Kura Oncology (NASDAQ:KURA) has provided a comprehensive update during its second quarter earnings call, underscoring significant advancements in its oncology pipeline, particularly with its flagship drug ziftomenib. The company announced that it has completed enrollment for the registration-directed portion of the KOMET-001 trial for ziftomenib, with over 85 patients enrolled. Ziftomenib also received a breakthrough therapy designation for relapsed/refractory NPM1-mutant acute myeloid leukemia. Additionally, Kura Oncology reported positive preliminary data from the KOMET-007 trial and received FDA clearance for an Investigational New Drug application for ziftomenib in combination with imatinib. Despite these advances, the company reported a net loss of $50.8 million for the quarter, with increased research and development expenses. However, with $491.5 million in cash and short-term investments, the company expects to have sufficient funding to continue operations into 2027.
Key Takeaways
- Ziftomenib received breakthrough therapy designation for a specific leukemia treatment.
- Enrollment completed for KOMET-001 trial registration-directed portion.
- Positive preliminary data from the KOMET-007 trial.
- FDA clearance for Investigational New Drug application for ziftomenib with imatinib.
- Net loss of $50.8 million for Q2 2024, with increased R&D expenses.
- Cash reserves expected to fund operations into 2027.
Company Outlook
- Kura Oncology plans to present updated data from the KOMET-007 trial later in the year.
- The company will report topline data from the ziftomenib registration-directed trial.
- Initiating a proof-of-concept study for ziftomenib and imatinib in advanced GIST.
- Nominating a next-generation menin inhibitor development candidate for diabetes.
Bearish Highlights
- Net loss of $50.8 million reported for the second quarter of 2024.
Bullish Highlights
- Breakthrough therapy designation for ziftomenib may accelerate its development and review.
- Positive preliminary clinical data from trials suggest potential efficacy of the drug.
- FDA clearance for Investigational New Drug application indicates regulatory progress.
Misses
- Increased research and development costs contributed to the net loss for the quarter.
Q&A Highlights
- CEO Troy Wilson discussed the potential of ziftomenib at higher doses and plans for combination pivotal trials.
- The focus on leukemia and GIST, with potential for future compounds in other therapeutic areas.
- Wilson highlighted the importance of safety in developing menin inhibitors for diabetes.
- Upcoming conferences were announced, with invitations to contact the company for further questions.
Kura Oncology (ticker: KURA), has shown a strong commitment to advancing its pipeline, with ziftomenib at the forefront of its efforts. The company's focus on developing targeted therapies for various cancer indications, along with its strategic planning for future developments, positions it as a proactive entity in the biopharmaceutical sector. While the financial losses reflect the high costs of innovation, Kura Oncology's robust cash position allows it to continue its research and development endeavors with an optimistic outlook for the coming years.
Full transcript - Kura Oncology Inc (KURA) Q2 2024:
Operator: Good day, and welcome to the Q2 2024 Kura Oncology Conference Call. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to Pete De Spain, Head of Investor Relations. Please go ahead.
Pete De Spain: Great. Thank you, Amy. Good afternoon, and welcome to Kura Oncology's second quarter 2024 conference call. Joining me on the call are Dr. Troy Wilson, our President and CEO, and Tom Doyle, our Senior Vice President of Finance and Accounting. Before I turn the call over to Troy, 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.
Troy Wilson: Thank you, Pete. And thank you all for joining us. This past quarter was highlighted by strong execution across the organization as we continue to generate a robust clinical data package to support broad development of our menin inhibitor program beginning with ziftomenib. In April, ziftomenib became the first investigational therapy to be granted Breakthrough Therapy Designation for treatment of relapsed/refractory NPM1-mutant acute myeloid leukemia. FDA awarded BTD based on data from our KOMET-001 trial, recognizing ziftomenib's potential as an innovative medicine for patients with this devastating disease. In May, we announced completion of enrollment in the registration-directed portion of KOMET-001, enrolling more than 85 NPM1-mutant AML patients in fewer than 16 months. We believe this important milestone reinforces ziftomenib's potential best-in-class profile. As a reminder, NPM1-mutant AML represents approximately 30% of new AML cases annually, and is a disease of significant unmet need for which there's no approved targeted therapy. With the KOMET-001 study now fully enrolled, we look forward to sharing topline data early next year as we continue to work closely with FDA to expedite development and review of ziftomenib as a monotherapy. Meanwhile, we continue to evaluate ziftomenib in combination with current standards of care in patients with both NPM1-mutant and KMT2A-rearranged AML. Earlier this year, we reported preliminary clinical data from 20 patients enrolled in the Phase 1 dose escalation portion of our KOMET-007 trial. Ziftomenib demonstrated an encouraging safety and tolerability profile, as well as meaningful evidence of clinical activity when administered in combination with cytarabine plus daunorubicin, commonly known as 7+3, as well as with venetoclax plus azacitidine. Notably, no differentiation syndrome events of any grade were reported. Furthermore, no dose-limiting toxicities, QTc prolongation, drug-drug interactions, or additive myelosuppression were observed. Continuous daily dosing of ziftomenib at 200 milligrams was well tolerated, and the safety and tolerability profile was consistent with features of underlying disease and backbone therapies. Since that update, our team has continued to demonstrate outstanding execution and the KOMET-007 study has now enrolled more than 100 patients. I'm pleased to report that the safety, tolerability and clinical activity of ziftomenib continue to support advancement into both the FIT and UNFIT frontline populations. Two of the four cohorts have cleared the 600 milligram dose and advanced into the Phase 1b expansion study. The two remaining cohorts are expected to clear the 600 milligram dose and advance shortly. The Phase 1b expansion study includes multiple combination cohorts, most notably ziftomenib plus Ven/Aza, in newly diagnosed NPM1-mutant or KMT2A-rearranged AML, as well as ziftomenib plus 7+3 in newly diagnosed NPM1-mutant or KMT2A-rearranged AML, removing the requirement for patients to have high risk disease. Each combination cohort is enrolling independently, and we expect to enroll approximately 20 patients per cohort. We believe the Phase 1b expansion study will continue to lay the groundwork for helping us to redefine the current standards of care for newly diagnosed patients with both NPM1-mutant and KMT2A-rearranged AML in both the FIT and the UNFIT populations. We look forward to presenting updated data from the KOMET-007 combination trial of ziftomenib at a medical meeting later this year. It should be a meaningful update. In addition to the progress our team has made with the KOMET-007 study, we continue to dose patients in our ongoing KOMET-008 study of ziftomenib in combination with additional standards of care, including the FLT3 inhibitor gilteritinib, as well as FLAG-IDA, and low-dose cytarabine. Roughly half of all patients with relapsed or refractory NPM1-mutant AML have co-occurring FLT3 mutations, and the prognosis for these patients is poor. Preclinical data for ziftomenib in combination with FLT3 inhibitors has shown strong synergistic effects compared to either single agent alone. When we look across the FIT, UNFIT and FLT3 mutant AML frontline populations, we believe a best-in-class safety and activity 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 patients with acute leukemias whose disease is driven by the menin pathway. Over the past couple of years, we've generated a growing body of preclinical data that supports opportunities for menin inhibitors beyond acute leukemias, including the potential for ziftomenib in certain solid tumors. Earlier today, we announced FDA clearance of our Investigational New Drug application for ziftomenib in combination with imatinib for treatment of advanced gastrointestinal stromal tumors. GIST is the most common form of sarcoma, characterized as KIT-dependent solid tumors. KIT inhibitors are associated with favorable outcomes for patients with GIST, and imatinib is the frontline standard of care in this patient population. For patients who progress on imatinib, subsequent treatment options consist of other KIT inhibitors. However, these options are limited by moderate efficacy and challenging tolerability. The Menin-MLL complex regulates KIT expression in GIST cells, and menin inhibitors display additive therapeutic activity in combination with imatinib in imatinib-sensitive GIST models. Our preclinical data suggests ziftomenib has potential to resensitize patients to imatinib and induce deep, durable responses. Building upon an initial report from the Armstrong Lab, we've generated a substantial amount of preclinical data that further support the opportunity for ziftomenib in GIST. We look forward to presenting these data for the ziftomenib-imatinib combination at an upcoming scientific meeting. And following the IND clearance announced this morning, we plan to initiate a proof-of-concept study evaluating ziftomenib in combination with imatinib in patients with advanced GIST after failure of imatinib early next year. If successful, the potential opportunity in GIST appears to be mutationally agnostic, enabled by ziftomenib's favorable pharmaceutical properties, with an addressable market as significant as our frontline opportunities in AML. In June, we reported preclinical data supporting the potential therapeutic utility of menin inhibitors in the treatment of diabetes. The new findings were presented at the American Diabetes Association Scientific Sessions in Orlando. Type 2 diabetes is marked by an inadequate number of functional pancreatic beta cells, which results in insufficient insulin production leading to hyperglycemia. Ziftomenib demonstrated meaningful levels of glycemic control in the preclinical in vivo model, including reduced fasting blood glucose levels and %HbA1C within 27 days, as well as consistent improvement in both insulin sensitivity and insulin production. The preclinical data showed that the effects of ziftomenib were fully maintained following dose discontinuations, suggesting restoration of beta cell mass. A decline in pancreatic beta cell function and/or mass has been defined as a key contributing factor to disease progression in Type 2 diabetes. Notably, in human islet microtissues originating from donor samples, ziftomenib induced beta cell proliferation while non-beta cell proliferation was not detectable, demonstrating menin is a viable therapeutic target for beta cell mass-specific expansion. We're advancing multiple next-generation menin inhibitor drug candidates targeting Type 2 diabetes and potentially, Type 1 diabetes, and we expect to nominate the first of these next-generation development candidates in early 2025. Now let's turn our attention briefly to our farnesyl transferase inhibitor programs. Despite success of targeted therapies, a considerable need remains to drive enhanced antitumor activity while addressing mechanisms of innate and adaptive resistance. We're developing our next-generation farnesyl transferase inhibitor, KO-2806, to address these needs. 2806 was designed to improve upon the potency, pharmacokinetic and physical chemical properties of earlier FTI drug candidates. Last year, we presented compelling preclinical data supporting the potential for KO-2806 to address mechanisms of innate and adaptive resistance in distinct classes of targeted therapies, including tyrosine kinase inhibitors and KRAS inhibitors. Late last year, we began dosing patients with KO-2806 as a monotherapy in a Phase 1 dose escalation trial that we call FIT-001. FIT-001 uses an innovative design that enabled us to begin dose escalation of 2806 in combination cohorts very early on in the study while continuing to dose escalate concurrently as a single agent. In February, we dosed the first patient with KO-2806 in combination with cabozantinib in clear cell renal cell carcinoma just four months after KO-2806 entered the clinic. And I'm pleased to report we recently dosed the first patient in its combination study with adagrasib in KRAS G12C-mutated non-small cell lung cancer. As a reminder, the study of KO-2806 and adagrasib is supported by a clinical collaboration and supply agreement with Mirati, now a Bristol Myers (NYSE:BMY) Squibb company. If successful, we believe KO-2806 could drive enhanced antitumor activity and become an ideal combination partner to multiple targeted therapies in large solid tumor indications. Meanwhile, we continue to evaluate the combination of tipifarnib with the targeted therapy alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma in a Phase 1 dose escalation study that we call KURRENT-HN. We remain pleased by the manageable safety and tolerability profile of tipifarnib in combination with alpelisib, and we're encouraged by the clinical activity observed at multiple dose levels. We remain on track to complete enrollment of the two expansion cohorts to help inform selection of the optimal biologically active dose for the combination by the end of this year, and we look forward to presenting preliminary clinical data from the KURRENT-HN trial of tipifarnib and alpelisib at a medical meeting in the first half of 2025. With that, I'll turn the call over to Tom for a discussion of our financial results.
Thomas Doyle: Thank you, Troy. And good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the second quarter of 2024. Research and development expenses for the second quarter of 2024 were $39.7 million, compared to $28.2 million for the second quarter of 2023. The increase in R&D expenses was primarily due to increases in clinical trial costs related to our ziftomenib and KO-2806 programs. General and administrative expenses for the second quarter of 2024 were $16.7 million, compared to $11.8 million for the second quarter of 2023. Net loss for the second quarter of 2024 was $50.8 million, compared to a net loss of $37.2 million for the second quarter of 2023. This included non-cash share-based compensation expense of $8.4 million, compared to $7 million for the same period in 2023. As of June 30, 2024, we had cash, cash equivalents and short-term investments of $491.5 million, compared to $424 million as of December 31, 2023. We believe that our cash, cash equivalents and short-term investments will be sufficient to fund our current operating plan into 2027. With that, I turn the call back over to Troy.
Troy Wilson: Thanks, Tom. Before we jump into the question-and-answer session, let me just quickly lay out our anticipated upcoming milestones. For our menin inhibitor program, present updated data from the KOMET-007 trial of ziftomenib in combination with Ven/Aza and 7+3 at a medical meeting in the fourth quarter of 2024. Report topline data from KOMET-001 registration-directed trial of ziftomenib in NPM1-mutant relapsed/refractory AML in early '25. Present preclinical data supporting the opportunity for GIST - for ziftomenib in GIST, excuse me, at a scientific meeting in the second half of 2024. Initiate a proof-of-concept study evaluating ziftomenib and imatinib in patients with advanced GIST in the first half of 2025. And nominate a next-generation menin inhibitor development candidate targeting diabetes in early 2025. For our farnesyl transferase inhibitor program, identify the maximum tolerated dose for KO-2806 as a monotherapy in the second half of 2024. Complete enrollment of two expansion cohorts in KURRENT-HN. And identify the optimal biologically active dose of tipifarnib and alpelisib by the end of 2024. And present data from the KURRENT-HN trial of tipifarnib in combination with alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma in the first half of 2025. With that, Amy, we're now ready for questions.
Operator: [Operator Instructions] Our first question comes from Li Watsek of Cantor Fitzgerald.
Li Watsek: Hi, great. Congrats on the progress. Maybe just first on the update in Q4. Troy, can you tell us a little bit about, in terms of patient distribution in the expansion cohort among - I believe there are 100 patients, and so we're looking at multiple cohorts at different doses. So maybe a little bit of information there will be helpful. And then the second question is on GIST. I saw there was very interesting biology. So just wondering what other gating steps are before you move into proof-of-concept study in first half of next year and what would be the bar for success? Thank you.
Troy Wilson: Sure, Li. Thanks for the questions. So on the update for 007, as we've said, we've dosed at this point more than 100 patients in the ongoing 007 study. Just to remind everyone, we need to dose a minimum of 72 patients across the four different genetically driven cohorts at each of 200, 400, and 600 milligrams. So that's, four genotypes times three doses times at least six patients per dose. The reason we've enrolled more than the 72 is, we think, due to investigator and patient enthusiasm to get access to ziftomenib, as well as the fact that we leave these cohorts open for enrollment while we're moving to the next dose level. So patients that are in screening are eligible to go into that cohort if the next cohort hasn't yet opened. So we've actually seen, I believe, over-enrollment in nearly every cohort at every dose. Li, what we're encouraged by is the fact that the safety and tolerability continue to be very consistent with what you saw in our January update. I think enrollment has been robust, and we would expect once we get into these expansion cohorts, enrollment should continue to be robust because we are, in the case of 7+3, removing the restrictions on adverse risk. I'll just remind everyone the escalation is in the adverse risk population. And in the case of Ven/Aza, we will move from the relapsed/refractory setting to expand in both the frontline Ven/Aza as well as to expand in the relapsed/refractory setting. So by the time we get to the end of the year, Li, we'll - that's why I say, I don't think we know exactly today what the update will be completely, but it's going to be a meaningful update with a lot of patients, a lot of data, good durability across the cohorts. Obviously, the 200-milligram cohorts having been on the longest, we're looking forward to sharing that update when the time comes. In terms of GIST, you asked about the gating steps for the trial. At this point, the study is in study startup. So, we'll do this with relatively few U.S. sites initially. Now that we have an open IND, we can move as quickly as possible through the site initiation and contracting phase. Things have changed quite a bit from when I started in this industry. You used to be able to do this in a couple of months. It's a bit longer now to get up and running. We do think, first half next year is a reasonable guide for first patient in. We use - we worked with multiple leading KOLs in GIST, both to evaluate the data and to help design the study. You asked, what does success look like? That really came from those KOLs. So we're going to deliberately be in the population that is progressing or has just failed imatinib. So what you're looking to do is to reverse that. Again, you'll see that the nonclinical data, it goes quite a bit beyond what Dr. Armstrong and his colleagues presented in their paper. But if you can, either - if you can drive responses, right, durable responses, that would be the gold standard. That's really what we're looking for. And we are going to do some amount of dose optimization to ensure that we meet the requirements of the FDA's Project Optimus initiative, right? That continues as you move through these combos. So we'll talk more about, Li, kind of - once we show you the nonclinical data, we can talk a little bit more about what to expect. Obviously, if we get a good signal, our goal would be to go straight into the frontline. Because this combination is so powerful and so orthogonal to how people have treated GIST, we think it really could be transformational for those patients and really help, drive durable responses. But let's take it one step at a time.
Operator: The next question comes from Jonathan Chang at Leerink Partners.
Jonathan Chang: Hi, guys. Thanks for taking my questions. First question, with a Phase 2 registration-directed KOMET-001 study fully enrolled, as you look ahead to interactions with regulators, how are you thinking about what you can do to minimize any potential hiccups along the regulatory process? And second question, on KOMET-007, can you provide any color around your experience with the different ziftomenib dose levels and going with the 600 milligram dose in the expansion combination cohorts? Thank you.
Troy Wilson: Sure, Jonathan. Thank you for the questions. So with respect to 001, we said consistently that we were looking to secure - if possible, to secure Breakthrough Therapy Designation ahead of engagement with FDA. This is where it becomes really important, right, as you interact regularly with the FDA. We are actively doing that. We are preparing the modules for the ultimate NDA submission. Obviously, the long pole in that tent is the clinical data, but you have to do CM&C and Clin pharm and all the various modules of the NDA. We are, as we've done with - we're going to talk about 007 in a second. We've, I think, been steady in how we've managed things and guided to things. We've done a lot of work around dose optimization, a lot of work around safety, extensive characterization of the Clin pharm and the dose. We're not, Jonathan, planning on taking advantage of RTOR. We're planning on pursuing just the normal path through, leveraging the interactions through BTD. We look forward to continuing to have a pretty engaged interaction with FDA. We are meeting with them regularly, and I think very much on track to where we want to be. There are obviously no guarantees, but I think we're doing everything we can. We've got an expert team both internally and through various outside experts to help us guide that. On your second question relating to 007, the - so you've seen a couple of things. You've seen the data from the monotherapy at the 200 and 400 and 600 milligram doses, and you've seen the initial combination data from 200 milligram in our January update. What we can tell you is, as with the monotherapy, the safety and tolerability is consistent as you go up in dose. We don't see drug-drug interactions, we don't see dose-limiting toxicities, we don't see any kind of safety signals that aren't attributable to either the backbone or the disease. So you might say, well, why do you choose the higher dose versus one of the lower doses, particularly as those cohorts are still maturing. And what I would tell you here is the monotherapy data says very clearly, there is enhanced activity at 600 milligram relative to 200 milligram. If the safety is equivalent and the safety, augurs in favor of the higher dose, you're going to go with that higher dose. But let me go one step further. One of the advantages we think that ziftomenib has over potential competitors is its very high tissue penetrance, its whole-body exposure. On the downside, this is ultimately what led to a higher incidence of DS as a monotherapy in the KMT2A-rearranged population. But now that we've mitigated that, it's what we think will ultimately drive long-term whole-body exposure, potentially delay, micro metastases or extramedullary disease, and ultimately, we hope, lead to better outcomes. So all things being equal, Jonathan, if the data supports it, we'll go with the higher dose. The safety monitoring committee accepted the team's recommendation on the first two cohorts. I have every expectation that will be the case here imminently on the remaining two cohorts, and then we'll be expanding at 600 milligram. We think that's going to give you the best benefit risk in these combination populations.
Jonathan Chang: Understood. Thanks for taking the questions.
Troy Wilson: Our pleasure. Thank you.
Operator: The next question is from Jason Zemansky at Bank of America.
Cameron Bozdog: Hi, team. This is Cameron on for Jason. Congrats on the quarter, and thanks for taking our question. I'm curious how we should be benchmarking success for activity in the expansion cohorts. I guess, how do you expect the goalpost to shift once you enter 7+3 and non-adverse risk AML? And then what about for the first-line Ven/Aza combo? And then a follow-up, if I may.
Troy Wilson: Yes. So it's a good question, Cameron. I won't give you specific numbers, I mean, today. There are references there, things like the VIALE study, for example, in Ven/Aza. Clearly, you do expect higher response rates, better outcomes as you go to these frontline populations. By the same token, in general, you're dealing with healthier patients - I mean, they're healthy, relatively speaking, right? They still have life-threatening AML. But all things being equal, they're healthier than patients with adverse risk or relapsed/refractory. So given the outstanding safety and tolerability that we're seeing, given the encouraging activity, you saw the 200 milligram dose in January, you will see - when the abstracts come out in November, expect to see 200 and 400 milligram data. The 200 milligram is the most mature; the 400 milligram, a little less mature; the 600 milligram at that stage, given that was as of a June data cut, relatively less mature when you - because that'll - we submitted the abstracts in August. You will see - you'll see them in November. I think by the time we get to the end of the year at the medical meeting, you'll have a much more mature sort of comprehensive picture of how to think about that combination data. And then you had a - Cameron, you had a second follow-up question as well.
Cameron Bozdog: Yes. I'm just curious, as you look towards additional updates, maybe what would be encouraging in terms of duration response in these cohorts, as well as maybe MRD negativity rates, what's differentiating and what are physicians ultimately likely to focus on here?
Troy Wilson: Yes, so that's a really good question. And I - Pete and I talk regularly. I think we will spend much of the second half of the year probably in an expectation setting exercise. There's a few things here, Cameron. Ideally, you want to - so the real benefit of menin inhibitors and ziftomenib in particular. Once these patients come off of standard of care, and let's just take the simple example of 7+3, that's seven days you want to keep them on a menin inhibitor for as long as they're in response, receiving clinical benefit. Whether or not they go to transplant, that's really, I think, where ziftomenib has an advantage. We offer the potential for physicians to take their patients to transplant, but at least in the NPM1 setting, they don't need to. As you know, transplants are more common in the KMT2A patients. They're quite common in the relapsed/refractory with the KMT2A, but with the much larger - I mean, NPM1 is 10 times larger than KMT2A. In that population, you're going to look at the depth of response, the durability of response. Do they go to transplant? Essentially, how long can we keep them in a response. And I think the safety and tolerability that we've seen from zifto is looking very attractive relative to other targeted therapies that people might use as benchmarks. Again, we can talk about that more offline, but that's sort of how we think about it and I think how, at a high level, how the physician community is going to look at it as well.
Cameron Bozdog: Got it. Thank you so much.
Troy Wilson: Sure.
Operator: The next question is from Roger Song at Jefferies.
Roger Song: Great. Congrats for the progress, and thank you for taking our question. So maybe we - looking ahead for your expansion cohort for 007, how should we think about the data release versus the potential pivotal for those standard of care combination, given you will potentially have the label for monotherapy soon? And then how should we think about a combo into the label? Thank you.
Troy Wilson: Roger, I'm sorry, can you repeat that question? I'm not sure I understand the interplay between the expansions and the monotherapy, and I want to make sure I answer the question you're asking. Can you just run that by me one more time?
Roger Song: Yes, sure. So the expansion cohort, just curious about the data timing versus the potential pivotal plan for the combination. And then the monotherapy you're going to have the data next year, but how we should think about the combination pivotal plan. Thank you.
Troy Wilson: Oh, okay. Thank you. Thank you, Roger. I appreciate that. So I can tell you this, we are preparing at risk for combination pivotals. And exactly how we prosecute them, the tactics by which we do it, let's set that to the side for now. Everything that we're seeing gives us increasing confidence that there are meaningful opportunities both for patients and for shareholders to move into the FIT, the UNFIT, and I'm optimistic, the FLT3 population as well. Our goal is really - we talk about potentially being applicable to up to 50% of AML patients. Everything we're seeing suggests that that's the right aspirational goal. We will - what the agencies or the health authorities, Roger, care about from the standpoint of the pivotal is safety and tolerability and have you defined your dose. We will have that information in time to inform those discussions with health authorities and start the pivotal, I think, in the first half of next year. So we're on track to do that. The question of activity, we are already moving at risk, again, based on what we're seeing, believing that we can design a trial or trials that will potentially support a marketing application in the combinations. So we're not necessarily, in other words, waiting for the efficacy data to read out in the expansions. I think we're optimistic it will be as good as, if not better than, what we've seen in the escalations. And what we've seen is encouraging given, again, we're in adverse risk in the 7+3 escalation, we're in relapsed/refractory in the case of Ven/Aza, but we look at our own data, we look at data from our competitors, and I think we feel pretty good. As far as the monotherapy, again, we've said topline data, early '25. I think we're looking likely at an NDA submission sometime next year, I don't think we've guided specifically, but we're going to move as quickly as we can. We want to do the right thing and get it in there as smoothly as possible. Whether physicians use these drugs in combination in the real world, Roger, I think, that is partly what's driving the incredible interest in the combinations. We'll, of course, promote - we'll promote ziftomenib initially within that monotherapy label. But that's why - and we're not alone here. Everybody wants to get to these frontline populations as quickly as we can because that will make it - that will be the best for patients. It will also - for the two or three leaders in the field, it will make it that much more difficult for anyone to come behind us. Because the chance of dosing a menin-naive patient will go down dramatically when you have two or potentially three sponsors running frontline studies. So there's a lot going on, Roger, and we're going to try to do as much as we can in a staged way to both impact patients and drive value for shareholders.
Roger Song: Excellent, thank you. Thank you for the guidance regarding the combo pivotal next year, early next year. Okay, maybe just a follow-up question related to the next-gen menin inhibitor. So I think you mentioned it's mostly focused on the diabetes, Type 1, Type 2. Just curious, would you be also considering next-gen menin inhibitor in other therapeutic areas, including the oncology solid tumor, et cetera? Thank you.
Troy Wilson: Yes. So there's two answers to that question, Roger. The first answer is - and you'll - again, you'll see this when we show you the nonclinical data for GIST. All menin inhibitors are likely to be active in this setting, but there's something very special about the drug-like properties of zifto. Those properties that give you high tissue penetrance, a very high volume of distribution, are ultimately what you want, whether you're treating disseminated AML or solid tumors. So -
Operator: One moment, please.
Troy Wilson: Sorry, Amy? Okay. So you're - we think ziftomenib is ideal from the standpoint of both liquid and solid tumors. Is there a reason for a follow-on compound? Potentially. But at the moment, I think you're seeing us put the focus on zifto in that setting. And we're talking right now just about leukemia and GIST. We have other things that Francis Burrows and his team are working on. If and when the time is right, we'll share additional opportunities with you. I think we've been very deliberate, very measured in how we bring out this data for you. Shifting gears to diabetes, there you - it's safety, safety, safety. If you look at the preclinical data for zifto, in our view and in the view of many experts, it says one should move forward and evaluate a menin inhibitor - a reversible menin inhibitor in diabetes. We will - we intend to do that. We have a number of different molecules that we are advancing. There's really a premium - at the risk of stating the obvious, there's really a premium on safety in that indication. So we are being very, I think, deliberate, very measured, again, in moving those compounds forward. I think we're going to find that menin continues to show us new sides and new opportunities. There's a lot of really interesting emerging biology. At AACR, there was some interesting biology with Cat6. I would say stay tuned, menin has more to teach us. But Roger, that's how we think about it; zifto on the oncology side, next-gen on the diabetes side, and let's move those forward as quickly as we can.
Roger Song: Thank you so much, Troy.
Troy Wilson: My pleasure.
Operator: Our next question today will come from Brad Canino of Stifel. Please go ahead.
Brad Canino: Hi. Thank you. And impressive enrollment here. I wanted to ask about what we saw from J&J (NYSE:JNJ)'s menin combos at EHA. Last year in '23, they reported the monotherapy DS rates around 12%, but they had one Grade 5 event. And then recently at EHA '24, they showed the combo work where they did the schema, where they pre-dose with Ven to reduce blast burden, which is very similar to what you're doing, and the combo did cut rates down to about 3% in 60 patients, which I think is very validating for your approach. But when they had DS, it was again a Grade 5. So first I want to know, do you think it's unfair to draw parallels here to zifto? But under that assumption, I'm wondering how you think about the level of assurance that you can have for a menin inhibitor with a heightened monotherapy DS signal when it comes to the ability to completely avoid Grade 5 even in combos. Thank you.
Troy Wilson: Yes, Brad, it's a good question. I don't - do you know, Brad - I don't, off the top of my head. Do you know whether that second Grade 5 event or that combo Grade 5 event was in a KMT2A-rearranged patient?
Brad Canino: I don't believe it's disclosed in the deck.
Troy Wilson: Okay. In our experience - again, I said in January, I said two things. With respect to 100% CR rate in the frontline 7+3, I said don't get emotionally attached to 100%. And I said don't get emotionally attached to 0% as far as DS. You are going to see some measure of DS. And just for everyone on the call, for these relapsed/refractory patients, many of them are hospitalized. If you're hospitalized, you are by definition, Grade 3. You want it to be, ideally, sufficiently mild that you can treat it with steroids. You don't have to withdraw the menin inhibitor and the patient essentially rides through it. I will say, Brad, there is a learning curve on these compounds. And we've seen that both in the monotherapy and the combos. The physicians who've treated a handful of patients have a much better time, they just know what to look for versus physicians who perhaps this is their first experience with a menin inhibitor. And you will see, for example, if you do a time course, it may look like the patient still has blast. Those blasts are actually in the process of differentiating. If you give them a week or two and the patient comes back, the patient may be clear. There is a learning curve, Brad. I don't know that we're ever going to reduce it to zero. We've been fortunate to this point that the DS that we've observed has been mild and very manageable. But I do think there is that off chance that you get a patient who's unlucky, a complicated medical history, the physician who maybe there's some confounding factors. I don't think we can rule it out. But that's not unlike venetoclax with TLS. It's not unlike CRS, in some of the other therapies. It is definitely a measure of activity. And we are making real efforts toward education and just informing physicians, as I'm sure our competitors are as well. The entire field is learning as we go. And I think we're - all of these physicians are benefiting from one another's experience. So it's not something we're overly concerned about, but I do think you have to be watchful.
Brad Canino: Thanks, Troy.
Troy Wilson: My pleasure.
Operator: The next question is from Phil Nadeau from TD Cowen.
Phil Nadeau: Thanks for taking our questions. A couple on the combo data and then one on just in terms of the combo data for zifto. You're not calling the 600 milligram dose yet the recommended Phase 2 dose at least it doesn't sound like it is. We're curious why that is. Is it just a question of semantics or is there another step that's necessary before 600 milligrams the formal Phase 2 dose for combo therapies? And second, on the combos, do you anticipate providing overall survival data from the combos when you report it at - presumably at ASH? And is there an overall survival profile you need to see before moving into pivotal studies? And then on GIST, our understanding is that the vast majority of patients who are resistant to imatinib have secondary mutations. So we're kind of curious as to the mechanism by which zifto can resensitize. We don't want to steal the thunder of the upcoming medical presentation, but we're curious if you'd give any details.
Troy Wilson: Yes. Three good questions, Phil. Brad, you had a good question too. Sorry, I didn't mean to say you didn't. But three good questions, Phil. So let's - on the RP2D, I think it's doing a disservice to the process and to the agency to call it semantics. We've identified the recommended Phase 2 dose. We made a recommendation to the Safety Monitoring Committee. They gave the go-ahead to move into the expansion. Where this becomes relevant is it doesn't really get tested until you take your next design, in this case, a combination pivotal, to the appropriate health authority and say, this is the study we're going to run at this dose and this is the data supporting that dose. And that's where we're calling it - we're saying we identified it. I wouldn't want to beat our chest and say this is it. Because ultimately, that is a decision of a health authority. But the agency was very clear in - when - when we designed the 007 study, we did not need to go back to them and share data after the escalation before we moved into the expansion. They felt comfortable that Kura, as sponsor, in collaboration with the Safety Monitoring Committee and the IDMC, make that determination as to what is the right dose to move into the expansions. So for all intents and purposes still, that is the identified RP2D. Let's just - as with everything relating to the ultimate combination pivotal, it is something that will ultimately be reviewed by the health authorities. I hope that makes it clear. More than semantics, but not a whole lot more. On your question around survival. I wouldn't call it survival. Survival is -, that - it's something more appropriate for kind of a randomized study. You will see durability. You will see both time on study and, I suspect, time on therapy. And that is instructive. Again, what we can tell you - so we've had - we've started dosing this study in July of last year. We have, patients who are coming on a year now. I think we're feeling good about what we're seeing in terms of safety, tolerability, ability to drive clinical activity. You'll see that. I would characterize it, though, more as durability, duration of response, rather than survival. But we're going to show you the patients, and of course, the 200 milligram will be longer than the 400 milligram, will be longer than the 600 milligram. But I think it's - as I say, I - it was a bit understated on Pete's part when we were putting the written comments together. It'll be a meaningful update. We're looking forward to sharing it. On your third question around the secondary mutations. Yes, that's our understanding as well. I did say something in the prepared remarks that's important. So with the exception - there is a mutation in GIST that prevents the binding of imatinib. So you do need imatinib to be able to bind. If imatinib is able to bind, then you can - then that synergy will occur. In our experience, there's really only one mutant that actually blocks imatinib. The other mutations that people are going after - as long as imatinib is still active, the combination is - this may be - Francis might slap me upside the head, but it's synthetic lethal at this point. So the interesting opportunity here is you don't need - potentially, you don't need a companion diagnostic, potentially you don't have to slice and dice the population. If you can go on top of generic imatinib in the frontline, or let's say the 1LB setting, you're going to come ahead of everybody else. And that's the target population that we're going to be shooting for. You'll see that nonclinical data when we show it to you later this year. That's the manner in which the study is designed. I will say this mechanism works equally well with the other KIT inhibitors that are used in GIST. The reason we're going with imatinib is that's - obviously go after the largest part of the funnel and make it as simple as possible for both physicians and patients. So that's the rationale.
Phil Nadeau: That makes a lot of sense. Thanks for taking our questions.
Troy Wilson: My pleasure.
Operator: The next question comes from Peter Lawson at Barclays.
Alex Bouilloux: Hi, good afternoon. It's Alex on for Peter. Thanks for taking the question. Another one 007 and the update later this year, specifically on the Phase 1, the dose escalation with 7+3 in the adverse risk population. Just maybe remind us the benchmark there, how we should think about, CR/CRh and durability in that specific group of patients.
Troy Wilson: Yes Alex, good question. The reference that we've cited previously is the control arm to the registrational study that was conducted with Vyxeos. That showed, I think it's approximately a 35% CR/CRh rate. It's - that's about - and just to remind everybody, adverse risk here - KMT2A are adverse risk by definition. The other - the NPM1 are adverse risk if they are over age 60, if they have a treatment-related AML, or if they have the ELN criteria that make them adverse risk. It's one or more of those three categories. So, Alex, to the best of our understanding, that's kind of the benchmark of what you would expect for 7+3 in this adverse risk population. In terms of durability, I'll be honest with you, Alex, I don't have that number right off the top of my head. You can look it up in the Vyxeos reference. I'm sure it's there.
Alex Bouilloux: Okay, thank you. And then just maybe a quick question on the KOMET-008 study. Wondering if you could make any comments on enrollment dynamics here. And then I'm guessing initial data from this is probably in 2025. Thank you.
Troy Wilson: Yes, right. So two parts to your question. So 007 is being conducted at - presently at approximately 30 U.S. sites. We've not taken the study internationally yet. The 008 study, Alex, is being conducted at even fewer sites at this point. And that was done deliberately so that the enrollment in 008 didn't cannibalize patients from 007 or 001. So the team, our clinical operations team and our development colleagues were very deliberate in how they did it. 008, the enrollment is now beginning to tick up because as 007 crests and moves into the expansion, now you put 008 into the next slot. And so we're beginning to see a pickup across all three arms there, gilteritinib, FLAG-IDA, and LDAC. I would - we haven't guided, Alex, yet to timing for data. There is a lot of interest in that gilt combo because, again, half of the NPM1 patients are believed to have co-occurring FLT3 mutations. So that's a combination - I mean, all combinations are - we do them for a reason, but that one's of particularly high interest. So I would say stay tuned. And when we have more visibility as to when you'll expect data, we'll provide that in a future update.
Alex Bouilloux: Great. Thank you.
Troy Wilson: Sure.
Operator: The next question comes from Justin Zelin at BTIG.
Justin Zelin: Thanks for taking the question, and congrats on the progress. So, Troy, you made a comment earlier about patients on zifto may not have to go on to transplant, they might be able to stay on drug here. But just wanted to hear your latest thoughts about use in the maintenance setting. And, do you expect the usage of zifto in the maintenance setting after you get your first approval here? Thanks.
Troy Wilson: Yes, Justin, it's a good question. So again, I think you have to be - Mollie, who's not on the call, has taught me to be precise in my language. In the KMT2A - in the frontline and in the relapsed/refractory for KMT2A, those patients are typically younger. You want to get them to transplant as quickly as you can, in general. Not always, but in general, that's true. In the case of NPM1, those patients are often older, and so there may not be as much of a desire to move them to transplant. What we're seeing, Justin, is quite interesting, and that is they seem to do well in either case. This is focused more on the NPM1 than the KMT2A because your question is about transplant. But I think we give physicians the option. If they want - if they believe it's in a patient's best interest to go to transplant, they have that option, and then they can put them back on ziftomenib. All of our protocols allow that, allow the physician or the patient to go back on zifto post-transplant. If, on the other hand, they feel that perhaps they'd want to save that transplant, delay that transplant, then they can do that. And they seem to get very good benefit. You might say, well, why would they save the transplant. And the reasons are we forget - I mean, it's, in many cases, still the best option for a cure, but it is not cost-free. There is a 20% to 25% risk of mortality, you typically have graft versus host disease, you're on lifelong immunosuppressants. There are a lot of complications associated with transplant. So in that older population, particularly NPM1, Justin, you may actually - if you're able to drive a durable CR, you may greatly delay the time to transplant and really save that. The final thing I'll say, Justin, is we are also pursuing a formal post-transplant maintenance study. That's the 012 protocol. That is currently in a safety run-in phase as part of an IST. That would ideally allow any patient who fits the genotype to come on post-transplant. Whether that patient has come from zifto, from a FLT3 inhibitor, from another menin inhibitor, they would be eligible to go to that. Let's break that out separately. We're basically, Justin, going to do it all. And I think the beauty of it is, again, because of the safety, the tolerability, the activity of zifto, you're giving physicians this optionality. They can take patients to transplant or not. And you'll see - we're looking forward to sharing this data with you at the end of the year. I think it'll become clearer as we walk you through the data that has been generated in the 007 protocol to date.
Justin Zelin: Great. That's helpful. Thanks for taking the question.
Troy Wilson: Our pleasure.
Operator: The next question comes from George Farmer at Scotiabank.
George Farmer: Hi, good afternoon. Thanks for taking my question. Troy, I was wondering if you could elaborate a little bit more on your diabetes data. Other than safety, how do you think zifto compares and maybe one of your follow-on compounds compares to existing menin inhibitor data that's out there in the clinic? And how does this program differentiate itself from others?
Troy Wilson: Yes, George, it's a great question. Thank you for the question. So what you saw in the ADA poster was ziftomenib in the various assays, in the rodent assays, as well as in the INSPIRE assay. We have run the competitor compounds against those same assays. That data remains unpublished. I will tell you, the safety, the tolerability, the activity look different. And, what is clear - I think an open question was at least preclinically, George, could you drive the activity with a reversible menin inhibitor? And I think the answer is unequivocally yes. And again, having my team pioneer the KRAS covalent inhibitors, I've had my fair share of experience with irreversible inhibitors. That is - those electrophiles are not to be underestimated. What's important is you can - with a compound that has the safety and tolerability of zifto, or even better, potentially with a next-gen compound, you can get all of that activity that you see in the ADA presentation. So we are planning on moving it forward. For many reasons, we think it makes more sense to prosecute the oncology applications with zifto, the diabetes applications with one or more additional compounds. That's our approach, rather than trying to do it all in one. We'll have more to say about that, as this year progresses and we get into next year.
George Farmer: Okay, great. That's very helpful, Troy. Thanks.
Troy Wilson: Our pleasure. Thank you.
Operator: There are no further questions at this time, and that concludes our question-and-answer session. I would like to turn the conference back over to Troy Wilson for any closing remarks.
Troy Wilson: Thank you, Amy. Thank you all once again for joining the call today. We're going to be participating in a series of upcoming healthcare conferences, and we look forward to seeing many of you there. In the meantime, if you have any additional questions, you know how to reach us. Please feel free to contact Pete, Tom, or me. Thank you again, and have a good evening, everyone.
Operator: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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