would be this year because a lot of that data just takes time to run it out. And we're also determining the best way in which to create value for that menin diabetes program. Do we do it alone? Do we do it with a potential partner? How do we think about it? So at this point, the only milestone we've given is nomination of a menin inhibitor development candidate.

Our next question comes from the line of Justin Zelin with BTIG.

This is on for Jeet on for Justin. Congrats on the data and the progress. Just 2 questions from us. To get a bit more granular on the mode of disclosure for the 001 update at a medical conference, will everything be fully presented as part of a conference abstract or will perhaps more be saved for the conference itself?

I mean, more -- yes, so that -- within the question is the answer. So the abstract will be the abstract. It won't have all of the data. There will be obviously more data at the time of the presentation. I -- we sense there's some questions, some frustration. Folks saying, show the data, blow the embargo. In our view, you got to do what's best for patients, and you have to do what's best practice. And so you will see the data -- the top line results are not only statistically significant, they will support, we believe, approval. They will support it being competitive. Let me just make that clear to all the twitterati out there. And we think we will compete very effectively with the competition. We also have to take a lot of stakeholders into account. And while some people may not like it, it is the right thing to do to respect the embargo. If we blow the embargo and everybody says, well, why didn't you present the data, then you can't take that back. So you will see the abstract, then you'll see the full data presentation. And as you can imagine, we're in the process of actually analyzing the data for purposes of the NDA submission. So we look forward to giving you a very thorough look into it at -- again, at an upcoming medical meeting a little bit later this year.

And just as a follow-up, can you speak to the process that led to the alignment for settling on CR and overall survival as the dual primary end point for the ven/aza study, whereas others in the space appear to be using overall survival alone?

Ultimately, we saw a path forward for an accelerated approval endpoint and decided to pursue it. Our assumptions, our clinical arguments and our scientific rationale were all agreed to by the FDA, and so we can't help, but be encouraged by that support from them and trying to help us get to approvable endpoints sooner for these patients.

Our next question comes from the line of Joe Pantginis with H.C. Wainwright.

First, just a quick thank you for taking the most canonical path forward to reporting data and medically sound approach. So 2 questions, please. First, on 001, I know you might not be able to answer this, but directionally speaking, did you hit targets for both CR and CRh, number one. And then for 017, regarding the SAP, can you talk about or anything about the alpha spend for the first look for CRs?

Yes, Joe, let me take that. So we can't break out. You see our CRh is really what matters, right, for the monotherapy approval. Let's save the further analytics to the data presentation of the top line data. Bless you for making the comment, by the way, citing the canonical approach. On the alpha spend, I think it's premature to try to answer that. We need to, again -- need to make sure we've got alignment among the global health authorities for the trial and are fully through. As Mollie indicated, there's a lot of different ways to skin these cats, and we want to make certain that we have one thing that's locked down and that we disclose this in the right way. So we'll be in a position to answer that question a little later in the year once we are -- have really locked down on numbers of patients, time lines, statistical assumptions and so forth, it's just premature.

That concludes today's question-and-answer session. I'd like to turn the call back to Dr. Wilson for closing remarks.

Thanks, Elizabeth. Thank you all. Thank you for the very many questions. We look forward to seeing all of you. We have an earnings call here a little later in February. So we'll give you another update at that time. In the meantime, thank you for your attention, and we wish you a good afternoon and good evening.

This concludes today's conference call. Thank you for participating. You may now disconnect.