Kura Oncology, Inc. Aktie

Good day, everyone. My name is Stefan, and I'll be your conference operator today. At this time, I'd like to welcome you to Kura Oncology's investor call to discuss the long-term results of ziftomenib and 7+3 in newly diagnosed AML. [Operator Instructions]

At this time, I'd like to turn the call over to Troy Wilson, President and Chief Executive Officer of Kura Oncology. Please go ahead, Dr. Wilson.

Thank you, Stefan. Good morning, everyone. We're coming to you from Stockholm, Sweden, the European Hematology Association meeting, and we're delighted to share with you the latest update from our frontline results of ziftomenib with 7+3.

If we could please go to the next slide. In today's presentation, we're going to be making forward-looking statements. So of course, we'll refer you to our website and the SEC's website for more information about Kura Oncology and the risks and uncertainties of an investment in the company.

Take us to the next slide, please. It was just a couple of weeks ago that we came to you from ASCO where we brought you an update on our darlifarnib program. We're really at a point now where we're executing across the company. The KOMZIFTI launch is going very well. We have robust new patient starts and early momentum. Today is part of our effort to help provide data and talk about how we think we can advance ziftomenib to achieve our goal of addressing up to 50% of AML patients. And this is the next in a number of important readouts around the program.

If we can please go to the next slide. I'm joined this morning by 2 other participants, Dr. Amer Zeidan. Dr. Zeidan is Professor of Medicine at Yale Cancer Center as well as Dr. Mollie Leoni, who, of course, is the Chief Medical Officer of Kura Oncology.

We can go to the next slide, please. The agenda for today is Mollie is going to spend just a moment or 2 on the results that were published in blood on the combination of ziftomenib and venetoclax/azacitidine in the relapsed/refractory NPM1-mutant AML setting. Dr. Zeidan will take us through the presentation at EHA, where he'll discuss the long-term results for ziftomenib and the 7+3 combination in the newly diagnosed NPM1 and KMT2A populations. And then Mollie is going to take over and relate the results from the 007 trial that Dr. Zeidan is discussing to how you should think about our ongoing KOMET-017 study in frontline AML.

If we could go to the next slide. And with that, I'll turn it over to Mollie. Mollie?

Thank you, Troy. So now that ziftomenib or KOMZIFTI is approved as a monotherapy, Kura has been dedicated to generating data in the combination setting. To this end, we have a robust development program that has the ability to benefit patients with menin-dependent AML across the treatment continuum. Next slide. In today's presentation, we will be discussing 2 important pieces of the continuum, the combination of ziftomenib with venetoclax and azacitidine in the relapsed/refractory setting and the combination of ziftomenib with 7+3 in the frontline setting. Both of these data sets come out of the KOMET-007 trial. The sample sizes have been robust and able to support and inform the KOMET-017 registrational trial that is evaluating ziftomenib in newly diagnosed patients. While frontline data and their applicability in the KOMET-017 trial are a primary focus of today's presentation, we wanted to begin with an important update in relapsed/refractory setting.

If we go to the next slide. The important results of ziftomenib in combination with ven/aza in the relapsed/refractory setting have recently been published in blood. Moving to the next slide. And the results are very important to patients with relapsed/refractory NPM1 mutant AML. This study enrolled patients that were heavily pretreated, many of whom had already received venetoclax-based therapies. In the venetoclax-experienced patient population, where we would expect minimal patient benefit, we saw a 48% ORR with 24% achieving a CRc of significant durability.

Importantly, we saw in patients that were ven-naive an 87% ORR with 70% of patients reaching a CRc with a meaningful duration that appears to have also translated into survival for these patients as the median OS has not been reached. These data are remarkable when we consider the poor ORR and OS expected for these patients. These deep and durable responses exceeding what one would expect with ven/aza alone in this relapsed/refractory setting with a well-tolerated combination regimen speaks volumes with regards to the importance of menin inhibition early in the treatment paradigm.

And with that, I will pass it over to Dr. Zeidan, who will discuss the data surrounding zifto's use in the frontline setting.

Thank you so much, Dr. Leoni. So I'm going to be talking about the combination in the frontline setting with ziftomenib. This is the presentation we will be doing in EHA meeting this weekend. Next slide, please. So these are my disclosures, including consulting for Kura and Kyowa. So as you just heard, ziftomenib is an oral menin inhibitor that is given once a day that has been already approved as a potent selective inhibitor in the relapsed/refractory setting for patients who have refractory leukemia, acute myeloid leukemia with NPM1 mutations.

But at the same time, it has shown promising preclinical activity in combination with standard of care therapies that we have been using for AML for a long time, including intensive chemotherapy with 7+3. And as you just heard with aza and ven. So the KOMET-007 has been exploring these combinations in a large ongoing international study that includes dose escalations as well as dose expansions, both in the frontline setting as well as in the refractory relapse setting for both subsets of leukemias that have been shown to benefit from menin inhibition, primarily NPM1 and KMT2-arranged leukemia.

Next slide, please. So the focus of the presentation in EHA this year is going to be on the frontline combination with intensive chemo 7+3, and this is in patients who are deemed to be fit to receive intensive chemotherapy by their physician. So the way the trial was conducted is that we have 2 separate cohorts, one for NPM1 and one for KMT2A rearranged leukemias. Both of those underwent a dose escalation starting with a 200 milligram, 400 milligram and then 600 milligram of ziftomenib in combination with 7+3 in the dose escalation phase that went subsequently into a dose expansion phase using the optimal dose, which was determined to be 600 milligrams of ziftomenib.

And what we are presenting in the meeting is all the patients who have been enrolled on both the dose escalation and the dose expansion part of the study that have received the optimal dose, the 600 milligram, which I would note is the dose that's also being tested in the randomized registrational Phase III trial that you will hear about later in this meeting. So here, you can see the patients who were enrolled in terms of their disposition. We are presenting data in 99 patients, which I believe is the largest experience in the frontline setting reported to date of any menin inhibitor in combination with intensive chemotherapy.

49 patients had NPM1 mutations and 50 patients had KMT2 translocations. You can see that at the time of this data cutoff, which was April 10, 2026, the median follow-up at that point was 17.6 months for NPM1 and 11 months for KMT translocation. And at the time of the cutoff, 90% of the patients with NPM1 and 62% of the patients with KMT2A patients were still on study either on treatment phase or in the survival follow-up phase of the study.

Next, please. So these are the baseline characteristics. I would note for the NPM1 mutation, and I think this is important as you interpret the results that the dose escalation part of this study required patients who had NPM1 mutation to also have what we call factors that make them adverse risk. So they had to be either older than 60 or they had what we call therapy-related AML or they had adverse cytogenetics. All of these predict worse outcomes. So those were the patients who were treated in the dose escalation part. But once we have gone to the dose expansion part of the NPM1 mutation patients, it was open for all newcomers.

And what this resulted in is that the median age of the patients who had NPM1 mutations in this study was 60 years old. So half of them were older than 60 basically. While the KMT2-arranged patients were slightly younger with a median age of 43, we have slight predominance of females on this. And some of the patients, as you can see here, had co-mutations as is expected in this setting, including a small number of patients who had FLT3. The FLT3 patients who had those mutations were generally considered to be too low to receive in terms of their variable allele frequency to receive a FLT3 inhibitor or had a FLT3-TKD.

Next, please. So these are the -- an overview of the side effect profile. What you can see here is the treatment-emergent adverse events that occurred in 30% or more of all patients. This does not really add much in terms of the safety beyond what we have seen in previous presentations from the study. Primarily, most patients will experience treatment-emergent adverse events because this is given in combination with intensive chemotherapy and the safety profile is very well recognized in this setting. So I think the primary conclusion from this data set is that it does not seem that the addition of ziftomenib to 7+3 is causing additional toxicities. What we are primarily seeing here is count suppression in the form of thrombocytopenia and neutropenia as well as febrile neutropenias, some GI side effects in the form of diarrhea, some pruritus. However, again, all of these are within what you typically expect with no new or unexpected adverse events with the longer-term follow-up of this patient cohort.

Next, please. This slide on the safety front is looking at the severe treatment-emergent adverse events defined as Grade 3 or higher that occurred in at least 10% of patients. And again, the same focus being count suppression, which is primarily driven by the intensive chemotherapy that's given to those patients as well as a small incidence of other things such as pruritus and GI side effects.

I think what is important to note is that the treatment adverse events of interest such as differentiation syndrome and QTC prolongation occurred in a small number of patients, for example, differentiation syndrome occurred only as a Grade 3 in 4 patients. There were no Grade 4 or Grade 5. All of these DS events completely resolved with protocol mitigated interventions and 3 of them were actually able to continue on ziftomenib therapy. And the same thing for QTC prolongation. There were 3 cases that were Grade 3 that were assessed by the investigators and there were no Grade 4 or higher and all of them resolved and the patients were able to continue on therapy.

Next, please. So I think here, we are seeing, in my opinion, the most impressive data of this presentation in the next 2 slides, focusing on the responses and the survival data. So I'm going to present the data kind of looking at each cohort separately because I think there's important differences between these patients that are important to note. So I would start by the complete response, which is really understood in the context of intensive chemotherapy to be one of the most important endpoints to achieve in this setting.

And what you can see in NPM1 mutated patients out of a relatively large sample size for a Phase II trial of 49 patients, we are seeing a stable CR rate of 94%. This number actually over the previous 3 presentations we had of this data set, not only has been in this range, but actually went up, indicating the stability of the CR rate, which again is, I think, one of the highest we have ever seen in the context of intensive chemotherapy for any acute leukemia patient subset. And again, most of those were full CRs, meaning you have complete count recovery. The MRD negativity, which is another indication of the depth of the response was observed using local assessment in the vast majority of patients for the NPM1, it was observed in 85%.

I will be talking about the central MRD negativity, which is we are presenting for the first time in this presentation in the next slide. And I would also observe that the median time to CR MRD negativity was quick at 1.5 months. When you look at the KMT2A, again, those patients generally have a more severe disease. They are generally expected to have worse outcomes than the NPM1 and this is -- reflects what we see. But at the same time, I think those outcomes compare favorably to what we typically expect with 7+3. For example, the complete response rate was 82%, the complete -- the composite CR was 90%. And again, the CR -- MRD negative CR was the majority of patients at 86%, and it was observed to occur relatively quickly with a median time to MRD negative CR of 0.9 months.

Next, please. Here is the central molecular MRD negativity. And this is important because MRD negativity locally has been assayed by different methods, including flow cytometry and genetic studies, but also it was done locally by different centers. So here, the advantage is you are using one highly sensitive genetic test that's done in a central lab, giving you, I think, a lot of confidence in the findings. And here, what you can see is that the MRD negative composite CR was also quite high, as you can see. And we looked at it at 2 different thresholds using 0.1%, 1 in 1,000, which was observed in 79% of patients. And again, this is only in NPM1 mutated patients where MRD negative CR has been really, I think, shown to be a surrogate for long-term outcomes, including EFS and OS.

For using the threshold of 0.01% or 1 in 10,000, it was observed in 56% of patients. And again, those MRD negativity results were obtained relatively quickly with a median time of around 2.2 months. So by the second cycle, by the end of consolidation 1, which is generally has been considered the most important endpoint time for the MRD negativity, all of those patients who have achieved MRD negativity have already reached by the end of the second cycle of intensive chemo, which is usually the end of the first cycle of consolidation therapy.

Next, please. And concurrent with the safety profile that I think was impressive and the fact that we think one of the problems of adding drugs to intensive chemotherapy in general has been the concern about additional myelosuppression, which can translate into adverse events. One of the -- I think one of the most reassuring aspects of this particular combination is that it does not seem to add additional myelosuppression. And this is here reflected by the time to count recovery with a neutrophil count of more than 1 and a platelet count of more than 100, which constitute the CR. You can see that the time -- median time to count recovery for both was around 28 days, which is what we generally see with 7+3 itself. So that suggested that the myelosuppression is not being worsened by the addition of ziftomenib to intensive chemotherapy.

Next, please. So these are swimmer plots that demonstrate the durability of the response. So it's not only a very high rate of complete responses, but those CRs appear to be durable, as you can see in this figure. So with the median follow-up of 17.6 months, the median duration of the CR, and this is for the NPM1 mutated patient cohort, was not reached. At 12 months, 80% of patients were still in CR, 10 patients underwent transplant of the NPM1 mutated patients.

And most of those patients were able to continue on maintenance, which was allowed in the protocol in which ziftomenib again was started on day 8 and was continued throughout and the protocol allowed the patients to go into maintenance either post transplant if their physician elected to go to transplant or after the completion of consolidation chemo. So most patients were able to proceed to the maintenance phase, 31 patients were able to do that. 8 of them were after -- on study transplant. And only 8 patients discontinued at any point due to relapsed or refractory disease with a very low rate of discontinuation due to adverse events, only 4 patients, one of them only was ziftomenib related.

Next, please. In the KMT2A rearranged leukemia, again, we see here the durability of the responses, noting again that this patient subset have a higher-risk disease and generally, not only they have a lower chance of achieving responses with 7+3, but generally, their durations are lower. So I think when you look at the data in combination with ziftomenib, you can see that these data are exciting. Here with a median follow-up of 11 months, median duration of CR was 12 months. Most of those patients have undergone transplant, again, reflecting the belief by the physicians that those patients are at high risk of kind of adverse outcomes and relapse. So this is why most of those patients are being geared toward transplant in general whenever possible. And many of those patients continued on ziftomenib maintenance primarily after the transplant performance. 10 patients discontinued due to relapsed or refractory disease and 7 due to adverse events. Only 2 of them were ziftomenib related.

Next, please. So I think, in my opinion, this is the most important slide in this presentation. If I was going to show one slide summary of what I think is most exciting, this would be the one. So this is what you can see here is the overall survival curve in NPM1 mutated patients. You can see a very nice, almost straight line with the survival. Of course, here after a median follow-up of 17.6 months, the median overall survival was not reached. At 12 months, the overall survival rate was an impressive 94%. And I would add here one of the things that we also monitor when we give patients intensive chemotherapy is what I call induction mortality or early mortality, which is the chance of dying in the first 60 days from complication.

This was very low at 2%, which again is extraordinary low. Remembering, again, that this is a large international study. Those patients were treated in many centers. This was not only one highly specialized single center. So I think to see such a low induction mortality is quite impressive. And the other point I would make also is that those patients, as I mentioned at the beginning, those are older and higher risk than your average patient because of the patients who were included in the dose escalation part of the study, in particular.

The median age was 60. So when you try to compare historically generally in terms of the CR rates, in terms of the durability of the CR as well as the overall survival rate, I think these numbers compare very favorably. And at the same time, this is combined with good safety where time to count recovery is only 28 days and the risk of adverse events is generally along the lines of what you expected with 7+3 itself. And as you can see, most of those patients are still alive and continued on study, and we will continue to follow these data until maturity on the longer run.

Next, please. So these are similar data for the KMT2-arranged patient subset. Again, the outcomes here look a little bit worse than the NPM1, but this reflects the higher risk nature of this particular entity of acute leukemia. Still here with a follow-up of 11 months, the median OS was not reached. And 60-day mortality was still good at 4% and 62% of those patients were still on study either on the treatment or on the follow-up phase of the study and the 12-month survival was 71%.

Next, please. So I think in conclusion, in this analysis from the KOMET-001 study, which, as I mentioned at the beginning, I believe to be the largest data set of intensive chemotherapy treated patients who received it in combination with a menin inhibitor that has been presented to date, the combination was very well tolerated with a safety profile that is consistent with previous reports and also doesn't seem to be significantly different than 7+3 by itself, in particular, when it comes to lack of additional myelosuppression, quick time to count recovery. And I think the adverse events of special interest, in particular, differentiation syndrome seems to be very largely mitigated.

This is one of the advantages of giving a combination of chemotherapy along with the menin inhibitor, not only to enhance the synergistic activity and the efficacy, but also it mitigates the risk of the differentiation syndrome. Beyond the safety, I think the clinical results are extremely exciting, in particular, the NPM1 cohort with a CR rate of 94% and a CR that is very durable. The median duration has not been reached and 80% are still -- of those in CR were still in CR at 12 months, but also the median OS not reached and OS at 94% for NPM1 patients at 12 months. And similarly, for KMT2A, a high rate of complete remission of 82% with a median CR duration and median OS that were not reached. So I think all of these data support the ongoing registrational Phase III trial, KOMET-017 for the intensive chemotherapy part of it that combines ziftomenib with 7+3 against randomization to 7+3 by itself. With that, I think this is the last slide. Thank you.

Thank you. And every time I see those data, I get more excited and more confident in our ongoing frontline registrational trial, the KOMET-017 trial. And I want to highlight that the experience with KOMET-007 has been able to inform the development of this important registrational KOMET-017 trial with that. The basics of KOMET-017, the trial was designed to generate clinically and registrationally relevant data for global markets.

The trial contains 2 large independently and conservatively powered Phase III studies, which have the ability to detect clinically meaningful benefit for patients. We are enrolling across North America, Europe and Asia Pacific with the intention of generating a geographically diverse data set pertinent to all major commercial markets. However, our trial sites have a limited focus on markets that potentially have significant differences in their treatment paradigm, thus reducing potential risks to 017 that could manifest via differences in clinical practice or supportive care.

This multiregional clinical site footprint will support commercial readiness by building investigator experience and familiarity globally. Our ultimate goal with the design of KOMET-017 was to optimize for speed, but just as importantly, for regulatory and scientific credibility, statistical probability of success and commercial relevance. KOMET-007 data are instrumental in facilitating this design.

If we go to the next slide. So first and foremost, the safety and tolerability emerging from the KOMET-007 trial is reassuring for the conduct of KOMET-017. The overall safety profile for ziftomenib in combination with 7+3 is consistent with that seen with the 7+3 backbone. The rate of differentiation syndrome, a known risk when administering a differentiating agent like ziftomenib is considerably decreased compared with monotherapy rates. The events have been readily resolved with supportive treatment.

QT prolongation was seen infrequently in the trial. When events were detected, they each had causes likely unrelated to ziftomenib therapy that were resolved so that treatment could continue. The ziftomenib therapy -- the concurrent use of zifto with 7+3 does not result in delayed count recoveries for these patients. Neutrophils and platelets returned to normal ranges within 28 days of treatment initiation, indicating no additive myelosuppression with 7+3. And finally, the addition of zifto to this backbone regimen does not adversely affect induction-related mortality rates. This totality of data from the KOMET-007 trial supports and recommends the ongoing registrational KOMET-017 trial.

Going to the next slide. Even more striking is the efficacy we are seeing that more than recommends continued momentum in the KOMET-017. Here, I am focusing on the NPM1 mutant solely because they will make up the majority of patients enrolled into the registrational trial. However, as you can see in Dr. Zeidan's presentation, the same apparent benefits and outcome measures are seen with the KMT2A patient population. Starting with the CR rate, we are seeing even our older patients having a 90% to 100% complete response rate, far exceeding the expected benchmarks of 56% to 88% for this patient population.

The 7+3 portion of KOMET-017 was designed to have an accelerated approval endpoint of CR MRD negativity in the bone marrow. The reference for this in NPM1 patients is 44%. We saw 56% of our patients achieved this bone marrow MRD negativity, which again supports the design of KOMET-017. And the most important of outcomes is the overall survival. MRD-negative CR is expected to predict an improvement in overall survival. Our median OS has not been reached for NPM1 mutant patients, but at 12 months, 94% of the NPM1 mutant patients are alive in sharp contrast with historical numbers ranging from 45% to 80% in these age groups. Again, this supports and recommends continuance of the KOMET-017 registrational trial as designed.

If we go to the next slide. What we have seen with the KOMET-007 trial gives us great confidence in KOMET-017. But with KOMET-017, we have put additional measures in place. Important among them is central MRD testing. Having a central method in place improves reliability and maintains regulatory standards. With local MRD testing, there are multiple laboratories performing different types of tests with the likelihood of creating site-to-site variability and making comparison difficult. With central MRD samples are tested at a single lab with the same test, allowing uniform assessment in accordance with regulatory requirements.

Moving to the next slide. Assessing the MRD in this uniform way allows us to translate these deep molecular responses we have been seeing into an accelerated path towards value creation in frontline NPM1 AML. As a reminder, MRD-negative CR is the co-primary endpoint for accelerated approval in the 017 trial. As data has grown in the field, MRD negativity has consistently emerged as a predictor of long-term outcomes. The bone marrow MRD negativity we are seeing in 007 compares favorably with historical benchmarks. And these data that we believe are predictive of outcomes in 017 are clinically meaningful and appropriate to support FDA accelerated approval.

Moving to the next slide. As Dr. Zeidan was referencing, ultimately, it's this slide that tells the story better than any of us actually can, an OS survival curve for AML that extends at this level over a 24-month period. I don't know what other endpoints could actually matter more than that. The median EFS and OS have not been reached. The 12-month OS is superior to 7+3 alone. These data all tell you that menin inhibition is an important part of the treatment paradigm and that treating early with the combination appears to have a positive benefit risk balance that we will continue to explore, not only in the relapsed/refractory setting as we showed you in combination with ven/aza, but also for newly diagnosed patients.

And with that, I will pass it back to Troy.

Thank you, Mollie. We could go to the next slide, please. So this is part of our initiative with the launch underway in the relapsed/refractory NPM1 setting, as we've guided, we think that total addressable market opportunity in the U.S. is $350 million to $400 million. As both Dr. Zeidan and Dr. Leoni mentioned, the goal is go earlier, go in combination, and you can see that as we work our way up the curve. Ultimately, and I think the data support this, we're optimistic that if the KOMET-017 studies are successful, we could be poised to achieve a much more significant U.S. total addressable market of up to $7 billion. And I think you can see why we say that now. The goal is get these patients into response and then keep them on continuation therapy. Many of those NPM1 patients, in fact, did not go to transplant. They're just remaining on zifto cycle after cycle.

We go to the next slide, please. So where we are today? Again, a couple of weeks ago, we talked about darlifarnib. This week, we're talking about ziftomenib on the left-hand side. The launch is going well. We have robust momentum and gaining market share. And we are firmly focused on continuing to advance ziftomenib through a variety of different combinations to address up to the 50% of AML patients that we think could benefit. The 007 results, although they are Phase Ib results, we think that they support a best-in-class profile among menin inhibitors and that they continue to derisk the ongoing Phase III registrational studies. Both Dr. Zeidan and Dr. Leoni said it well. The survival data sort of speaks for itself. And we're very excited. The enrollment in the 017 studies is going very well. We're hopeful that with this data, it will only accelerate, and we remain committed to transforming the standard of care for patients with acute leukemia.

Next slide. And with that, that concludes our prepared remarks, and we'll now go to a question-and-answer session. Stefan?

[Operator Instructions] Our first question will come from Li Watsek with Cantor Fitzgerald.

Very impressive OS data. And I guess just given the impressive durability of the response and OS rate, what is your best estimate for duration of therapy in the frontline setting?

Mollie, would you like to -- I don't know if we can answer that question, but we would like to try.

I mean it's certainly still evolving. You'd see that it's going to be at worst about 24 months is what it looks like at this point. These patients are, in general, very successful on treatment, getting into a response and then staying on treatment with the monotherapy once they're in their response. So we don't have the exact answer yet because thankfully, for these patients, their treatment is still ongoing, and we're still able to follow them to get additional information.

Great. And let me just clarify, those of you who want to ask a question, if you'd like to ask a question and follow-up question, please feel free. We're going to limit it to just one question and one follow-up. But -- you're welcome to get back in the queue, but going forward, one and one is fine.

Stefan, next question.

Our next question will come from Jason Zemansky from Bank of America.

Okay. We'll move on from Jason in the meantime. We'll move on to Phil Nadeau from TD Cowen.

Congrats on the data. We have a question on the MRD negativity rates. What level of MRD negativity is correlated with survival? Is it the lowest threshold that you presented or the second threshold? And then kind of as a follow-up to that, how is MRD negativity going to be used to decide on the treatment plan for patients? So which patients would go to transplant, which ones would be more amenable to maintenance therapy without transplant. We're curious to hear your thoughts on that.

Mollie, do you want to start with that?

Yes, sure. So we showed you multiple treatment -- multiple MRD cutoff points because it would allow you to compare it to maybe the local values. And that's why we showed you the less sensitive and the more sensitive values. We ultimately -- obviously, the lower -- the more sensitive you go, the more predictive things generally tend to be. However, more data is going to come out over the next year or so that are going to show you probably even at less sensitive levels, even that the MRD negativity is quite predictive of survival in these patients. But I would offer it over to Dr. Zeidan to give his opinion on how this is going to influence treatment in the coming months.

Yes, I agree. So I think the more sensitive the test and kind of the deeper the response, we believe, is correlating with kind of longer-term outcomes. I think when it comes to how people are influenced, there has been generally with NPM1 kind of AML, a general practice that if the patient is still MRD positive beyond the first consolidation cycle or subsequently turns from negative to positive, the standard approach has been in patients who are otherwise a transplant candidate is to consider transplantation. There is a separate question about whether these patients need to receive a treatment that can convert into negativity to -- before they proceed to transplant. But I think that reflects the field belief and supports the clinical observation that MRD positivity beyond 2 cycles generally correlates with poor outcomes. And I think certainly, this is influenced in terms of how we kind of counsel and treat these patients.

And Phil, so maybe I'll just add a thought or 2. We wanted to be really clear and break this down because we see a lot of numbers for MRD negativity getting discussed. The treatment decisions are based on the local values. But ultimately, to support an application for accelerated approval, the FDA requires the central testing with that level of rigor that Mollie described. So that's why we're breaking it down for you. Both of them look to be quite clinically meaningful. But when one is thinking about are you going to meet the bar for an accelerated approval, you really need to be now talking about the central values. So hopefully, that will provide some clarity as we look at the menin inhibitor field continue to evolve in the front line.

Okay. And now we'll circle back to Jason Zemansky with Bank of America.

Apologies for the technical difficulties, but congrats on the great progress. I guess this is somewhat theoretical. But given what you've seen from that Kaplan-Meier curve, how much do you think you could realistically address the 1 and 5-year survival rates? And is this sufficient to support widespread use?

Dr. Zeidan, do you want to speak to that?

Yes. So I think we know with acute myeloid leukemia in general is that most patients who relapse generally tend to do so in the first 3 years, and the risk is highest in the first year, goes down a little bit in the second year and then a little bit lower in the third year. So we have patients who can still relapse after 5 years or after 3 years, but the number goes down significantly. Historically, some people used to use 5 years, but I would say 3 years is a pretty good indicator if the patient is cured or not.

So I think based on how this curve is looking, we showed the 12 months as a 94%, but because of the 17-month median follow-up, after the 12 months, there's some degree of [ sensing ]. So I think -- but when you look at the curve, it looks still quite good up to 24 months. So my estimation is that if this trend continues and especially those patients are still ongoing ziftomenib maintenance therapy, my expectation is that this continues. And I would add to that, I think Troy touched on this, is in patients who are older than 60, generally, there has been an ongoing discussion in the field about whether those patients should be transplanted because although they have NPM1, they tend to have worse outcomes.

And I think it was quite impressive to me, the very high rate of CR on this trial, 100%. I mean you cannot get any better than that with the menin inhibitor combination with 7+3, but also the favorable -- as you could see, the average survival and the CR rate is much lower in those patients with 7+3 by itself. So it's clear to me that combination is adding benefit in terms of the durability and the overall survival. I think in another year or so, we'll have a much better sense about the durability, but all the early indicators are going in the right direction in my assessment.

Great. And if I could follow up with a quick one. But to what extent is this data extrapolable to the KOMET-007 data of the ven/aza combination?

Mollie, do you want to speak to that?

So as we've discussed in the past, I believe, we will be showing you an update on the KOMET-007 ven/aza frontline as well in coming months because we think it's important for you to be able to see that translatability as well. But we have just as much confidence in the ven/aza data as we do in the 7+3 data. This just happened to be more mature and available for sharing. But I think you should assume that you're going to see us similarly excited about that data.

Sure. And maybe, Jason, just one more comment for you and the audience. Before we started these studies, we heard from all quarters, sort of a desire to move from 7+3 to ven/aza. And what has been interesting is the 7+3 enrollment has remained very robust throughout the Phase I and now into the Phase III. And I think Dr. Zeidan spoke to it, this combination of ziftomenib and 7+3 provides a really compelling option for patients, particularly those who may -- you may not need to go to transplant. So that's one of the things that has us excited about running the 2 studies as one protocol in 017, patients and their physicians can elect intensive chemo. They can elect ven/aza. They have the option to do either. And I think we're confident that each of these 2 independent cohorts are going to show meaningful clinical benefit for patients. It's great to give those patients options.

So if we can go to the next question.

Our next question will come from Salim Syed with Mizuho.

Great. Can you guys hear me okay?

We can, Salim. Yes.

Okay. Congrats on the data. Just one for us on the safety side of this, Troy. On the QTC prolongation, I know they -- as mentioned is unrelated, but just curious how those patients were managed with zifto paused in those cases and similarly on the differentiation syndrome for the 4 cases, what exactly was the mitigation protocol that was implemented here?

Sure. Mollie or Dr. Zeidan, whichever one of you wants to take that, leave it to you.

I can start and then Dr. Zeidan can fill in. For the QT cases, they were all clearly attributable to other underlying issues such as concomitant medications or electrolyte imbalances. And once those were corrected or dose adjusted, these patients were able to remain on ziftomenib therapy without any additional issues. The differentiation syndrome, we've developed that method of treatment and intervention over many years now. And so it does result in an interruption of therapy, although it probably doesn't need to in the combination setting. And again, these are all just Grade 3 and easily resolved with supportive care and these patients were able to continue on treatment. But Dr. Zeidan, you...

Yes. So I'll over my own also personal experience as I have treated quite a number of patients on this protocol. And I think some of that also speaks to the experience of the investigator in terms of like working with these drugs. I think in some sites where there might not necessarily be a lot of familiarity with ziftomenib, sometimes the initial reflects would be to stop the investigational drug when there's QTC prolongation.

But I think to Mollie's point and has been my own experience is that almost always there are other reasons such as low magnesium, low potassium. So we tend to correct these. We -- often in the context of intensive chemotherapy, we use a number of other drugs, in particular, antibiotics and antifungals. And all of these -- some of them can have QTC prolongation. So I actually always tell my team when we face the situation is that don't stop all drugs at the same time because this is what usually happens that they stop the IP and the antibiotics and it becomes tough to exactly know what's causing things.

So I tend to stop the antibiotic first for 2, 3 days and then see what happens with the QTC. And I can tell you when we did that, generally, the QTC would have normalized without stopping the ziftomenib. But I think sometimes it gets confusing when people stop the drugs at the same time. But my -- again, there were no Grade 4s. There were -- everybody was -- for me, since you are able to restart all the patients back on the drug without QTC prolongation, that's also empiric proof that it probably has not been caused by the drug itself.

And without dose adjustment.

Yes.

Our next question will come from Roger Song with Jefferies.

Congrats on this impressive survival data. This is Nabeel on for Roger. Just one from us. So we did see triplet therapy at ASCO with gilteritinib -- sorry, quizartinib necessitating dose reductions. How do you compare your menin inhibitor safety profile with regards to heme tox? And then anything else we should keep in mind for combos?

Mollie, do you want to take that?

Sure. But I also -- I'm going to then ask Dr. Zeidan to comment because he has some very definite feelings on this topic. I think the data shows you itself that we're not adding any hem tox. So we don't have to sit there and interrupt our therapy to allow counts to recover. We don't have to change doses to allow counts to recover. When the patients are solely on the ziftomenib therapy after their consolidation, they don't have to have a dose adjustment. They're not having thrombocytopenia or neutropenia issues. So we do not believe that we are having any additive myelosuppressive effects with this addition of ziftomenib. But again, I really welcome Dr. Zeidan to comment as well.

No, I fully agree with this. And actually, one of the fun things in my opinion, when you do the randomized Phase III trials is when you don't have a very good sense of which patient is getting what is because everybody is recovering very quickly, this is always very exciting. But I think in this particular context as someone who have given 7+3 with FLT3 inhibitors all the time because these are approved treatments, you could see that the time to count recovery is generally upwards of 35 days before you get like the ANC and the platelets.

So you could easily see that the drug is adding some degree of myelosuppression, which is not the situation with ziftomenib. With ziftomenib, it starts on day 8 and actually continues -- you don't stop it, like I don't know if you are aware of this, but with the FLT3 inhibitors, most of them, they only are given from day 8 through day 21. We have to hold them because if you keep going with them, the patient count recovery will even take longer. So here, you are able to continue throughout without interruptions and still the patients are recovering within 28 days. So I think in my opinion, this is the best empiric proof that you have in terms of the count recovery.

But I would add one of the functional consequences of prolonged time to count recovery and additive myelosuppression, why we hit it is because it leads to infections, bleeding and inpatient induction mortality. And again, on all of these fronts, the combination is doing very well. To have only 2%, 1 patient out of 49 in the NPM1 die within first 40 -- within the first 60 days. And again, remember, the median age of those patients was 60. Half of your patients were older than 60. And to get intensive chemo, only have 1 death out of 49 and no increased significant risk of like severe infections. I think all of this speaks to the lack of additive myelosuppression and the tolerability of the combination.

Our next question will come from Jonathan Chang with Leerink Partners.

Dr. Zeidan, can you discuss your experience with ziftomenib in the commercial setting? How are you using the drug currently? And how do these recent results potentially impact that?

Yes. So I think the drug certainly has a safety profile that has been very good. Primarily, my use has been in the context of the clinical trial because the drug has just been recently approved. But my own experience has been similar to the clinical trial experience, in particular, in terms of how relatively easy it is to give it as a monotherapy. I would make the point that all of these -- that the patients after going into the intensive chemo, whether it's in induction and consolidation, they are going to monotherapy on this particular trial, the 007 drug and 007 trial.

And this is a setting in which you can really see the isolated part of the kind of what is resulting from the drug itself compared to when you are giving it with 7+3. And in that context, I can tell you most of the patients are tolerating it quite well, not only lack of severe toxicity, but sometimes we see what I call chronic low-grade toxicities that are not severe, but they are taken a toll on the patient life that they have to discontinue. And that's not something we see with ziftomenib. Patients are able to continue on it. And again, in the setting of maintenance therapy where the chronic use is going to be even much longer than the refractory relapse setting, I think this becomes very important.

Our next question will come from Charles Zhu with LifeSci Capital.

This is Peter on for Charles. Just thinking about the patients who have relapsed on this trial, what therapies are they getting after? Are any of them getting menin now that a couple are approved in these settings? And is there any role for menin inhibitors actually after relapse on frontline menin combinations?

Mollie or Dr. Zeidan, if one of you wants to take it.

I can say from the overall study perspective, we are certainly tracking that. And it's something that we have seen even within the 007 trial, where we had both frontline and relapsed/refractory patients that patients that may be relapsed after the frontline therapy even in the same trial then went on to our relapsed/refractory ven/aza, which also obviously included a menin inhibitor. But I think Dr. Zeidan's experience with his own patients would probably be more pertinent.

Yes. So I would say, historically, when you had a patient relapse after 7+3, we historically have used other intensive chemos such as FLAG-IDA. But with -- once venetoclax became available, although aza-ven is not approved as a refractory relapsed regimen, it has become very widely used as a salvage regimen after intensive chemotherapy in the case of relapse, in particular, for patients with NPM1 or IDH, which are thought to be subsets that are quite sensitive to venetoclax.

So the practical question became is what do you do with menin inhibitors in that setting? And I think this is where the blood data that Dr. Leoni showed at the very beginning is very relevant because right now, if you have a patient who relapses after 7+3, your question is, do I give a menin inhibitor or do I give aza-ven. And you can just give all 3 together where you are getting kind of, I think, encouraging results. And you can do that indefinitely for patients who are on -- who are candidates for transplant or you can use it as a bridge to get to transplant and then subsequently continue some form of maintenance.

Now to the second part of your question, I think, about what do you do if the patient has got a menin inhibitor as part of their frontline treatment. This is going to be primarily a clinical trial question because these drugs are not approved as combination of frontline intensive chemo yet. I think we are going to collect data from this trial and other trials and understand the issue of the sequencing and whether there are certain mutations that are predictive of responses to certain drugs. But I think this is something that still needs time to be answered.

Our next question will come from Etzer Darout with Barclays.

Congrats on this data update. Just given a meaningful proportion of patients proceed to transplant, particularly in KMT2A, how should we think about the relative contribution of ziftomenib versus transplant and driving the durability in OS outcomes you're seeing? And then would this be something that the Phase III KOMET-017 would allow to isolate to get a better understanding of the contributions?

I actually think you've answered your own question. We don't know for sure exactly what the contribution is with the post-transplant maintenance. And if it influences the outcomes, we think it does. But that's what the 017 trial is specifically designed to look at. That's why there are 3 arms in the trial so that you can look at the effects of post-consolidation maintenance as well. So you have the one arm of patients who are receiving ziftomenib during induction consolidation and post-consolidation maintenance and that consolidation can be transplant or chemo.

You have the patients that are getting zifto through induction consolidation followed by placebo during that post-consolidation maintenance and you're getting patients that are getting placebo throughout. So we really did design it to be able to answer that question. But so far, we think that it's adding to the equation. And really when you have a drug that's not bringing on additional toxicities even with incremental benefit, it becomes worthwhile to keep the patient on. And Dr. Zeidan, would -- could you please also?

Yes. So I'll add my clinical perspective actually not only to the KM2 but also to the NPM1 because I think this is also relevant to some of those patients. So I think it's very important to remember that with KMT2-arrange leukemia, the vast majority of patients would still relapse post transplant. So transplant is not something that you do and then you are all set. Most patients are still relapsing and dying from their leukemia. So it's the community and the patients are really in need of something that would improve their survival beyond.

Now I think like when you approach these therapies, and I'll tell you, for example, if the trial is positive and the drug is available. And I would tell you many people are already probably using this off-label. We are trying to give something post transplant for these patients that has any chance of success because we know that their outcomes are poor even with transplant. So if you have a drug that is easy to take, that does not add to the myelosuppression that's once a day and it's approved in that setting, I think there is going to be a lot of interest to use it. Now in terms of the NPM1, I wanted to add that part because NPM1, again, it sort of has a favorable risk disease, but still a significant number of those patients who relapsed in particular among older patients, patients who are older than 60.

And there is still controversy in the field in terms of recommending transplant in older patients. Some centers still recommend transplant, especially in the lack of -- or in the presence of MRD positivity. But one of the things that patients find extremely, I think, intriguing about this combination as well as the doctors is the potential to be able to get rid of the need for transplant even for older patients. I think something that Troy alluded to is that we only had 10 patients who went to transplant in the context of NPM1. I can't recall the age difference, but I suspect some of them were older patients because, again, this is where we tend to think of transplant for patients. And I think if you have a drug that will improve the outcomes by adding it to consolidation, induction and maintenance post chemo, I think there will be a lot of interest in moving away from transplant completely.

Our next question will come from David Dai with UBS.

Congrats on the data as well. So you mentioned that the MRD negativity is favorable compared to historical 7+3. Maybe just can you clarify how the baseline characteristics for the patients and transplantation rates in KOMET-007 compares to the historical 7+3 cohorts?

David, I'm sorry, I'm not sure I understand. Can you ask the question again? I'm not sure -- you're asking how do the baseline characteristics and the transplant rates that we're seeing in 007 relate to historical precedent? Is that the question?

That's right. Yes. Just any thoughts on how the baseline characteristics of your KOMET-007 study compares to the historical 7+3 treatments in the real world?

Yes. And let me -- I think, David, the key slide is the slide that breaks down the CR rates by age. You've heard Dr. Zeidan speak to it. You've heard Mollie speak to it. Typically, you see a disconnect between the younger patients and the older patients. The older patients have much worse outcomes. Here, I mean, it's very early days. These are small numbers. But I think that's what you -- and Dr. Zeidan cited is you have 100% CR rate at patients older than age 60. So that jumps out at you.

You're seeing lower rates of transplant because we have the ability to keep these patients on continuation therapy. It's difficult. We've really made an effort to try to break down the various components of what all of you should be comparing and to give you appropriate references because we get this question regularly. We can't parse the data too much further. But I think you've heard this consistently, you're seeing great benefit in both younger and older patients, no additive toxicity, possibly the ability to prevent transplant. I mean everything is sort of going in the right direction. So I hope that answers the question.

Well, this was our last question for today. So I'd now like to turn the call over to Troy Wilson for any closing remarks.

Great. Thank you, Stefan, and thank you all for joining the call today. We're just -- we're absolutely thrilled with this data. It's another step toward our goal of improving outcomes for patients with acute leukemia. I want to thank Dr. Zeidan for being so gracious with his time today. I want to thank my team, and I want to thank all of you for your questions. We're available. Most of our team is at EHA, but we're available if you have additional questions. And so you can reach out to Greg or me. And we hope this was helpful and look forward to the next time. So thanks very much. We'll adjourn the call.

Good day, everyone. My name is Megan, and I will be your conference operator today. At this time, I would like to welcome you to the Kura Oncology Investor Call to discuss recent clinical data and the company's updated development strategy for darlifarnib. [Operator Instructions]

At this time, I would like to turn the call over to Troy Wilson, President and Chief Executive Officer of Kura Oncology. Please go ahead, Dr. Wilson.

Thank you, Megan. Welcome, everyone. It's a pleasure to come to you today and share the darlifarnib clinical results from ASCO as well as our strategy and next steps for the program.

If we can go to the next slide. In today's presentation, we're going to be making forward-looking statements. We would refer you to the -- to our website and to the SEC's website for more information about Kura Oncology and risks and uncertainties relating to an investment in the company.

Next slide, please. Today's participants include where Dr. David Hong, from MD Anderson Cancer Center. We're delighted to have him here today as well as my colleagues, Dr. Mollie Leoni, our Chief Medical Officer, and Dr. Francis Burrows, our Chief Scientific Officer.

Next slide. This is an exciting time for Kura Oncology in addition to the substantial momentum that we're making in our -- with our ziftomenib program, both in the commercial marketplace as well as in the clinic. We're now in a position where darlifarnib is moving into a position that's quite exciting. And that's really the purpose of today's sessions to share with you the data some translational data and thoughts around strategies and next steps.

Next slide, please. At Kura, 1 of our key focus for the company is on a concept we call precision combinations. And that is the idea that patients will do better, drive better outcomes through use in combinations.

And if we can please go to Slide 6. Sorry, if we can go forward to the next slide, please. One more, please. Thank you.

So here, some of the challenges of developing an effective companion therapeutic to enhance clinical activity. This is really the opportunity and the challenge with darlifarnib. This is not a new concept. People have been trying to develop combination therapies, particularly against targets on the MAP kinase and PI3 kinase pathways for quite some time. Some of the requirements are, of course, that the targets have to be druggable. They have to be selective. Often, these combinations are limited by toxicity. We've seen this with various combinations. Sometimes those toxicities prohibit actually being able to reach doses where you can drive maximum activity. Similarly, there are pharmacokinetic or pharmodynamic interactions that can limit dosing.

We go to the next slide, please. That's what we think we've addressed here with darlifarnib. We have a companion therapeutic. We've now demonstrated in multiple settings that we're going to walk through today the ability to combine and the ability to suppress this pathway signaling and enhance activity. With that, we think there's really a significant opportunity for patients and potentially for Kura's shareholders.

Next slide. So darlifarnib is our next-generation farnesyl transferase inhibitor. As many of you know, we've been working on this program for a number of years. And this compound is really as optimized as 1 could be. Importantly, not to take anything away from others. We're not working on another tyrosine kinase inhibitor, another KRAS inhibitor, we're developing an approach with darlifarnib where we think we can enhance the clinical activity across multiple targeted therapies and multiple settings. And in that, we think FTIs represent a mechanism-driven, targeted therapy-agnostic combination platform approach. So it's quite different, we, think, complementary and really positions us quite favorably relative to these rapidly evolving landscape.

Next slide, please. So here, this pathway diagram, really several key points. First of all, we've shown you now 3 different examples where darlifarnib is able to enhance the activity of a targeted therapy. Working from left to right, we have that adagrasib, which the data we'll show you today. A few weeks ago, we showed you the combination data with cabozantinib, and last year, we showed you combination data of tipifarnib plus alpelisib. In each case, we've been able to see an enhancement of clinical activity.

The common mechanism of action here is blocking RHEB PAR insulation. RHEB is responsible for the localization of TORC1. So by darlifarnib blocking the farnesyl transferase, that's able to attenuate pathway signaling, MAP kinase pathway signaling and PI3 kinase signaling. This gives us opportunities both within each of these classes. As you'll see, we think this approach can apply to adagrasib as well as other KRAS inhibitors. It gives us opportunities to go it alone, it also gives us opportunities to collaborate with others.

So it's quite an extensive menu, and you'll -- this is why we wanted to give you the strategy update to help you understand our proposal for a platform study, which will really help us to evaluate these different combinations efficiently.

Next slide, please. The opportunity for patients is really quite significant, just working our way around the circle here at the top, you have the indications that are relevant for the tyrosine kinase inhibitors, kidney cancer as well as neuroendocrine tumors. We have, of course, the PI3-kinase alpha mutant tumors in the lower right. And then really what will be the focus of today's presentation, the KRAS mutant tumors, pancreatic, colorectal and non-small cell lung. These are significant numbers. And we have now, as you'll see a little later in the presentation, clinical proof-of-concept data in a number of these indications.

We won't -- Kura won't be able to prosecute all of these on our own. We will, however, be able to advance some of them on our own, and we think to work with others to really be able to do what's best for patients.

Next slide, please. With that, I'm going to turn it over to Dr. David Hong and let him walk you through the data that was presented this weekend at ASCO. Dr. Hong?

Hey, guys, I don't know who's on the other line, but I'm sure I've met many of you talking about KRAS in general. I'm going to walk you through the combination that we've now started looking at with adagrasib. I'm very familiar with adagrasib. I help lead a number of other combinations of adagrasib.

Next slide, please. This was a closure presentation that we presented in ASCO.

Next slide, please. Yes. Okay. So really 3 dose levels from 3, 5 and 8. We really didn't feel like 8 was going to be able to be advanced further, but I think you'll see from the data on 3 and 5 that those doses also show some significant activity.

Next slide, please. So this is the overall demographic profile of the patients, there are 15 patients at the 3 milligram darlifarnib and at 15, as you know, adagrasib was set up 100% standard of care dosing. And then pretty much given distribution here. Most patients with good ECOG and really 3 tumor types that we're looking at non-small cell lung, PDAC and colorectal, you can see the distribution.

Next slide, please. Typical of most Phase I trials. These patients had lots and lots of prior therapy. As you can see here, the majority of these patients had 2 or more -- many of them had prior either sotorasib or adagrasib, which is now the standard care in non-small cell lung and to some extent and also colorectal, and also had other investigational agents such as daraxonrasib and divarasib and smaller inhibitors.

Next slide, please. And you can see here the distribution of tumor types, PDAC, non-small cell lung, and colorectal. Some of you may know KRAS G12C PDAC is a much harder subset of patients to identify. It's probably less than 5% of all PDAC. And you can see here that the majority of patients who had prior G12C were non-small and colorectal, which, as you know, there are 2 drugs approved in both areas. The majority of these patients got either sotorasib or adagrasib.

Next slide, please. Yes, these are the adverse events. Pretty much it to compare that to like adagrasib especially the diarrhea, nausea, really no significant add-on toxicities, clearly, there's no rash as we see with daraxonrasib and the overall neutropenia, anemia that is probably associated with darlifarnib, we rarely see that with adagrasib, looks like pretty much no significant synergistic toxicities noted here.

Next slide, please. But this is what is really, really, really interesting. And there's still small numbers. I'm going to be honest with you. But if you look at these numbers, look at the number of patients, particularly in the pancreatic subset. As you recall, both adagrasib and sotorasib, the response rates are not -- in the -- for sotorasib because I ran that trial is in the low 20s. And adagrasib maybe low 30s. This is like -- it's 60-some percent with darlifarnib here in the pancreatic setting. And every 1 of these patients are having some kind of tumor shrinkage. That is significant. I don't -- you don't know until you obviously add another maybe 10, 15 patients here. But that, that I don't think that's something that we can dismiss and that's what was really intriguing about this combination.

Next slide, please. And again, you can see here, especially in the pancreatic subset. These are not just like one and done responses. They are ongoing. And so it tells me that this may definitely be something that plays out and not only in responses but also PFS and possibly overall survival.

Next slide, please. And you can see the spider plot, again, looks good.

Next slide, please. And overall, again, 67% response in pancreatic. Non-small cell lung, the overall subset is 50%, but in the naive was also 67%. If you recall, adagrasib was probably in the high 30s to low -- sorry, mid-40s subsets. So there is something going on here. And especially with -- also colorectal cancer, you're seeing a 29% response rate. Remember, with sotorasib is -- it's literally in the single digits but adagrasib may be a little bit higher, like 11%, 12%, but the fact that 29% is -- could tell you that there is something there.

I really think that the colorectal subset I think you would see significant increase in response if we would add an EGFR inhibitor, which, as many of you know, is 1 of the reasons that single-agent RAS inhibitors don't seem to respond. But there's something about blocking red and row that definitely adds, if not, additivity maybe even synergy. Next slide, please.

So this is an example of just a really nice, nice response. Fifth-line treatment, somebody who's had non-small cell lung, cisplatin, gemcitabine and durva, went on to see second-line docetaxel and then got sotorasib, progressed, got third-line cisplatin, pemetrexed and then got vinorelbine and then went on darlifarnib and adagrasib and had this amazing response. Next slide, please.

So against all small numbers, but I do think that there is something, a definite signal here, in all 3 given. And particularly PDAC, I just -- I've not seen a combination where you're seeing things like that to date. Next slide, please.

Okay. I mean, here's -- let me give you -- the reason I've been interested in this combination. In fact, I had approached -- I mean I was running this trial since -- my first trial, by the way, ever was tipifarnib many, many years ago. And I -- at that time, we didn't have NGS. And we -- I tried putting patients with KRAS hotspot and they weren't responding. But many years afterwards, Kura picked this up and realized in patients with HRAS, we could induce responses.

But in addition to this, which I think is really important, there have been several really prominent investigators, including Channing Der, who's a good friend of mine, 1 of the godfathers of RAS, who would argue to you that the combination -- the next iteration of RAS is really combinations. And what they've seen is that there are certain key molecules downstream that may significantly combine AXL, ERK, MYC and [indiscernible]. And right now, there's not a good, real, clean AXL inhibitor. There are not really good MYC inhibitors and the ERK inhibitors have been tried in the past, but they were just too toxic. And so the fact that this thing appears to have a strong signal really validates that preclinical data that Channing Der and others have generated.

Next slide. I think that's my -- that's the end of my presentation.

Thank you, Dr. Hong. Francis?

Thanks, Troy. Hello, everybody. I'm here today to give you a little bit of the highlights of our translational work with darlifarnib in combination with RAS inhibitors. This work was recently published in Cancer Research. So I'm just going to touch on a few of the highlights here. Here's the pathway diagram again, as Troy showed you, the reason why RAS is such a big dog in oncology is that it drives signaling down both from MAP kinase and the PI3K-AKT pathways, but its control of MAP kinase is much stronger than on the other side. And the red mTORC node is downstream of both of those.

And what I hope you can appreciate from these charts here is that in all 3 major RAS-driven solid tumor types, RAS inhibitor monotherapy fails to either completely suppress mTORC1 activity, as you see here with adagrasib in the non-small cell lung cancer model, or if we move on to a better RAS inhibitor, daraxonrasib in CRC or PDAC. In this case, you do get a nice suppression, but it does not last, and under continuous exposure conditions, we see a pretty robust bounce back of the mTORC1 activity. But in all 3 cases, this can be rescued by combining the RAS inhibitor with the darlifarnib to suppress mTORC activity over a longer period of time. Next slide.

When we started this work probably about 4 years ago now, there was only a few RAS inhibitors in the clinic, the first few G12C and other selective compounds. Now, clearly, there is a really growing field here. But we've looked at all 3 of these classes. Mutant-selected G12C or G12D or pan-RAS or pan-KRAS. And with all classes, we're able to get robust enhancement through blockade of the RHEB/mTORC node. So we think that this is going to be a broadly applicable combination approach. Next slide.

As I mentioned that the early work was all in non-small cell lung cancer G12C mutant and we modeled that in combination with adagrasib or divarasib, another similar RAS inhibitor. And what I hope you can appreciate from this is that irrespective of how active the RAS monotherapy was on its own, we were able to enhance it. So on the left-hand side of the chart, you see models that were pretty refractory, but you throw in darlifarnib on top of that, and we can at least slow tumor growth.

On the right-hand side, you see models that -- where you get regressions on the monotherapy, but we can deepen those regressions and extend their duration. Most excitingly, perhaps, in the middle there, you see a number of moderately responsive models, which, when we add in the darlifarnib, we can move from progressive disease to some pretty deep regression. So we think that we shouldn't need to do any kind of patient selection to take these trials forward.

On the right, there's some data with daraxonrasib in a CRC panel. Again, this is a slightly more challenging tumor type for RAS inhibitors and the daraxonrasib is only able to generate best tumor stasis on its own. But again, we see across the range of activities that by adding in the FTI, we can enhance the activity and get some pretty decent regressions in some models. Next slide.

As we've been talking about and the reason we're all here is that RAS inhibitor clinical development, it's really taken off. And even when we started this work, we anticipated that we were going to be recruiting a lot of patients to our trials who had already seen a RAS inhibitor before. So we thought we would model that and it worked out quite well. As you can see here, this is a non-small cell lung cancer model, which does respond for a while to either adagrasib with a stasis or daraxonrasib with regressions, but it only lasts for a few weeks and then the tumor starts to progress.

If we add darlifarnib at this moment, next, we can recover tumor control and induce deep regressions in these relapsing tumors. And indeed, next one, it doesn't look that different from if we did the combination upfront. So that's giving us -- gave us at that time, some optimism that we were perhaps not going to see huge differences in the types of responses in patients who are KRAS inhibitor-naive versus those who are experienced, receiving that class of drugs. And I think our clinical data have confirmed that.

We see a similar situation in the colorectal model on the next slide. In this case, we've compared it to the G12D mutants. So we look at the RAS G12D selective compound MRTX1133 and also daraxonrasib on the right, and both of these do very nicely. They induce good regressions for a solid month. But at that time, the tumor control dissipates and the tumor starts to grow again. If we add darlifarnib at that time, we can recover the regressions and one more, please. You can see that the outcomes are not that different from upfront combo.

So what we concluded from this work on the next slide is that we could see enhancement of activity of all the classes of RAS inhibitors we looked at. We've looked at a total of 7 or 8 now in various models. And we see that whether they work well or less well in a decent panel of preclinical CDX and PDX models, the combination is able to induce regressions even in these preclinical models where there has been previous exposure and progression on either mutant selective or pan-RAS inhibitor monotherapy. So we feel that this preclinical data supports evaluating darlifarnib with both pan-RAS and mutant-selective inhibitors. And as such, darli represents a mechanism-driven, RAS inhibitor-agnostic combination platform with potentially very broad applicability. Thank you.

So what have we seen thus far? We have seen preclinical data that has translated to clinical data across the combination partners and indications. We have seen a mechanism-driven, targeted-therapy-agnostic combination platform. Next slide.

Across 3 different combination partners and 5 different tumor types so far, we have shown you that the combination consistently outperforms what you would expect with backbone therapy. Let me emphasize, we would not expect darlifarnib to have more than minimal to no monotherapy activity in these settings. So what does that mean? It means that darlifarnib is able to augment the activity of these targeted agents. And based upon the preclinical data we know that this mechanism can augment more than cabo in renal cell carcinoma, more than alpelisib in PIK3CA mutant head and neck, more than pancreatic, non-small cell and colorectal in combination with adagrasib. This truly is a mechanism-driven, targeted-therapy-agnostic combination platform, and we can consistently make good therapies better for patients. Next slide.

And the number of patients that could potentially benefit is extraordinary, likely with more to come, one therapy that can improve outcomes across PDAC, CRC, non-small cell lung cancer, breast cancer, head and neck cancer, neuroendocrine tumors and renal cell carcinoma so far. Next slide.

So how do we get this drug to patients? What are the next steps? So for renal cell carcinoma, we are currently enrolling our Phase Ib that is evaluating darlifarnib in combination with one of the commercially available VEGF-TKIs, namely cabozantinib. We anticipate having these data that confirm the recommended Phase II dose as well as continue to support the overall hypothesis in 2027. We are also preparing for a registrational path with the same combination that would at least allow for a third-line registration and likely second-line plus that can be initiated in 2028. From there, we can expand to the frontline. Darlifarnib is easily combinable, making triplet regimens the likely and best next step for patients. Wherever the TKI can go, be it in combination with HIF-2 alpha or IO therapy, darlifarnib can follow and augment the activity. Next slide.

And with regards to KRAS-driven tumors, we are currently operationalizing our platform trial that will allow evaluation of darlifarnib in combination with any pan-KRAS, pan-RAS or KRAS-mutant selective agents. Our first cohort in the trial will be a combination with daraxonrasib in pancreatic cancer, anticipated to initiate in early 2027. From there, we will continue to build on this mechanism-driven, targeted-therapy-agnostic combination platform and move towards a registrational path in second-line plus KRAS-driven tumors, and ultimately to the front line as we look to improve patient outcomes. Next slide.

Exploring these combinations and indications through a platform study allows us to evaluate outcomes in parallel rather than sequentially and overall demonstrates the broad applicability of this mTORC1 inhibition. The design is flexible and both approved investigational therapies could be evaluated, making way for the ability to collaborate with multiple partners. If new and interesting possibilities become available, they can be evaluated in the same trial. Each combination and indication can be individually evaluated for milestones that will result in a graduation to the next phase of development. As I said, daraxonrasib and PDAC will be among the first combinations evaluated. However, colorectal cancer, possibly in combination with EGFR inhibitors as well, and other indications are subsequent opportunities that need to be explored. This trial will allow us to demonstrate the vast applicability of this mechanism to enhancing the targeted therapies already available. And I look forward to being able to share these data as we progress.

With that, I'll turn it back to Troy.

Thank you, Mollie. We can go to the next slide, please. As Mollie mentioned, our initial focus is going to be in third-line plus kidney, the potential to go earlier as well as third-line plus PDAC. These are significant opportunities. We talk about ziftomenib as being a multibillion-dollar opportunity in AML. These large solid tumors, there's just, unfortunately, so many patients who are in need. So we really see this as a meaningful opportunity for the company and for shareholders. We've also prioritized, as Mollie mentioned, combinations with agents that are either available in standard of care in the case of cabozantinib, or that everyone anticipates will very shortly be the standard of care in the case of daraxonrasib in PDAC. So we are open to additional combinations as the science and the development plans and the interest from potential collaborators guide us. Next slide, please.

And just to summarize it again, a whole set of milestones for ziftomenib. We really are going to be the market leader in not only relapsed/refractory NPM1-mutant AML, but we think we've got the opportunity to dominate the front-line setting. And now with darlifarnib, we have a completely separate wholly-owned asset where there's going to be a lot going on. There's been a lot of inbound interest. Everyone wants to be involved. Everyone wants to do the best for patients. I think everybody recognizes the need for these precision combinations, and we think we're in a very good spot.

So if we can go to the next slide, we're happy to at this point end the prepared remarks and open it up for questions. Before we do, I will just say, Dr. Hong was very generous to share his time with us. He has a hard stop at the top of the hour. So we would ask you if you have questions for him to please prioritize those. We'll get to as many questions as we can. [Operator Instructions]

But with that, Megan, we're happy to open it up to Q&A.

[Operator Instructions] Our first question will come from Li Watsek with Cantor Fitzgerald.

I guess for pancreatic cancer, how should we think about the translatability of the G12C data that you've seen to the G12V and D and other RAS isoforms?

Francis, do you want to give that a short answer?

Yes, yes, yes. As I said, we see the same kind of patterns with all of the different classes of RAS inhibitors. The pan-RAS are more active than the mutant-selective in most models and it will be in part because of resistance mediated by the wild-type RAS. But nonetheless, in -- even with daraxonrasib, which is an awesome compound, it takes a lot to get a standing ovation at ASCO and that's a truly great compound. Even with that compound, it is able to suppress the mTORC pathway, but you need 10x as much drug to achieve that as you do to suppress the MAP kinase pathway. So our goal is to combine with the FTI and enable us to get at those more resistant cells.

One thing we all know about PDAC is that it has the fibrotic TME, which retards drug access and really has made PDAC a drug graveyard for decades now. So we feel that in order to get most efficient and as efficient as it needs to be suppression of the pathway throughout these pancreatic tumors, you are going to need a combination like this.

Thanks, Francis.

I can comment?

Yes. Dr. Hong, please.

So history often does not repeat but it rhymes. I'm serious. So if you look at the BRAF story, right, BRAF plus cetuximab in colorectal that translated into what we -- as Scott presented, like the first time the BREAKWATER study, right? It's going to -- it's translated into G12C with cetuximab. Likewise, I think what's going to happen is you're seeing in pancreatic, possibly and also colorectal and non-small cell lung this combination, which in C it's less of a leap and even RAF to KRAS that you're going to likely have the same kind of mechanism in D, V, whatever, pan-RAS, whatever. I think that's just the reality of the situation. And I am a big fan of Mark Twain.

Our next question will come from Jason Zemansky with Bank of America.

Congrats on the data. Maybe a quick one for Dr. Hong. Obviously, the efficacy looks pretty potent. Just curious about the safety dynamics. Do you think the thrombocytopenia is going to be an issue at all? And are there ways to mitigate it especially as you explore some of those higher doses?

Yes. No, I'm not worried about thrombocytopenia. We don't get worried about thrombocytopenia until patients' platelets get below 10,000. But most of these patients and with darlifarnib, the vast majority of the time, we would just hold it for a couple of days and bring the patient back and it would come back. And I just -- thrombocytopenia is not an issue. Neutropenia, as you know, we have ways to mitigate that. So -- and even now Nplate is actually approved in patients with low platelets. I don't -- it's not like -- it's not a quality of life issue, right? Like you get -- you have a platelet of 50,000 and people aren't like worried about nausea, vomiting or anything like that. It's -- so I'm not too worried. And there's no -- and the good thing is that there's really no overlap with daraxonrasib, none of the -- I mean there are some small percentage of these patients who get cytopenias, but the vast majority don't. And I don't see where we're going to have troubles combining these drugs. The overlap in toxicity at all is very minimal, maybe some GI. But even then, it's -- I think it's going to be manageable.

Our next question will come from Charles Zhu with LifeSci Capital.

I know Charles.

Charles, please unmute your line and ask your question. Not a problem. We can come back to Charles. The next question will be Jonathan Chang from Leerink Partners.

What settings in pancreatic cancer are you expecting to evaluate the darlifarnib plus daraxonrasib combination in?

Mollie, do you want to take that?

Sure. We're initially going to start in the second-line plus area. Obviously, easiest to always see the signal in that relapsed recurrent setting. And then as our plan shows you with the potential for the platform trial, if we see what we expect to see, we can have it graduate to the next level towards a registrational program and then obviously start branching out further into earlier line of therapy.

Next question, we will check on Charles Zhu with LifeSci Capital. Charles Zhu, if you could unmute your line and ask your question, please.

Charles is having a problem with his mic.

Not a problem. We will move on to the next question. Erik Lavington with Mizuho.

So very curious about your thoughts on rationale and biology, if darlifarnib is kind of in your upfront, right, data, it kind of looks like you are getting breakout mutations. And I'm just curious if there's some underlying biology that might explain that if you have data on the mutation landscape through time to explain that or to tease that out? And wouldn't that kind of point to bringing darlifarnib in earlier as early as possible to prevent RAS mutations.

Yes. Erik, maybe I can take that question. There's a lot going on in these pathways in these tumor types. I think we have to balance the biology that you're seeing with the ability to run the study. At the moment, we're talking about Phase I dose escalation and then potentially expansions. So we'll start there. Our goal would be to move as quickly as the data supports to earlier lines. We really think of this as a potent means of attenuating pathway signaling, as Francis mentioned, through both MAP kinase and PI3 kinase. The tumor is always going to be looking for other ways to get around it. But I think Dr. Hong said it nicely. This is a very potent way of adding to inhibitors at the top of the pathway. And we do see patients that their disease is failing therapy, but we'll move as quickly as we can.

Your next question will come from Phil Nadeau with TD Cowen.

Congrats on the data. Just 2 follow-up from us. So first, you said second-line in pancreatic cancer, what do you define as second-line? Is that post chemo? Or will you allow patients who have had daraxonrasib monotherapy experience before? That's first.

And then second, in terms of the adagrasib dosing, you mentioned 400 milligrams is what's moving forward. We're under the impression that in some indications, 600 milligrams BID is standard. What's the rationale for using 400?

Mollie, do you want to take those 2?

Sure. So as we get the trial started, we will be looking kind of at an all-comer patient population in that recurrent metastatic setting. So it will be a second-line plus trial for the dose escalation where, yes, we would consider them having failed front-line chemo to define them as now being eligible for trial. In those initial dose escalation cohorts, we would also allow prior daraxonrasib exposure, just as we've done in pretty much all of our other trials. So we really do think it proves the point and proves the mechanism to see -- to be able to see those responses.

With regards to adagrasib, there's a lot of debate right now as to what the appropriate dose is, and BMS is actually performing studies in both 400 milligrams and 600 milligrams in order to satisfy some regulatory requirements. A great deal of their combinations right now are at the 400-milligram dose, and it does seem to still be very effective dose for these patients. But Dr. Hong, do you have any additional comments on that?

Yes. Daraxonrasib is a very good drug. I mean, I was -- I led the Phase I on that thing. But it's not a cure. I don't know about you, but if you're a pancreatic cancer patient in the second-line after chemo, which it won't be approved for a while, if it does get approved, which I think it will. But you want something better. So if you -- if I was a pancreatic cancer patient who finished FOLFIRINOX, and somebody said, hey, I have daraxonrasib plus a new drug that's going to make this better, I'd enroll. I don't think that we'll have trouble finding patients, if that's your question.

Your next question will come from Charles Zhu with LifeSci Capital.

This is Peter on for Charles. Just wondering how do you feel that FTI plus daraxonrasib could be positioned against daraxonrasib plus KRAS-mutant selective inhibitors?

Mollie, do you want to take that or Dr. Hong? I don't know that they're mutually exclusive. I think we need to do everything we can.

Right now, like, for example, probably the one that's most ahead right now is zoldonrasib. They're trying to, I think, Revolution Medicines is trying to position zoldon plus dexon in the front-line setting, right? They've already announced that they're doing that trial. And we'll see how it goes. I think ultimately, like pancreatic cancer, 5 years from now is going to be a lot like treated like non-small cell lung. You're going to have KRAS, but you may have like KRAS plus MTAP loss. People are going to try to position themselves for that. We're going to try to position -- if you talk to any pancreatic doc, you saw that in the PR on daraxonrasib, they don't like chemotherapy and they don't want to give chemotherapy. And so if this darlifarnib plus whatever looks amazing in the second-line, I mean, I definitely think it's going to have a likelihood that it could position itself in the front-line.

And then so you could have possibly zoldon -- you could combine this with zoldon. Ideally, they can't obviously combine dex. I mean I'm not sure I'm not -- maybe they'll come out with some data that I haven't seen, but they can't combine the daraxonrasib with EGFR. So right now, at some point in colorectal, they're going to try to combine zoldon plus EGFR. And then what if -- if this thing augments that, holy cow, you can also combine it with that. I mean there's just so many different reiterations as to how it's going to pan out. But I think in the pancreatic space, everybody is going to try to push chemo out of the picture at some point. And this could be one of those situations where you either have a D inhibitor or the pandexon-RAS inhibitor, whatever in the frontline setting.

And Peter, just to add on to Dr. Hong's comments. This is part of the motivation for the platform study. We're getting approached, as you can imagine, by folks with all manner of targeted therapy looking to do combinations, we're not going to be able to do it all. We'd like to do the ones that make the most sense for patients and ideally not have regimens competing with each other. But there's a clear opportunity, we think, in pancreatic to test this combo. There are -- Dr. Hong was alluding to it, there are combinations in colorectal that we look to pursue. Stay tuned throughout this year and early next year. I think we'll have much more to say about that.

I have to go, guys. Thank you.

Thank you, Dr. Hong. We appreciate your time.

I'm just going to say, I'm excited. I'm very excited with this combo. So please support them so I can do this combo. Thank you. Bye.

We appreciate your time. Thanks, Dr. Hong.

[Operator Instructions] Your next question will come from Reni Benjamin with Citizens.

Congrats on the progress. I guess since Dr. Hong has gone. Troy, maybe you can answer this. You talked about how darlifarnib is broadly applicable through a variety of these indications and combinations. How important is it to have additional combination agents on top of the KRAS inhibitors? And maybe just as a follow-up, I think Dr. Hong had mentioned EGFR on top of KRAS. I'd love to kind of get your thoughts as to how you're thinking about it.

And as a follow-up, I probably missed it in the poster, but how many patients remain on treatment? And kind of what's the median duration of response? And any comments on resensitization of patients who are refractory to KRAS monotherapy?

Mollie, do you want to take that second question first, and then I can address Ren's sort of broader question?

Yes. So a good amount of the patients still remain on treatment as of the time of this data cut. Almost all of the pancreatic, all but one, are still on treatment and 37% of patients overall are on treatment. So they're doing very, very well. So not just deep responses, but actually durable responses. And we are seeing -- these are small numbers.

So my statistician would kill me if I gave you true median duration of responses because they're so unstable to actually estimate. But for non-small cell, we have seen about at 8 months. PDAC is still evolving in 4 months. So these are still evolving numbers, but they're already starting to exceed what we would expect from the background therapy alone. So stay tuned. We'll discuss more as we get more data.

Yes, Ren, to your first question, I mean, there's no accident that, that second box in the platform study is darlifarnib plus compound A in colorectal. There is a clear need. I think we all recognize it's likely to be a triplet. One of the advantages you have with darli is it combines nicely with EGFR inhibitors. There was a trial run with tipifarnib and Tarceva, for example, was run in the wrong patient population, but there was good safety and tolerability. Part of this is we're juggling kind of what we can do internally with the folks who are approaching us. And -- but colorectal is of high interest, both for mutant-selective inhibitors and for pan inhibitors. We'd like to find a way to move darlifarnib further along in that area for sure.

Your next question will come from Daniel Brims with Lake Street.

Just curious what you saw or didn't see in the 8 mg dose that you decided not to push that forward?

Sure. Mollie, do you want to take that?

Yes, sure. Obviously, every protocol has its defined toxicity limits. And while we didn't see any drug-drug interaction between the 2 molecules, as we got into the higher doses, we did start to see some overlap of the neutropenia. And that was simply -- we reached a level that we didn't think the benefit outweighed the risk enough to keep pushing it forward. But overall, it wasn't any different safety profile. It was just we felt that 3 and 5 were the more tolerable options and still efficacious.

And Dan, as a reminder to everyone, you don't mitigate toxicities in a Phase Ia dose escalation. You're -- the whole goal is actually to understand the tolerability profile. So as Dr. Hong indicated, I mean, many of these are clinical values, and they can be mitigated as we go forward. But for the dose escalation, that wasn't possible. And as Mollie said, it didn't -- the benefit/risk didn't justify going forward at 8. But either 3 or 5, as you can see, are very active. It is going to be -- the only one tolerability or toxicity that I think we have to watch for is neutropenia. We've now been able to combine FTIs with cabozantinib, with alpelisib. Previously, J&J combined with both chemo and a couple of targeted therapies. There's a very broad combinability. You do have to watch for neutropenia.

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

Yes. Thank you, Megan, and thanks, everyone, for joining the call today. We're at a really exciting inflection point with this darlifarnib program. Apologies that we couldn't corral Dr. Hong for longer. He had patient obligations, which obviously have to take priority. You can hear from his comments the enthusiasm around both the daraxonrasib combination and other combinations. He's been a tireless advocate for this program. So it sounds like a number of you have relations with him and would invite you to engage with him as you will.

We will come back to you in about a week with another update back on our ziftomenib program and the front-line AML results out of EHA. That will be one to pay attention to. Those results, I think, are very encouraging for the potential for ziftomenib to drive clinical benefit in a front-line setting. And Mollie will walk you through what that data means for the ongoing intensive chemotherapy arm in the KOMET-017 study. So we look forward to talking to you again then. If anyone has additional questions, you can reach out to me or Greg, and we're happy to get back to you. We appreciate your time. We appreciate your interest. And with that, we'll conclude the call. Thanks, everyone.

[Audio Gap] BofA Health Care Conference in very [ thirsty ] Las Vegas. My name is Jason Zemansky. I'm one of the SMID cap analyst here at BofA, and I'm very pleased to have with us on stage, Kura. Troy Wilson, CEO; and Brian Powl. Thank you so much for joining us.

Thank you, Jason.

Thank you.

Maybe to start it broadly for those who aren't familiar with the Kura story, could you please provide a brief overview of zifto and darli?

Sure. Yes. So on the 1 side, you have ziftomenib, or commercial name KOMZIFTI. We have approval in the relapsed/refractory NPM1-mutant setting. Our goal is to be the market leader to drive sustainable quarter-over-quarter growth there. We have, I think, the largest most comprehensive Phase III development program in both the intensive and nonintensive frontline setting. We'll be giving a data update on that here in a few weeks. And then we have extensive studies, looking at different combinations to really be able to advance the standard of care and get ziftomenib throughout the treatment continuum in AML.

We're also studying ziftomenib in gastrointestinal stromal tumors or GIST. We're making good progress in dose escalation, probably not looking at a day to update until next year, but definitely some potential there as well as investigating other solid tumors.

Shifting to the darlifarnib side, darlifarnib is really trying to address the problem of innate or required resistance to targeted therapies. We have a data coming out at ASCO looking at darlifarnib in combination with adagrasib, the KRAS G12C inhibitor that's approved. And that will be the third installment of an FTI plus targeted therapy. The first being in PIK3CA mutant head and neck, the second being in renal cell carcinoma. That's a really interesting opportunity. FTI is potentially combined with and can enhance targeted therapies in kidney cancer, breast, lung, colorectal and pancreatic. So there's quite a significant opportunity. We're going to have a poster presentation on May 30 and an Investor event June 3 to really give a strategy update on that program. So each of those 2 programs, Jason, I think, drives value for cancer patients. I'll just remind everybody, the ziftomenib-AML program is in a partnership with Kyowa Kirin and fully funded through to initial top line results. That gives us a significant running room and really the ability to maximize both ziftomenib and darlifarnib for patients.

Thanks, Troy. You've -- let's focus initially on ziftomenib. You framed sort of the key driver here in the market as physician preference. So I'm curious, what has initial feedback been like from prescribers and treatment centers on Ziftomenib.

Sure. Brian, do you want to take that?

Sure. Yes. Thanks. And we announced in our earnings just yesterday, which I think is a good proxy for how physicians are responding. So yesterday, we reported $5.8 million in net revenue for the first full quarter of launch. This equates to coming from 85 new patient starts. And of the patients in this population of the NPM1-mutated population, that equates to about 40% of the new patient starts among the menin inhibitor class. That's a great start for us. I think what that shows is the profile of KOMZIFTI is competitive. Physicians see it as a compelling choice for them. And of those patients, one more stat just to share with you. Of those patients that started about 40% of those were actually treated in combination, which is off-label, outside of our approved indication, but based on physician choice were used in combination with either ven/aza or in combination with the FLT3 inhibitor gilteritinib.

You've flagged the administration profile as being a major source of differentiation and its combined ability as well, which you sort of alluded to in the previous answer here. But any sense that these are starting to resonate? Is it something else you think that's getting physicians excited?

I think what this has shown us is that physicians are getting excited and they have a choice, right? I think before we came to the market, there was 1 choice available for a menin inhibitor. And you're starting to see uptake in a lot of centers, both those who are experienced with KOMZIFTI in ziftomenib, in our trials, but also those who are experienced with other menin inhibitors. And it's really the profile, the balance of the efficacy, the safety, combinability and the convenience of once-daily dosing, in a very complex patient population, puts KOMZIFTI in a potentially favorable position that we think will help us get to leading the market share coming out of that first year.

You mentioned a good point is that a lot of your prescribers participated in the clinical studies. So in terms of how do you reach new prescribers? And I think from a maybe broader perspective, what about the community prescribers that maybe are less familiar with some of the more nuanced profiles of both assets?

Sure. So I think that in the treatment of relapsed/refractory AML, largely the treatment is happening in the academic centers, right? So it's probably 85% to 90% of those patients are going to be treated where that -- these are sick patients, they tend to go to those academic centers. So the decisions are being made are really more focused right now at the academic centers. And these are kind of those tertiary -- the large tertiary centers. I think from our objective to reach those patients, we have our current sales force, which is out in the field engaging with those physicians. But we also have our partner, Kyowa Kirin, who has their field force also spending a percentage of their time also raising awareness and focusing. So it allows us to get breadth and depth to educate on the differentiation. And that's what we're starting to see already kind of in this first launch -- first full quarter of launch, strong uptake. We expect to extend that even more centers as the launch progresses this year.

Yes. And I might -- Jason I might just add to that. We were actually pleasantly surprised by the extent of combination use, spontaneous combination use, as Brian mentioned. A lot of these academic physicians are very sophisticated and they're really experimentalist. Almost every patient history is different. And so they're up on the literature, they're talking to one another all the time. And I think it speaks to KOMZIFTI or ziftomenib's profile that they can combine it. They can use once a day. It has a very benign safety and tolerability profile. That's allowing them to really find the best solution each patient. This is very much in the relapsed/refractory setting kind of a bespoke treatment that the physician does for each of his or her patients. And KOMZIFTI, although we're promoting that, we're really promoting the monotherapy, it gives them that flexibility and that ability to find just the right solution. So I think it's giving us a real momentum and real potential to continue to not only take market share, but ultimately grow the market in this relapsed/refractory NPM1 setting.

We -- sometimes we talk about leading indicators of how well launch is going. Is the combination percentage, is that kind of what you would point to as being something investors should focus on? Or Is there another sort of indicator that would help indicate that everything is resonating and the trajectory is inflecting well?

I would say the 2 things that would account for that to kind of show some of that lead -- those leading indicators. One is the new patient starts. The number of new patient starts are much more rapid than even we expected. We knew we would be able to come out strong, but 40% of those new patient starts in the first full quarter is a strong start, couple that with the combination use of the physicians choosing to use KOMZIFTI in combination, those also will lead to potentially -- it's finding the right patient to be treated potentially in the earlier lines of therapy rather than salvage lines of therapy, and they potentially may get a longer benefit because they're earlier in their treatment course. And in combination, there may be a benefit that the physician sees to add KOMZIFTI and then potentially treat longer and get a better benefit for those patients.

You might also add the access and the payer preferences. I think those are also good leading indicators.

Yes, I think that that's -- to add to that point. We did also share that we have -- over 93% of covered lives are now on policy and on plan for our payers. So we've largely in that first [ quarters and a half ] essentially since we got our approval, have very good coverage that is at parity. We do have a number of plans. I think we have 10 plans that have actually put favorable positioning of KOMZIFTI either step edits or tiered formularies where they prefer KOMZIFTI over other therapies in this space. It equates to about 12 million lives right now.

Lots of good leading indicators.

Absolutely.

Given how relatively small the patient population is and the level of high unmet need, how quickly do you think it will take for menins to reach that peak penetration in the relapsed/refractory setting? And then could we potentially see KOMZIFTI taking measurable share of the, what you call -- what you've estimated as a $300 million to $400 million market opportunity?

Yes. So I think that -- as we've shared before, as you said, it's a $350 million to $400 million market, we think in that relapsed/refractory NPM1-mutated setting. This -- the market dynamics for those patients is that there are several options already available to them, ven/aza, FLT3 are co-mutated, other therapies that need to be able to penetrate in. So what we're trying to do is build out grow the market for menin inhibitors and show that menins are the preferred treatment choice for those patients but also then ultimately become the market leader in this space. we feel confident that there's going -- it may be a slower growth in areas where there's no options available for those patients. But ultimately, we think we'll be able to get to become that leading class share in the menin class by the end of the year.

In terms of making ziftomenib foundational across all of AML. I mean you've talked about a very comprehensive first-line development program moving forward. But there's certainly more menins coming up the pipeline. What does it take? And what does sort of the time lines look like?

Yes. There are 3 or 4 menin inhibitors Jason, that are in active clinical development. I would say us J&J and Syndax, we're all in registrational studies of some sort. There is a -- the Dainippon Sumitomo compound is quite a ways back. They have a dose in KMT2A, they don't yet have a dose in NPM1. One of the challenges for subsequent drug developers in AML is as you see triplets getting approved, and that's why we're sprinting as fast as we can to the front line, the next company coming along has to run its investigational triplet against an approved triplet. And unfortunately, for Astellas, we saw just recently, just a few weeks ago, they did not have a successful trial when they were in the triplet of gilteritinib 7+3 versus midostaurin 7+3. That was a 700-and-something patient trial, but not enough to ultimately deliver the survival-based end point. So I think you're going to find the AML development limiting. There are other options for menin inhibitors in solid tumors, potentially in diabetes, we may see later entrants going elsewhere. Our goal is to be the market leader throughout the treatment continuum in AML. We've been -- we were there first. We were in menin first. And continue to drive leadership not only in AML, but in solid tumors, diabetes and elsewhere.

Got it. Let's talk about some of the specific catalysts near term. The KOMET-007 study, we'll see first half of 2026. It's the update in intensive chemotherapy. What -- how would you frame the outcome? And what should investors be looking for?

Right. So we just yesterday announced the abstract was published for that study. For everybody's benefit, this is Ziftomenib plus intensive chemotherapy in both NPM1 mutant and KMT2A-rearranged patients. This is a data update from the 007 study that we've had ongoing. The last update we gave was at EHA 2025. So we're now a year on from that. And it also forms the basis for the KOMET-017 registrational study that's being run in the same populations. What are you looking for? You're looking for high rates of CR, you're looking for high rates of MRD negativity, you're looking for extended durability. Each of those will be important. And you can see from the abstract, the CR rate for NPM1, I think, is 96%. The MRD negativity is 80%. The median patient has been on something like 17 months. And fortunately, for the NPM1 population, there -- we can't -- we don't yet have a duration of response. So I think that bodes well. It's -- the study is ongoing. One of the interesting learnings, Jason, from intensive chemotherapy is we believed, and I think the dogma was before any of us had started that in the intensive setting, you'd maybe get patients on a menin inhibitor for 1 or 2 cycles and you'd lose them to transplant. Interestingly, when you look at the 007 data, that's not what you're seeing in the NPM1 patients, you do see the KMT2A patients going to transplant because that's really where -- what they need to do. But if an NPM1-mutant patient is -- has an MRD-negative CR transplant is contraindicated. The mortality risk doesn't outweigh the clinical benefit. As a result, you have these patients and you look at swim lanes, and they're all just on ziftomenib cycle after cycle, that's important from really improving the standard of care. It's also important from a commercial perspective. 18 months of therapy is, if you take the incident patient population of 11,000 patients, that's a $10 billion opportunity. Now we'd look to take just a portion of that. But I think we're starting to see -- the difference between ziftomenib and all everything that's come before is these patients can stay on for 18 cycles or longer. We've not seen that with chemo, with venetoclax, with other targeted therapies due to tolerability concerns. Everything you asked, Brian, about those attributes, combinability, convenience, cost, safety, those become even more important as we're thinking about the frontline population in that continuation therapy setting.

Great. Let's extend this a little bit further. You have the KOMET-008 update coming up. How much of a driver can this be just given how common you see a FLT3 mutation with a menin mutation?

FLT3 is 1/3 of and it's half of the NPM1, the patient population, their co-mutations. There are 3 FLT3 inhibitors out there. We're actually working with 2 of them. we have the 008 study ongoing with gilteritinib in the relapsed/refractory setting and a study with quizartinib in the frontline setting. In preclinical models, Jason, that combination is curative. And I think the update that you referred to, the 008 update, we're expecting at the end of the year at a major medical meeting. That will be important because if you can improve on both a FLT3 inhibitor and a menin inhibitor as monotherapy by putting them together, nearly half of your NPM1 mutant patients are going to have that genotype. So in terms of both creating a solution that's best for them and giving physicians choice and then market leadership, we're well ahead of the competition on pioneering these combinations with FLT3 inhibitors. So I think that will be a meaningful update.

Got it. You referenced the KOMET-017 programs as these are the frontline settings. Can you give us your expectations on enrollment time lines? What's the status look like, especially now that, as you mentioned earlier, we have multiple menins advancing?

Yes, happy to. So we made a deliberate decision a number of years ago to combine the 2 Phase III studies into 1 protocol, and that is KOMET-017. We call it the one-stop shop. As a result, it's easier for sites, they activate on protocol. Any patient that presents at their clinic has a space in either the intensive or non-intensive study. It's one budget, it's one sort of stand up, and we're essentially standing up 2 Phase IIIs at the same time. Enrollment has been brisk. I think we've demonstrated with 007 and 008, the 007 update that we talked about is nearly 100 patients in the relapsed/refractory setting. So enrollment is going very well. We're well ahead of the competition by a year, maybe 2 in the intensive chemotherapy setting. I'm not aware that our competitors have yet started their trials or started enrollment. In the nonintensive the ven/aza combo, that's there, everybody is working together. But by combining the 2 studies together, Jason, we were able to attract many of the leading sites in Europe, in the U.S. and in Asia Pac. And that does 2 things, right? These are many of the leading practitioners in AML. They're also our customer base. And part of this is winning hearts and minds, if they're having good experience in the 017 studies, we know that's going to read through into the commercial landscape. So we're taking kind of a whole holistic approach that very much commercial and development working in partnership.

Great. You mentioned earlier, there's opportunities outside of AML, GIST being one of them, diabetes, there's cardiometabolic indications as well. Why does a menin make sense in this population?

Yes. So menin is an epigenetic modifier, right? So menin acts by regulating gene expression of other downstream genes. In AML, these are genes involved in either in differentiation or in leukemogenesis. In GIST, menin regulates KIT expression. So you have a KIT inhibitor that blocks catalytic activity, and you have a menin inhibitor that blocks KIT transcription. In diabetes, menin regulates the CDKs in pancreatic beta islet cells. It actually -- by blocking menin, you take brakes off the CDKs and you get selective proliferation of pancreatic beta islet cells. So it's context-dependent but it also gives you a sort of the Swiss Army knife of therapeutic targets.

You have discussed a potential $7 billion opportunity for the menin. I mean what are some of your key assumptions here? And time lines in terms of getting to that potential?

Yes. Very simply, in the U.S., you have -- we think half of AML patients are going to be eligible for menin therapy. And very simply, that's FLT3, NPM1 and KMT2A. There are likely additional mutations as well, but let's just keep it simple. That's 50% of all of AML. There's 22,000 patients a year diagnosed with AML. So let's 10,000 patients to make the math easy. If you could keep those patients on therapy for 12 months. You're talking about $5 billion. If you can keep them on for 1.5 years, as I said, it's $10 billion. We're being -- I think we're being conservative in saying, you're going to get a stacking year-over-year, but $7 billion peak sales for the class seems very reasonable. How do you get there? You need, of course, to get the patients on drugs and then to keep them on for many cycles. But that's why I think the 007 update from EHA will be so illustrative because that's as close to both the Phase III study and the real-world population of what one would expect as you're going to get at this stage. All indications are, Jason, I mean, what you'd like is to delay the onset of disease recurrence. The drugs are very good at eliminating the leukemia. The problem is the leukemia comes back. And in -- for example, in the intensive chemotherapy setting, 60% of patients recur within 2 to 3 years. That's what you're trying to prevent. So by having a therapy on board with the patient that's very well tolerated, you can prevent that recurrence, you can delay the time to transplant. Have we seen this before, yes, in myeloma right? This is exactly -- it's the multidrug regimens that both allowed to get disease remission and then to extend that. And we've seen dramatic transformation of the landscape in myeloma. The hope is this is the beginning of the same thing in AML.

Got it. Well, let's shift gears to darlifarnib. Obviously, the FTI class has been a focus of development for some time. Why do you think agents like tipifarnib fell short? And I guess, where is the confidence that darli can deliver?

Yes. So we needed 3 things for FTIs to work. you needed an understanding of how to use them because they're not like a kinase inhibitor. They block farnesylation of different therapeutic targets. So you need to understand the biology. You need next-generation sequencing to be able to find patients. And Jason, most importantly, you need the other targeted therapies. And FTI on its own is really not effective at driving responses except in something like HRAS-mutant tumors. And that was really Chapter 1 with -- or maybe Chapter 2 with tipifarnib in HRAS-mutant solid tumors. What Francis Burrows, Shivani Malik and our translational team figured out is, if you can assault a tumor with a targeted therapy, TKI, a KRAS inhibitor, you can actually make that tumor cell then dependent on an FTI. The FTI is working by blocking a protein called RHEB, Ras homolog in brain. RHEB localizes a protein called TORC1 or complex called TORC1. TORC1 sits right at the bottom of the MAP kinase and the PI3 kinase pathways. So everything I've just mentioned, TKIs, PI3 kinase inhibitors, KRAS inhibitors, they all ultimately signal through those pathways. It's like turning the [ stop clock ] at the bottom of the cascade, you get a very effective block. The question is now, can you safely combine, and we've shown twice, we can. You'll see the adagrasib data here shortly. And can you enhance the activity. This is just to be clear with everybody. This is not a new problem, right? People have been trying to find companion therapeutics since I've been in this industry. We've tried AKT. We tried MEC, we tried SOS1, we've tried SHP2, nothing's really worked. FTIs may actually be the solution. I think the data that you're going to see at ASCO will be very illustrative of what we can do in KRAS-driven tumors.

Got it. Why does it make sense to start in RCC? I mean you've shown promising preclinical efficacy in tumors like NSCLC, colorectal, HNSCC?

Yes. So this is where you have to take the science and you have to overlay it with the business realities. So one needs to be able to have a clear path to get to the market where you have only 1 investigational agent. So I mean, you can do novel, novel combinations. But from a development perspective, those are much more difficult, right? How do you show the contribution of individual components. As an alternative, if you go on the back of cabozantinib, cabozantinib is the accepted standard of care in second-line renal cell carcinoma. It continues to grow market share. It has other applications. That's well established. You then build on that and you have to show what can darlifarnib do to add to cabo. It's just simpler from a development, regulatory and commercial perspective. You could do a similar thing. There will be a KRAS inhibitor here approved relatively shortly, we think, in pancreatic, going on the back of that just greatly simplifies your development in regulatory as well as your commercial strategy. Then you can start to get more creative, if you want, you can add other novel agents. But I think you need to, Jason, have your base case and then your upside cases. That's where we translate the research and the early development to how do we think about being good fiduciaries and making choices. Ultimately, FTIs can go a lot of places, you have to prioritize. And we'll talk more about the strategy at our Investor Analyst Event on June 3. That will be after the ASCO data is presented, but we're going to have a very well-known KOL in the KRAS space. And we'll explain kind of the background. We'll go through the clinical data with adagrasib and then we'll talk about the next steps and what's the development and commercial strategy going forward. I think that will -- and the KOL will be able to add valuable perspective on why a companion therapeutic, why an FTI, why darlifarnib?

Got it. you reported some fairly encouraging numbers last month at IKCS, ORRs of 44%, DORs of 94%. Obviously, it's still early, but where does that translate in terms of overall benefit in these later line settings? And is there a compelling enough case do you think where you can move not only second line, but first?

I think so. I think at this point, Jason, we feel confident we have a play in third line based on the data we have today. I'll just remind everybody, we are conducting a Phase Ib study in combination with -- darlifarnib in combination with cabozantinib, we're investigating a 5- and 8-milligram dose of darli with a 60-milligram dose of cabo. We're doing a third arm of cabo monotherapy where patients who progress on cabo and then roll over into the combination, and we can further test this hypothesis that we can rescue them by adding darlifarnib. Based on what we have today, the KOLs are telling us, we've got a clear shot in third line. you'd like to obviously go earlier. We need to get -- we need to finish the Phase Ib and understand, it's a second-line strategy, the doublet on top of cabo or do we consider a triplet. Let's -- we'll hold that thought. The tolerability, what we hear from the physicians, and I think saw it in the darlifarnib is extremely well tolerated. The only real AE we see is neutropenia. We didn't make any effort to try to mitigate that in the dose escalation because you want to see toxicity. Now in the Phase Ib, we allow the physicians to use G-CSF. So that will be mitigated. I think there is an opportunity to combine in the front line. Something we hear from physicians is as they're considering these combinations of IO, TKI and HIF-2 alpha, if a patient's disease progresses on those 3, what else are you going to give them? You're going to give them some subset of that? Not ideally. So that physicians are really attracted to the idea of a novel mechanism of action coming into renal cell carcinoma. Now we have to sort of figure out what's the development plan year 1, 3, 5 and onward? And you'll see us elaborate that throughout the rest of this year.

Wonderful. Exciting year. Thank you so much, Troy. And Brian.

Thank you, Jason.

Thank you.

Good day, everyone. My name is Leila, and I will be your conference operator today. At this time, I would like to welcome you to the Kura Oncology First Quarter 2026 Financial Results Earnings Call. [Operator Instructions]

At this time, I would like to turn the call over to Greg Mann, SVP of Investor Relations and Corporate Affairs of Kura Oncology. Please go ahead.

Thank you, Leila. Good afternoon, and welcome to Kura Oncology's First Quarter 2026 Conference Call. Joining the call today are Dr. Troy Wilson, President and Chief Executive Officer; Brian Powl, Chief Commercial Officer; Dr. Mollie Leoni, Chief Medical Officer; and Tom Doyle, Senior Vice President, Finance and Accounting.

We remind you that today's discussion 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 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 call the call over to Troy.

Thank you, Greg. Good afternoon, everyone. Kura's at an inflection point. What we've been building over the last several years is now showing up clearly in the clinic, in the market and in the way physicians are making treatment decisions. Our first commercial launch is off to a strong start. Our Phase III programs are ahead of plan. And over the next 12 to 24 months, we expect a steady flow of data that we believe will define leadership in the menin inhibitor class. Most importantly, we're executing with focus, discipline and a very clear strategy.

Let me start with KOMZIFTI. In our first full quarter of launch, we generated $5.8 million in net product revenue ahead of expectations. But what matters more to us is what's underneath those numbers. We're seeing repeat prescriptions. We're seeing broad uptake and use expand across treatment centers. We're seeing increasing payer preference and we're seeing early instances of physicians switching patients from other menin inhibitors to KOMZIFTI.

That tells us something important. This is not just a class story anymore. Physicians are starting to differentiate based on product profile and we believe KOMZIFTI is standing out. We see that differentiation coming from a combination of compelling efficacy, a predictable safety profile, simple and convenient dosing and potential for broad combinability. In real-world practice, these things matter and they're driving how physicians choose therapy. It's early, but based on what we're seeing, we believe KOMZIFTI is well positioned to emerge as a leader in the treatment of adult patients with relapsed or refractory NPM1 mutant in AML.

At the same time, we're not building this as a single indication product. Our focus is to expand ziftomenib across the AML treatment continuum and establish it as a backbone therapy in combination. This year, we expect to generate multiple data readouts to support that strategy, including updated data from our 7+3 combination in newly diagnosed AML at EHA, publication of our venetoclax/azacitidine combination and initial data from our gilteritinib combination in relapsed and refractory AML patients with NPM1 and FLT3 co-mutations.

Taken together, these data sets are designed to answer a simple question. Can KOMZIFTI be used broadly, safely and effectively in combination across AML? Based on what we've seen so far, we believe the answer will be yes.

In parallel, our frontline Phase III program, KOMET-017, is progressing ahead of plan with strong enrollment for both studies across leading global science. Our one-stop shop design is doing exactly what we intended, accelerating execution without compromising rigor.

Beyond AML, we continue to build a broader pipeline with meaningful upside. Darlifarnib is a good example. The data we've generated, reinforced its mechanism and potential to overcome resistance to targeted therapies. We'll have additional combination data this year, including in KRAS G12C mutated cancers, where we think there's an opportunity to open up new treatment approaches across large solid tumor indications.

So when we step back, we think Kura is in a very strong position. We have a commercial product beginning to gain -- that is gaining traction and beginning to differentiate in the real world. We have a pipeline with multiple anticipated near-term clinical catalysts that can expand that opportunity significantly, and we have the balance sheet to execute our strategy and reach key value-creating milestones.

The menin inhibitor class in AML is still early. The next year or 2 will determine how it evolves and who leads. Based on what we're seeing today in the clinic and in the market, we're confident in our ability to play a leading role in shaping that future.

With that, I'll turn it over to Brian.

Thanks, Troy. We're very encouraged by KOMZIFTI's performance in the first full quarter of launch. And although we're pleased by the first quarter results, we're even more encouraged by the underlying trends driving that revenue.

Our early momentum reflects 3 core strengths: strong preparation and experienced commercial team and most importantly, a clearly differentiated product profile defined by efficacy, safety, combinability and convenient dosing.

Our commercial strategy is focused on 3 priorities: drive broad awareness of KOMZIFTI's differentiated profile, deliver strong and consistent quarter-over-quarter growth and established leadership in relapsed or refractory NPM1 mutant AML, a $350 million to $400 million market opportunity.

In the first quarter, we generated $5.8 million in net product revenue with 85 new patient starts and nearly 160 total prescriptions. Patients were treated across approximately 60 activated accounts, including ziftomenib trial sites, other menin experience centers and accounts new to menin inhibitors.

More importantly, we are seeing clear signs of growing physician adoption. First, repeat prescriptions and expanding use across treatment settings indicate growing physician confidence with KOMZIFTI in real-world practice.

Second, following our approval, we have observed physicians switching patients from other menin inhibitors to KOMZIFTI. Although still early, this is a meaningful signal that physicians are making active treatment decisions based on the product profile.

Third, we are aware of early physician-initiated use of KOMZIFTI in combination with commonly used agents, including venetoclax azacitidine and with gilteritinib and FLT3 co-mutated patients. This physician-initiated use reinforces our belief that ziftomenib has potential to be a highly combinable backbone for use across AML patient populations.

Feedback from physicians, pharmacists and nurses consistently highlights the practical advantages of KOMZIFTI, particularly as dosing simplicity and convenience for patients which we believe are important factors in real-world treatment decisions when monotherapy efficacy is viewed as similar.

Collectively, these dynamics point to a clear conclusion. Increasingly, physicians, pharmacists and nurses are selecting KOMZIFTI, which offers strong efficacy with a well-characterized and manageable safety profile and convenient once-daily dosing compatible with concomitant therapies, what we describe as efficacy without compromise.

Turning to access. We secured coverage at parity or better for more than 93% of covered lives with no label restrictions. Achieving this level of access, this early in launch, particularly as a second to market therapy reflects the strong payer recognition of KOMZIFTI's value. We're also seeing favorable formulary positioning and step edit dynamics. I'm thrilled to report more than 10 plans covering more than 12 million lives has placed KOMZIFTI in a favorable policy position. These decisions reflect payer recognition of KOMZIFTI's differentiated profile and the predictability of its cost in managing patients in this setting.

Operationally, execution remains strong. Time from prescription to patient receipt is approximately 3 days, ensuring rapid access to therapy. And our field teams in collaboration with Kyowa Kirin are driving strong engagement across both academic and community settings.

Looking at the bigger picture, the combination of repeat prescriptions broad access, payer preferences, expanding real-world use and early instances of switching gives us confidence that KOMZIFTI is not just participating in the mein inhibitor class, but is increasingly defining its leadership position in the NPM1 market. The success we are seeing in this initial monotherapy setting is an important first step and reflects our foundational advantage of delivering strong efficacy with a predictable safety profile and convenient dosing that, in our view, represents efficacy without compromise. Importantly, this early momentum lays the foundation for our next phase of growth as we expanded the combination in frontline settings.

I'll now turn it over to Mollie.

Thank you, Brian. In 2026, we expect a continued steady cadence of clinically meaningful data for ziftomenib and darlifarnib. Our strategy for ziftomenib is focused on 1 clear objective, establishing it as a highly active and broadly combinable backbone therapy across the AML treatment landscape, supported by our registrational clinical programs, spanning multiple lines of therapy and patient populations.

As treatment paradigms evolve, physicians are increasingly looking for therapies that can be safely and effectively combined with existing standards of care and ziftomenib is specifically designed to address that need.

At the upcoming EHA meeting in June, we plan to present updated data from ziftomenib in combination with 7+3 in newly diagnosed NPM1 mutant and KMT2A rearranged AML. This updated data set will include extended follow-up with a median of approximately 16 months, including treatment course and response durability.

We also expect to publish data showcasing venetoclax and azacitidine in combination with ziftomenib in relapsed or refractory NPM1 mutant AML. These data expand upon our presentation at ASH 2025, where we reported a striking 70% composite CR rate in patients without prior venetoclax exposure. This is an important regimen as ven/aza remains a widely used standard of care.

In parallel, we are advancing combinations with FLT3 inhibitors. As a reminder, FLT3 mutations occur in approximately 1/3 of AML patients and notably half of NPM1 mutant patients have FLT3 co-mutations. We anticipate preliminary data in the second half of the year from ziftomenib in combination with gilteritinib and relapsed or refractory NPM1 mutant FLT3-mutated AML. We are also evaluating ziftomenib in combination with quizartinib in the newly diagnosed setting.

As a whole, these data are building a consistent picture. Ziftomenib can be integrated across multiple treatment approaches without compromising safety or activity in clinical studies, an attribute we believe, will be essential for long-term use in both relapsed and frontline settings.

Turning to our frontline development program. Our KOMET-017 trial is an innovative one-stop shop design, which enables simultaneous enrollment into 2 independent Phase III trials at each activated site. This streamlined approach is a meaningful differentiator and operational advantage, allowing us to accelerate enrollment while maintaining rigorous study, design and execution. We are very pleased with the progress to date. Site activation and enrollment are ahead of projections with strong participation from leading academic centers across the U.S., Europe and Asia. This level of engagement reflects both the clinical interest in menin inhibition and the confidence investigators have in ziftomenib's profile, particularly its potential to be combined with standard frontline regimens.

Beyond AML, we continue to explore the broader opportunity of menin inhibition. Our study evaluating ziftomenib plus imatinib in GIST is progressing well, and we hope to provide updates when appropriate. In addition, we are evaluating the role of menin inhibition in other solid tumors.

And turning to darlifarnib, which also continues to make important progress. Recent data presented at the International Kidney Cancer Symposium provided clear proof of mechanism, demonstrating activity in cabozantinib pretreated clear cell renal cell carcinoma, a setting where clinicians would not typically expect to reinduce responses with the same TKI after progression. These findings support the role of the REV mTORC1 resistance pathway and reinforce potential for darlifarnib to restore sensitivity to targeted therapies. Enrollment in the Phase Ib portion of the darlifarnib plus cabozantinib trial is now underway. In addition, we intend to present an update on the full Phase Ia data set later this year.

We see combinations of FTIs and KRAS inhibitors with a potential next advance for patients. At ASCO, we will present preliminary data evaluating darlifarnib plus adagrasib and KRAS G12C mutated solid tumors, and we look forward to discussing that data at a virtual event on June 3.

I'm incredibly proud of our teams at Kura for the disciplined focused execution behind these programs. Their cross-functional commitment and operational excellence are helping translate our strategy into meaningful clinical progress for patients.

And with that, I'll turn the call over to Tom for financial updates.

Thank you, Mollie. I'm happy to provide a brief overview of our financial results for the first quarter of 2026.

Our net product revenue from KOMZIFTI sales was $5.8 million compared to none in the first quarter of 2025.

Collaboration revenue from our Kyowa Kirin partnership was $12.5 million compared to $14.1 million for the same period in 2025.

Research and development expenses were $65.3 million compared to $56 million for the first quarter of 2025. The increase was driven by ziftomenib combination trials, including the start of enrollment in our KOMET-017 trials in the second half of 2025.

Selling, general and administrative expenses were $31.6 million compared to $22.8 million for the first quarter of 2025. This increase was driven by the commercial launch of KOMZIFTI.

Net loss for the first quarter of 2026 was $73.3 million compared to a net loss of $57.4 million for the first quarter of 2025. This includes noncash share-based compensation expense of $8.4 million compared to $7.8 million for the same period in 2025.

As of March 31, 2026, Kura had cash, cash equivalents and short-term investments of $580.8 million compared to $667.2 million as of December 31, 2025.

We are maintaining our previously communicated guidance for collaboration. We expect this to be $45 million to $55 million in 2026, $90 million to $110 million in 2027 and $90 million to $110 million in 2028. This revenue reflects noncash based accounting recognition of performance obligations under our collaboration agreement with Kyowa Kirin.

Current cash, cash equivalents and short-term investments as of March 31, 2026, together with anticipated payments of $180 million under our collaboration agreement with Kyowa Kirin are expected to fund our ziftomenib AML program through the first top line Phase III results from KOMET-017 anticipated in 2028.

With that, I'll turn the call back over to Troy.

Thank you, Tom. As I said at the outset, the company is firing on all cylinders. Our first commercial launch is off to a strong start. Our Phase III programs are ahead of plan and we expect a strong cadence of data over the next 12 to 24 months that will further define leadership for ziftomenib and the menin inhibitor class.

With that, we'll conclude our prepared comments and we're happy to Leila to open the call up for questions.

[Operator Instructions] Our first question will come from Li Watsek with Cantor.

This is Dan Bronder on for Li Watsek. Congrats on the update and the commercial launch. Can you give us some color on how we should think about the duration of treatment with KOMZIFTI early on, given that it sounds like you have patients on monotherapy as well as some that might be receiving combination? Greatly appreciated.

Sure, Dan. Thanks for the question. Let me ask Brian if he can speak to them.

Sure. Thanks, Dan, for the question. I think it is difficult at this point to really give too much detail on duration of treatment because we have 1 full quarter. We've reiterated before that our expectation is to get around 6 months of treatment.

What I can say is that we're very pleased, of course, with the number of new patient starts. We think that's really the measurement at this early in the launch to measure how well we're doing. And I think the 85 new patient starts us up well. What we need to do is really track for several quarters to get a better sense of that.

Your next question will come from Peter Green with LifeSci Capital.

This is Peter on for Charles. Congrats on the results team. You mentioned a few times the frontline opportunity and also strong enrollment in KOMET-017. And in light of -- sorry, EHA abstracts today. I have a question there. I'm noticing from last year that complete response rates across both NPM1 mutant and KMT to rearrange AML, that's in the front line for zifto in combination with 7+3. I'm Noticing those CR rates are increasing. I'm also noticing that CR MRD negativity is an NPM1 occurring potentially out to 43 weeks in some patients. So I guess with all of that said, what have you learned from KOMET-007 about the dose profile in the front line, especially over longer-term use? Is there some response deepening? Happening? Or is this just kind of an artifact of increasing -- of including kind of less adverse risk patients?

So I think we've learned foremost that we're using it correctly. And that doing it with a staggered start and a start that enables patients to continue to remain on without having to interrupt or lower dose or discontinue for adverse events is a really powerful way to keep these patients both in a response, have that response deepen over time and have these patients be able to continue into some sort of continuation treatment, whether that be post-transplant or post consolidation. We continue to gather more data, and we continue to be extremely encouraged that the way we've designed 007, the data we continue to gather from 007 helps us to really reinforce that we've correctly designed 017, so that we can expect great outcomes for these patients in the front line as well.

Yes. Peter, this is Troy. Just to add to Mollie's comments, I agree with everything she said. One of the things you'll see at EHA is really this is probably the most mature set of data in the front line and it's really a story of durability and clinical benefit for patients. The data will be updated at the presentation, but response rate, MRD negativity are important. We'll really draw people's attention as well, as Mollie said, to the durability. We're really -- this is -- this data is pretty unprecedented and I think very encouraging from the promise of menin inhibitors and the 017 study, as she said.

Your next question will come from Jonathan Chang with Leerink Partners.

On the KOMZIFTI launch, can you provide more color on what you're seeing in terms of initial combination use and instances of switching from other menin inhibitors? How common is combination use in switching?

Yes. Thanks for that question, Jonathan. Yes. So what I can share about the combination use for this, of course, as you know, our promotional teams, our commercial teams are focusing on promoting on label as a monotherapy, but physicians are choosing to use in combination. The data we're seeing so far is that it's about -- probably about 40% of patients are getting -- using KOMZIFTI combination, either with ven/aza or in those FLT3 co-mutated also with gilteritinib. So that's what we're seeing early on. I think that getting to the expectation of how those patients will do is something will follow.

And regarding your question around switching, that is something that we -- as I said, we observed, especially as 2 products that became available. It just kind of drove where physicians are choosing to use KOMZIFTI based on the profile. I think that's going to be probably less of a trend than the combination use that we expect to go forward. But nevertheless, it does demonstrate the strength of the KOMZIFTI profile and really, I think, supports the strong initial early momentum we've had in this first quarter of launch.

Your next question will come from Etzer Darout with Barclays.

Just a follow-up on a question. Maybe you could comment on the primary reason patients have been switching from other menin inhibitors. I'm not sure how much data point you've gotten at this point, but just wondered if it's something you could comment on?

Yes. I don't think I can -- thanks for the question, Etzer. I don't think I can go into the detail of each patient that switched really. It's probably more at a high level. We're seeing that physicians now they have a choice between multiple menin inhibitors and there have been physicians chose to switch those patients from another menin inhibitor to give them the opportunity to benefit from KOMZIFTI. So it could be based on the profile. Based on whatever the decision the physician feels. Based on if its efficacy, the safety profile, the simplicity of use, all of those things are what we've heard has resonated from a number of physicians.

Yes, Etzer, just to jump in for a second and build on that. I mean the switching is, to some extent, what we expected. I don't -- I agree with Brian. I don't think it's probably the most significant aspect. What we draw your attention to is, as Brian said in his prepared remarks, the new patient starts. The other menin inhibitor had approximately 130 new patient starts. We've had 85 in our first full quarter. That's about 40%. Given that the story prior to this was kind of a winner take all, we think we've got really strong momentum to be able to take leading market share in NPM1. You are going to see some switching. I mean, as we've said, we think we have a superior overall profile, but where we really think you're going to see it is in the new patient -- increased new patient starts again, use in combination, although that's not our labeled indication, that's physician discretion. Those are some of the elements we draw folks' attention to.

Your next question will come from Reni Benjamin with Citizens.

Congrats on the progress. Maybe just sticking with the new patient starts. I guess, any other or additional color you can provide, anything regarding gross to net dynamics? And when you talk about the 157 total prescriptions, are these -- are the scripts typically like 1 month on average, are they 3 months on average? Can you give us some sort of details there. And just if I can throw 1 more in regarding the commercialization, you said 60 activated accounts. Brian, what's kind of the total number of accounts that you're targeting? Just to give us a sense as to where we are in the cycle.

Yes, sure. So thanks for the question, Reni. So with regards to these new patient starts, the color we're seeing, and I shared a little bit, these are the relapsed/refractory patients to kind of fit across -- we're seeing it across accounts that are either KOMZIFTI trial sites. We're seeing it from those who have experience with other menin inhibitors as well as those who haven't had any experience. What we're seeing is a very strong start this early on that we're able to get, as Troy mentioned, 40% of the kind of new patient starts in this first quarter alone gives us a lot of confidence that there are patients out there who may benefit from KOMZIFTI, and we're very pleased with the opportunity we have to move forward with that at this point in time. We do say, and as I mentioned in the remarks, we're going to continue to see quarter-on-quarter growth. We'll continue to go deeper into other accounts and ultimately become the market leader in this space based on that menin class share. So we're very encouraged by the start right now. We look forward to that in the future.

And Reni, the scripts are 1 month, right? These are 1 month scripts.

Got it. And the gross to net dynamics?

Thanks, Reni, for that question. Those are within normal ranges, so in that 20% to 30% range.

Your next question will come from Roger Song with Jefferies.

This is Nabeel on for Roger. I'm encouraged to hear on the open label, the combo use at 40% in combination. So I'm just kind of curious if you could give us color on how this looks in academic and community settings? And then as we get more data, the ven/aza publication and then the second half data with the FLT3 combo, how do we expect this to sort of evolve? And does the KOMZIFTI have any advantage here?

Yes. So I mean, I think that as we said, this is -- the combination use is not what we're promoting actively, but it's based on a lot of the data. I think that in the remarks that as we've shared here, Mollie's remarks around the combination use. This really shows that we have a potential to become that strong leader, both in the relapse/refractory, but in the front line setting. The data that we'll be presenting in the publication with ven/aza, will be coming, as we said, in the first half of the year. We think that will help to draw momentum. Of course, our objective is to submit that to NCCN guidelines, but we can't determine whether or not that will be incorporated. But we have heard feedback from physicians that the publication of the data are very important for them. So we'll see that plus the potential unique combination to be able to combine with the FLT3 inhibitor, I think also gives us a strong avenue to build strength in a market where there's 50% of the NPM1 patients who have a FLT3 co-mutation, which may be unique to KOMZIFTI's profile to be able to do.

Your next question will come from Phil Nadeau with TD Cowen.

Congrats on the progress. In regards to the frontline data that's going to be at EHA, we're curious to get your most recent thoughts as to what measures you think investigators and physicians are going to look to you when thinking of adopting the menin ins in the front line. Do you think ultimately the most powerful data will be the durability of the response? Could it be progressing to transplant, ultimately, overall survival? I guess in your conversations what are physicians evaluating most prominently as they think about moving the menin ins forward?

Sure. I actually think it's a combination of all of those things you said. Ultimately, survival is the primary endpoint. You want these patients to live. There's some ability to get to curative intent with transplant, and we want to be able to expand patients' ability to get to curative intent. So the durability, I think, is going to be your best prognostic indicator for our ability to increase the survival. And I think the MRD negativity is going to be what actually predicts the durability as well. So all of them are extremely important. We're seeing extremely high response rates. You'd expect to see maybe 70% to 80% of patients having a complete response to 7+3, and we're seeing things in the high 90s. You'd expect to see about 45% of patients have MRD negativity in the bone marrow, and we're seeing that in the 80s. So again, I think that all signs are pointing to these patients having really strong, really deep responses and a great chance of having an effect on survival overall.

Your next question will come from Salim Syed with Mizuho.

Great. Congrats on the quarter, guys. Just 1 for us on that 40% number, Troy. Could you maybe comment on the cadence through the quarter? Is that something that is also representative of your exit NBRx share for NPM1? Or was it higher kind of coming out of the quarter? And similarly, I guess, is that similar to the dynamics you're seeing for this current quarter?

Yes. Salim, I mean we're talking about small numbers. Our goal here is to be the market leader in relapsed/refractory NPM1, that's 51% or more. I think you're going to see us push that as high as we can. There's -- as you can -- as you know, I mean, you've been doing this a long time. There's a lot of variability, week-to-week, month-to-month. What I think we're really encouraged by is we're second to market behind another product that's been on the market now for 15 months, and we've taken 40% of new patient starts in the first full quarter. That's what we set out to do. That's just the beginning. I think we're very optimistic. You're hearing it whether it's in the performance of the field force and the commercial team, whether it's the EHA abstract, this -- ziftomenib or KOMZIFTI in the commercial setting has a real opportunity. So look for us to build on that, as Brian said, I think we're just getting started. We're still learning. We're still educating. This is the first step, but I think a very, very encouraging first step.

[Operator Instructions] Our next question will come from David Dai with UBS.

Congrats on the quarter. So a few questions from me. One is on the $5.8 million revenue. How much of that is inventory stocking? And then how should we think about the combo use could extend the duration of therapy beyond the 6 months on monotherapy? And then lastly, do you think the patients will actually continue to use menin inhibitors beyond progression?

So just a reminder to everybody. David, I'm going to -- I don't mean to single you out, but we're trying to limit people to 1 question. So there isn't any meaningful stock in. I mean this is -- you can see this in the numbers. But Brian, maybe you can speak to durably -- the question on durability of combo?

Yes. I mean I think that, as I said earlier, David, I think duration of treatment is something we'll be seeing over time. It's difficult to say within a first full quarter of how much that duration is used. Our expectation is that patients who are on therapy in combination will likely have a longer duration. But we need a little more time to play that out because you need to understand which type of patients are getting on therapy. Is it more second line versus third or fourth line or something. Those are the things that we're tracking. We're pleased with where we're heading now. But I could ask if we could get a couple more quarters under our belt to get a better sense on what that durability could be. But we would reiterate that our -- we believe that this overall market opportunity in the relapsed/refractory setting still remains around that $350 million to $400 million.

Yes, David, what I might add to that is we were not surprised to see some spontaneous combination usage. I think we were pleasantly surprised to see physicians choosing to combine with gilteritinib, given that we're not even planning to present that data until sort of towards the end of the year. But given the overall profile, the combinability of zifto, it's nice that physicians have that option for their patients, and we're starting to see that kind of work its way into the commercial setting. That's very gratifying. It's not anything we're promoting, but it is nice to see.

Your next question will come from Daniel Brims with Lake Street.

Congratulations on the strong launch. For ASCO, I was just curious, will we be seeing any monotherapy data there or just combination data for darlifarnib with adagrasib?

Yes. So we've actually previously presented the monotherapy data last year. And to give you an idea of the really wide therapeutic window that we have with the monotherapy, balancing both efficacy and safety so that we'll be able to do an extensive amount of combinations over time. At the ASCO presentation, you're going to see it in combination with the KRAS inhibitor adagrasib. You will see dose escalation data, and you will see it across multiple time types, including non-small cell lung, PDAC and colorectal cancer. And we're very excited to be able to share this with you, kind of our third installment of the REV mTORC inhibition pathway that is helping to overcome adaptive and innate resistance for these patients with suffering from cancer.

Your next question will come from Peter Green with LifeSci Capital.

This is Peter again on for Charles. Just wondering, you mentioned that the KOMET-017 trials is going -- ahead of schedule. Just wondering if there's any more details on that, what you're hearing from investigators? And then remind me, does that change any guidance for potential future readouts?

Yes. Maybe Mollie can speak to anything we're hearing, Peter, and then I can address your question about guidance. Mollie?

All we hear is excitement. Excitement for new sites to get up and running, the regions to get up and running. I can tell you that participation both in the U.S., Europe and Asia is extremely strong and has come to that level of strength very, very quickly. So I would say 007 was a great indicator of how quickly we could enroll 200 patients into a Phase I trial. The Phase III is going incredibly well, and it's really well predicted by that enrollment rate we saw in 007.

And on the guidance question, Peter, we haven't changed anything at this point. We've guided to the initial top line results from the first -- from the intensive chemotherapy combo in 2028. We haven't been more specific. We might tighten that up as we get closer. I will highlight, we're significantly ahead as far as we can tell the competition in that setting. But even in the ven/aza setting, which is the other side of 017, we're -- the team is making just incredible progress. And really credit to Mollie for combining these 2 Phase IIIs into a single protocol, since that every time we activate a clinical site, we're getting 2 Phase III starts for the price of one. And so you're going to -- I think you're going to see that continue to get pulled through. The excitement has just been helpful. We did an investigator meeting recently, and it was incredibly well attended and well received. So onward we go.

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

Thank you, Leila, and thank you all for joining us today. We're encouraged by the early performance of the KOMZIFTI launch, the momentum we're seeing across our clinical programs, the clarity of our strategy moving forward. With continued commercial execution, multiple clinical catalysts and including EHA and ASCO and a strong financial position, we believe, Kura's well positioned to drive meaningful impact for patients and to create long-term value. We look forward to updating you again soon and to engaging with many of you at our upcoming investor event later this month. Thank you all once again, and we'll adjourn.

Good day, everyone. My name is Jenny, and I will be your conference operator today. At this time, I would like to welcome you to Kura Oncology's 2026 IKCS Investor Event. [Operator Instructions]

At this time, I'd like to turn the call over to Troy Wilson, President and Chief Executive Officer of Kura Oncology. Please go ahead, Dr. Wilson.

Thank you, Jenny. Hello, everyone. Today, we're delighted to share with you some updates that were presented at the International Kidney Cancer Symposium that's being held over the next couple of days in Paris, France. This relates to our the ongoing study evaluating darlifarnib and cabozantinib in patients with kidney cancer.

If we can go to the next slide, please. In today's presentation, we're going to be making forward-looking statements. I would refer you both to our filings and our website, our SEC filings on our website for more information about Kura Oncology and the risks and uncertainties of an investment at this time.

I'm joined on today's call by 2 participants. Dr. Adanma Ayanambakkam is Assistant Professor of Hematology Oncology and Medical Director of the Genitourinary Medical Oncology Research at Oklahoma Health Sciences Center. And also joining us today is Dr. Mollie Leoni, Kura's Chief Medical Officer.

Both of them are going to be presenting slides through this presentation. This is an incredibly exciting and dynamic time at Kura. We are squarely focused on the launch of our first commercial product, KOMZIFTI, which was approved just last year in relapsed/refractory NPM1 mutant AML. We're looking forward to giving an update on how the launch is going at our earnings call next month.

We're also broadening out the opportunity with ziftomenib or KOMZIFTI as it's known commercially to be able to treat up to 50% of AML patients. What we're here to talk about today is one of our pipeline programs. And we have a thesis at Kura that cancer is best treated in combination. And we'll talk more about that today. But as you'll see with both our menin inhibitors and our Farnesyl transferase inhibitors, we're advancing innovative therapies that I think have the potential to combine with other agents to really drive better outcomes for people with cancer.

If we can please go to the next slide. So we call these precision combinations. And if we can go to the next slide, on the left-hand side, you can see the combinations that we're undertaking with ziftomenib. Many of these are familiar to you. We're, of course, evaluating ziftomenib in acute myeloid leukemia, both in the relapsed/refractory and in the newly diagnosed setting.

Importantly, we'll be giving an update on the intensive chemotherapy combination in newly diagnosed patients middle of this year. We're looking toward a publication with the non-intensive chemotherapy combination to be published a little bit later this year. And then finally, we'll give an update on the FLT3 combination specifically with gilteritinib in the relapsed/refractory setting.

Our view is and always has been, while menin inhibitors offer tremendous promise, we want to move them forward and move them into combination as quickly as we can. Continuing that theme, we've got ziftomenib in GIST, and we're looking forward potentially to an update next year for that program. On the right-hand side, if we can go to the next slide, we're going to focus today on our pipeline program, darlifarnib, which is just now beginning to come into its own. And specifically, as you know, we're evaluating darlifarnib in 2 contexts.

Today, we're going to talk about the data combining darlifarnib with cabozantinib, which, of course, is an anti-VEGF receptor inhibitor. A little bit later this year, we're looking forward to sharing with you the darlifarnib data in combination with adagrasib, which, of course, is a KRAS G12C mutant specific inhibitor. And there, we'll be showing you data in lung, colorectal and pancreatic cancer. This idea of precision combinations is not new, but we think it's really the right way to go.

Cancers use a number of different mechanisms to be able to grow and evade and metastasize everything from genomic instability, inducing angiogenesis, avoiding immune destruction. And our view is -- and our focus is to develop therapeutic agents that can combine with other therapies.

If we go to the next slide, That's, in fact, what we've seen in renal cell carcinoma, the evolution of treatments in kidney cancer. And Dr. A is going to speak to this as he goes through the data slides. But initially, the first approvals were with classical immunotherapy, then we saw a wave of tyrosine kinase inhibitors as well as mTOR inhibitors.

Now increasingly, we're seeing doublets and triplets. And that's, in fact, where we anticipate darlifarnib will go ultimately is in combination, but we think it's important to demonstrate the mechanism of action and validate that as well as to get a sense of what is the safety, tolerability and activity as we think forward.

Mollie will be able to speak to this as she goes through our strategy building on this initial data. So if we go to the next slide, darlifarnib, as all of you know, is our next-generation farnesyl transferase inhibitor. We've been working on farnesyl transferase really since the inception of the company. Darlifarnib is as good as it gets as far as a farnesyl transferase inhibitor is concerned, extremely potent, has great safety and tolerability.

We took everything we knew about tipifarnib and we optimized it. And we're really delighted. We did share some early data from the Phase Ia study late last year. This is now an update of that data. And ideally, we'll provide yet another update here in kidney cancer a bit later this year.

If we go to the next slide, these are the last couple of slides before I turn it over to Dr. A. What's the rationale here? Well, we know that cabozantinib and other tyrosine kinase inhibitor therapies block various signaling pathways. And in particular, they block VEGF receptor, but they also block PDGFRs, they block other targets as well.

TKIs have become a mainstay of treatment in kidney cancer. They're used throughout the treatment continuum. The challenge is once TKI therapy fails a patient, the treatment either with the same TKI or another TKI or really any subsequent treatment is reduced. So there's a significant need to be able to either drive deeper, better responses or ideally to resensitize patients to treatment with these TKIs.

If we go to the next slide, that's really where darlifarnib comes in. So darlifarnib acts in this context in renal cell carcinoma by blocking a protein called RHEB. RHEB is Ras homolog expressed in brain. And the significance of RHEB is that RHEB controls the transport of TORC1. TORC1 is one of the two TOR complexes that sit at the bottom of the MAPK kinase pathway. And when you defarnesylate RHEB, RHEB can no longer get TORC1 to where it needs to be.

So what that does effectively is it provides a second complementary block on the signaling pathway. And each of the targets that these TKIs are targeting are signaling through these signal pathways. So one has the ability -- if we can go to the next slide, once we introduce a combination, for example, of cabozantinib and darlifarnib, one can see you're blocking at the receptor level, you're also blocking down much further in the pathway. And the consequence, as we've seen both preclinically and clinically is you get less angiogenesis and tumor death.

We've validated this. We have presentations available on our website and that have been put in the published literature on the mechanism of action and preclinical data with various combinations. I think it's important to generalize these results. What we're going to show you today is the specific combination of cabozantinib and darlifarnib. But what we've seen, at least preclinically is that these results are generalizable to any tyrosine kinase inhibitor.

And as we talked about, we've been quite encouraged by the safety, the tolerability and the clinical activity that you're about to see. If we go to the next slide, I'm going to turn it over to Dr. A to walk us through the slides. These slides were presented by Dr. Zakharia in a poster presentation at IKCS, but Dr. A is kind enough to present the slides and put them in the appropriate context. Dr. A, I'll turn it over to you.

Thank you. Good morning, everyone. My name is Adanma Ayanambakkam. I'm a GU Medical Oncologist at the University of Oklahoma. And on behalf of the FIT1 team, I'm happy to present the data and give you a perspective on how things are moving along in this trial.

Next slide, please. Briefly, disclosures all pertaining to research or consulting and advisory roles. Next slide, please. So the FIT-001 trial is a Phase Iab dose escalation dose expansion study, and that evaluated both darlifarnib monotherapy and darlifarnib monotherapy plus cabozantinib. Now the darlifarnib monotherapy, the dose escalation cohort was not in renal cell carcinoma. It was in predominantly KRAS-mutated tumors. And what we found was that it was an efficacious drug and also safe and the recommended dose for expansion was around 8 to 10 milligrams.

We moved on to the dose escalation trial, and then this was when we combined it with cabozantinib and evaluated renal cell carcinoma patients. So this is the portion of the study that we're talking about today. And in order to evaluate the safety, we started off at a lower dose of cabozantinib at 40 milligrams, which is a lot more tolerable, but not as efficacious as the recommended dose, which is cabozantinib at 60 milligrams.

So the study started at darlifarnib at 3 milligrams, escalated to 5, 8 in addition to cabozantinib 40 milligram. And when that was considered safe and we did not meet our DLTs, we moved ahead to the second part of the study, which looked at the ideal dose of cabozantinib, which is 60 milligrams in combination again with escalating doses of darlifarnib to 3, 5 and 8. Currently, the study has moved on to the expansion phase where cabozantinib at 60 milligrams is being evaluated with darlifarnib at 5 and 8 milligrams.

Next slide, please. In the dose escalation, our patients were a mixture of patients who are cabozantinib naive and cabozantinib resistant. But for this talk and the poster that's being presented by Dr. Zakharia at IKCS, it was focused on those patients who had been cabo exposed. All these patients had prior line of cabozantinib or some TKI during their course. About 67% of patients had exposures to other TKIs apart from cabozantinib and almost 56% or half of the patients had cabozantinib as their immediate prior line of therapy and all had progressed on cabozantinib.

So about 56% were what we would consider cabozantinib refractory, a total sample size of around 18, a small population, but still an important population to evaluate, pretty evenly distributed from all the different cohorts, but important to highlight that a predominant portion of this study includes patients, about 15 or the 18 patients had cabozantinib at 40 milligrams, not at 60 milligrams.

Next slide, please. Overall, the safety profile was pretty consistent and tolerable. And for the safety profile, we look at the whole dose escalation patients, not just the cabozantinib refractory patients. Here, what we found was that darlifarnib was a pretty tolerable and safe regimen. Now if you look at any grade TRAEs, the most common ones were neutropenia, fatigue and diarrhea. But for the grade 3 or more TRAEs from darlifarnib, neutropenia and anemia were by far the most common.

Now it's important to understand that while neutropenia has increased, it is an expected event from farnesyl transferase inhibition, and it is also something that's easier to manage. So in comparison to the other side effects from cabozantinib, which are discussed elsewhere in the poster, what we are showing here is that darlifarnib did not add to the toxicity profile of cabozantinib and neutropenia, anemia and thrombocytopenia, while our TRAEs are usually asymptomatic to the patient's perspective. So it did not lead to any significant deterioration in quality of life, which is very important in this patient population.

Next slide, please. Overall, darlifarnib was well tolerated. There were obviously some dose reductions predominantly due to cytopenias, predominantly in neutropenia. There were interruptions in about 60% of patients, but most of them were able to continue on it. 13% had to dose reduce the darlifarnib. A good portion were able to go back without any discontinuation in their -- or dose reduction in the darlifarnib.

Overall, the number of patients who needed discontinuation of darlifarnib was around 6 patients, so 4 out of the 70, so a pretty good number. In comparison, cabozantinib needed dose reduction in about 26%. Cabozantinib needed to be interrupted in about 70%. And to put it in context, other trials that have looked at cabozantinib like the recent LITESPARK-011 trial or the CONTACT-03 trial that had cabozantinib as the control arm had about dose interruption in about 90% to 100% of these patients.

We know cabozantinib longer duration is toxic and can have some AEs. So within that context, I think this is pretty reassuring in terms of the tolerability of darlifarnib and how we are able to manage the AEs that arise from it.

Next slide, please. The clinical activity is pretty encouraging. What we noticed was that in these 16 patients, about 15 of them had disease control rates, so a disease control rate of about 94%. But what was even more promising is that the objective response rate in this population was around 44%. So to put it in perspective, these are patients who had prior line of cabozantinib, about 60%, 56% to be precise, had cabozantinib as their immediate prior line and had progressed on cabozantinib.

And even among those patients, we had a good amount of response, 4 out of the 7 responders who had cabozantinib as immediate prior line of treatment had an objective response rate on this study. So in that context, pretty promising objective response rates of 44%.

Next slide, please. What is even more interesting is that the objective responses that were seen on the study seems to be seen along multiple doses of the darlifarnib. You can see darlifarnib at 3 milligrams also having significant partial responses and darlifarnib at 5 and 8 also following. Now what's also important to understand is that most of these patients were on cabozantinib 40 milligram as depicted by those poker dot bars and very few patients as in the solid bars were patients who had cabozantinib at 60 milligrams.

Why this is important is that we know cabozantinib 60 milligrams has a better objective response rate than the 40 milligram. And it's interesting to see that this combination in a cabozantinib pretreated or cabozantinib refractory population still has considerable responses at the lower dose of cabozantinib at 40 milligrams, which is also the more easier to tolerate dose of the cabozantinib.

Next slide, please. Duration of response is still evolving. We don't have a long-term follow-up as of yet, but it's important to note that many of these patients continue to respond. We have a follow-up of around 50, 56 weeks for the longest patient in this cohort. The responses do seem to be durable, but we will need to wait to see how durable these responses are in the long term. But what we are seeing is there is slow evolution of disease that goes from stable disease to partial response, some people with partial response pretty earlier on in the disease course.

And what we have not identified is a long duration of stable disease before we see a response. At most, most patients had a partial response by the 8- to 10-week mark around the first couple of scans. But important to note that so far, the responses do seem to be durable, but long follow-up is required.

Next slide, please. We'll highlight a couple of different patient vignettes for us to put this in perspective. This is an 80-year-old patient with TSL RCC diagnosed in 2022, starts frontline treatment with nivolumab and cabozantinib with a best objective response of stable disease was on this treatment from around 2023 to 2025. Our initial study treatment was on June of 2025. So about 3 years after he was on nivolumab and cabozantinib. Get started on cabozantinib 40 milligrams and darlifarnib at 8 milligrams. And at week 8, he did have a partial response. He had 36% reduction at 8 weeks, and these responses seem to be durable. And his last scan at 16 weeks shows a partial response with a RECIST score of 32%. So patient continues to remain on treatment, and this highlights that despite progression on cabozantinib as prior line of treatment, patients continue to respond at the lower dose of cabozantinib without significant side effects.

Next slide, please. This, I think, is a little bit more relevant to the ongoing discussion. And here, again, another younger patient, 53-year-old female diagnosed in 2021, get started on frontline immune checkpoint inhibition doublets with nivolumab and ipilimumab, progresses to nivolumab and cabozantinib, and this was done before we knew that IO beyond progression is not meaningful.

And importantly, this patient also had HIF inhibition with Belzutifan, the FDA approved HIF-2 alpha inhibitor, and she subsequently started study treatment in October 2024. What's important is that in this heavily pretreated patient population, prior IO doublet, prior cabozantinib and prior HIF-2 alpha inhibition, the darlifarnib at the lower dose of 3 milligrams and the cabozantinib at a lower dose of 40 milligrams PR, about 38% reduction at week 8 and continues to evolve with a 53% reduction at week 48, indicating an ongoing response in this heavily pretreated population. So pretty promising responses, pretty good safety profile that has got us excited about this novel combination.

Next slide, please. This is a little bit exploratory. We always thought not to make cross-trial comparisons, but in oncology, we always end up making cross-trial comparisons, and this is one such scenario, not to highlight the superiority of any such regimen, but to highlight the tolerability and the safety profile of these different regimens. There has been Phase II trials looking at lenvatinib–-everolimus showing that they had better outcomes. There was a recent LenCabo trial that was presented at ESMO last year that looked at len–va-everolimus in a randomized manner. And importantly, the control arm of that trial was cabozantinib, in a cabozantinib-naive patient population.

In that trial, what they did show was that cabozantinib objective response rate in a naive patient population was around 40%, and it was inferior to the superior objective response rate of lenvatinib–-everolimus. So making big jumps, it's interesting to see that the combination has an objective response rate of 44% in a cabozantinib refractory population compared to cabozantinib monotherapy of 40% and odd responses in a naive population. But what's important to understand is that the safety profile seems to be a lot more tolerable.

I would want to focus your attention on the second column, which is lenvatinib– plus everolimus and mTOR inhibition combination doublet with TKI and the darlifarnib combination to look at the different safety profiles. And what we are not seeing here is an increasing toxicity profile from the combination. We are definitely not seeing a significant amount of pneumonitis, arthralgia and other side effects that we see with everolimus. And so as demonstrated in the preclinical rationale, the selective mTOR1 modulation via the RHEB pathway does seem to avoid certain side effects that we don't want while still retaining the efficacy that we want.

Next slide, please. So overall, I think it is a very good combination that has a proven safety and tolerability profile. We will need to wait for longer follow-up to evaluate the durability of the responses, but it's important to highlight that even in this heavily pretreated population, in this population of patients who are cabozantinib refractory, we had an impressive objective response rate of 44% with a disease control rate of about 94%.

The study is now actively enrolling in the expansion phase, which is looking at cabozantinib naive patients in combination, and we're excited to see how the study will fit in the evolving landscape for RCC. Next slide, please.Thank you.

All right. Thank you, Dr. A. And with that, I want to discuss the company's next steps. So these data are spectacular, and we have to ask ourselves what's next. We are currently in our dose refining Phase Ib. It is a randomized trial enrolling into 2 different darli doses, the 5 and 8 milligram as well as the cabo monotherapy arm, where upon progression, patients can then roll over on to the darli combination. These patients will have seen IO, but be cabo-naive and with no more than 3 priors. Endpoints will include response rate, durability and of course, safety.

Going to the next slide. These data encourage us to move forward exploring second-line plus and demonstrate a novel mechanism to add to the RCC armamentarium. We are currently enrolling into this randomized Phase Ib and expect to be able to share data next year. We are excited to be exploring an option for the IO refractory patient population. There are limited options for patients that have progressed on IO-HIF-2 alpha combinations and adding darli to these combination backbones provides new options for patients.

We recognize that the field is appropriately moving to combination approaches in the advanced setting. As HIF-2 alpha continue to move towards the front line, we believe darli combinations offer a potentially new way to address disease after failure of HIF-2 alpha. We believe that darlifarnib and cabozantinib have the potential as a combination to establish a new standard in IO refractory second-line plus clear cell renal cell carcinoma.

And with that, I will turn it over to Troy.

Thanks, Mollie. Please go to the next slide. So as Mollie said, we're really pleased with this data. This is just the first of multiple data updates on our precision combinations. You can see them laid out here. It's going to be an eventful year. And from our perspective F, which we couldn't be happier. We have a strong launch. We have outstanding execution on the Phase IIIs, and we have a lot of upcoming clinical data of these precision combinations that will help us figure out how do we position them in order to achieve the best outcomes for patients.

In particular, I'll draw your attention to -- this is the kidney cancer side of the darlifarnib story. We expect to present to you the KRAS side of the story here before too long in the context of an upcoming major medical meeting.

So with that, if we can go to the next slide. We're happy at this point, Jenny, to turn it over and open it up for questions and answers.

[Operator Instructions]

Our first question comes from Charles Zhu with LifeSci Capital.

Congrats on the data. Recognizing that these data are from about 4.5 months ago and not that many patients were evaluable at 60-milligram cabo combinations. Could you talk about the decision to expand at some of these 60-milligram cabo combinations, maybe what you've seen? And is there a potential to see enrichment in response rates as you treat patients at these higher doses and potentially introduce prophylactic G-CSF?

Yes, [indiscernible], thanks for the question. I'm going to ask Mollie to speak. You have a couple of subparts in there, but Mollie can take the question.

Yes. I just want to remind you that what we're showing you here are the patients that had already seen cabozantinib therapy. So it is not the full data set. And by the time we got to the 60-milligram portion of that dose escalation, we were not enrolling patients that had seen cabo previously. So that's why you see less data at the 5 and 8, the 60-milligram combination doses. But when we present the updated Phase Ib data a little bit later this year, you'll see the full patient profile. So you'll see all the patients that were treated, and it will be clear to you why we think that the 60-milligram dose with either 5 or 8 milligrams of darli makes the most sense.

With regards to your safety-related question, now that we're done with the dose-limiting toxicity portion of the trial, meaning we're done with kind of the initial dose finding and safety portion, we'll be able to do prophylactic treatment. So we will be able to use G-CSF or give the transfusion, et cetera, in order to mitigate these events. So I expect patients to be able to stay on at least as long, if not longer, and again, continue to have an easier time on treatment because we'll be able to use prophylaxis.

Our next question comes from Jonathan Chang with Leerink Partners.

Maybe for Dr. Ayanambakkam, where do you envision darlifarnib fitting into the RCC treatment landscape? And how has that changed with HIF-2 alpha inhibitors?

Yes. Thanks for the question. I think it's an important question, and it's something that's very promising from a treating kidney cancer doc because now we have a lot of options. But I think the landscape is evolving and it's evolving really quickly, and we're going to change how we do stuff over the next few years. We have seen in the LITESPARK-022 trial that looked at adjuvant therapy with HIF inhibition, pembrolizumab plus belzutifan. We know that there are frontline trials looking at IO combination with HIF-2 inhibition. There's also a triplet approach IO plus TKI plus HIF2 alpha inhibitors in the frontline setting.

Triplet therapy in frontline kidney cancer has been an elusive strategy. This is not the first time we've tried it, but we've not had success before. Maybe things will change and we will move on to combination therapies. But as of now, I would argue that there is a combination therapy that's recommended in the frontline setting. And 2 important trials have looked at combination therapy against the best TKI second line that we had, which is cabozantinib, which is LITESPARK-011 and also the LenCabo trial.

The LenCabo looked at lenvatinib-everolimus versus cabozantinib. The other trial, lenvatinib and belzutifan looked at cabozantinib as the control arm. In both of the trials, objective responses with cabozantinib was around 40%, median PFS was around 10 months or odd. The CONTACT-03 trial, which had cabozantinib in the control arm, all these 3 trials are cabozantinib at 60 milligrams. So they're very strong control arms.

And all of them objective response of 40%, PFS of 10 months, showing that a combination approach is probably better. But as more people start using pembrolizumab and lenvatinib upfront, maybe with another HIF-2 alpha depending on how that other trial pans out. And as people start using lenvatinib-belzutifan more, it begs the question of what other options there are. We know that the mTOR pathway is an important pathway to inhibit an important pathway that adds to mechanism resistance.

So I see this as being a doublet strategy for second line and above whether this combination is sequenced before lenvatinib, belzutifan or after lenvatinib, belzutifan depends on if the patient has had HIF alpha inhibition before or not. And it will be interesting to see. But this is probably in subsequent or in sequence with the combination with HIF-2 alpha.

Our next question comes from Etzer Darout with Barclays.

Congrats on the data. Just given what we've seen here from an efficacy safety standpoint, maybe your view around the mechanism translating into sort of the KRAS update on both efficacy and safety, if you could comment on that?

Mollie, do you want to take that?

Sure. I mean, for us, just as well as our PIK3CA data that we presented last year now, I believe it was. This is showing that the mechanism is what we say it is. This inhibiting the ability of RHEB to activate mTOR is really shutting down that additional pathway that cancer uses to evade treatment with targeted therapies, including KRAS inhibition.

So I think you should take away from this that mechanism of action, we have once again shown you evidence of its activity in this particular combination in PIK3CA, and we'll be moving forward into that KRAS inhibitor, where we think that you'll take away the same message that this works. This is an appropriate combination partner to help get rid of some of the acquired or the acquired resistance mechanisms that these cancers use to abate.

Our next question comes from Daniel Bronder with Cantor Fitzgerald.

This is Daniel Bronder on for Li Watsek. Could you elaborate on the 10 patients of the 18 that you had noticed had disease progression on prior cabo? And what were the reasons the other patients discontinued cabo and whether or not you see responses across the whole spectrum of prior cabo exposure?

So just in answering the last part of your question first, yes, we see responses across the continuum of how and when and where they've received cabozantinib previously. So for the patients that -- especially in the 40-milligram group, they either came off for progressive disease or potentially intolerance. And that makes sense with why they would want to come back on in the 40-milligram combination because that's usually how they reexpose these patients to cabo after they've previously seen it.

But I think the most important piece to recognize is that of the 7 responders, all of them had progressive disease on their cabo. And 4 of those 7 had come directly on to our trial from cabo therapy, so from a cabo failure and we're able to have their responses rescued from use of darli as well. And their best response on their prior cabo was only stable disease. So we were able to actually not only get them out of a progression, but move them into a response using a combination where the monotherapy was not able to even get them into a response originally.

Our next question comes from Erik Lavington with Mizuho Securities.

Erik on for Salim. Congrats on the progress. Recognizing it's really early days yet, just curious about the dosing of darlifarnib, if you have any interest or capacity in protocol to look at dosage above 8 milligrams. Your thoughts on that?

Sure. So we did a monotherapy dose escalation in addition to these combination dose escalations. The cabo 1 of what you're seeing right now. In the monotherapy dose escalation, as we've previously described, 10 milligrams appeared to be really the maximally tolerated dose, but you have a very wide therapeutic window with anywhere from 3 to 10 producing efficacy in expected patient populations and being safe enough to keep patients on.

So we would be able to increase the dosing between that 3 and 10 milligrams in any combination that we're looking at. That's probably the escalation pattern we would look at. But here, we felt that the 8 milligrams offered the appropriate safety and efficacy and really moving to 10 milligrams would have only increased the toxicity. And so that's why we're moving forward with the 5 and 8.

Yes. Erik, just to add to Mollie's comments, I mentioned that darlifarnib is a next-generation FTI, and that really is kind of on 3 axes. One is significantly greater potency relative to tipifarnib. Tipifarnib was dosed at 600 milligrams twice a day. And one really needed to be at that dose in order to see activity in HRAS mutant solid tumors.

As Mollie indicated, here, we have obviously a much more potent compound beginning with activity at 3 milligrams, but we also interestingly have this window between 3 and 10, probably 3 and 8, where we can balance safety, tolerability and activity. So it gives us a lot more flexibility, and it's also once-daily dosing versus the twice daily dosing of tipifarnib. It really is an ideal set of properties for these precision combinations, whether it's cabozantinib, adagrasib as you'll see for other TKIs and KRAS PI3 kinase inhibitors in the future.

Our next question comes from Jason Zemansky from Bank of America Securities. We will come back to Jason.

Our next question comes from Roger Song with Jefferies.

This is Nabeel on for Roger. Congrats on the data updates. So curious on the treatment durations, we still have a couple of patients on therapy. How are we interpreting durability at this stage?

Yes. It's a great question. It's still early, but you saw that there's patients that have been on even in this subset of the Phase I that we're showing you for getting close to a year. So it's an evolving story with the patients still on. And I think that it will be nice for you to get a broader picture when we show you the additional Phase Ib data in coming weeks where you'll be able to see even more patients, even more patient stories and even more of the durability story.

Our next question comes from Roger Song with Jefferies. Apologies that is Jason Zemansky with Bank of America.

Congrats on the progress. Maybe just a quick follow-up to Mollie regarding the mechanism, but appreciating RCC is just one indication of a broader strategy. Has the data set changed your outlook about which indications to pursue next? Are there any read-throughs to other solid tumors here that make them more attractive indications?

So what it does reassure me is that we can do this with any of the compounds that we can really -- it's more than just indication, it's really the combination partner. So anywhere cabo can go, we can go. Anywhere lenva can go, we can go. And then I would generalize that also to the KRAS inhibitors and the PIK3CA inhibitors. So that's really your landscape. Wherever those particular compounds can go, we can make them better. And that's why we'll continue to evaluate potential options and pick the right one to get this to patients as quickly as we can.

Yes. And Jason, just to add to Mollie's comment, again, you should be seeing the KRAS data, hopefully here before too long. I think that after we show you that, we may be in a better position to talk about the balance between going fast and getting to registration versus going broad. If anything, this data reinforces that there's a significant opportunity here in solid tumors. We are actively working through what's the right development strategy for Kura, both alone and in collaboration with others. And we'll be in a position kind of as the year goes on, I think, to speak more to that.

[Operator Instructions]

Our next question comes from Phil Nadeau with TD Cowen.

Congrats on the data. We wanted to follow up on the activity in the refractory patients. So it seems like based on our math, approximately 4 out of 10 patients who were refractory to cabo had a response. That's a very similar response rate to the 3 of 8 roughly who were refractory to cabo. Is that analysis correct that you're relatively seeing the same efficacy across those 2 populations? And if so, I guess our question is, for the next trial, you're looking at cabo-naive patients, why not continue in cabo refractory given the pretty strong efficacy there?

What we do think is that this combination gets the cabo exposed up to what you'd expect to see with cabo monotherapy in the naive patient population. I think that actually more of the patients were refractory than maybe your calculations are taking into account, like I said, of the 7 responders, all of them were refractory to cabo at the time of coming on the trial.

And as for our Phase Ib trial, it's part of the reason we're doing the cabo monotherapy arm is one to establish a good baseline in this patient population that has this ever-evolving landscape. So we want to see what our patients look like now today with HIF-2 alpha IO, et cetera. But having that rollover potential really allows us to continue to demonstrate the mechanism of being able to save or induce responses in patients that progress on the monotherapy. So we'll still be able to see additional data in that regard. But just to get the clearest signal, we wanted to make it so that we cabo-naive patients.

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

Great. Thank you, Jenny, and thank you to everyone who participated in the call today. We will look forward to our -- the next time we talk to you, I think, will be our earnings call in early May. I look forward to that. If in the meantime, you have any questions, feel free to reach out either to Greg or me. And we appreciate it. We hope everyone enjoys the Friday and the weekend. And with that, we'll adjourn the call. Thanks very much.

Hello again, everyone. My name is Etzer Darout, senior biotech analyst at Barclays. It's my pleasure to welcome Kura Oncology to our next fireside chat. With me this morning, I have Troy Wilson, President and Chief Executive Officer; and Brian Powl, Chief Commercial Officer.

Just maybe just to get us started, Troy, if maybe you can just make some introductory remarks for the team, and then we'll go into a Q&A.

Yes. Thanks, Etzer. Thank you to you and Barclays for inviting us to attend the conference. It's always terrific. So as folks probably know, Kura is now a commercial stage fully integrated biopharma focused on developing targeted therapies for both liquid tumors and solid tumors. We have sort of 3 priorities this year that we're going to -- I'm sure we're going to talk about in your Q&A. But the first is to drive the launch of our marketed product, KOMZIFTI to majority market share. The second is we have, I think, the broadest and most aggressive development plan for ziftomenib, which -- or KOMZIFTI throughout the treatment continuum, most notably the front line. And then we have a pipeline of therapies to come that at this point, I think, are just a really attractive call option, and we'll move those forward. Company is very well capitalized, and 2026 is going to be an exciting year.

Great. And maybe just again, given the recent launch of KOMZIFTI, can you just maybe kind of comment on at least what you're observing so far, the feedback that you're getting from KOLs on that sort of initial ramp. And then we'll obviously ask a little bit more around that. Sure. Brian, do you want to take that?

Brian, you wanna take that?

Yes, happy to. Thanks, for the question. So KOMZIFTI, as we know, was approved back in November of last year. We've had a very successful launch so far. We've really built the messaging and the focus of our discussions with KOLs and prescribers around really 4 points of differentiation for KOMZIFTI. One, we have built on a strong base of efficacy in the relapsed/refractory NPM1-mutant space. The safety profile for KOMZIFTI is viewed by KOLs as differentiated and really meaningful for those -- for the physicians and the patients.

Third, the combinability of KOMZIFTI with concomitant medications, the ability not to have to change a lot of your dosing is important. And then finally, the simplicity of once-daily dosing is also something that's resonated. The feedback we've heard so far has been very positive. KOLs are seeing that there is an opportunity to bring KOMZIFTI into the market, and we believe that we'll be able to achieve that majority market share based on -- in this space.

Great. And as you think about 2026, what do you sort of see as the puts and takes to adoption of KOMZIFTI?

Yes. I think it really starts back to the profile. We think that there's opportunity that this is a market where the population of patients are coming in as they progress from their prior line of therapy. We think the opportunity to get patients on KOMZIFTI as a monotherapy really is at that point of decision-making. We see that working for us well so far.

In the longer term, we also see the ability, while it's not within our label, a lot of the physicians want to combine with other standard therapies. And within the NPM1 space, patients have other options. They may be able to get things like venetoclax/azacitidine. If they're co-mutated with FLT3, there's an opportunity for them to get gilteritinib. And we're hearing that there may be opportunity to rather than sequence a menin inhibitor after those therapies to potentially combine. So that's one of the areas that we see as an opportunity.

Great. And are you observing any friction points, if you will, I guess, similar experience to other companies potentially in the space around center logistics, prior authorizations, comfort positions, DS monitoring. Anything that you'd want to highlight?

I would say the one thing I'd like to highlight is we haven't really seen a lot of friction so far. In fact, one of the things that's been quite compelling for us is the rapid uptake from payers to put KOMZIFTI onto their policies has been almost more of an upside surprise. We've had over 80% of private payers have put us on policy in the first 90 days, and that's well ahead of benchmarks. So we've seen a lot of open access for KOMZIFTI to go forward. Haven't really seen any major barriers. It's more than just you got to have the patients that come forward. It's an incident market where patients will be considered for KOMZIFTI, and that's what we're going to be working towards with our field teams.

Great. And obviously, the longer-term plan is to move into earlier line settings, particularly the frontline AML setting and several menin inhibitors moving forward in clinical trials to evaluate their drugs in frontline settings. What do you view as a key differentiator for you as you're working to execute your plans around KOMET-017, which is your frontline trial?

Yes. So I think it's sort of 2 pillars, if you will, Etzer. One is the properties of ziftomenib and the other is the manner in which we're executing on the trials. On the properties of ziftomenib, it goes back to something that Brian was saying. Oftentimes, investors are hearing it's all about efficacy, efficacy, efficacy. That's true. But if we -- with the, I think, the differentiated safety, combinability, convenience, you can drive better activity. You can drive better efficacy, whether that's in the relapsed/refractory setting or the frontline setting. You can see that from our frontline data. I would put it up against any of our competitors. We're going to give a data update on the 7+3 frontline Phase Ib. And I think, again, you're going to see that pull through. That's on the molecule side.

On the execution side, a number of years ago, we made a deliberate decision to put the 2 Phase IIIs under a single protocol. And we did that because when we went out and we talked to clinical sites in the U.S. and Europe, they said to us, we said, look, you're going to have multiple sponsors. How can we win your love. And what they said was put both trials in one protocol. It's easier, it's simpler to get up and running. It's on 1 IRB. You're standing up really trial. And most importantly, Etzer, any patient who walks in the door can come on 1 of those 2 trials. So as a result, we are rapidly activating. We're going to have up to 200 sites globally. We're rapidly activating. We've got many of kind of the premier sites in the U.S., Europe and Asia Pac. And I think we're just going to outexecute everybody else. We haven't really totaled it, but we've enrolled at this point, 350 patients in the Phase I studies to date with 30 sites. So now the goal is 1,300 and like the game is on.

Right. Great. And in the Fit AML patient population, you're evaluating combination with 7+3 in both NMP1 and KMT2 patients. I guess what does the biology tell us about where conviction can lie in either both of those patient populations? And I guess, ultimately, how could that translate into durable responses and outcomes for those KMT1 patients and NMP1 -- KMT2A and NMP1 patients?

Yes. Good question. So the -- the biology that you're addressing in frontline is you are trying to get patients to MRD negativity. Why is that so important? You can have 5% leukemic blast counts and be at a CR. If I have 5% leukemic blast counts, you still have full-blown leukemia, right? But if you're MRD negative, as measured in bone marrow, which is the accelerated endpoint for the 017 FIT study, you don't have leukemia down to the limit of detection. There is a very strong meta-analysis that we and the [ Impact ] consortium use to convince the agency to allow MRD negativity as an accelerated endpoint. And that's the association between MRD negativity and survival.

So the biology, as you asked about it, is you use the combination of intensive chemo and zifto to drive the MRD negativity down and then you use zifto in continuation therapy to maintain those patients ideally in an MRD-negative state. You called out the 2 genotypes. Let me just spend a moment on each of them. What we're seeing in FIT much to our surprise is that the NPM1 patients, in general, are not going to transplant. And the reason for that is pretty simple. If you're MRD negative CR as an NPM1 patient, transplant is contraindicated. If you're -- the KMT2A patients are going to transplant because that disease is different, it's more aggressive. It has an 8-month EFS versus a 22-month EFS for NPM1. But you -- what we are seeing is we're driving patients, KMT2A patients to transplant and then putting them back on zifto on the other side.

And when we think about MRD negativity and want to sort of understand the bar for success here. Can you give us a sense of the expectations around MRD negativity in the control arm?

Yes. So that's -- let's be clear. There is the MRD negativity assessment that the site makes that's typically done in plasma or in blood. And there's the MRD negativity assessment that you're doing that's centrally confirmed. And those numbers are different. The site numbers are typically higher. The benchmark for intensive chemotherapy in MRD negativity rates in bone marrow after 2 cycles for NPM1 is about 45%. 45% of patients are MRD negative after 2 cycles. Our goal is to demonstrate a rate of MRD negativity using, again, a high-sensitivity assay in bone marrow that's clinically meaningful above that. That's typically 10% to 15%. When we show you the update middle of this year on the intensive chemotherapy combo, look for that rate of MRD negativity that is assessed in bone marrow. The local assessments will always be higher, but the FDA wants to see the central assessment in both the control arm and the active arm.

Great. And then in the unfit population, maybe also your sense around bar for success when you think about CR and overall survival.

Yes. So the bar for success in the unfit population, this is the venetoclax/azacitidine combination. And we're there, we're only enrolling NPM1. You're in the range of about 60% CR rate in NPM1 and your OS is about 22 months for the NPM1 population. So that's what you're -- for both of those, either accelerated or full endpoint, those are the benchmarks you're looking to exceed.

Great. And you've highlighted a couple of updates from other zifto studies, KOMET-007, we'll get an update in the first half of 2026, 008 in the second half of 2026. Maybe starting with the 007 update where you presented some data at ASH. Maybe help us to understand what additional data we would get in the first half of this year. And then again, what should investors be focused on as those data sets are rolled out?

Yes. Thanks. There's actually 3 updates. Maybe I can just clarify. So we're going to present a publication that was really a continuation of the data you mentioned at ASH. That's venetoclax/ azacitidine, ziftomenib in the relapsed/refractory NPM1 setting. The significance there, particularly when you put zifto on top of ven/aza, your ORR goes to almost 80%. So to Brian's point, that's not going to be within the label, but we heard very clearly from clinicians get this data out, like we want to be educated. The physicians want to use these drugs in combination.

So you'll see that probably around midyear. We don't control publication timing. That's -- that will be a peer-reviewed publication. There will be a frontline update. What I would look for there is the sort of the median patients had been on the Phase Ib frontline study last year for about 5 or 6 months. This is now a year later. So that means your median patient will have been on almost 18 months. The significance of that is if you -- thinking about the frontline opportunity, if you can -- you have 10,000 patients, if you can keep them on therapy for 18 months, that is a $10 billion market. So investors should be paying attention to that. You're still going to want to see a positive Phase III, but these Phase Ibs are so large and robust, they'll go a long way to derisking it. The last data set is the one you mentioned that is the ziftomenib gilteritinib combo in relapsed/refractory NPM1 FLT3 co-mutated patients.

I'll just remind folks, that's half of your NPM1 population in every line of therapy. We have already said we were successfully able to dose escalate and get into an expansion with no DLTs, you're going to see that data back to the point that Brian was making, right now, there's -- what we hear is physicians will sequence FLT3 NPM1 co-mutated patients through gilt and then give them a menin inhibitor because gilt has a survival advantage. It went through a randomized trial. If you can give them data that says, don't do that, actually give the 2 together, you'll drive a better outcome, we think that will be very informative. Look for that data around the end of the year.

And what sort of data will kind of help us inform us, if you will, on sort of whether or not these patients are seeing a better outcome of the combination?

So the CR rate for gilt in that setting is less than 20%. The CR rate for zifto is 21%. The CR rate for our competitor is, I think, 23% you want to see a CR rate that is meaningfully better than those numbers and good durability. If you see that, I think you're in good shape. I'll also remind you, Etzer, that we're also evaluating quizartinib plus zifto in the frontline setting. That study is still in dose escalation. But to date, we've had no trouble at all combining with either of the 2 marketed FLT3 inhibitors.

Great. And then TOMET-015 study ongoing in GIST. Maybe if you can just comment on that study and perhaps where you are in dose escalation?

Yes. So what you're referring to is the study to assess imatinib plus ziftomenib in recurrent metastatic GIST. These are patients who have failed imatinib. The significance here is menin controls the transcription of KIT. So by combining a menin inhibitor and a KIT inhibitor, you're attacking KIT from 2 different directions. You're blocking the catalytic activity and you're blocking the transcriptional activity. What we've seen preclinically is we can resensitize KIT failures to almost any KIT inhibitor. If we're successful, this is the first novel MOA in GIST since the advent of KIT inhibitors, right? Believe that's like 25 years ago. So that's a big deal.

I think we all appreciate from Cogent, from GSK, how big that GIST market could be. We're currently in dose escalation. I think we're encouraged by what we're seeing. We're at doses now that are higher than the AML doses, and it's going well. I think, Etzer, you're probably looking at a data update next year. We want to have enough data that we can come forward and really have a conversation about where we go from here.

Maybe we can spend the last few minutes on darlafarnib. A couple of programs there, KRAS G12C mutant solid tumors, RCC. Maybe just first on the KRAS mutant program, what -- how much data, again, could we see across the different KRAS mutant types? And we can have some follow-up questions on that.

Yes. So we are in that study, combining adagrasib, the KRAS G12C mutant selective inhibitor and darlafarnib. We're evaluating it in patients with non-small cell lung, colorectal and pancreatic cancer. Many of those patients have actually already seen a KRAS inhibitor. You're going to see Etzer, between the -- well, actually, this is just the escalation. You'll see 30 to 40 patients. It's a meaningful data set.

And when you think about sort of the KRAS space, there's always been a lot of focus around PDAC. But is there a particular histology that you think could be more meaningful than others? Or just maybe where sort of the benchmarks line and be able to sort of come ahead of those benchmarks?

Yes. Our goal is -- maybe just to frame the problem, and it's a common problem in both RCC and KRAS. Resistance is the problem, right? So even with all of the successes that we've seen, it's not like we're curing patients, right? Half of them respond off those half most of them eventually relapse. What you're doing with darlafarnib is you're blocking a major resistance mechanism. To your question, what we'd like to show with this data is we're bringing forward a novel mechanism of action that is broadly combinable and whether you have a mutant selective, a pan-selective, you're going to want to combine with darli. What are people doing right now? They're combining with cetuximab, right? They're going back 20, 30 years because they're trying to overcome resistance. So that's really going to be the focus. You'll see us articulate a development plan. Is it pancreatic? Is it colorectal, doublets or triplets.

Look for us to do that a little later. At this point, I think we want to get everybody saying, yes, that's obviously an MOA. I would want to combine with these KRAS inhibitors.

And I think to your point around sort of KRAS cancers and then the inevitable escape mechanisms that develop, right, to be able to keep patients on longer, durability matters. So I guess, is there another data set later on that could be more telling in terms of whether or not you're seeing the durability associated with being able to stop that resistance mechanism? Or could we get that type of update at this first?

I mean the hope is -- so whether we're talking about RCC or KRAS, what you're looking for is if a patient had adagrasib and progressed, a physician wouldn't normally think to put the patient back on adagrasib, right? Same thing with cabozantinib. So if we can show you examples of patients where we've been able to put the patient back into response, the only thing we've done is to add darlafarnib that's pretty interesting in terms of overcoming the resistance mechanism.

Part of the reason we're just now much more mature and disciplined. Part of the reason we've waited to show this data is you want to give your responses time to confirm. You want to have enough durability data that you can say something meaningful. It's still a Phase Ia, but we're also using that data in confidential conversations with a number of the players in the KRAS and RCC space because everybody has the same problem, right? And just to go to RCC for a second, there's a view that we're going to see a triplet of HIF-2 alpha TKI-IO go to frontline. If a patient fails that, you've just exhausted the 3 mechanisms in RCC. What do you do, right? And we're hearing a lot of enthusiasm if we can introduce a new mechanism of action that resensitizes patients to one or more of those MOAs, that's a big deal. The second-line opportunity is going to look different and is going to continue to be quite significant in RCC. So lots of exciting data to come in the darli program.

Great. And with combinations, particularly with KRAS, I think the question around safety always comes up just given sort of the KRAS historically being a problematic molecule to combine with. Maybe your thinking around like what sorts of safety signals should we be looking out for? What's problematic? What is reasonable to assume from a manageable safety perspective?

So I can say this, right? And folks who have followed this story for a while have heard me say this. I always talk about safety and tolerability because if you can't combine, you can't drive efficacy. The fact, Etzer, that we can combine at a full dose with cabo, alpelisib and adagrasib, full dose of each of them, full dose of darli kind of tells you everything you need to know. Do we -- the only AEs we see are on mechanism myelosuppression, which you're not going to address in a dose escalation because you want to see the tox, but you just give supportive care, you give G-CSF, for example, for the neutropenia, and you can address that quite meaningfully.

The beautiful thing about FTIs is this is why I keep pushing this mechanism. We have 5,000 patients worth of data, right? The safety profile is as good as it gets. It's better than cetuximab, for example, no disrespect, right? The -- I think people will be very pleasantly surprised. We hear from the clinicians in the RCC study. The remark at how well tolerated the cabo/darli combo is relative to other things they've seen. And I think that's going to allow us to drive interesting activity.

Right. So we're up on our time. Troy, Brian, thank you so much for your participation, and thank you to our listeners, and then we'll be back shortly with our next session.

Thanks Etzer.

Thank you.

Good day, everyone. My name is Abigail, and I will be your conference operator today. At this time, I would like to welcome you to the Kura Oncology's Q4 and FY 2025 Financial Results Earnings Call. [Operator Instructions] At this time, I would like to turn the call over to Greg Mann, SVP of Investor Relations and Corporate Affairs of Kura Oncology. Please go ahead.

Thank you, Abigail. Good morning, and welcome to Kura Oncology's Fourth Quarter 2020 Conference Call. Joining the call today are Dr. Troy Wilson, President and Chief Executive Officer; Brian Powl, Chief Commercial Officer; Dr. Mollie Leoni, Chief Medical Officer; and Tom Doyle, Senior Vice President, Finance and Accounting. We 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 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, Greg, and good morning, everyone. 2025 was a defining year for Kura, marked by FDA approval of KOMZIFTI and initiation of a successful commercial launch. As we enter 2026, our priorities are clear: execute commercially, move aggressively into frontline AML and combinations and build long-term leadership in men and inhibition while advancing a data-rich pipeline. KOMZIFTI generated $2.1 million in net product revenue in the final weeks of 2025. Although it's early, the launch is off to a strong start.

Feedback from physicians, pharmacists and payers has been consistent. KOMZIFTI delivers meaningful efficacy with differentiated safety, simplicity and combinability with concomitant medications in medically complex AML patients that matters. We believe leadership in relapsed and refractory NPM1 mutant AML will be determined by preference, not by who enters the market first. Importantly, KOMZIFTI is now listed in the FDA's Orange Book with patent protection through July 2044. That runway strengthens the long-term value of the franchise, particularly as we expand into frontline AML and combination settings.

Our strategy extends well beyond the initial approval. Enrollment is underway in our pivotal KOMET 017 frontline trials and 2026 will bring important data in both the frontline and relapsed/refractory settings. We're positioned Ziptomenib as a foundational combination partner in AML, including with FLT3 inhibitors and standard backbone regimens across relapsed/refractory and frontline nail we estimate the total U.S. opportunity at approximately $7 billion. Beyond AML, we're advancing a focused solid tumor strategy -- our ziftomenib combination with imatinib in gastrointestinal stromal tumors, or GIST, is progressing in dose escalation and our next-generation menin programs are advancing.

Darlifarnib, our furnace transferase inhibitor is designed to address resistance mechanisms across multiple oncogenic pathways. It's combination flexibility, including with cabozantinib, KRAS inhibitors and PI3 kinase inhibitors gives it potential to impact more than 200,000 patients annually in the U.S. We expect multiple clinical ups this year. In short, we're executing commercially, expanding development of ziftimenib across the AML treatment continuum and advancing a pipeline with meaningful catalysts in 2026.

WillWith that, I'll turn it over to Brian.

Thank you, Troy. Good morning. Our commercial objectives for KOMZIFTI are straightforward, establish clear differentiation in the menin inhibitor class, delivered strong quarter-over-quarter growth and achieve leading class share in relapsed/refractory NPM1 mutant AML. The early launch is exceeding expectations. I could not be happier with the execution of our world-class team who have been laser-focused on delivering a strong launch. Prescription trends are strong and the quality feedback has been consistent and encouraging.

Positions, both academic and community-based consistently KOMZIFTI clinical activity and ease of use. Once-daily dosing and lack of required azole dose adjustments are meaningful advantages in real-world AML practice, institutional pharmacists firmly echoed this in complex patients on multiple medications, safety and predictability drive confidence. We also hear clearly that the safety profile matters. KOMZIFTI carries a single boxed warning for differentiation syndrome compared to multiple box warnings for a competitor. That difference is resonating. Importantly, KOMZIFTI was added to the NCCN guidelines as a category 2a recommendation within a week of Kura's submission.

That rapid decision reflects enthusiasm and strong alignment among clinical thought leaders. Operational execution has been strong. KOMZIFTI was shipped within days of approval, and our experienced sales force brings an average of more than 20 years of industry experience and deep hematology expertise. The team was trained and fully deployed and in partnership with [indiscernible] is targeting more than 4,000 hematology professionals. Our message is simple. NPM1 mutations are now actionable and KOMZIFTI offers a differentiated profile.

Access has been a major strength and highlights a powerful leading indicator early in the launch. We engage payers covering approximately 90% of insured lives prior to approval. Within 90 days, approximately 84% of private payers had established coverage aligned with the label and without additional restrictions. That speed of coverage surpasses both industry benchmarks and our internal expectations. We're also thrilled to report that certain Blue plans are now requiring patients to go on KOMZIFTI before allowing coverage for the other approvement in inhibitor.

It's our understanding that their decision to implement this stat was based on the efficacy, safety and predictable price per patient. Step editing is uncommon in oncology. We view this as a meaningful independent validation of KOMZIFTI's profile and competitive advantage as the class evolves. KOMZIFTI is distributed through a focused network of specialty distributors and pharmacies through CuraRxConnect the average time for prescription to payer decision is 2 days. Patients are getting rapid access. We estimate the initial U.S. market for NPM1 mutated relapsed/refractory AML at approximately $350 million to $400 million annually. This is our starting point.

On top of our enthusiasm about our early launch, we strongly believe that long-term leadership across the AML continuum will be determined by breadth. By who can combine effectively with ven/aza 7+3 and FLT3 inhibitors and take the lead in frontline disease. KOMZIFTI it's profile, particularly at safety, combinability and simplicity position us to maximize the efficacy benefit across settings and drive class leadership. In the near term, we'll remain focused on quarter-over-quarter growth net revenue and new patient starts. Over time, we anticipate providing additional metrics to track progress.

I'll now turn it over to Mollie to discuss our pipeline.

Thank you, Brian. FDA approval in relapsed refractory NPM1 mutant AML was a major milestone, and it's just the beginning. We are building a durable expanding franchise backed by the most comprehensive development strategy. Our will is clear, makes Zipametib a foundational therapy across AML. We are executing the most comprehensive development strategy in the category. We expect to deliver multiple updates this year across key programs at major medical meetings supported by an expanding publication plan. Relapse rates in AML remain high, up to 70% within 3 years.

We believe deeper and more durable outcomes require moving effective therapies earlier in treatment. This drives our first to frontline strategy. We are rapidly advancing our registrational COVID-17 program in newly diagnosed AML, which will recruit patients at approximately 200 global sites. The program includes 2 independently powered trials, intensive and nonintensive chemotherapies, each designed to support potential U.S. accelerated approval and full approval.

Data from the Phase I KOMET-007 trial support this strategy in newly diagnosed patients treated with 7+3 or venisomenib, we observed high CR rates and deep MRD negativity Importantly, the addition of zitamenib did not meaningfully delay platelet or neutral account recovery in either combination. We expect to present updated intensive chemotherapy data from KOMET-007 in the first half of 2026. In parallel, we are preparing a manuscript detailing is implemented in combination with [indiscernible] in the relapsed/refractory NPM1 mutant AML setting.

Data last December showed encouraging safety, tolerability and clinical activity in this population. The combination was generally well tolerated without additive toxicity and meaningfully improved overall response rate composite CRE and overall survival relative to ziptamenobolone. We view this as an important component of our strategy. and we believe it has the potential to significantly improve outcomes in patients with relapsed/refractory NPM1 mutant AML. FLT3 co mutations present another significant opportunity and 1 we are well ahead of competitors.

We are evaluating zitimedibin combination with gilteritinib in the relapsed/refractory setting and with quizartinib in the frontline setting. If we can demonstrate the ability to combine with FLT3 inhibitors, we believe that will be a key differentiator Outside AML, KOMET-015 is evaluating cytomatinib in patients with advanced GIST. Dose escalation continues without dose-limiting toxicities in a broad range of doses. We remain very encouraged and plan to provide an update when appropriate.

Turning to darlafarnib. We are advancing this FTI in combinations to address resistance biology across solid tumors. We announced today the initiation of the Phase Ib dose expansion of FIT 001 with cabozantinib in advanced renal cell carcinoma. The Phase Ib portion comprises of randomization into 3 arms in line with project Optimis, including on cabozantinib monotherapy arm. This third arm provides a controlled benchmark and enables us to evaluate the combination in patients who are not responding to or just beginning to fail cabozatinib therapy. Phase Ia dose escalation data from FIT 001 showed encouraging safety and tolerability as well as antitumor activity, including in patients previously treated with cabozantinib.

Updated data will be presented in the second half of the year. We also plan to present preliminary data from our Phase Ia study evaluating darlifarnib with adagrasib in patients with KRAS G12C mutated lung, colorectal and pancreatic cancers in the first half of 2026. Finally, our menin inhibitor programs continue to advance, including preclinical work in solid tumors, as well as diabetes and cardio metabolic indications. In summary, we are working to move zitiminib earlier in the AML treatment paradigm, expanding our combination strategies and advancing a second growth pillar with the FTI platform with multiple catalysts this year.

And with that, I'll turn it over to Tom for a financial update.

Thank you, Mollie. I'm happy to provide a brief overview of our financial results for the fourth quarter of 2025. As we preannounced in January, our net product revenue from KOMZIFTI sales was $2.1 million compared to none for the fourth quarter of 2024. The first commercial sale triggered a $135 million milestone payment under our collaboration agreement with [indiscernible]. Collaboration revenue from our [indiscernible] partnership was $15.2 million compared to $53.9 million for the same period in 2024.

Research and development expenses were $64.4 million compared to $52.3 million for the fourth quarter of 2024. The increase was driven by zitomentid combination trials, including the start of enrollment in our KOMET-017 trial in 2025. Sales, general and administrative expenses were $39.1 million compared to $24.1 million for the fourth quarter of 2024. The increase was driven by the commercial launch of KOMZIFTI. Net loss for the fourth quarter of was $8 million compared to a net loss of $19.2 million for the fourth quarter of 2024. This includes noncash share-based compensation expense of $11.3 million compared to $8.6 million for the same period in 2024.

As of December 31, 2025, car at cash, cash equivalents and short-term investments of $667.2 million compared to $727.4 million as of December 31, 2024. Our $667.2 million balance at the end of 2025 reflects fourth quarter 2025 receipts of $195 million for the first commercial sale of KOMZIFTI and KOMET-017 enrollment milestone payments. Kura is providing guidance for collaboration revenue, which reflects noncash-based accounting recognition of performance obligations under our collaboration agreement with [indiscernible]. We expect this to be $45 million to $55 million in 2026, $90 million to $110 million in 2027 and $90 million to $110 million in 2028.

Current cash, cash equivalents and short-term investments as of December 31, 2025, together with anticipated milestones of $180 million under our collaboration agreement with [indiscernible] are expected to fund our Zetomented AML program through the first top line Phase III results from KOMET-017 anticipated in 2028.

With that, I turn the call back over to Troy.

Thank you, Tom. Kura enters 2026 with strong momentum. We have a launched product, which is performing well. We have the broadest frontline AML development strategy underway. We have multiple data readouts ahead and we have a second platform advancing in solid tumors. Our priorities are clear: accelerate uptake of KOMZIFTI in relapsed refractory NPM1 mutant AML and delivered strong quarter-over-quarter product revenue growth, advance and execute on our first to frontline strategy, generate and publish combination data, which guides treatment decisions and deliver clinical updates across our FTI platform.

2026 will be a year of execution, expansion and data. We're building a durable franchise in AML and a broader oncology pipeline with both breadth and depth. Everything is moving forward commercially, clinically and operationally and we're focused on converting that momentum into long-term value for patients and shareholders.

With that, Abigail, we'll conclude and open the call for questions.

[Operator Instructions] Our first question comes from Lee Watsek with Cantor Fitzgerald.

Congrats on the progress. Maybe a commercial question for Brian. You made a very interesting comment about step editing that some peers may require to use concept before the competitor product. I just wonder if you can give us a little bit more information about that. What percentage of payers have implemented the stock through policy and any specific feedback you can share from peers regarding [indiscernible] ?

Yes. Thanks, Lee, for the question. I'm going to -- just to remind everyone, we're going to try to limit to 1 question per analyst so that we can get through everyone. But Brian, I'll let you -- there's 2 or 3 questions tucked in there. I'll sort of let you speak to them.

Right. Thanks. And thanks, Lee, for the question. Yes. Yes, as we shared in the remarks, I think -- we think that this news of a step at it in required from some payers that's just come forward is a powerful leading indicator that supports kind of our overall assertion about KOMZIFTI being differentiated. I will say that our team -- the market access team has done a phenomenal job securing access and working with payers so broadly to get this access so early. What I can kind of share around the step edit and as you know what that recommend, the recommendation from some of these payers is that a patient should -- would be recommended to receive KOMZIFTI before receiving any other menin inhibitor.

Our understanding is the basis of that is built on a report from a group called IPD analytics. It's an independent consulting firm who is influential to many payers. And their recent reports of the relapsed refractory market in evaluating comset, recommended the step that for adult patients with relapsed/refractory and PM1 mutant AML. We know that there are some payers that have started to implement that, as I shared.

The biggest driver from what we can understand from this -- from the consulting summary from IPD, is that really, the 4 pillars we talked about around the differentiation of Comfy stood out, particularly because of the predictability of the cost. If you look at the -- based on their assessment, the annual WACC for KOMZIFTI in this setting is about just under $600,000 a year. But with our competitor MET inhibitor because of the different dosing schemes and SKUs that come forward, it comes up to almost $1 million a year. And I think that's where we see they're driving the difference when you also add in the safety profile, the combinability and the predictability of that.

So I can't really give you an overview of how many plans there are a handful, and we can't predict how many other plans may do this in the future, but it's encouraging for us as we look to become the class leader here in the NPM1 space.

Your next question comes from Roger Song from Jefferies question.

I should congrats for the update. And then the very encouraging early launch Signal. So the stablity certainly very interesting, maybe just given the excess is very rapid and broad, can you comment on the patient demand side versus the revenue generation, if any thing you can comment on the trend for the rest of the year? That would be helpful.

Yes. Thanks, Roger. I'm happy to do that. So we haven't we're not going to be giving you guidance specifically on the trend. What we can tell you is that the launches, as I said, has been off to a very strong start. We are seeing patient demand the feedback we've heard from physicians has echoed back the differentiation pillars that we've talked about, payers, physicians and pharmacists have all kind of given us similar feedback.

So what we anticipate and as we get into our next quarter, we'll start to see a little bit more data, we'll be able to share around new patient starts of things. I can tell you that the demand has been strong and that we've been pleased with the direction that the launch has gone so far.

Our next question comes from Jonathan Chang with Leerink Partners.

This is Albert Austin on for Jonathan Chen. Congratulations on all your progress. So my question is what do you see as the biggest hurdle now for KOMZIFTI to gain market share in 2026. Now is it just prescribers inertia or something else?

Yes, sure. Sure. Thanks, Albert, for that. Yes, I mean, I think that we're -- what we anticipate with the NPM1 market, this is a market that is really going to be driven on new patients coming forward and kind of incident patients as they're diagnosed into -- or progress into the second, third, fourth line setting. So it really will come down for us as to getting those patients into our queue. One of the part -- I think 1 element of this market that's a bit unpredictable for us as you as you well know, is that we're approved in a monotherapy setting, and that's where our teams are going to be promoting.

But we do -- we've heard a lot from physicians that they're looking to use menin inhibitors and KOMZIFTI in combination. That will be 1 of the questions for us to understand is how that uptake comes out in the combination setting. That will be something we'll be able to see coming forward in the future. But we don't see -- the payer hurdles have been really nonexistent. We're really pleased with how quickly our uptake has been getting on policies. So we don't really see any major hurdles other than just getting those incident patients onto therapy.

Albert, this is Troy. I might just add a comment or 2 to Brian's response. This is why we've laid out in our milestones for 2026 the significance of the publication in relapsed refractory NPM1 mutant AML with ven/aza that Mollie mentioned, as well as the combination with gilteritinib. As Brian mentioned, this is a very different market than KMT2A. We're obviously going to have the sales team promoting on label with monotherapy -- but what's clear, and I think we'll continue to be clear, is the ability to combine the ability to drive better outcomes for patients is ultimately going to be of great value.

And what we see, it's why we feel confident that we're going to take leadership not only of the NPM mutant class, but ultimately, of the much larger opportunity because it's going to be about combinations and the attributes that Brian mentioned that were highlighted in the IPD Analytics report, those become ever more important as you move into combinations. Just to make an example, we're well ahead of the competition in terms of combining with inhibitors. As you know, that's half of the NPM1 population. So it's an important part of our leadership strategy.

Your next question comes from Salim Syed with Mizuho Securities.

Congrats on the progress. Just 1 for us on the 50% that you noted here, Troy, the market feedback suggests you get up to 50% of AML patients here trying to -- just what is the assumptions that you put in from these doctors when you're kind of doing your market feedback work? And is it just based on the existing data? Or is there something that you're still planning to get to sort of get to that leading the leading share, I think, as you put it?

Yes. And Salim, I take from your question, you're referring to the relapsed refractories segment. Is that your question point the market feedback Yes, I'll ask Brian to speak to that. Thanks for the clarification, Brian?

Yes. No, absolutely. And. And we've gotten feedback as we -- both from physicians, but we do physician market research as well -- and it's interesting, we've had -- we basically provide the profiles of the products. It's blinded. We don't ask them which company, they don't know who's asking the questions. And of those, we found that have had familiarity with the men in class the profile that we've outlined seem has come back to be the preferred profile, both across efficacy, safety, the simplicity, combinability, compatibility of working with other agents. So those are -- the feedback we've heard is that gives us the confidence that as we build into this market, we'll have an opportunity to become that market leader and take the delete share in the mid in class.

Yes. And I'll just add to that. Salim just add to that. I mean at this point, we're not really talking about FLT3 in terms of doing the market research. This is really focused on the monotherapy -- but 1 of the differences between this market and the KMT2A market is, obviously, if you have a FLT3 mutation, gilteritinib has a survival advantage. And so it's reasonable to assume a menin inhibitor is going to be sequenced after Gilt.

If you can demonstrate as Mollie indicated that you can safely combine and that, that's beneficial to the patient, that's going to ultimately drive kind of a next leg within that relaxed refractory segment. We're not really yet there with the physicians because we obviously have to do that with data. But that's what gives us the encouragement. Today, it's monotherapy tomorrow, it's the combination with ven/aza, the day or 2 after tomorrow, it's the FLT3 combination and it just builds 1 after the other.

Your next question comes from Reni Benjamin with JMP Securities.

Congratulations on the early launch and hopefully it's going well for 2026. You talked a little bit -- Mollie talked a little bit about the combination of bazartinib and gilteritinib and the FLT3 opportunity. Can you talk a little bit about what you're hoping to see in your FLT3 data? And how important is kind of maximizing the opportunity when we're thinking about the potential $7 billion TAM for zifto?

Yes. Thanks for that question. So the most important thing you can see when you look at our combination data is going to be safety, safety indicating that you actually can combine. And obviously, after that, to improve upon the agents in isolation. So as I said, we'll be presenting our relapsed/refractory gilteritinib data towards the end of the year. We will be presenting both the dose escalation and the expansion, which should tell you that we were able to combine the drug successfully and safely for these patients.

With the front line, we are in the process of dose escalation with quizartinib, a combination was famed plus 7. And again, that continues to advance -- so overall, we expect to be able to show you not just the fact that we can combine, but that we can improve upon the outcomes of these drugs in isolation.

Yes. And Ren, just to build on Mollie's comments, we've seen commentary recently from Astellas that have identified gilteritinib as 1 of their blockbusters 1 of the 5 sort of emerging blockbusters. They have a frontline trial that's was conducted with HOVON that is expected to read out any day now. As we said, FLT3 is 1/3 of all of AML patients. It's hard to imagine you can have a market leadership strategy without including FLT3.

That's why we're combining with both quizartinib and gilteritinib you will see us over the next quarter or 2 move more aggressively into the 3 frontline setting because that -- we haven't really yet broken it out, but that will be -- it's a major driver in that $7 billion TAM ultimately as you look across all lines of therapy.

Your next question comes from Charles Zhu with LifeSci Capital.

Congrats on all the progress. I'll ask one on a slightly different topic regarding FTIs. We had a lot of updates from the recent ASCO GU conference, particularly in renal cell carcinoma and some of the emerging HIF2 alpha or emerging an approved HIF2 alpha inhibitors in that space. Maybe could you help contextualize your upcoming second half data for Daly plus cabo, not only within the current standard of care, but also amongst the potential emerging standard of care as well?

Sure. Yes. We're following that data very closely as well, and it's looking very good for patients. In fact, I think as you're referring to, it's looking so good that it probably will end up moving up in line in line of therapy for these patients. We, as we announced, have just started our Phase Ib which is a randomized Phase Ib so that we can both contend with project optimist, but also set some baseline data for ourselves with cabozantinib in this particular line of therapy.

And we will be able to also see if patients that are randomized to the cabo monotherapy can cross over and successfully either gain or regain responses when you combine it with darlifarnib, which I think is an important demonstration of our mechanism of action. We do think that our data as progress as they are, and we have limited follow-up time compared to some of these other studies are still competitive with a lot of these data that are being presented, and we look forward to sharing that updated information with you.

But what we do think is again, that these good outcomes for patients alphas we'll move them earlier in lines of therapy. So you'll see them in the front line. And ultimately, it can open a rather big vacuous space in the second line. that we could then jump right into with this cabo-dalafarnib combination.

Your next question comes from Jason Zemansky with BofA.

Congrats on the progress. Brian, I was hoping you could share some of the early feedback from your prescribers that are new to come if maybe that haven't been associated with any of your clinical programs or at least minimally associated. We recognize this is a small community, and it's early days, but maybe for those, especially I participated in a trial associated with your rival or don't have a large AML population, how has the product profile resonated?

Yes. Thanks for that question, Jason. And I'd speak to it both from physicians we've heard from, but I'd also point to pharmacists like the pharmacists that are -- have maybe not been involved so much with treating the patients outside of the trials. The feedback that we've heard has really -- they recognize that there are -- there's multiple menin inhibitors available the efficacy we've heard seems to be table stakes essentially.

I think both products have similar efficacy. What really does outline is the questions around how to manage QT understanding what monitoring for QT prolongation means versus edits the not just having to monitor, but to understand the potential implication of a higher risk of cardiac issues has come back from us as well as -- I mean, even the simplicity of treating patients once a day without having to do a lot of dose modifications based on the complexity of other therapies they have. So we've heard that.

I mean I think what we know is that, of course, a lot of probably early scripts are going to be those for people who've had a lot of experience with us. But we have received feedback from physicians who are new to the men in class, and we've been spending our time educating them around comp. So we're as we said, it's early days, but we're pleased with what we're hearing so far and it seems to be consistent from what we've heard from those who do have experience.

[Operator Instructions] Our next question comes from Etzer Darout with Barclays.

I'd like to ask about KOMET-008, guided to showing data in combination with gilteritinib in the second half of this year. Can you remind us where you stand with regards to the combination of Zip to with flag IDA and with the low-dose coterbine?

Sure. No. As you said, we have been guiding to release the gilteritinib data because -- in large part, we think that is very informative to physicians and how to treat DeBlase refractory NPM1 mutant co-mutated with FLT3 as well. but also within that study are our flag IDA combination, which sees mostly second-line patients and our LDAC combination, which allows for an easy combination with zippimetit that gives time for this differentiating agent to really take effect while keeping disease control simultaneously.

So we haven't guided to when we'll be releasing that data. But I do think that it will be we'll do it pieces at a time to keep the information coming and also be writing a publication. But again, we haven't guided as to when those additional cohorts will be shared.

Your next question comes from Phil Nadeau with TD Cowen.

It was great to see the team this week in Boston. We have 1 commercial question. I think you suggested that the relapsed refractory NPM1 market is about $300 million to $400 million. in revenue. We're curious to hear how quickly you think the menin class can penetrate the market. It seems like the value proposition is pretty clear today. But we're wondering if there's any gating like combo therapy data, in particular, that could be necessary to fully penetrate the opportunity?

Great. Thanks, Phil, and thanks again for seeing you. Good to see you yesterday. Yes. The -- as we've said, this TAM of $350 million to $400 million is kind of representing that relapsed/refractory space. We think because of the dynamics of the NPM1 population, where physicians have previously had choices for their patients to either get ven/aza or a FLT3 inhibitor for those who are co-mutated we anticipate early on, there will probably be more of the -- kind of the relapsed refractory in the third or fourth line setting. Combinations will help to drive that into the second line where you'd be able to see more patients get therapy and benefit earlier.

Our expectation is that there'll be a lot of -- as we said, there's a lot of use likely in the -- as a monotherapy, but the physicians are very excited about using in combination. It's not something we can promote on actively, but we will educate based on publications around like the ven/aza publication that we plan to publish in the -- with -- based on KOMET-007. So what we anticipate is that there will be a ramp-up based on incident patients coming forward, probably starting more in the in the third, fourth line, but we will see and we are starting to see those second line patients as well. We'll need a little bit of time to really get an understanding as to how the how companies being used in combination relative to monotherapy.

Your next question comes from David Dai with UBS.

On the quarter. Just 1 question on the duration of therapy. So I understand it's early innings, but any thoughts on duration of therapy or cost so far. And as you are thinking about combination with ven/aza or gueritinib, how do you think the duration of therapy call evolve over time?

Great. Thanks, David, for that question. Obviously, we're sharing 5 weeks of data. We can't really give you a lot of detail around duration of therapy at this point. Our expectation is that patients will be able to get therapy for up to -- we think an average of 6 months, our label suggests that patients are treated for up to 6 months to maximize the depth of their response. And for those patients who do get a response, we've seen duration of therapy of 5 months duration of response of 5 months and oftentimes it takes 3 months or so then to get that response to achieve the response.

So we think that we'll get to -- we're not seeing any signs yet because it's too early to see -- we are seeing repeat prescriptions but it's too early to talk through any duration right now. To your question around FLT3 inhibitors, I think that any combination is expected to give a longer duration of treatment than you would expect as a monotherapy.

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

Thank you, Abigail. Thanks, everyone, for joining the call today, and thanks for all the questions. We will see many of you next week in Miami at the various events and conferences. If you have any additional questions, please reach out to Greg or me. And we wish all of you good morning and a good rest of the day. Thanks, again.

Good day, everyone. My name is Abigail, and I will be your conference operator today. At this time, I would like to welcome you to the Kura ASH 2025 Update Call. [Operator Instructions]

At this time, I would like to turn the call over to Troy Wilson, President and CEO of Kura Oncology. Dr. Wilson. Please go ahead.

Thank you, Abigail, and good afternoon, everyone. Welcome to our ASH 2025 analyst and investor event. This is -- this has been a big day, and it's been a great conference for menin inhibitors in acute leukemia. If we can go to the next slide.

We're going to be making certain forward-looking statements today in the presentation. And I would just refer you either to our website or to the SEC's website for more information about Kura Oncology and about the risks and certain investment in the company.

If we can go to Slide 3. Here, you can see the agenda. Today, we're going to be reviewing the data that was actually just presented in the oral session here at ASH. That is ziftomenib combination with azacitidine and venetoclax both in the newly diagnosed NPM1 mutant AML setting as well as in the relapse and refractory NPM1 mutant and KMT2A rearranged AML setting.

We're going to aim to have prepared comments approximately half an hour. That should leave us plenty of time for Q&A. So if we can go to the next slide. It's really my pleasure to welcome and to thank the 2 key opinion leaders that we have on today's call. Dr. Wang is the Chief of Leukemia Service as well as Professor of Oncology at Roswell Park, and Dr. Zeidan is the Chief of Hematologic Malignancies and the Director of Hematology and Early Therapeutics Research as well as Associate Professor of Medicine at Yale.

Each of them are intimately familiar with ziftomenib and, I think, can really speak to the data that we're going to go through today. We're, of course, thrilled because this is the first ASH where ziftomenib is now approved and the branded name is, of course, KOMZIFTI, available as 200-milligram capsules. For Kura Oncology and our partners at Kyowa Kirin, this has really been a very exciting ASH.

The feedback has been extremely positive. Physicians, caregivers, patients, the entire community are thrilled to have another option available for patients. And it's our goal, as you'll see today, to build on this initial approval in the monotherapy setting, and continue to evaluate ziftomenib in combination with various standards of care.

If we can go to the next slide. We'll talk about this, but we like to frame the opportunity for KOMZIFTI as one is evaluating this data really around 4 pillars, and they're shown here: efficacy, safety, compatibility and simplicity.

We'll touch on each of these in turn in the data, both in the frontline and in the relapsed/refractory setting. We think this combination of these 4 features really provides a compelling option to physicians as they think about how best to treat their patients with AML. And we'll touch on these, I'm sure in the prepared remarks, and in our answers to your questions.

So if we can go to the next slide. It's my pleasure to turn it over to Dr. Zeidan, who's going to take us through the ziftomenib and ven/aza data in the newly diagnosed NPM1 mutant population. Dr. Zeidan?

Yes, thank you so much. So it's my pleasure to be here today. So I'm going to preview the data that was actually just presented this morning about the combination of ziftomenib with venetoclax and azacitidine in newly diagnosed NPM1 mutated acute myeloid leukemia from the ongoing Phase Ib trial on behalf of my colleagues.

Next slide, please. So this is overall schema of the trial. There was a dose escalation, as many of you are familiar of ziftomenib in combination with ven/aza in the refractory relapse patient population, and we have settled on 600-milligram daily of ziftomenib as a dose to go forward.

And this what was tested in the frontline setting in patients who are newly diagnosed with acute myeloid leukemia who were mutated for NPM1. So here, ziftomenib was started on cycle 1 day 8 is -- was given as a standard for 7 days, and venetoclax was given as per the label continuously with interruptions of venetoclax based on the bone marrow clearance by the end of cycle 1, and then adjustment based on the blood count recovery.

The primary endpoint of this study was complete response as well as assessment for adverse events, and we observed a number of secondary end points focusing on duration of response, other important clinical responses as well as MRD readings from this trial. This is the first presentation of data in the frontline setting.

Next, please. So here, you can see the study flow for the patients who were enrolled. We had a total of 40 patients who are included in this data cutoff as of September 2025. Of those 40 patients, all of them are safety evaluable and 37 were efficacy evaluable.

As you can see, the median follow-up on the study was 26 months. And at the time of the data cutoff, 70% were still on study and 55% were still receiving ziftomenib. Of the patients that discontinued 16, you can see are the causes of discontinuation, but the discontinuation due to death on study was only on 4 patients, which aligns with what was seen with aza/ven as without a third agent. 5 patients went to transplant, and subsequently, 3 of them went to maintenance with ziftomenib.

Next, please. Here are the baseline characteristics of this patient population, and this is very typical for older unfit patient population. So the median age of this group was 75 years old. We have as old as 93-year old going on this study. 53% of those patients were females primarily white patient population. And there, as common concomitant mutations, including FLT3 and IDH2 as you can see here.

Next, please. So these are the most commonly seen adverse events that were seen in 25% or more that, as you can see here, can be categorized by ziftomenib-related as well as all treatment-related adverse events. This is basically very similar to what we would expect with aza/ven doublet. The most common side effects are in the form of GI adverse events such as nausea vomiting, some diarrhea and the blood count suppression, neutropenia, leukopenia and some incidence of liver enzyme abnormalities.

However, again, those are very common in patients with AML who undergo aza/ven therapy. And once you look at the 3 ziftomenib-related adverse events as designated by the investigator, again, most of these were in line of the previous experience with ziftomenib.

Next, please. Here, we are focusing on the Grade 3 and higher treatment emergent adverse events that occurred in 10% of more. Again, mostly blood count suppression in the form of neutropenia, thrombocytopenia and leukopenia, which are very common in patients with acute myeloid leukemia getting treatment as well as febrile neutropenia and very rarely cases of sepsis.

Importantly, differentiation syndrome was very rare, occurred only on one patient out of the 40 and it was Grade 2 and successfully treated and the patient was able to continue on ziftomenib or resume ziftomenib. And there was also one case of QTC prolongation that occurred in the setting of concomitant electrolyte abnormality and other medication. And again, this is a very common situation that we see in patients with acute myeloid leukemia because of the low magnesium, low potassium, other antifungal drugs to see some QTC prolongation.

Next, please. In terms of the efficacy, this is an overall view of the efficacy, evaluable patient population, the 37 patients who are efficacy evaluated at the 600-milligram dose. And you can see that the CR rate, which is the most important readout from this trial was very high at 73%. And when you look at CR plus CRH, the total was 78%. And when you look at the overall response rate, it was 89%. The composite CR was 86% and the median term to first CRC in weeks was 3.4 weeks so [Technical Difficulty] the first response.

Next, please. Importantly, the MRD in this trial was assisted both centrally as well as locally, using a very sensitive assay to the level of 0.005%. And we looked at 2 thresholds. Both of them, I think, showed very favorable results with the MRD negative rate being 68% when you look at the threshold of 0.1%. And when you look at 0.01%, it was 44%. And you can see very clearly that the patients who were able to stay on treatment had deepening MRD responses where by the fourth cycle, almost all patients, 100% achieved a very deep level of MRD negativity, which we think correlates well with long-term outcomes.

Next, please. This is a study that is still ongoing and the data continues to mature. So for that reason, the median follow-up is 26 weeks. The median duration of complete response was the median OS duration or the median overall survival was not reached either. As I mentioned earlier, some patients with this disease will go to transplant, 5 patients did go to transplant, and 3 of them continue to receive subsequent ziftomenib maintenance. And at the time of this cutoff, 68% of patients were alive and still on study.

Next, please. Importantly, each time when we add a drug to aza/ven , we think about additional myelosuppression and delayed count recovery because this can cause problems in terms of infection and bleeding. But the good news in this trial is that the addition of ziftomenib to aza and ven did not seem to prolong recovery of neutrophil count and platelet count beyond what has been the historical experience with ven/aza. You can see here by 2 cutoffs that the median time to ANC recovery to more than 500 was 36 days and platelet count more than 50, 24 days. When we look at the higher thresholds of ANC of 1, it was 37 days and more than 100 of platelets, it was 30 days. And again, these are in line of aza/ven doublet therapy.

Next, please. So in conclusion, this is the first readout of the frontline NPM1-mutated older patient population on the KOMET-007 receiving the triplet of ziftomenib at 600-milligram daily and combined with aza/ven, and we are seeing high rates of CR. Almost 73% of patients achieving CR, 86% achieving composite CR ,68% achieving molecularly defined MRD negativity, deepening MRD responses over time as the patients continue on trial and the median duration of the complete response and the median overall survival was not reached.

Importantly, the addition of ziftomenib to aza and ven did not seem to worsen the safety profile of aza/ven. The myelosuppression was in line with what we typically see with the doublet. The time to count recovery was also in line and adverse events of special interest such as differentiation and investigator-assist QTC, were very limited and generally well managed.

So taken together, I think this data speaks very well for advancement of this combination to the registrational approach in the randomized ongoing Phase III trial, KOMET-017 that will this combination against aza/ven and hopefully, will lead to the approval of this combination in the frontline setting. Thank you so much.

Thank you very much. This is Eunice Wang, and I'm pleased to present the results of ziftomenib in combination with venetoclax and azacitidine in the relapsed/refractory NMP1 or KMT rearranged acute myeloid leukemia. This is an updated Phase Ia/b safety and clinical activity results from the KOMET-007 study.

So as shown here, this is an ongoing Phase I combination study. We previously presented data with the Phase I dose escalation, which established ziftomenib dose of 600 milligrams as the dose to move into Phase Ib dose expansion and recommended Phase II dosing.

For this trial, patients were enrolled on ziftomenib following then aza. Ziftomenib was started on day 8 and administered continuously thereafter. The primary endpoints of the study were similar to the ones described by Dr. Zeidan, primarily CR and adverse events. And secondary endpoints, we're looking at other clinical endpoints of efficacy, including MRD-negative disease and duration of remission.

Shown here are the dispositions of the 83 patients who are enrolled and treated with the combination of ziftomenib 600 milligrams and ven/aza. There were 51 patients with NMP1 mutant relapsed/refractory AML and 32 patients with KMT2A rearranged relapsed/refractory AML.

There were a couple of patients on the NPM1 cohort who did not have a response assessed at the time of the data cut, so we present data here on response evaluable [indiscernible] patients encompassing 48 NMP1 mutant and 32 KMT rearranged patients. Shown here are the baseline patient characteristics of these relapsed/refractory AML patients. As we would expect in adult patients with AML, the median age of patients enrolled in the study was in the mid-60 range.

The ECOG performance status was anywhere from 0 to 2 and about 24% or 29% of our patients had co-mutations in FLT3, again, as would be expected in our NPM1 mutant cohort. Of note, patients had a median of one prior therapy with up to 4 and these included the prior allogeneic stem cell transplantation, almost 20% of patients, the overwhelming majority, 58% of patients had received prior venetoclax-based therapy and 10% of patients had even received prior menin inhibitor therapies.

The median follow-up for these patients was 25 weeks or approximately 6 months and there are currently 25% of patients that remain on treatment. The safety and tolerability of ziftomenib combined with venetoclax azacitidine in the relapsed/refractory AML population was very favorable.

As you can see here on the right-hand side, zifto-related treatment-emergent adverse events were uncommon. You have nausea, vomiting, diarrhea, which is consistent with any oral chemotherapy administration and you have very low rates of cytopenias, anywhere from 10% to 15% that were attributed to the chemotherapy drug. There was about a 13% or 15% incidence of pruritus, but the majority of these were low grade and easily manageable with supportive medications.

Of note, ziftomenib-related adverse events of interest included QTC prolongation and differentiation syndrome. There was no ziftomenib-related QTC prolongation reported with the combination of ziftomenib 600 milligrams combined with venetoclax azacitidine. Only 2 patients discontinued therapy due to zifto-related adverse events of sepsis and stomatitis. And there was only one patient who developed differentiation syndrome.

This was an NMP1 mutant patient who developed Grade 3 differentiation syndrome, which was successfully mitigated with protocol-specified interventions. And the patient was subsequently able to resume ziftomenib therapy after this occurrence. You can see here again thrombocytopenia, neutropenia, leukopenia and anemia were under 10%. And the rate of sepsis in these pretreated relapsed/refractory AML patients attributed to ziftomenib was only 5%.

The clinical activity of ziftomenib with venetoclax azacitidine in relapsed/refractory AML patients was impressive. In this heavily pretreated patients, the CR rate was 27% in NMP1 mutant patients, 6% in KMT rearranged patients, but in patients who achieved some sort of clinical remission, the numbers were 48% or almost half of NMP1 mutant patients and 28% of patients with KMT rearrangements.

You can see here that MRD negativity rates were 60% in the NMP1 mutant patients, 43% in the KMT rearranged patients. And overall, the response rates were 2/3 of NMP1 mutant patients and 41% of KMT rearranged patients. Of note, 58% of these patients treated with this combination had a history of prior venetoclax exposure.

So when we took a specific look to examine the activity level in patients with and without prior venetoclax exposure. As you can see here in patients who had received no prior venetoclax therapy, i.e., for example, patients who had received prior 7+3 induction chemotherapy and then relapsed. We noted very high overall response rates and NMP1 patients of 83% and 70% in KMT rearranged patients.

CR rates were 44% in NPM1 mutant patients and 20% of KMT to be arranged and MRD negativity in NMP1 patients was over half of patients. Patients who had received prior venetoclax did still have responses, but these responses were less than those who had not received prior BCLA inhibitor therapy.

For NMP1 mutant patients follow up of 27.4 weeks, the median duration of a CRC response was 39.9 weeks. Then venetoclax-naive patients had the same response, 39.9 weeks and 14 NPM1 mutant patients were able to undergo allogeneic stem cell transplantation with 5 of these individuals continuing on to ziftomenib maintenance. The median overall survival for NMP1 mutant patients in the relapsed/refractory NMP1 setting was 54.9 weeks.

Patients with relapsed/refractory KMT rearranged, acute leukemia also had benefit from this combination. The median duration of CRC in these patients was 12.4 weeks and 2 KMT rearranged patients were able to undergo subsequent allogeneic stem cell transplantation followed by ziftomenib maintenance in both of these individuals.

The median overall survival in these relapsed/refractory patients was 21.1 weeks. Similar to the upfront data presented by Dr. Zeidan, we see here that times to neutrophil and platelet recovery with the combination of ziftomenib ven/aza, were comparable to those for ven/aza backbone therapy alone and shown here ranging anywhere from 27 to 36 to 45 days.

So in conclusion, in the ongoing KOMET-007 study, ziftomenib 600 milligrams once daily, combined with venetoclax azacitidine was well tolerated in patients with relapsed/refractory NMP1 mutant and KMT rearranged leukemia. There were very low rates of zifto-related myelosuppression. There was no appreciable ziftomenib-related QTC prolongation reported in any patients and only one case of differentiation syndrome in a patient with NMP1 mutant disease was reported and was successfully mitigated with protocol-specific measures.

There is evidence of encouraging clinical activity demonstrated in this patient population, particularly in patients with prior venetoclax exposure and more prominently in patients without prior venetoclax exposure. As you can see here, 2/3 of patients with NPM1 mutant disease achieved an overall response with therapy with a median duration of response of 40 weeks. Venetoclax-naive patients had an overall response rate of 83%, 70% of which was CRC, then exposed patients still benefited with 48% overall response rates and 28% CRC.

And in the KMT rearranged population, the overall response was still an impressive 41% with the 28% CRC and a median duration of response of over 12 weeks. Taken together, these data support further investigation of ziftomenib-based combination therapies in relapsed/refractory NMP1 mutant and KMT rearranged acute leukemia patients.

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

Yes. Thank you so much. So we are extraordinarily excited to be approved in the relapsed/refractory monotherapy setting, we were able to offer new hope for patients. We now remain committed to developing KOMZIFTI in the combination setting. And as we presented, the combination yields high rates of response and better activity than either the doublet or zifto alone.

In fact, there are some evidence of potentially enhanced activity with the backbone in the relapsed/refractory then naive patients. In addition, the combination was well tolerated with no meaningful added toxicity and no increased burden in administration. Combinations have low rates of DS, no additive myelosuppression and no zifto-related QTC prolongation.

We have a robust and comprehensive clinical development plan that is producing significant data with other combinations such as quizartinib, gilteritinib, FLAG-IDA and LDAC. We will continue to generate these data and publish potentially paving the way for future NCCN guideline submissions.

All of this supports our confidence in our registrational KOMET-017 trial in the newly diagnosed patients, which we are showing here on this slide.

As you can see, this trial encompasses 2 different independently powered trials on the left for our non-intensive chemotherapy patients and on the right for intensive chemotherapy patients. On the left, for non-intensive patients will be randomized to either ziftomenib or placebo with the venetoclax-azacitabine backbone and the outcomes we are looking at are complete response is an accelerated approval point and overall survival for full approval.

In addition, on the right is our intensive chemotherapy option. And here, we have 3 arms that the patient could be randomized to. One involving the administration of ziftomenib throughout induction and consolidation and into the post consolidation maintenance space, one where we discontinued ziftomenib at the time of the post-consolidation maintenance phase and one where they received placebo throughout.

This will allow us to really evaluate the contribution of ziftomenib to the post-consolidation phase. The endpoints under of interest here are CR MRD negativity and EFS that we will be continuing to measure. So the opportunity is significant and meaningful in this frontline where we hope to prevent more patients from becoming relapsed and refractory. And our goal is to be the first approved menin inhibitor in the newly diagnosed setting, and our team is laser-focused on execution.

With that, I should turn it back.

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

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

[Technical Difficulty].

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

Our next question will come from Roger Song with Jefferies.

Can you hear me?

We can hear you, Roger. Thank you.

Excellent. Okay. Congrats for the data. Yes, I will limit my question to one. Troy, maybe the KOL as well. So as we start to see more data in the frontline and then with a different combination, can you help us to further compare the efficacy kind of level particularly for the depth of the efficacy, maybe the durability of the efficacy.

Do you start to see some different among all the menin inhibitor? Because we definitely heard the comments saying, "Yes, it's -- we no longer call this a menin party because every menin inhibitor may be different."

Sure, Roger. And I'm actually going to -- I'm actually going to turn it over to Mollie for that. I mean just with the caveat that these are -- it's difficult to do cross-trial comparisons. We're not comparing head-to-head.

But that being said, I think what you're asking is if we can look at MRD negativity and durability. So maybe I can ask Mollie, if she can speak to that to get us started.

Sure. So obviously, the backbone alone, especially in the frontline, does provide a good amount of responses for these patients. But it is not curative. And it is how do we judge whether we're making a difference by adding something on an addition. We think our best marker for that is MRD negativity. And that's why we chose to present MRD negativity using a central assay.

And as you can see, we did it at 2 different cut points. One, which would be the more traditional point one where you see flow and things like that at the local level come around. And the more conservative cut point of 0.01, which is favored by the FDA. So when we did that, let's say, just looking at the point one, the more conventional site level cut, we see a 68% MRD negativity rate.

Now if I look at other trials like Beat AML, we were seeing more like a 31% MRD negativity rate in that -- in a similar cut point. So we do think that there's reason to believe that we are adding significant benefit as our differentiated menin inhibitor, if you will, since we aren't all part of the same menin party anymore.

And then again, when we go down to the even more stringent cut point of 0.01, we saw the 44% MRD negativity rate. And realistically, it was more like 60% because there were 4 additional patients who buy 0.001, missed the cutoff. And so obviously, with even running the assay again, probably would have hit that cutoff. So we're very encouraged that we are seeing evidence via MRD that our responses are of greater depth than we've previously seen, which would hopefully translate into longer durability and ultimately better overall survival.

Our next question comes from Jonathan Chang with Leerink Partners.

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

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

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

Sure. So I think the PARADIGM is an incredibly important study. It was very much anticipated and the results were beautifully presented by Dr. Fathi, however there are some significant caveats with the study. It's a randomized Phase II study, and they screened over 300 patients, but only were able to enroll about 50% of that population onto their studies. So it leads you to a question which patients did not get enrolled upon the study and the reasons why and whether the physicians that were enrolling the patients decided to move forward with one treatment versus another.

The other point of contention is that NMP1 mutant patients which is the primary population that we're looking at with ziftomenib were excluded from the trial unless they were 60 years and above. Third, the NMP1 mutant and IDH2 patient population was much enhanced in the patients that received the venetoclax azacitidine with about double the number of NMP1 IDH1 mutant patients treated with ven/aza as opposed to those treated with standard induction chemotherapy.

So that, again, introduces a bias because we know that patients with NMP1 and IDH2 mutations tend to have favorable outcomes with a less intensive regimen. And lastly, the patients that have NMP1 tend to be in the intermediate risk category and 76% of the patients enrolled on the PARADIGM study had adverse carrier type. So again, it's not relevant for the patient population that we receive KOMZIFTI. Dr. Zeidan?

Yes, I think I agree with all of this. And again, while this is an important study, I'm not quite sure it changes much in terms of what we were already doing. I think the general practice, if you are treating with aza/ven is to go to transplant if you are trying to go for a cure. So I think the main decision continues about are you trying to cure patient or is a patient potentially curable without transplant?

In my opinion, the addition of a third agent to whether intensive chemo was 7+3 or to aza/ven could offer the opportunity to change the natural history of the disease without necessarily going to transplant. And I would also note -- and again, I give the Kura team a lot of credit for this, is that having 2 protocols and under -- or having 2 studies in the same protocol offers the patients to be able to go on the study whether the doctor thought they were intensive chemo candidates or not.

So they don't have to go to another study just because they are deemed to be intensive chemo candidate or not. But I do not foresee the PARADIGM study to have like a meaningful impact on our ability to conduct the study.

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

This is Peter Green on for Charles. Congrats on the data. Really great to see the thesis potentially start to play out of, honestly, frankly, really nice safety in combination and potentially even better safety than for monotherapy, if do. So congrats again.

Just wondering if these data give you any line of sight or any confidence into a potential frontline label as KOMET-017 begins to read out in the future and whether there's any read-through from the first label in monotherapy relapsed/refractory setting, whether potentially a lot of the language around inclusion criteria and monitoring criteria might stay through or whether if you can show an even safer profile in the combination here, whether that's kind of grounds for negotiation for potentially even a less stringent label.

Thanks, Peter, for the question. and agree with you on your interpretation, particularly around the differentiation syndrome that it gets better in combination, right? As well, it gets better, I think, as the community generally gets experience with these agents.

We see that kind of across the board. But let me let Mollie start off by answering your question about maybe how this reads into the ongoing Phase III trials and what that differentiated label might look like, Mollie?

Sure. So the 007 trial has been enormously helpful in how we've designed and planned for the 017 trial. So all of these results continue to support us moving forward. They tell us we've made correct assumptions. They help us understand the likelihood of success. And I think every time we look at the data, we are more excited, but I think your second point is very important.

Having a randomized study with a placebo control is going to absolutely be able to impact the safety and the labeling for KOMZIFTI. Ultimately, it's very difficult to interpret a single-arm trial. And thus, the FDA is always going to take a more conservative route and attribute things to the investigational agent even if they might be due to the underlying disease alone or to the concomitantly administered medications.

So having a randomized controlled trial with that data to be able to show for example, a lack of QTC prolongation with ziftomenib therapy will be extremely important and will absolutely be useful in amending the label and making it so that patients really do have the ability to make an informed decision about their treatment options.

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

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

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

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

No, I agree. I think the paper needs to come out so that we kind of clearly discuss this particular aspect. But I personally feel very comfortable with the frontline results both in the intensive and the non-intensive chemo in terms of the CR rate being 73% in terms of the MRD negativity using very sensitive assays being very deep.

So I do not have any concerns about how does that translate when you compare it by other techniques, whether it's PCR or flu. One point I just want to highlight quickly kind of Mollie mentioned is that the MRD negativity seems to deepen with time. So by the fourth cycle, for the aza/ven cohort, actually all the patients who got 4 cycles basically became MRD negative. And this is very important because this speaks to the importance of adding a drug where the patients are able to stay on therapy. You don't want to have a drug that causes a lot of myelosuppression that patients fall off the drug and the trial.

So I think this, in my opinion, could differentiate ziftomenib from some of the other drugs that are other menin inhibitors that could add additional myelosuppression. So I don't think the issue of the MRD is going to be a problem. Of course, MRD is more relevant in terms of a regulatory front to the intensive chemo front because this is where it's going to be used for accelerated endpoint.

But we know that in the non-intensive setting, there is a good correlation between MRD negativity and survival. In the VIALE-A, the MRD negativity was around 30% to 35%. So I do think we are seeing some differentiation in a 40-patient sample size. So clearly, we have to wait for the randomized data, but I think everything looks promising from what has been presented. I don't know if Dr. Wang wants...

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

Next question will come from Hunter Hurley with Guggenheim.

And again, congrats on the data. Again, this is Hunter Hurley on for Brad Canino from Guggenheim. Just wanted to kind of as a segue for this MRD conversation. And I guess, how we're kind of using this in combination. Have you reported anything on reductions for this combination as I didn't really see that in the presentation?

And as we're kind of thinking about this with treatment long term for this combination, what are your kind of expectations for the regimen as far as like durability, long-term usage? And then in combination, are you planning on keeping ziftomenib on indefinitely or potentially reducing ven/aza? And how is this kind of combination going to look over time?

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

That's correct.

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

Yes. I think one of the best ways to be able to look at that in our data is to look at our swim lanes. We -- well, not necessarily the dose reductions, the dose continuation, which was the second half of your question, where we can see that we started zifto and we continue it from cycle 1, day 8 on, while the backbone might be modified to lesser days or lesser doses depending on covenantly administered medications, the zifto remains.

With regards to ziftomenib reductions, we're really not seeing very many at all. I'm hard-pressed to think of more than 1 or 2 that have been seen. And most often, even with our monotherapy, we see a return back to the initial dose even after an initial interruption or reduction.

So we're really not seeing a requirement for the ziftomenib to be changed in order for these patients to successfully remain on the treatment regimen. And as we will see, we'll see the data play out in both 007 and then ultimately 017 to see what effect that has on the backbone therapies as well because we know that physicians are trying to modify and make sure that these patients are not overly myelosuppressed and once they -- especially once they've reached response. And so we'll be watching the ven/aza dosing a lot over the coming months. But so far, I would really direct you towards those swim lanes to see how it's being handled currently.

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

Yes. I just want to add like my own personal experience as someone who has treated many patients on both of the 007 trial as well as 008 trial. And many of those patients are actually able to continue on the drug in my own hands. I don't believe we have reduced anybody in terms of the dose. And I think from discussion with patients, this is one of the easier drugs to give in terms of being -- especially in the maintenance setting, where you are giving it without other drugs.

So you have a very good sense of what is actually related to the drug and what is not related to the drug. And it's really very easy for most patients to be on. This is, again, very important because I do believe strongly that patients need to be on the drug especially in the frontline setting for as long as possible to try to minimize the chance of the leukemia relapsing. So I think my own experience kind of goes in line with what Mollie has mentioned in terms of the overall trial.

So I just wanted to mention just if I could throw in that, this is in contrast to what we see with some revumenib HMA and venetoclax combination. So for data presented with the combination of oral decitabine with revumenib and HMA that the SAVE trial that was presented yesterday, they noted that there was a 48% incidence of Grade 4 febrile neutropenia, 24% thrombocytopenia and 19% neutropenia.

So they had significantly Grade 3, Grade 4 neutropenias with that triplet combination of revumenib, venetoclax and HMA. Similarly, if you look at the BEAT AML trial in newly diagnosed older unfit patients, they had significant cytopenias with delay of subsequent cycles of that triplet for 40 or 50 days.

That neutropenia cytopenia incidence is not present with the combination of zifto. I also want to point out that the QTC prolongation and the need for dose adjustment of revumenib with azoles and concomitant medications may also impact on the ability to give revumenib long term, particularly elderly individuals with concomitant meds, cardiac issues, et cetera.

And as we mentioned, the durability and the overall survival of these patients in the newly diagnosed as well as refractory setting is really highly dependent on patients being able to take it in the long term for months or even years.

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

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

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

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

That's exactly right. We'll be presenting our FLT3 data next year. And keep in mind, we're generating data both with gilteritinib, which is known to cost prolonged QTC, as well as quizartinib, which actually has a black box warning for having a different mechanism of QTC prolongation.

And so far, we have yet to show the data. But obviously, if we are continuing to escalate and go through with our expansions, it's probably going well. I would draw your attention to the combination of revumenib plus gilteritinib where we saw dose-limiting toxicities at every dose level tested. And I believe the vast majority were QTC prolongations.

So obviously, in combination, the safety profiles of these different drugs are going to play out with the ability to use them. And I think that the FLT3 inhibitors, in particular, are going to be difficult for some of our competitors to combine with.

I think -- Yes. I just want to add quickly that I think that the quadruplet frontline combination that's ongoing now with the quizartinib and ziftomenib plus 7 and 3, I think, would be very important because one of the kind of main questions in the field is what do you give these patients? Do you give them a menin inhibitor with 7+3 or do you give them a FLT3 inhibitor?

And I think currently, most people are giving FLT3 inhibitors because this is where we have the survival advantage. But having good data with the quadruplet, I clearly will open, hopefully, the ability to use menin inhibitors in the frontline sitting intensive chemo FLT3 positive setting with the communication with NPM1.

And Ren, just to add to that, we often get -- the ziftomenib label is limited to NPM1-mutated relapsed/refractory AML adults. We do -- we're doing many, many trials, evaluating ziftomenib in various combinations. We're promoting specifically on label, but we often get the question of how to use combinations, how to think about sequencing.

And as Dr. Wang commented in her presentation with ven/aza, there's interesting data on sort of how you use these agents and in what sequence. We think the same thing will be true in the FLT3 case. What our responsibility is to generate robust data where we're talking about tens of patients, not sort of -- more than single digit, really to give our collaborators, the physician experts, the data that they need to make the determination of how best to use these menin inhibitors. So you're going to -- again, that's 2026 goal and objective, but I think that will be an exciting next chapter.

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

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

Mollie?

Yes. No, you're correct. At least right now, the 7+3 and the ven/aza are dominating the frontline space and times will change. More therapies will come out and be approved, more targeted therapies. And so it will continue to evolve. A lot of the data that we've been generating that I think you're referring to is in the relapsed/refractory setting.

And that is data with FLAG-IDA, that is with gilteritinib, that is with low-dose cytarabine. And it is so that physicians have the optionality because not all patients can handle ven/aza, not all patients can handle 7+3. Unless they're relapsed/refractory, they really need to have multiple options depending on what they've previously seen.

So our plan is to obviously generate as much data as we possibly can, robust data. I don't -- we generally don't tend to present our data until we have really good patient pool to be able to make some calls off of. And so that's what we'll continue to do. And like we said earlier, we will be presenting a lot of these data in the 2026 time frame.

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

So since the approval of ziftomenib, I've received a lot of calls from colleagues and other physicians, clinicians asking about, for example, should they use ziftomenib? Or should they use revumenib, for example, for an NMP1 mutant relapsed/refractory patient? And out call as should we -- is it combinable? Can we use it in the post-transplant setting, which would be preferable?

And I feel that for a lot of practical reasons, we are recommending potentially that ziftomenib has certain advantages. It is easily combinable with venetoclax and even azoles because those drugs may have a predisposition to prolong the QTC. There's no dose adjustment with azoles in a patient with baseline neutropenia. There's no concern -- less concern about the risk of significant QTC prolongation in a patient that has concomitant cardiac meds or in the relapse setting maybe on some immunosuppressive meds, again, that can cause interactions. It's a once-a-day dosing.

So that also is preferred by patients. And in combination with ven, we have seen actually a decrease in the ven/aza combinations of differentiation syndrome to be concerned about and having it really be 1 or 2 patients among 50. So I think in the real-world setting, as these drugs start to populate out into clinical practice, I think we are going to see greater adoption, ziftomenib particularly in combinations because of those reasons.

I think that revumenib has been largely adopted by providers because they had no other option. But moving forward and discussing some of these features with people in the real world, almost all of the colleagues that have asked have said that those are valid concerns. And this is also a drug that my patient may be taking for weeks, months, and those are things that my practice or my providers may not want to be seeing the patient and adjusting the medicines on a daily basis. Dr. Zeidan?

Yes. So I agree with all of this. And just to put this in a kind of practical situation. So when you have a patient with NPM1, your first decision is generally do I give intensive chemo or do I give is aza/ven? And when you have good data in both settings, many doctors tend to be kind of progressive ahead of the formal approvals when there is very good data, especially in terms of the safety and the efficacy.

So when you have a drug that's easily combinable doesn't add to the myelosuppression from a logistical point of view, does not cause problems with the other drugs like the antifungals and easy for the patient to take. I think certainly, there would be preference to using this drug. We have similar experience, for example, in the CML setting where some of the TKIs have to be taken twice a day, and they have QTC issues.

And I can tell you, most physicians prefer not to use these and go with the drug that's given once a day and does not have issues in terms of drug interaction. But I wanted to emphasize that aza/ven, zifto and the refractory relapse setting because the practical question that we face as physicians right now is that if you have an NPM1 mutated patients who got 7+3 in the frontline setting, what many of us would do is they would give aza/ven in the refractory relapse setting, although it's not approved, but it's very commonly used.

We prefer that rather than a second line of intensive chemo. However, with the menin inhibitor evolution, many doctors are asking the question, do I give menin inhibitor, do I give aza/ven?

And I think having the data about the triplet with aza/ven, ziftomenib will remove that issue because you can just give all 3 of them because, again, the combination is safe, the durability is better, the survival, as you saw, is 1 year, which on the relapsed/refractory setting is very good. You probably can't bridge many patients to transplant because they are MRD negative.

So I think this kind of data, even it does not lead in the refractory setting to a label and it's very unlikely that you can do randomized big Phase III trials in that setting. It's very, very important because we face these decisions all the time in terms of how to combine and which drug to use.

So I think the same potentially could apply, hopefully, once we see the data with gilteritinib and ziftomenib in the relapsed/refractory setting because we currently face the same discussion. So I think -- in real life, I think, is probably going to follow the same patterns you are seeing with these clinical trials.

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

Your next question comes from Jason Zemansky with BofA Securities.

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

Dr. Zeidan, do you want to?

Yes, I think we kind of touched on some of these kind of points. But when -- I'm just going to put it again in a practical context. When you are giving a drug for, let's say, a few months in the refractory/relapsed setting where the patient is coming to the clinic every day or -- sorry, once a week or twice a week and the patient is very easily monitored and you are doing EKGs, you are monitoring their drugs.

I think you could do that for a few months, but as the drugs move in the frontline setting where the patient is going to be on the combination for years, it's very unpractical to be doing EKGs continuously and to be worrying about if the primary care doctor is going to give a drug that causes an interaction.

So having that logistical component of a very convenient drug to give once a day, I cannot tell you how important it is on the chronic use of medication, the big difference between once a day versus twice a day. And we know this is -- we don't have data in this setting, but I can tell you in CML setting, for example, missing a few days every month can significantly worsen the outcome.

So having a drug that is given once a day rather than twice a day could be a huge differentiator. Having a drug that you don't have to worry about other doctors giving a drug that could interact with the drug or cause QTC. These things are very important. So even if you take the viewpoint that there could not be huge differences in the efficacy, which I personally don't think that's the case.

I think as the data matures, ziftomenib is probably going to differentiate on that front as well, but I think on the convenience on the myelosuppression in terms of the other adverse events, this is very important in the chronic use of the drug, which eventually, I think, would be the most important value of these menin inhibitors.

So I just wanted to bring up some additional points in addition to those, which we've already mentioned. I think the fact that we do not see any additional toxicity or side effects or adverse events with the addition of ziftomenib to both 7 and 3 and/or ven/aza, I think is pivotal because -- when you look at overall health care costs, you don't want to be having extra days of hospitalizations.

You don't want extra transfusion days, extra admissions for febrile neutropenia, what is going to add to the health care costs and the admissions and the clinic visits for the patients. So we look at the financial cost of adding a drug that's adding significant toxicity, and we look at quality of life issues to patients, okay?

Patients taking a drug once a day, not having transfusion dependence, not having to go in, not having to have potentially excessive QTC monitoring or have to go into their cardiologist. I mean these are significant other parameters of the success of upfront and a relapsed/refractory regimen that should not be ignored in addition to all the efficacy as well as the interactions with other drugs. But just looking at the overall spectrum of health care costs, visits, quality of life, patient reported outcomes, et cetera.

Your next question comes from Phil Nadeau with TD Cowen.

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

Dr. Wang?

Yes. I mean I think it's clear when we look at our response rates in the relapsed/refractory setting, there is more benefit for patients who, for example, got 7+3, plus or minus geo upfront and did not have prior even, but we still see benefit 20% to 40% response rates in patients who've had prior ven exposure.

This is in contrast to some of the single-agent data with revumenib that showed significantly less benefit in prior ven-exposed patients. And so when you look at the revumenib data, there really is a significant -- practically no response to revumenib in patients with prior ven. If you look at the monotherapy data with ziftomenib, we retain the same response rate in patients regardless of whether they had prior transplant, regardless of whether they had prior ven.

So I do think that this is a distinguishing feature. Prior ven is always considered to be something that predicts for lack of response to targeted therapy. There's data showing that prior ven exposure reduces or eliminates the response to subsequent IDH1, IDH2 and FLT3 inhibitor therapy. The fact that we don't see that same phenomenon with zifto but that we do still see resistance to revumenib could be a distinguishing remark. So I would disagree with that particular commentary based on just the data that's been presented by the 2 trials.

Your next question comes from David Dai with UBS.

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

I would -- this is Amer Zeidan. I think that the menin inhibitors in general, but in my opinion, ziftomenib would be widely used in this setting because in the frontline setting, either the patient has received 7+3 and then the patient relapsed and the practical question we were having at that time, do I give aza/ven or do I give menin inhibitor. And now we have good data on the combination of the triplet. So that patient would be getting all 3 drugs, which would be what I would recommend if I'm asked about a patient like that.

If the patient has gotten aza/ven in the frontline, I think the question would be what Dr. Wang just kind of discussed is do I give menin inhibitor by itself or do I give that triplet? And I think in that setting, you have to consider things like how long was the patient on venetoclax and was it -- did the patient was primary refractory or subsequently relapsed?

But in my opinion, in both scenarios that I just outlined, the patient would be getting an inhibitor likely ziftomenib. So I think most of these patients will likely get exposed in the second line. I just want to add like kind of to the earlier question, I think what we are trying to aim in the AML world is really not to be in situations where you have venetoclax resistance or you have -- because these situations are very difficult.

And even if you get responses, generally, they are not durable and patients would ultimately in most situations pass from the leukemia. What we are trying to do is hit the leukemia very hard from the very beginning with these combinations. And we have a very nice paradigm, outstanding paradigm in multiple myeloma where all these drugs were good in the second-line setting and third, fourth line.

And now the combinations in the frontline are just transforming the field, number of patients who are achieving very deep responses, MRD negativity and do not relapse for many years is outstanding. So I think this is where we are going to go with menin inhibitors. I think they are going to really transform the field in the frontline setting so that hopefully, we don't have to worry as much about the situations like venetoclax failure.

I just want to mention, there's data presented at this ASH meeting that if you don't respond to menin inhibitors that your median overall survival post menin inhibitor single-agent therapy is about 4.4 months. And there are certain features like FLT3 ITD disease that can predict for lack of response to monotherapy.

So given that, the data in the relapsed/refractory patient population with a median duration of response of 40 weeks, with the triplet therapy certainly is a reason for people to utilize the ziftomenib plus ven/aza even potentially now with these results to try to improve upon like 4, 5, 6 months with single agent that we're seeing. So I definitely think this data is highly relevant with the approval of ziftomenib right now.

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

Thank you, Abigail, and thank you all for the questions. I want to just touch on 2 themes quickly before we conclude. And they relate to what Dr. Zeidan and Dr. Wang were saying. So we are tremendously grateful for the advice, the guidance, the support that we get, not only from the two doctors here, but from our entire group of investigators and key opinion leaders. We were originally planning to just present the frontline ven/aza data, but we were strongly encouraged by the investigators and by our -- sort of our advisory board to present to you the -- or to present at ASH, the relapsed/refractory data as well for, I think, just the reasons that were mentioned.

Hopefully, we're providing safety and tolerability data that makes it so that we can provide more and better options to patients. In a similar vein, and we've alluded to it, we're working on the FLT3 zifto combination in the relapsed/refractory setting. We're working on the quad in the frontline setting.

We'd like to -- as Dr. Zeidan alluded, we'd like to follow from the lessons in the myeloma and ideally bring quads -- at least quad, let's start with that to these patients to drive deeper and better responses and bring them hope for long-term durable remissions and a cure. We think ziftomenib has an ideal profile to really be able to set up to do that. That's obviously going to take us a number of years and the efforts of many talented people.

But that's what we're building on now with this initial approval. This is the first ASH with KOMZIFTI approved, hopefully, the first of many successful ASHs and EHAs and other conferences to come. So I want to thank Dr. Wang and Dr. Zeidan. I want to thank the tremendous efforts of all of the study teams, the investigators and, of course, our team.

I want to thank all of you for your questions. And with that, we'll conclude. We wish you all a good rest of the afternoon, and thank you again very much.

At this time, I would like to welcome you to the Kura Oncology FDA approval conference call. [Operator Instructions]

At this time, I would like to turn the call over to Greg Mann from Kura Oncology.

Thank you, operator. Good day to all. I'm Greg Mann, Senior Vice President, Investor Relations incorporate Affairs Kura Oncology. Welcome to our conference call to discuss the FDA approval of ziftomenib. Today's press release, the U.S. prescribing information in the slides we'll be reviewing today are available on our website, www.kuraoncology.com. Joining our call today are Dr. Troy Wilson, President and Chief Executive Officer of Kura; Dr. Mollie Leoni, Chief Medical Officer; Brian Powl, Chief Commercial Officer; and our guest speaker, Dr. Unis Wang, Chief of Leukemia Service and Professor of Oncology at the Russell Park Comprehensive Cancer Center. .

Before beginning our prepared remarks, we 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 now turn the call over to Troy.

Thank you, Greg. Today, FDA granted full approval of KOMZIFTI or ziftomenib, a groundbreaking once daily oral menin inhibitor for treatment of adults with relapsed or refractory NPM1-mutated acute myeloid leukemia or AML. We believe KOMZIFTI has a best-in-class benefit risk profile for patients and marks a significant step towards transforming AML treatment. It's noteworthy that KOMZIFTI's PDUFA target action date was November 30, 2025. The fact that FDA approval came early speaks to the compelling benefit risk profile for patients. .

The approval is a pivotal moment for Kura Oncology. With this milestone, we transition into a fully integrated commercial stage company as we advance the development of KOMZIFTI as well as our robust pipeline of therapeutic programs. Together with Kyowa Kirin, we're committed to delivering KOMZIFTI and improving the lives of patients. We're thrilled for the approval and confident in KOMZIFTI's potential to make an impact for patients. Its favorable benefit risk profile positions it as a best-in-class menin inhibitor by delivering meaningful efficacy with a differentiated safety profile. KOMZIFTI did not require a boxed warning for QTC prolongation or [indiscernible].

In addition, the KOMZIFTI prescribing information does not require dosage reduction when KOMZIFTI is concomitantly administered with CYP3A4 inhibitors. Although this initial approval in the relapsed refractory setting is an important first step, we believe the greatest potential impact for KOMZIFTI lies ahead. KOMZIFTI is being studied across the range of AML treatment settings, including frontline therapy and combinations with 7+3 venetoclax-azacitidine as well as CYP3 inhibitors, supported by its best-in-class balance of safety and efficacy we believe KOMZIFTI has potential to serve as a foundational therapy for acute leukemias, marking a significant step in redefining the standard of care in AML.

I'll now turn it over to Dr. Mollie Leoni, who will review the U.S. prescribing information and key clinical data supporting KOMZIFTI's approval. Following her, Dr. Eunice Wang, lead investigator on the KOMET-001 study will share her insights on the approval significance for the clinical community. Then Brian will outline our commercial strategy. Over to you, Mollie.

Thank you, Troy, and hello, everyone. At Kura Oncology, we are proud and grateful for the opportunity to deliver KOMZIFTI to our patients. Our heartfelt thanks go to the patients and their families, investigators and their teams, FDA reviewers, our partners and collaborators at Kyowa Kirin and the dedicated Kura teams whose efforts made that comes up the approval possible. Relapsed/refractory NPM1-mutated AML has been a disease with limited treatment options and poor outcomes, underscoring our determination to make KOMZIFTI available to patients in urgent need. .

Approximately 20% of patients are refractory to frontline treatment and 50% of those who do achieve a complete remission will relapse. Despite recent advances, fewer than 10% of these patients will survive 5 years. NPM1 mutations represent about 30% of AML cases and are among the most common genetic alterations in AML. KOMZIFTI's approval introduces a new once-daily oral treatment offering hope for patients with NPM1 mutated AML. KOMZIFTI is approved for adult patients with relapsed/refractory AML with a susceptible NPM1 mutation who have no satisfactory alternative treatment options. Treatment for at least 6 months is recommended for patients without confirmed disease progression or unacceptable toxicity to allow sufficient time for a clinical response.

The recommended dosage is 600 milligrams once per day, making KOMZIFTI the first and only approved once-daily oral menin inhibitor. The approval of KOMZIFTI is based on data from the COMET-001 clinical trial, which evaluated KOMZIFTI in 112 patients with relapsed or refractory NPM1-mutated AML at the 600-milligram dose. I'll now summarize some key data from the KOMZIFTI label, as shown on Slide 7. In 112 patients treated, KOMZIFTI demonstrated a 21.4% complete remission plus complete remission of partial hematologic recovery rate. The median duration of that response was 5 months with a median time to response of 2.7 months. Of the patients who achieved a response of CR or CRH, 88% of those patients responded within 6 months of starting KOMZIFTI therapy.

Almost 50% of patients maintained or achieved transfusion independence. Results from KOMET-001, which were recently published in the Journal of Clinical Oncology, provide further insight of patients who achieved a response, the median overall survival was 18.4 months compared to 3.5 months for nonresponders. A prespecified subgroup analysis showed consistent response rates across age, performance status, types and number of prior therapies and co-mutations. The patient population in KOMET-001 reflects real-world clinical practice and the consistency of clinical activity underscores KOMZIFTI's broad applicability offering hope to diverse patient groups within relapsed/refractory NPM1 mutated AML.

Safety data from the KOMET-001 trial in 112 patients, so KOMZIFTI was generally well tolerated, with most adverse reactions being grade water 2. Serious adverse reactions are occurring in more than 5% of patients, including infection without identified pathogen, febrile neutropenia, bacterial infection, differentiation syndrome and dyspnea. Similar to other differentiating agents, the KOMZIFTI label does include a boxed warning for differentiation syndrome or DS. Low frequency and duration of QTC prolongation were observed in the KOMET-001 trial. Importantly, the data did not meet criteria for a box warning. Grade 3 QTC prolongation of entity cause occurred in 8% of patients with no Grade 4, Grade 5 events.

NPM1 mutant patients tend to be older in age diagnosis. Notably, only 10% of patients over the age of 65 experienced a QTC prolongation of any cause. The mean change in QTC integral across the study population was 7.7 milliseconds, even when including patients on concurrent QTC prolonging drugs such as azolantifungals. While the upper bound of that confidence interval process FDA's 10 millisecond threshold for inclusion as a precaution on the label, this degree of change remains well below the 20 millisecond level, generally associated with a clinically meaningful increase in cardiac risk.

We're already in dialogue with FDA about potential steps post approval that could help refine the labeling as some of the observed QTC changes appear to be influenced by concomitant medications rather than by KOMZIFTI itself. KOMZIFTI has no significant drug-drug interactions or DDIs, and does not require dosage reduction when concomitantly administered with strong CYP3A4 inhibitors. Patients with AML are often prescribed agents that interact with CYP3A4, such as azole antifungals and calcium channel blockers as part of supportive care. The absence of significant DDIs is important because a competing menin inhibitor is a sensitive CYP3A4 substrate and requires careful titration of monitoring. KOMZIFTI's lack of clinically meaningful drug-drug interactions enhances its compatibility and combinability with supportive therapy and potential combinability with standard of care AML regimens.

Patients relapse refractory NPM1 mutant AML deserve new hope. KOMZIFTI's approval marks a turning point, offering a new treatment modality with a strong benefit risk profile that makes NPM1 mutations actionable for more patients. It is my privilege to introduce Dr. Eunice Wang, Chair of Leukemia Service and Professor Oncology in the department of Medicine at the Roswell Park Comprehensive Cancer Center.

Dr. Wang is the principal investigator of the KOMET-001 trial and lead author on the recent publication of the KOMET-001 data in the Journal of Clinical Oncology. And she will discuss the significance of KOMZIFTI's approval for patients with NPM1 mutated AML. Dr. Wang?

Thank you, Mollie. The FDA approval of KOMZIFTI validates its compelling profile, convenient one-day dosing, deep and durable clinical responses and its potential compatibility with other anti-leukemic therapies and supportive meds which are commonly used in this patient population. From a safety and tolerability perspective, treatment-related adverse events are infrequent and manageable with standard concomitant medications. I just wanted to add my thoughts to Mollie's on the importance of the differentiation benefit/risk profile for ziftomenib.

This absence of drug-drug interactions and the fact that syptometin is not associated with the boxed warning for QTC prolongation [indiscernible] points represents a significant clinical benefit for our patients. These patients are frequently on a number of medications, which can interact with CYP3A4 and/or prolong the QT interval. As a practicing clinician, if one could choose a menin inhibitor without a drug-drug interaction or a boxed warning, one would prioritize the menin inhibitor with a better benefit risk profile. This favorable benefit rate profile of Zibtominib has direct relevance to the real world.

Several approved AML therapies are CYP3A4 substrates. In the case of a different FDA-approved man inhibitor, concombinate use with CY3PA4 inhibitors can increase drug exposure and toxicity, including QTC prolongation and the risk of [indiscernible]. And thus, every single patient treated with those drugs require close monitoring. I believe that the interplay between the QTC prolongation and the drug-drug interactions is important across treatment for AML settings. Variability in drug exposure due to drug-drug interactions would be less concerning in the absence of a pronounced risk.

Drawing from my multiple extensive years of experience with ziftomenib in clinical practice, I've observed meaningful outcomes for my patients, and I'm exceedingly grateful to have a new option to treat patients. I believe that ziftomenib has the potential to benefit a large number of patients with NPM1 mutated AML.

And with that, I will hand it back to the Kura team for additional information.

Thank you so much, Dr. Wang. With our partner, Kyowa Kirin, we are advancing KOMZIFTI across the AML treatment continuum. Ongoing trials are evaluating KOMZIFTI in frontline, post-transplant maintenance and relapsed/refractory settings, combined with 7+3 chemotherapy, venetoclax and azacitidine FLT3 inhibitors and other standards of care.

Data from the Phase Ia/Ib KOMET-007 trial presented earlier this year, showed high rates of complete remission and MRD negativity in newly diagnosed patients with NPM1 mutant and KMT2A rearranged AML treated with KOMZIFTI in combination with 7+3 chemotherapy. Composite CR rates of 93% and 89% were observed in NPM1 mutant and KMT2A rearranged response evaluable patients, respectively. KOMET-007 also evaluates KOMZIFTI in combination with Banesa in the frontline and relapsed/refractory settings. We're excited to present preliminary ven/aza data next month at the ASH 2025 Annual Meeting.

A new cohort investigating KOMZIFTI with quizartinib, a FLT3 inhibitor in frontline AML patients is now open. Additionally, our registration-enabling KOMET-017 trial is evaluating KOMZIFTI a newly diagnosed KMT2A rearranged and NPM1 mutant AML in combination with standard of care chemotherapy. To maximize KOMZIFTI's impact, we are continuing to generate and publish robust clinical data. Our medical affairs team will continue to share data with the NCCN Guideline Committee to ensure prescribers are informed about KOMZIFTI's clinical benefits.

Our clinical development plan is ambitious and deliberate, aimed at maximizing the potential of KOMZIFTI across lines of therapy, mutational combinations, and standards of care. We're confident in our ability to move our programs forward and widen our lead ahead of others in the field of [indiscernible]. Brian Powell will now discuss our strategy and plans for the commercial launch of KOMZIFTI. Brian?

Thank you, Mollie. I want to echo what's been said. This is a transformative moment for Kura Oncology. Our commercial team has prepared for this pivotal moment. We built the talent, systems and strategy needed for a successful U.S. launch of KOMZIFTI. And we've worked hand in hand with Kyowa Kirin to align our launch strategy, commercial execution, field engagement and patient access. Today, our preparations are complete. Our teams are ready, and we're confident in our ability to deliver a strong launch for this important new therapy. .

Market research highlights KOMZIFTI's best-in-class profile and ease of use as highly compelling for prescribers. We believe its proven efficacy, superior safety profile and once daily oral dosing will make it the preferred option in the relapsed/refractory and PM1 mutated AML setting. We've built a seasoned commercial organization, which is fully trained on AML, KOMZIFTI and its supporting data and are ready to drive a robust launch.

The KOMZIFTI launch is now underway with product delivery expected within the next few business days. Our energized field teams are actively working to ensure eligible patients can access KOMZIFTI, maximizing the reach and impact.

The next slide, building on Mollie's discussion of the KOMET-001 data and the KOMZIFTI label we think KOMZIFTI is differentiated on the 4 pillars of efficacy, safety, compatibility and simplicity. And our market research supports that this differentiated profile aligns with the priorities of key opinion leaders for a menin inhibitor. We believe the efficacy profile of KOMZIFTI is best-in-class. KOMZIFTI meets the high bar for monotherapy activity in heavily pretreated patients including 1/3 of patients who were treated with KOMZIFTI in the second line where no satisfactory option was available to these relapsed/refractory patients, delivering strong CR/CRH rates a 5-month media duration of CR CRH response and improved survival among responders versus nonresponders as demonstrated in our JCO publication.

We believe the safety data for KOMET-001 is also best-in-class. KOMZIFTI has a manageable safety profile with most adverse events being Grade 1 or 2. The KOMZIFTI prescribing information includes clear dose modification guidelines for physicians to follow when DS is suspected. The label is unburdened by the boxed warning for QTC and Torso DuPont, a major advantage in real-world clinical practice. Regarding compatibility, KOMZIFTI's lack of significant DDIs is a key advantage. Unlike other therapies, which require dose adjustments when co-administered at infective, KOMZIFTI can be co-administered without dose modification, offering predictability to practices and reducing complexity and risk.

And unlike the other commercially available menin inhibitor, KOMZIFTI does not require extensive monitoring and dose modification when administered with standard supportive therapies. Finally, KOMZIFTI is the only once-daily oral option, which is beneficial to patients who are often elderly on several concomitant medications. To support KOMZIFTI's adoption upon approval, our medical affairs team has been actively engaging with AML key opinion leaders to educate them on the products emerging clinical profile and the KOMET development program.

In parallel, we launched a disease state education campaign to raise awareness on the role of menin inhibition in relapsed/refractory AML last year. Our prelaunch research confirms these awareness efforts have generated strong physician enthusiasm exceeding our expectations. Our commercial strategy positions KOMZIFTI as the menin inhibitor of choice for adult patients with relapsed/refractory NPM1-mutated AML built on 3 imperatives: drive adoption, ensure broad access and leverage our partnership with Kyocera. Our experienced field sales team members were hired and traded this summer with an average of more than 20 years of industry experience our outstanding group of sales professionals bring deep hematology expertise as well as established relationships at key institutions to help facilitate uptake.

Our field teams will target over 4,000 HCPs to engage with priority accounts and maximize their reach. Their focused messaging will establish that NPM1 is now an actionable mutation, communicate on KOMZIFTI's best-in-class profile as the first and only once-daily oral menin inhibitor and ensure patients can start and stay on treatment.

Speaking to our partnership with Kyowa Kirin, we remain firmly aligned in our mission and culture. Kyowa Kirin global infrastructure and hematology expertise provide a strong foundation for the KOMZIFTI launch. Kura will benefit from Kyowa Kirin's existing presence in hematology oncology practices and build on their advanced patient finding capabilities in rare diseases to help identify and engage practices with patients eligible for KOMZIFTI. Between both organizations, we have over 60 highly experienced oncology account managers who will promote KOMZIFTI. Our joint launch readiness meeting was held last month and prepared both teams to introduce KOMZIFTI effectively to HCPs.

To ensure broad access, our market access team has educated payers on KOMZIFTI's clinical profile, emphasizing the potential value for AML patients for whom there are limited options. We have engaged in preapproval information exchanges with the clinical teams at 100% of the targeted payer organizations who are responsible for coverage decisions affecting over 90% of insured lives. We have set a U.S. launch price for the 1-month supply of a once-daily fixed dose of KOMZIFTI at $48,500, reflecting its clinical benefit to patients, prescribers and the health care system. KOMZIFTI is available through a select network of specialty distributors and specialty pharmacies to optimize access, provider satisfaction and uptake.

Our Kura RxConnect program is now live and offers tailored support for assistance with prior authorization, insurance education and appeals, financial assistance and patient resources. Shifting now to our market opportunity. Approval in the relapsed/refractory AML setting is a critical first step towards establishing KOMZIFTI as a commercial success. Its best-in-class profile in the relapsed/refractory NPM1-mutated AML setting positions us to capture significant market share in this high unmet need population.

We estimate the U.S. market for NPM1 mutated relapsed/refractory AML is in the range of $350 million to $400 million annually based upon up to 30% of relapsed refractory AML patients who could benefit from an average of 6 months of KOMZIFTI treatment. Its efficacy, safety, tolerability and convenience support this market leadership. This launch will lay the foundation for a larger opportunity for KOMZIFTI in frontline AML. With up to half of the 22,000 annual U.S. AML diagnoses being potentially addressable with a menin inhibitor in combination we believe KOMZIFTI can become a foundational therapy across newly diagnosed and relapsed/refractory AML.

Our clinical development plan targets 12 to 24 months of treatment for these populations, representing a U.S. market potential exceeding $7 billion annually. We are grateful for the opportunity to serve the relapsed/refractory NPM1-mutated AML community with KOMZIFTI. It's robust label and compelling value proposition, coupled with our clear commercial strategy and world-class team position us to launch KOMZIFTI successfully and usher in a new era of AML care with a potential transformative therapy for patients.

I'll now turn the call back to Troy for closing remarks.

Thank you, Brian. On behalf of everyone at Kura Oncology, we are honored to deliver KOMZIFTI to the adult AML community. This milestone marks an important next step in our journey to transform AML treatment and to advance Com throughout the continuum of care. Years of focused execution have brought us to today. With a robust commercial strategy and a dedicated and passionate team, we're ready to deliver a successful launch and to drive lasting value.

With that, we'll conclude our prepared remarks, and we would welcome your questions.

[Operator Instructions] Our first question is from Li Watsek from Cantor Fitzgerald.

This is Daniel Bronder on for Li. First, congratulations on [indiscernible] approval. It's a great achievement. Can you comment on the warning around QTC prolongation -- and what gives you confidence that at a future time point, it won't get updated or upgraded to a box warning similar to your competitors?

Yes. Daniel, thank you for the congratulations. Mollie, would you like to take Daniel's question?

Yes. So the FDA guidance that I was discussing, it is based entirely on experiments done in healthy volunteers. Ours, of course, was a one-arm study that was done in patients with AML and in patients that are elderly and on many concurrent medications, a lot of which cause QTC prolongation. But that being said, the magnitude of the change that we see in patients on these concurrent therapies in their QTc interval is relatively small and is considered not of high -- not to be a great clinical risk for patients. It is only once you're crossing that 20-millisecond barrier that there's really an increased risk for sudden cardiac events.

So with that small change in the QTC interval that was observed in these patients, I think it's extraordinarily unlikely that we will see the QTC labeling become more rigid since it is all completely databased. And as I said during the prepared remarks, we have already started to discuss with the FDA ways to refine the language in the label because we do believe that when we show our patients that are not on these concurrent CYP3A4 prolonging medications that cause QTc prolongation, I'm sorry, that we do not see any change in the QTc interval. And as we get more data in settings with placebo-controlled arms, we'll be able to further refine the messaging. But overall, we think that it's demonstrative -- the labeling is demonstrative of a relatively low risk for QTC prolongation for these patients.

Thank you, Mollie. Daniel, I would just add to that. Looking forward to this ASH, we'll see data from us as well as competitors and look at the continued low rates of QT prolongation in the combinations, as Mollie mentioned. Again, in a single-arm study, you can't exclude. But as you start to look out into a broader and broader data set, I agree with Mollie. I think, if anything, we may see a relaxation of the requirements, certainly not a risk of it becoming a more severe restriction. Thanks for the question.

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

Congrats on the approval. I might have missed it, but can you talk about the pricing of KOMZIFTI and maybe help set expectations for the early launch?

Yes. Brian, would you like to take that question?

Thanks, Jonathan, for the congrats as well. Yes. So as I said in the prepared remarks, our pricing will be listed for 30-day supply of KOMZIFTI at $48,500 per bottle. That's based on our research to test kind of the benefit that we would anticipate of KOMZIFTI and has been tested within the comparators within the market. In terms of setting our expectations for launch, as I said in the remarks, our team is ready to go. Product is getting ready to be out in the channel within days. And given that we've had a good dialogue with FDA, the team had been able to do a number of activities at risk that will help us to get to product out as quickly as possible. The teams will be certified to launch this week. So we'll have an opportunity to get the team out in the field, and we start to anticipate that expectation of a launch. It's a little early to say what that comes from, from a revenue perspective, as you can imagine, but I think that's the approach we're taking.

Our next question comes from [indiscernible] Benjamin from JMP Securities.

Congratulations on this really momentous occasion. The question for me is, when you think about how many patients you treat, what percentage are on these concomitant medications? Like how many are elderly? And of the patients -- maybe this is for Dr. Wang, of the patients you're currently treating, how many would you put on zifto?

[indiscernible] that question. So the median age of presentation of acute myeloid leukemia in the general population is 70 years. So you can imagine that as the population ages, the majority of these individuals are going to have underlying diseases, including cardiac and other autoimmune diseases, diabetes, hypertension, hyperlipidemia, et cetera. So the overwhelming majority of patients are probably taking multiple other medications. And therefore, drug-drug interactions and even the frequency of taking these medications can have a big impact on clinical practice. So I do think this is potentially a very differentiating clinical scenario.

We also know that given the concomitant cardiac diseases that they have that QTc prolongation can be somewhat onerous. The need for weekly EKGs in our clinical practice and monitoring and differentiating and dose reductions, these are all significant barriers to patients being able to take this drug. And these drugs require continued administration for benefit to have the efficacy of the drug be evident because the major mechanism of these drugs is differentiation. So you can't just take them for 2 or 3 days and expect to see benefit. You need to have continuous administration and delivery of drug in order to see efficacy. So these are clinically very important in our practices.

Maybe how many patients?

I'm sorry.

Just like in your practice, about how many patients would you think would be getting on to zifto?

So I think any patients that -- so NPM1 mutated AML represents up to 1/3 of newly diagnosed patients and about 50% of them are going to relapse. And so I am very comfortable starting all of the patients at the time of their relapse on ziftomenib in preference to other agents that may or may not be as effective and/or going to provide challenges in terms of weekly management.

Our next question is from Charles Zhu from LifeSci Capital.

Great. Excellent. Congratulations on the early FDA approval for ziftomenib. I had one. At risk of splitting some hairs, can you talk about some of the nuance differences between your label versus the competitor's label, specifically on the boxed warning around differentiation syndrome. For whatever reason, it seems to -- the box warning seems to have ziftomenib being interrupted on suspected DS, but that's absent from your competitor. I wanted to see, is this mounted out of Mohill or what's going on here?

Mollie, do you want to take that?

Sure. So you've got Eagle Eyes, we've already seen that. That was actually something that was part of our differentiation syndrome guidance from the very beginning because ziftomenib has such a long half-life. So if they suspect DS, we feel that it is appropriate to interrupt drug while they're evaluating whether or not it is, in fact, DS just because they will obviously still have drug on board for significant periods of time even after that interruption, whereas a competitor has an extremely short half-life and thus requires the twice daily administration. And so it doesn't really require an interruption because the drug is out of system so quickly. So really, that was our proposed language all along for our treatment of differentiation syndrome. And so it was carried over into the label.

Our next question is from Salim Syed from Mizuho Securities.

Congratulations on the approval. This is Eric on for Salim. Just real quickly on the CYP3A strong inhibitors. Just could you give any color on the differences between what you've been talking about as not clinically meaningful CYP3 substrate versus where it is and the language on the label?

Mollie, do you want to take that?

Sure. Well, I think that what you have to notice is that we do not require any dose adjustments for CYP3A4 concurrent -- inhibitor concurrent administration, which demonstrates, and there is wording, I believe, in the pharmacology portion of the label that states there is no clinically meaningful interaction with CYP3A4 inhibitors. Thus, it's more predictable and easy to treat patients with ziftomenib because most of these patients or the large number of these patients will be on concurrent medications that are CYP3A4 inhibitors, and our drug does not need to be adjusted in response to those concurrent medications.

Our next question comes from Roger Song from Jefferies.

Great. And my congratulations to the early approval as well. I think it will be very good to see how you will refine the label to update the QTC prolongation. Just want to confirm, is that also possible you will get rid of this monitoring requirement because so far, we still see the first 4 weeks weekly and then later on monthly, the monitoring. And then also another thing for the CYP3A, I just want to confirm, you don't require the dose adjustment. But if you're using the CYP3A, would you be able to dose adjust as you start to see some side effects?

Mollie, do you want to take that?

Sure. So during our label negotiations, it was -- the real sticking point with regards to the QTC language was around simply the data and the guidance documents that are out there and whether or not that this would require any additional monitoring. And we have initially discussed with them that their feeling is that because it's a single-arm trial without a placebo control, it's difficult to say definitively whether it's our drug or a concomitant therapy that is causing any -- any QTC prolongation. But again, just looking at the low rates and low level of any QTC prolongation, it becomes obvious that it's not a significant clinically meaningful significant adverse event for these patients.

And we will be generating additional data. We've been generating data in various clinical pharmacology settings and studies that we have ongoing. And we'll obviously have data from the blinded 017 trial as it goes on. And so we do think that there'll be opportunity to help reassure FDA that our drug does not result in QTC prolongation. And that's what I meant by how we'll be able to further refine the label as we move forward and have more data.

Can I make a clinical comment? So...

Please, Dr. Wang.

Sure. So I'm just saying -- so we have treated potentially more patients with ziftomenib in the clinical trial setting than anyone in the world. So number one, we've never seen any evidence of clinically significant QTc prolongation. Secondly, it's an extremely easy drug to give. So if patients are on concomitant meds, we don't have to look at the meds to see whether it needs to be dose reduced. It's a once-a-day drug, and we do not feel that there needs to be the same adherence to close EKG monitoring as with other drugs. So from a clinical perspective, this makes a huge difference.

We are not worried that we need to -- if a patient goes to see their primary care doctor and they get put on other meds that we have to do a literature search and see whether they're affecting CY3P3A and dose reduce and so forth. So just from clinical practice, it's an extremely easy drug to give. And therefore, we feel confident that this would be a significant clinical advance as opposed to other drugs that are in practice.

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Our next question is from Brad Canino from Guggenheim.

Congrats on the approval. I recognize some of the comments around kind of working through some labeling updates in the future. But I guess just on the QTC, how do you think the monitoring requirements are going to provide general community physicians with any sort of logistical differentiation versus what they have now with the requirements on EKG with revumenib.

Yes. Maybe I can take a swing at that, Brad, and then I'll let Dr. Wang comment. It isn't -- there are a number of drugs in AML that induce QT. Some of them like quizartinib have box warnings. Others are in the warning and precaution similar to zifto. I think it's a matter of severity, right? Yes, there is a -- you do have to be watchful, but as Dr Wang commented, we have not seen anything. You can't prove a negative in a single-arm trial and the FDA is always going to take the view that safety is paramount. They do have grave concern about a competitor compound, so much so that they put a boxed warning on it due to the magnitude of the QT prolongation. I think they are being prudent in making sure that there isn't a border effect. It isn't as Dr Wang mentioned, this is a once a day oral drug. We've not seen any serious QT. Had we, I think you would see a boxed warning. Because certainly the agency is not shy about imposing a boxed warning when it feels it's needed. But Dr. Wang maybe you can speak to that if there is any -- any impediment to the monitoring requirements that are in the label from your -- from the clinical practice perspective.

I think the FDA was being overly cautious in their labeling and providing a warning. However, I would highlight that in the KOMET-001 study, we enrolled 92 patients onto this monotherapy. Out of those 92 patients, only 3 individuals had evidence of QTC prolongation and all 3 individuals had other reasons for them to have QTC prolongation, concomitant medications or electrolyte abnormalities. That is significantly different from the 20% or more QTC prolongation observed in all patients treated with the competitor drug. I mean it's just a world of difference. And I feel that with further evidence provided to the FDA regarding the role of concomitant medications and other factors that could have led to the QTC that this is not going to be a significant clinical barrier to the use of this drug.

Thank you, Dr. Wang.

Our next question is from Bill Nadeu from TD Cowen.

Let us add our congratulations on the approval. Actually, 2 quick questions from us. So first, on the CR/CRh rate, it looks like it's 21%, a little different than the JCO publication. Can you give us a sense of what analysis the FDA did that was different versus what was in JCO. And then second, just a brief follow-up. Will you be blocking scripts? Or will the prescription services have accurate data on the launch?

Bill, you snapped 2 questions in. Despite our admin, I only ask one. Mollie, do you want to take the question on the [indiscernible]?

Sure. You got to notice that in the JCO, there was also a different denominator. We were just showing you the Phase II portion of the trial with that data. And in the FDA review, they actually looked at all of our patients together. So all the patients that have been treated at 600 milligrams because they were the same patient population and more numbers get you closer to the truth when you look at that. So that's the main reason for seeing a difference between CR/CRh rates in the publication and in the label.

Yes. And then, Brian, I'm going to indulge Phil, but only this one time. Brian, do you want to answer Phil's question on information.

Yes. Yes. So as I mentioned, Phil, our distribution model is going to be a limited distribution network between a couple of specialty pharmacies and a few specialty distributors. It's going to be similar to other AML therapies. So there will be a block on a lot of that based on the distribution that we have.

Our next question is from Jason Zemansky from BoA Securities.

Congrats on the strong label. As a follow-up to some of the previous questions, I'm trying to understand how disruptive to patients the monitoring requirement is when there's a worry about to. I mean is it that the monitoring itself is more frequent or intense? Or is it something that just weighs on the patient when provided with a number of options out there?

Yes. Dr. Wang, do you have a perspective on that from a in terms of how you think about the 2 drugs now out in the marketplace and the monitoring requirement?

I feel like the need for black box warning. So black box warning means there absolutely is no question that you need to do this monitoring. And the issue with the other competitor drug is it's required that you have EKG monitoring weekly, okay, for the -- and then to do it with every subsequent consecutive cycle. That's a lot of visits. One of the advantages of having an oral agent and having it in the relapsed/refractory setting that these patients are -- they have very limited lifespan and the ability to have quality of life outside the clinic is really something that's very important to my patients.

So the fact that one needs to have an EKG done every single week means there needs to be weekly visits and that the patients need to not only have their EKG, they have to wait around, they have to make sure it gets read, that somebody is officially looking at the QTC. And I think that, that is a significant onerous thing. I think when there is a warning, what that means is that we need to be aware of it. We need to look for it if we have any thought about it, but it does not engender the same responsibility and rigidity in that if somebody has a black box warning, I absolutely need to do these things and the patient absolutely needs to come every single week to have that EKG done. Otherwise, I would not feel comfortable giving that drug. So that is sort of the clinical interpretation of the difference between a warning and a black box.

Yes. And just -- thank you, Dr. Wang. And just to add to that, I mean, if you look at the over 65 population, the rate of QT for zifto is 10% for the competitor, it's 46%, right? So not only are you talking about a much higher frequency, Yes, exactly. It's a much bigger difference. And the word Dr. Wang, you didn't use is liability.

It is a liability. So yes. So if I do not have somebody coming in every week to get their EKG and I missed a week or they went every other week or every third or fourth week and they get admitted to a hospital with an arrhythmia, I'm going to have a concern that it could have been due to the drug and that it could have been due to the fact that I did not check the EKG or have them come in for that monitoring. And I think that, that is a significant issue. If somebody said to you the risk of you having a cardiac problem on this drug is 46% versus 10%, yes, it's a relapsed/refractory disease. Obviously, you would pursue any therapy, but I think that's a significant difference even in counseling patients or consenting them for therapy.

Our next question is from Etzer Darout from Barclays.

Congrats on the approval. Just 2 quick questions, I guess, in terms of market dynamics. Just wondered around your expectations for maybe duration of therapy for NMP1 patients in the real-world setting, second line versus third line. Just curious about that, if you have any comments around.

Yes. Thanks, Etzer. Thanks for the question. Brian, would you like to take the question on duration of therapy?

Yes. And I think that -- it's a good question. And I think one of the things we'll have to kind of see is how that plays out in the data in the real world. Our expectation is that patients, especially those who are getting a response will benefit over 6 months. As you saw, the median duration of response was 5 months in the label with about almost 3 months for patients to get to that response on average. So that gives us a sense of -- for those patients getting a benefit, it could be over 8 months. But on average, we think for most patients, it will be about 6 months is what we're expecting right now.

Obviously, there may be a different dynamic in the patients who are treated in the second line compared to the third line. The data in small studies, it's sometimes harder to really tease that out, but we do see that patients should be -- the earlier they're treated, and that's part of the comments and the strategy for our team is to try to get patients treated as early as possible because that's where we anticipate that a more significant benefit for them over the long term because the patients haven't had to go through multiple lines of therapy. So our strategy will be to get patients treated as soon as it's reasonable based on their other treatment options, which would be a priority in the second line or in some cases, the third line, depending on their prior therapies.

[Operator Instructions] Our next question is from David Dye from UBS.

I also want to add my congratulations on the approval. Great. So again, just to follow up on the previous question. I'm curious in terms of your thoughts around transplantation. -- maybe this is a question for Dr. Wang. Do you see sufficient evidence around these NPM1 patients potentially get to transplantation after treatment and also get into maintenance therapy with -- on zifto?

Thanks. So I do. We have rendered a number of patients MRD negative and for long-term response, particularly for our younger fit patients, the long-term benefit is achieved with being able to achieve a response or disease control and transitioning them on to subsequent allogeneic stem cell transplantation. So on the KOMET-001, we had a number of individuals now even a couple of years later that are still alive. Many of them have gotten an allo transplant.

We have successfully off-label continued ziftomenib in the post-transplant setting, which again offers benefit because you can combine the drug with potential ongoing other medications, immunosuppressive therapy, et cetera. So it is extremely well tolerated and the ability to render patients disease-free and under disease control and particularly MRD negative has the potential to move them on to a potentially curative regimen. So that's a very important question. And we do think that the longest survival for treatment of our patients is to move them forward. I think in the NPM1 mutant patient population, many of us consider this a favorable risk disease, a diagnosis. So we do not transplant patients upfront. Unfortunately, that's not always true. And so when they relapse, our ability to get them to a transplant in that secondary setting, I think, is very important. And this drug, I think, has a nice track record of being able to do that.

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

Thank you, operator. I want to start by thanking Dr. Wang for joining us. She took time away from her practice and her patients to speak to all of you about some of the real-world implications and usage of zifto. So Dr. Wang, thank you so much. I want to thank everyone at Kura, all of the investigators and the care teams and most importantly, the patients and their families who have contributed to this day. This is a momentous day for patients that motivates everything that we do at Kura. And so we're looking forward to a strong launch and to a continued broad development program. We will be at Jefferies London next week. And of course, we have a number of publications and presentations, including 2 oral presentations at ASH in Orlando. So we look forward to seeing many of you there.

In the meantime, if you have any questions, please reach out to Greg, me or anyone else on the Kura team. And we thank you for your time. We thank all the analysts for their questions, and we wish you all a good day. Thanks very much, everyone.

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" Cantor Fitzgerald & Co., Research Division

" BofA Securities, Research Division

" LifeSci Capital, LLC, Research Division

Good day, everybody. My name is Danny, and I will be your conference operator today.

At this time, I would like to welcome you to the Kura Oncology Third Quarter 2025 Conference Call. [Operator Instructions].

At this time, I would like to turn the call over to Greg Mann from Kura Oncology.

Thank you. Thank you, Danny. Good morning, and welcome to Kura Oncology's Third Quarter 2025 Conference Call. Joining the call today are Dr. Troy Wilson, President and Chief Executive Officer; Tom Doyle, Senior Vice President, Finance and Accounting. Dr. Mollie Leone, Chief Medical Officer; and Brian Powl, Chief Commercial Officer, are also on the call and available to answer questions.

Before I turn the call over to Dr. Wilson, we 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 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, Greg. Good morning, and thank you all for joining our third quarter financial results conference call.

Over the past quarter, we've continued to significantly advance both our clinical pipeline as well as preparations for the anticipated commercial launch of ziftomenib, our once-daily investigational menin inhibitor for acute myeloid leukemia.

I'll begin with an update on zifto, followed by brief remarks on our commercial readiness and our farnesyl transferase inhibitor program.

The FDA review of ziftomenib for treatment of patients with relapsed and refractory NPM1-mutated AML remains on track with a PDUFA target action date of November 30, 2025. Communication with FDA continues to be open and constructive, and we remain focused on achieving a successful review outcome.

Based on clinical data from the KOMET-001 study, which has been presented at a major medical meetings and published in the Journal of Clinical Oncology in September, we're confident ziftomenib has a differentiated and favorable benefit risk profile. And if approved, ziftomenib could potentially reset the commercial landscape and become the menin inhibitor of choice for eligible patients.

Although while the regulatory review process for ziftomenib progresses, our clinical team continues to execute on a strategic development plan targeted at addressing the large unmet need beyond the relapsed/refractory setting where we believe ziftomenib's benefit risk profile will be even more competitive and more impactful for patients. At EHA earlier this year, we reported updated combination data for ziftomenib with 7+3 intensive chemotherapy in newly diagnosed NPM1 mutant and KMT2A rearranged AML. These data were very encouraging, showing high rates of complete remission and MRD negativity in over 70 patients across the combination cohorts with a safety profile consistent with what is expected in patients treated with 7+3 alone. These results highlight ziftomenib's potential as an early intervention, offering a meaningful opportunity to improve patient outcomes.

Yesterday, we announced acceptance of 2 oral presentations at ASH, which will feature data on ziftomenib in combination with venetoclax and azacitidine chemotherapy. Both abstracts, one in the newly diagnosed setting and the second in the relapsed/refractory setting reported high response rates and MRD negativity with a safety profile consistent with previous reports. The abstracts used data cutoff of June 20, 2025, and updated results reflecting additional follow-up will be reported in the oral presentations next month. We plan to host a virtual investor and analyst event to discuss these ASH presentations on Monday, December 8, at 12:30 p.m. Eastern Time. Details will be available on our website.

Encouraged by these positive results, we've advanced rapidly into our KOMET-017 frontline Phase III trials. KOMET-017 comprises 2 randomized, double-blind, placebo-controlled trials to evaluate ziftomenib in combination with both intensive 7+3 and non-intensive ven/aza chemotherapy regimens in patients with newly diagnosed NPM1 mutant or KMT2A rearranged AML. The program aims to advance ziftomenib to the frontline setting with potential to treat patients earlier in their disease course when the opportunity to alter its trajectory is greatest.

We're targeting enrollment at over 150 global sites with a large proportion in the U.S. Each KOMET-017 trial includes dual primary endpoints to support potential U.S. accelerated and full approvals. The intensive chemotherapy combination study evaluates MRD-negative complete response, or CR, and event-free survival. The nonintensive chemotherapy combination study assesses CR and overall survival. Site activation is accelerating in each of these company-sponsored registrational trials and patient enrollment is progressing well.

Continuing this momentum, last month, we opened a trial cohort to assess ziftomenib combined with 7+3 induction chemotherapy and quizartinib, an approved FLT3 inhibitor in patients with newly diagnosed AML harboring FLT3-ITD NPM1 mutant co-mutations. FLT3 mutations represent one of the most common and challenging genetic mutations in AML with limited durable treatment options. Our preclinical studies suggest ziftomenib and quizartinib synergize to enhance activity without undue toxicity. Note, this effort also builds on our clinical experience with the combination of ziftomenib and gilteritinib in the relapsed/refractory NPM1 mutant setting. Enrollment in that trial has been robust, and we intend to present preliminary Phase I data at a major medical meeting next year.

With these studies now underway, ziftomenib development is active in all 3 major frontline settings, collectively representing up to 50% of incident AML cases in the U.S.

Turning now to commercial preparations. Our teams are launch ready and confident in our execution plan across the commercial organization from marketing, market access as well as patient support and sales analytics, field operations and sales, our teams are fully mobilized and prepared to execute as soon as ziftomenib is approved. Our disease awareness campaigns have exceeded their targets. Our preapproval information exchanges with key payers and other market decision-makers are complete, offering us confidence that we will facilitate rapid access and uptake.

Our limited distribution network is fully aligned and ready to support product upon approval. And our team of experienced oncology account managers is already engaged in profiling target accounts.

In early October, we and our partner, Kyowa Kirin, held a joint launch readiness meeting where our 2 field teams of Kura and Kyowa Kirin what we finally call 1K completed their training and precertification. The excitement and alignment across both organizations is palpable, and the 1K team stands ready to deliver upon approval.

Turning now to our farnesyl transferase inhibitor portfolio. Last month, we presented new clinical data, highlighting the potential of FTIs to safely combine with major classes of targeted therapies, including PI3-kinase alpha inhibitors, KRAS inhibitors and anti-angiogenic tyrosine kinase to overcome resistance pathways and enhance antitumor activity. In our FIT-001 Phase I trial evaluating darlafarnib, our next-generation FTI in combination with cabozantinib in patients with renal cell carcinoma, we observed a manageable safety profile across multiple dose levels of each agent, including at the full label dose of cabozantinib. Antitumor activity was seen across all dose combinations, including in patients with prior exposure to cabozantinib.

The objective response rate or ORR was 33% to 50% in clear cell renal cell carcinoma and 17% to 50% in patients with prior cabozantinib exposure. The KURRENT-HN trial evaluates tipifarnib, our first-generation FTI with alpelisib in patients with PIK3CA-dependent head and neck squamous cell carcinoma. This combination also demonstrated a manageable safety profile and robust antitumor activity in a heavily pretreated patient population, where meaningful benefit would not be expected from either agent alone. An ORR of 47% was observed at a dose of tipifarnib of 1,200 milligrams per day and alpelisib at 250 milligrams per day.

We see tremendous promise in darlafarnib and the broader potential of farnesyl transferase inhibition as a differentiated mechanism to extend the reach of precision oncology with the potential to enhance activity of PI3-kinase alpha inhibitors, KRAS inhibitors and TKIs, darlaifarnib represents a very substantial commercial opportunity with the potential to address more than 200,000 incident patients annually in the U.S. alone. We view our FTI platform as a strategically important pillar of growth that complements our leadership in menin inhibition. Our dual pipeline strategy positions Kura with 2 clinically validated mechanisms that address some of the most pressing needs in precision oncology. We expect to have more to share regarding our FTI clinical development plans and business development strategy in 2026, supported by a steady cadence of data presentations at medical meetings throughout the year.

Kura remains in a strong financial position to execute across our pipeline, advance the development of ziftomenib and support our commercialization activities. Our partnership with Kyowa Kirin has enabled us to invest in a robust, expansive and accelerated development plan for ziftomenib. We recently received 2 $30 million milestone payments payable for the first patients dosed in the 2 KOMET-017 Phase III trials, which brings the total milestones received this year to $105 million. We expect approximately $315 million more in near-term milestone payments, including a substantial milestone payment associated with commercial launch of ziftomenib. This is consistent with the $420 million in near-term milestones we announced at the inception of the partnership with Kyowa Kirin last November.

We reported pro forma cash of $609.7 million for the period. This figure includes milestone payments received in October and November 2025 and reflects a strong capital position to advance our pipeline through key clinical and regulatory milestones.

I'll now turn it over to Tom, who will review the third quarter financial results.

Thank you, Troy. Collaboration revenue from our Kyowa Kirin partnership for the third quarter of 2025 was $20.8 million compared to no revenue for the third quarter of 2024.

Research and development expenses for the third quarter of 2025 were $67.9 million compared to $41.7 million for the third quarter of 2024.

General and administrative expenses for the third quarter of 2025 were $32.8 million compared to $18.2 million for the same period of 2024.

Net loss for the third quarter of 2025 was $74.1 million compared to a net loss of $54.4 million for the third quarter of 2024. This included noncash share-based compensation expense of $11 million compared to $8.3 million for the same period in 2024.

As of September 30, 2025, Cura had cash, cash equivalents and short-term investments of $549.7 million compared to $727.4 million as of December 31, 2024. As adjusted for the $60 million in KOMET-017 milestone payments under our collaboration agreement with Kyowa Kirin, Kura had on a pro forma basis, $609.7 million in cash, cash equivalents and short-term investments as of September 30, 2025. Based on our current operating plans, we believe that our cash, cash equivalents and short-term investments as of the end of the third quarter will be sufficient to fund our current operating expenses in 2027. And if we include anticipated collaboration funding under the Kyowa Kirin agreement, Kura's financial resources should support advancement of our ziftomenib AML program through top line results in our frontline combination program.

With that, I'll turn the call back over to Troy.

Thank you, Tom. Before we open the call for questions, let me just briefly highlight the key milestones we expect over the coming months and into next year.

For ziftomenib and our menin inhibitor programs, we look forward to continued engagement with FDA reviewers as we approach our PDUFA target action date of November 30 for ziftomenib as a monotherapy for patients with relapsed/refractory NPM1 mutant AML, present preliminary clinical data in newly diagnosed NPM1 mutant AML and updated clinical data in relapsed/refractory NPM1 mutant and KMT2A rearranged AML from our KOMET-007 cohorts evaluating ziftomenib in combination with ven/aza at the ASH Annual Meeting to be held next month in Orlando.

And finally, presenting preliminary clinical data from the KOMET-008 cohort evaluating ziftomenib in combination with the FLT3 inhibitor gilteritinib in patients with relapsed/refractory NPM1 mutant AML in 2026.

For our farnesyl transferase inhibitor programs, we expect to initiate one or more expansion cohorts of darlafarnib and cabozantinib in patients with advanced renal cell carcinoma in the first half of 2026, to present updated dose escalation data from the combination of darlafarnib and cabozantinib in advanced renal cell carcinoma in 2026, to present clinical data from the combination of darlafarnib and adagrasib in patients with KRAS G12C mutated solid tumor indications in 2026.

With that, Danny, we're ready to begin the question-and-answer session.

[Operator Instructions]

Our first question today comes from [ Jonathan Chang ] at Leerink Partners.

This is [ Albert Agustin ] on for [ Jonathan Chang ]. What do you foresee will be the makeup of account types that you are trying to penetrate for zifto launch? Are there any particular account types that you are focusing on? And also, are there any plans to include zifto in the NCCN guideline?

Sure. Thanks, [ Albert ]. In general, we're going to try to limit it to one question.

The second one is easy, but please, if folks can limit it to one question so we can get everybody. Brian, let me ask you if you can take Albert's 2 questions in turn.

Sure, absolutely. Thanks, Albert, for the questions. So our expected account types here are typically going to be the specialty hematologists. We anticipate a mix of academic -- large academic institutions as well as in some of the larger community oncology practices. It's going to be similar. Well, I think we get into our overall targeting strategy. We have probably about 4,000 HCPs that we're targeting. Within that range, I'd say, probably 78% of that is going to be in the academic setting, and then we'll have -- the rest of the focus will be on the community oncology practices that are treating those AML patients and particularly the relapsed/refractory patients.

To your second question, just quickly to answer, yes, our plans are to submit the KOMET-01 data on the basis of our approval soon after approval. You can't submit to the NCCN for a listing until you have FDA approval. So our plans are to submit that within days of approval.

Our next question comes from Li Watsek at Cantor Fitzgerald.

On the progress. Maybe just one on the ASH update. Can you just talk about what we should expect for the actual oral presentations versus what's in the abstract release yesterday? Yes.

Thanks, Li, for the question. Mollie, do you want to take that one?

Sure. As Troy pointed out, the data cut was back in June for what was submitted to ASH. So obviously, we've got many months more worth of data. So you'll see not only more evaluable patients being able to be reported and the evolution of responses across the whole patient population. You'll also see new information about MRD negativity as well as just longer follow-up and safety information in general.

Our next question comes from Salim Syed of Mizuho Securities.

I love the revised format of the call. I appreciate it. I guess one for us, Troy, maybe just on the new label that we got from Syndax, which includes Tsad now and the black box. Just curious, there seems to be varying views on if this actually matters or not. Just what does it mean for you? What does it mean for the space as you think about your own NPM1 launch and also as you progress here towards first line in particular, which I guess there's a view out there that it doesn't matter because first line maybe is -- you wouldn't see Tad as much. But curious to just get your view as the space evolves here.

Yes. Salim, thanks for the question, and glad you're appreciating the new format. This is -- there's a lot that I think we can talk about here. We'll have more to say if and when we get approval of ziftomenib here coming up very quickly on our PDUFA action date.

A few thoughts. And I'm going to give my comments, and I'm going to ask Mollie for her because she really needs to speak to this from a clinical perspective. But first of all, Salim, maybe the magnitude of the risk. This is a box warning. So a box warning is as serious as one can have as far as warnings and precautions. It isn't so much the frequency, it is the severity, particularly tors, right? Tors for everyone on the call, I mean, we're talking about a risk of sudden cardiac death. There are numbers that are getting bantied around that it's 1 in 1,000, it's not. You don't typically see this as much in younger patients.

So you really need to focus on the NPM1 population. And we're looking at maybe somewhere between 1 in 100 or perhaps even more frequent than that. And I guess I would just put it to anyone, right? If you have 2 agents, both of which are efficacious, but one of which has a 1 in 100 or more chance of sudden cardiac death, what are you going to I think that's where we feel increasingly confident based on the clinical data that's been presented at major medical meetings that's published in JCO, we're going to have a differentiated and favorable benefit risk profile. And I think that will start in the relapsed/refractory setting. But to the comment about it's less relevant in the front line, the risk doesn't go away. In fact, what you're dealing with is those patients are healthier, therefore -- and they're presumably going to stay on therapy for much longer. So if anything, you want a more favorable benefit risk profile in that population, which means I think you -- your -- the ability to differentiate on a favo.

Let's see. I would -- the last thing I'll say before I turn it over to Mollie is the ASH abstract, there was a giant data dump. Despite comments from some others that there's really no room for another menin inhibitor, there's a lot of activity in the menin space from us and from other competitors. You can go -- you can parse through the abstracts. What I think you'll see is that the benefit risk profiles of the difUFnt agents are continuing to be defined as we go. And I would draw your attention not only to the activity and all of these agents are very active, and that's good for patients. But the safety and tolerability is also coming much more into focus, and I would invite you to look at the various combinations.

But Mollie, let me invite you to add any thoughts or comments maybe to build on mine.

Absolutely. As Troy said, it's not the black box warning that in and of itself is something to focus on. It's what it means the data has shown. And one of the best ways of understanding that is to look at the FDA's actual guidance document on the topic. It is very clear that once a drug causes at least a 20-millisecond change in the QTC prolongation, it is now considered to be significantly more likely to cause sudden cardiac death. It's not just torsades we're looking at. It's any ventricular arrhythmia. And so the risk just becomes so much more increased, that is why they put the black box. So it's understanding what data requires a black box warning that becomes really important in this situation and to patients who are trying to decide between options of what risks they are willing to take on and what risks they would rather avoid if they have the option to do so.

And as Troy pointed out, while something like differentiation syndrome is very well mitigated in earlier lines with combination therapy, you would actually potentially expect more issues with the ability to handle or at least equal issues with the ability to handle QTC prolongation just because of the various medications that are going to be given as concurrent therapies and as additional oncology therapies for these patients' treatment. And it becomes more complex when deciding how to administer a drug with QTC black box warning with other drugs that have QTC prolongation. And so dosing and monitoring become extraordinarily important versus if you're going to administer it as a monotherapy in the relapsed/refractory setting.

And again, as Troy said, the right denominator for looking at this is really your elderly patients, where in some of our competitors, we see almost a 50% rate of QTC prolongation. That is going to be your NPM1 mutant patient population. So your NPM1 mutant patient population becomes a denominator that really is more appropriate for looking at these more severe QTc prolongations and episodes of tors and sudden cardiac death.

Our next question comes from Charles Zhu at LifeSci Capital.

So I guess with all of that in mind for one, what kind of level of penetration or market share would you either expect or hope to achieve relative to your first-mover competitor in the space, at least in the near term in the relapsed/refractory setting?

And can you also perhaps give a little bit more color around the ongoing points of FDA regulatory engagement that seem to be continuing on as you head close to your PDUFA date?

So Charles, I don't want scold you. You asked 2 questions.

And so we're going to -- we'll answer the first one. And then if there's time after others, we'll come back and get the second one.

So Brian, could you please speak to Charles' first question relating to penetration and sort of how we're going to compete with our competitor, who is out there with a first-mover advantage?

Yes. Thanks, Charles, for that question. So we haven't guided on our market share penetration expectations quite yet. But what I can do is kind of just share some of the feedback and expectations we have. So we've conducted extensive engagements with treating physicians, KOLs, community practitioners, academics. And tested our profile relative to others. And I think that the benefit risk balance and between a strong efficacy, safety -- efficacy profile with good safety and tolerability that allows patients to be able to be well managed, along with the combinability and even the convenience of a once-daily oral medication, all come out to factors that suggest that ziftomenib has a best-in-class profile and that we'll be confident we'll be able to communicate on that best-in-class profile coming into the market. So without really guiding on any share calls quite yet, we anticipate -- well, we give credit that our competitor is already in the market, but we recognize that we anticipate both the skill of our team that we've hired that are ready to go and are ready to launch this product and the profile of the product are really going to help us to capture a majority share in this space.

[Operator Instructions] Our next question comes from Roger Song at Jefferies.

This is Na Phil on for Roger. As we -- just a quick one on the ASH data. So the early data look pretty encouraging with the CR rates and MRD negativity. As we head into the meeting, what other analyses or long-term outcomes are we expecting to see like durability? Will we have also subgroup insights?

Yes. Thanks, Na Phil, for the question. Mollie, do you want to... Take Na Phil's question?

Sure. As I said, the biggest thing you'll see is much longer follow-up. You'll see more granularity around the MRD negativity, breaking it down so that you have maybe some comparisons that you can make to previous ven/aza data to understand if there is additional impact with a targeted agent added on. And you'll see more durability, et cetera. And yes, we can -- we will be breaking it down by subgroups. You'll understand what our FLT3 patients look like that were in the trial, what our IDH patients look like that were in the trial. So it should just be a much more even comprehensive view of the data that we have seen thus far in our rather large patient pool that we'll be able to present in both the relapsed/refractory and the frontline setting where you're going to see 30 to 70 patients, which is extremely robust and able to really show you more maybe the truth of what these patient populations look like. So we're excited to share it with you.

Our next question comes from Jason Zemansky at Bank of America.

Congrats on the great progress. Troy, I wanted to ask a follow-up regarding the commercial launch in NPM1. But is having a differentiated label enough to overcome the second mover advantage when you think about sort of prescriber inertia? Is it more so that just, I guess, getting drug to patients? I mean, how do you overcome some of the hurdles here just given kind of the time lines?

Sure. Maybe I'll just make a quick comment, and then I'll let Brian take it because he's really the one who should speak to this.

These physicians, I mean, you all talk to them, right? They are very sophisticated, constantly taking in new data and looking for options that offer the best benefit risk for their patients. The patients are also extremely sophisticated. They have all sorts of access to information. And they are -- again, others might say it's efficacy, efficacy, efficacy. Yes, that's important. All of these agents are right? That's the great thing for patients. And we should all celebrate the fact that patients have multiple options. But these docs are now having conversations with their patients about the risk benefit. And there's a striking difference between the relapsed/refractory setting where a number of these patients are inpatient versus the frontline setting, where our hope is that we send them home and they're able to stay on continuation therapy for months or even years.

So Jason, I don't -- I mean, I'm not going to deny there is an advantage to an incumbent. But I think when you're coming forward as we believe we are with a superior benefit risk profile in a very competitive space, I think we will see the market reach its equilibrium.

Brian, any -- what thoughts would you like to add to my comments?

Thanks, Troy. I think -- I mean, you captured it well, I think, but what I'd maybe just add just a couple of points that -- the advantage, I think, right now that you're seeing -- there's a 1-year advantage in the market potentially, but it's a few weeks, 5 weeks at most advantage in the NPM1 space.

Our teams are out there, as I mentioned, we've been engaging. We've been spending the last year working with payers to ensure that there is not going to be any kind of blocking available. And the profile of ziftomenib, I think, really has resonated where payers wouldn't see a need to do something like that. So from an access perspective, we think that we'll have kind of a very powerful strong position in that space. Our goal is to build a distribution model that is seamless and easy for physicians and their practices to prescribe ziftomenib.

One of the things that might be even more simplistic as we talked about the simplicity is that we'll have one SKU. We're not going to have multiple SKUs of different products that they have to worry about inventory and dosing challenges, things like that. So there may be some advantages we think that we'll be able to capitalize on in the near term. But I would just go back finally to say that the field team that we've hired has extensive experience with these practices. They are itching to be out there speak about ziftomenib and they're ready to go. And I feel like that if you give us the time for launch, I think you'll see that the profile that Troy outlined and our ability to execute is going to be on par or better than anyone in the industry. So I'm very confident we'll have an opportunity to really overcome any second move or disadvantage that may be perceived.

And let me -- thank you, Brian. That was great. Let me just add just a couple more thoughts, Jason, to your question.

We are going to be promoting on label. The label is going to be relapsed/refractory NPM1 mutant AML, clearly, the adult population. But as we indicated in the prepared remarks and as you've seen, I think we have now the most comprehensive, and I would argue the most aggressive overall development program. We have 2 Phase IIIs underway in intensive and nonintensive. We're combining with both FLT3 inhibitors. We have combinations with LDAC, with FLAGIDA. And as Molly said, we're coming forward not with a handful of patients. We're coming forward with 20, 30, 40, 70, 100 patients at a time. So we're really giving -- and which is why I think we have -- our 2 presentations at ASH are both orals.

We have a massive development and medical affairs effort supporting our commercial launch. We won't be able to promote in those. We'll be publishing, we'll be educating, we'll be collaborating. But everyone is looking forward to combinations. Everyone is looking forward to earlier lines of therapy. This is not -- we're not looking at 1 quarter or even 2 quarters. Our goal is how do we make ziftomenib the cornerstone therapy throughout the treatment continuum. And I think we have the right strategy to do that. As Brian said, a few weeks coming behind isn't really going to make much of a difference at all. So I appreciate the question.

[Operator Instructions] Our next question comes from Reni Benjamin at JMP Securities.

Congrats on all the progress. I guess, Troy, you had mentioned in your prepared remarks regarding the joint launch meetings. I'd love to -- can you provide any sort of color in kind of what goes on in these meetings? How many people kind of what's the split between you and KK? Do you wait for the -- do you hit the ground running as soon as you get approval? Do you wait until next year? Just any sort of color as to how this will move forward.

Yes, Ren, thanks for the question. This was the best launch meeting I've ever attended. It was electrifying. It really was. I mean people are so excited to bring this therapy forward. But let me turn it over to Brian, who can maybe give you a bit more specificity about what the goals of the launch meeting were and how the 2 teams came together as 1K to really move this forward. Brian?

Yes, sure. Thanks, Ty. Yes, Reni so this launch meeting and typically what you will do as you prepare is to bring the field teams together so that they're well trained and ensured that they're ready to go in case we have an approval.

Timing of a launch meeting, you can do them after you get approval, you can do them before. We tried to build a bit of a buffer where we thought October gives us an opportunity for the teams to be ready as close as possible to a potential approval. And essentially, this is a team where we had all of the field members that are both from Kyowa Kirin and from Kura that not just for our sales organizations that are going to be working together. We'll have the 2 field forces are going to be putting their efforts towards raising awareness and selling ziftomenib to the target physicians, but they're basically we put that group together as well as our field market access teams, our field medical teams. And we spent several days just working through understanding the role of menin in AML, the challenges for patients with relapsed/refractory AML, did some certifications, precertifications for the team, so they're ready to go and are prepared.

As soon as we get to an anticipated FDA approval, the teams will then recertify on that final prescribing information, and we'll be able to get out in the field immediately. We've been planning our organizational readiness in case of an early approval. So the teams have -- I can say have been ready to go for -- at least since that meeting in October and probably even before that, we had all the rest of our organizational readiness put together. So we've been trying to pull together that full team. And as Troy said, it was a really well-executed meeting between both companies, and there's a tremendous amount of energy and readiness for that anticipated approval as soon as by end of November is our target PDUFA date, we'll be ready to go.

Our next question comes from Peter Lawson at Barclays.

It's Alex on for Peter. Just a quick one for me on the -- what the label could look like. I guess, is there any potential for the monitoring requirements, the differentiation syndrome to be different from other AML drugs?

Alex, you're asking is -- let me make sure I'm reading your question back. Are you asking is there going to be potentially a difference in the monitoring requirements for DS in the label? Is that your question?

Yes.

Mollie, do you want to...

Yes, for how to address it just versus prior drugs. Yes. No, absolutely. So I -- obviously, I don't want to comment on ongoing discussions. We're still nearing our PDUFA date. And so obviously, things are still evolving. However, our differentiation syndrome guidance has been laid out in our protocols and in our IB for years now, and it is unchanged. I don't think that it is any additional monitoring that would be unexpected for this patient population in general who is regularly getting labs tested, et cetera. So -- but let's wait and see and have a more fulsome discussion once we actually have hopefully the approval in hand.

Our next question comes from David Ruch at UBS.

And I just want to kind of come back to that sort of the market dynamics between you and your competitors. So I'm wondering based on your prelaunch work you and have been doing, could you maybe share some initial feedback from physicians on how they're efficacy and tolerability versus competitor inhibitors in the space, the IPM1 space?

Yes, David. I'm going to ask Brian to speak to that. As you can imagine, we've done kind of a lot of market research and sought the opinions of KOLs and practicing physicians. But Brian, maybe you can speak to the lessons learned thus far about our ziftomenib's profile relative to our competitors.

Sure. Thank you, David, for that question. So the -- I'll speak to the feedback we've received and really kind of align it around 4 key parameters or pillars, you could call them.

First is the efficacy. We've tested the profiles of ziftomenib relative to other potential menin inhibitor competition. And it seems that the view is that the efficacy is kind of the table stakes to get in. You'll see that the CR/CRh, duration of response, things like that are seem to be relatively similar. Safety and tolerability is something that did stand out as a differentiator between ziftomenib and other products, which that alone, as Troy said, is not -- safety is not something that wins on a product, but it's that balance of benefit and risk and the tolerability of that really things can hit the scales. The other 2 pillars around -- that we found really help to differentiate ziftomenib is one around the combinability with current -- with current concomitant medications.

As Troy mentioned, we're going to be focusing on our on-label use promotionally, which is going to be in that relapsed/refractory monotherapy space. But those patients typically get concomitant meds like azoles and others to manage the challenges of being a relapsed/refractory AML patient. And the combinability and the simplicity of a dose where you don't have to do a lot of modifications seems to be meaningful for physicians as well because -- and for patients because it's more straightforward.

And then finally, the third was around simplicity. Once a day, daily dosing, there's one dose that each -- most patients or all patients really need at that 600-milligram dose is very straightforward. And imagine for an NPM1 relapsed/refractory patient who is typically in the elderly population, the simplicity of having that once-daily dose is also meaningful. So that's really kind of what we've heard is that there are -- of course, we've also heard, as Troy said, anything -- any therapies for these patients are really going to be important that can deliver some efficacy. But when you have choices, that's when you start to parse out what those differences may be. And that's where we feel pretty confident in the profile of ziftomenib as a differentiated agent coming into the market.

Our first follow-up question is from Li Watsek at Cantor Fitzgerald.

And I guess just given the recent disruptions at FDA, including within CEDAR, just curious, have you noticed or anticipate any changes in terms of cadence and discussions with the agency?

Short answer, Lee, we haven't noticed any difference. We don't anticipate any difference. We're on track for our November 30 PDUFA date. I think we characterize the interactions with the agency as open and constructive. We don't know what we don't know. But I think at this point, we're -- we feel like we're in good shape, and we're tracking toward a positive review outcome.

The path to approval in AML is much more -- much better precedented than some of these other instances. The fact that we have a competitor who was just approved in the same indication just a few weeks before, I think, gives us good confidence that we're on track. But obviously, we'll continue to stay vigilant and Mollie and her regulatory team are doing a terrific job. But so far, it's all systems are go.

There are no further questions at this time. So I would now like to turn the call back over to Troy Wilson for our closing remarks. Thank you.

Thank you, Danny. Thank you all once again for joining the call today and for your questions and the discussion. We'll be participating at the Jefferies Investor Conference in London later this month. And just as a reminder, we'll also be hosting a virtual analyst and investor event on December 8 from -- at the ASH Annual Meeting in Orlando. So we'll look forward to speaking with many of you at these events.

As we move forward, our focus remains on executing with discipline, investing wisely and advancing a pipeline designed to make a real difference for patients. With our pipeline, our experience, passionate team and a strong balance sheet, we think we're well positioned to deliver long-term value for both our patients and our shareholders.

Until our next update, if you have any additional questions, you know how to find us. Please reach out. Thank you all once again, and we hope you all have an enjoyable Tuesday morning and a productive day. With that, we'll adjourn the call. Thanks, everyone.

Good day, and thank you for standing by. Welcome to the Kura Oncology Discussion of FTI Clinical Data at the ESMO 2025 Congress. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the conference over to your first speaker to Troy Wilson, President and CEO of Kura Oncology. Please go ahead.

Thank you, Dulum. Good morning, good afternoon, good evening, everyone. As Dulum mentioned, I'm Troy Wilson, Kura Oncology's President and Chief Executive Officer, and it's a pleasure to have us here with you today to review our farnesyl transferase program and in particular, our clinical updates from ESMO in 2025. This is the second in a 2-part series. The first part was a discussion of the preclinical data and rationale which was presented on September 16 last month. For those interested, that webcast and those slides are available on the Kura Oncology website. If we could please go to the next slide.

In today's presentation, we're going to be making certain forward-looking statements. I would refer you either to our website or to the SEC's website for more information about the risks of an investment in Kura Oncology. If we could go to the next slide, please. Slide 3, today's agenda. We're going to be reviewing each of the 3 data sets that are shown here.

First, we'll discuss the darlafarnib monotherapy data in advanced HRAS mutant solid tumors. Then we'll talk about the combination data of FTIs and TKIs in renal cell carcinoma. And finally, we'll conclude with a discussion of the combination of FTIs and PI3-kinase alpha inhibitors in PIK3CA mutant head and neck. With -- we expect that the prepared remarks should take about 30 minutes or so. There should be plenty of time for a Q&A session at the end.

We could go to the next slide, Slide 4. The participants in today's call in addition to me, include Dr. Mollie Leoni, Kura's Chief Medical Officer. And then we're very pleased to have with us Dr. Glenn Hanna, Dr. Hanna is Director of the Center for Cancer Therapeutic Innovation. He's a Medical Oncologist with a specialty in head and neck at the Dana-Farber Cancer Institute. He's also an Associate Professor of Medicine at Harvard Medical School. Dr. Hanna has been an investigator both with tipifarnib and darlifarnib, and he'll be presenting the data on the HRAS mutant solid tumors as well as the PIK3CA mutant head and neck data.

If you go to Slide #5, please. In our call on September 16, last month, we introduced to you for the first time, darlifarnib in the context of preclinical data. Now we're going to follow that up with the clinical data. But notably, darlifarnib, we took all of the lessons of tipifarnib as well as the other FTIs. We tried to improve everything that we could as you'll see, darlifarnib is an extremely potent, well-behaved molecule. We have efficacious doses that are in the single-digit milligrams with anticipated daily dosing, excellent drug-like properties. And of course, this is a novel chemical entity, a new chemical entity, excuse me.

And so it has an appropriate patent estate. And we're hoping it really forms a foundation for which we can now advance this concept of using FTIs as a companion therapy to various targeted therapies. But as an introduction, let's talk a little bit about the data that gave us confidence really that darlifarnib was giving us what we expected and what we wanted to see. And with that, if we can go to Slide 6, I'm going to turn it over to Dr. Hanna. Glenn?

Thank you, Troy. So as stated, I think the first step is to talk about darlifarnib or KO-2806 as monotherapy in advanced HRAS mutant solid tumors. And this data is being presented in the poster session at ESMO this weekend. On behalf of my co-authors it's a pleasure and my colleagues here to present the data to you. So KO-2806 or darli, the mechanism of action for monotherapy is described here. Just a reminder that in post-translational biology, we know that prenylation is an important process, whereby different carbon chains like little strings are attached to the ends of proteins and flag them for localization to the surface of the cell.

This is a key process, right? The signaling process requires farnesylation. And this is just based on the number of carbons that are added to the end of a molecule to localize it. And this can be important in oncogenic and cancer signaling. We know that HRAS and RHEB depends solely on farnesylation. There are other forms of farnesylation like geranylgeranylation. And again, don't get mixed up with these names. It just implies the number of carbon chains that are added, whether it's 10 or 13, like a little tail to the end of proteins. But this has important implications for how these are handled and how cell communications occur.

And so importantly, HRAS and RHEB, as we said, solely focus on this farnesylation function, whereas other RAS isoforms, which are a little bit different, are using a different carbon attachment mechanism and enzymatic process for their cleavage. And so this offers an opportunity to target HRAS mutant tumors. And we know from the tipifarnib experience that they're sensitive to these FTIs and tipi has very well demonstrated encouraging clinical activity in patients with HRAS mutant tumors.

So darlifarnib, as we heard from Troy is a next-generation, hopefully best-in-class optimized version of farnesyltransferase inhibition that offers enhanced potency. It has optimized pharmacokinetic properties. And importantly, it's a small molecule with even single-agent activity that has the ability to improve outcomes. And you can see on the cartoon at the right by blocking this important process in HRAS and RHEB, we disrupt the downstream signaling cascade that allows cancers to grow through the MAPK pathway.

So FIT-001 is a monotherapy study design that looks at first-in-human multicenter open-label usage of KO-2806 or darli alone, but also in combination, as we'll hear soon, in a number of advanced solid tumor types where preclinical data is supportive. So KO-2806 monotherapy was conducted in RAS-altered solid tumors. So we included HRAS mutant and highly amplified. Generally, cutoffs around 6 to 12 are used, but that can be a point of discussion.

HRAS overexpression in head and neck squamous cell cancer was permitted. And in non-small cell and colorectal, we did allow other RAS isoforms like NRAS and KRAS primarily because it's never perfect in science or in biology. There is farnesyltransferase used in some of the other RAS isoforms. It's just not preferential. And so there was a rationale in the dose escalation to get data quickly and to expose patients with KRAS and NRAS to the darlifarnib compound. This was administered orally once daily on days 1 through 7 and 15 to 21 in a 28-day cycles.

So on-off dosing, 1 week on, 1 week off. And this data cutoff that we'll share is as of August 15. You can see the dose levels on the right, starting at 3 milligrams daily dosing up to 15 as an estimated sort of cap point, and we'll walk through that in the dose escalation. We did anticipate monotherapy activity based on the tipifarnib experience and the potency of this molecule.

So here are the baseline characteristics and demographics of the population. From left to right, showing you monotherapy dosing 3 milligrams sequentially all the way to 15 milligrams. No need to read the entire slide. As a clinician, this is balanced for what we would expect in this population.

We see a proportion of men and women. The median age is on par. There is a larger proportion of white patients, and that's typical for the epidemiology of the disease we see with head and neck mucosal disease as well as an important point about the primary tumor opportunity here. So you can see head and neck was an important enrolling tumor as well as salivary gland and thyroid, but we also had some colorectal patients, GI with pancreas represented.

I think the other important point is prior lines of therapy. So these patients were heavily pretreated, and that's impressive when you start thinking about monotherapy activity for a novel agent more with some patients between 30% and even 60% in dose levels with more than 3 lines of treatment. And of course, HRAS alteration is highlighted at the bottom across each of the dose ranges as well.

So importantly, we see that KO-2806 demonstrates encouraging safety and tolerability. And this is on brand with what we experience in the clinic with the tipifarnib population. And so this is really a clean molecule. And I think the point I would make here as a drug developer and someone who leads a portfolio of more than 60 oncology drugs in development in solid tumor oncology. This is one of the easiest drug to dose in clinic. You have very predictable and manageable cytopenias. You can see there rates of treatment expected AEs in terms of neutropenia and anemia and even thrombocytopenia.

But most importantly, at the bottom in the blue chunk is the grade 3 or greater treatment-emergent AEs. And you're noticing that in the dose range of interest, the sort of optimal range between 3 and 8 milligrams, we're seeing manageable and modest rates of neutropenia, anemia and minimal thrombocytopenia. These other points of interest like fatigue, mild nausea, this is impressive for what you'd expect from contemporary small molecule inhibitors, which are plagued with a lot more issues related to rash, dosing disruptions and GI toxicity.

So again, it's a pleasure to work with this class of drug like it was with tipifarnib, and we were happy to see an encouraging safety profile for darlifarnib. So in terms of monotherapy activity in patients with HRAS mutant solid tumors, this is an important slide showing you that there's a number of tumor types represented. So this is a tumor-agnostic and molecularly selected compound for HRAS-altered patients across a number of different HRAS mutants and hotspots. We saw, for example, stable disease with tumor regression and even partial responses with maximum tumor regression in hard-to-treat tumor types across the 5-milligram and 8-milligram dosing range.

So as we heard, much lower doses, a more narrow but importantly focused therapeutic index where there's potency at low dosing. And we even see a hint of durability at that 5 milligrams with patients staying on beyond 20 months in some cases at data cutoff. So this was very encouraging, right? I think as a drug developer, we want to see excellent tolerability and now we're demonstrating in a molecularly selected population monotherapy activity, and that's exactly what we expected with darlifarnib.

Here's just a clinical case example showing deep and durable response. One of the comments we often get is, oh, you're just shrinking tiny tumors down to smaller size, not in this case. You can see examples of upwards of 4.5 millimeters of disease decreasing by a large percentage in this case. In this case, it's a salivary gland cancer, heavily pretreated -- excuse me, heavily resected and radiated patient with upfront surgery who had a very difficult-to-treat disease that has no standard of care options and with this molecularly targeted agent had a confirmed PR exceeding 60% and continues on treatment at week 80, so well over a year.

This is actually one of my patients, and she's thrilled to have gone on to the study and remains, I can say, even to this day, still in response and doing very, very well. So that's really important, right? A lot of drugs are plagued by the inability to dose consistently, the inability to demonstrate that resistance is not developing. This is proving on brand mechanism, good tolerance and durability. And that's what we want to see with novel agents.

Here's another example of a deep and early response in a fourth-line patient. This is now -- okay, that patient had come out as a first-line or early patient with HRAS targeting. We're talking about someone who's already had chemoimmunotherapy with advanced head and neck cancer, has already had EGFR modulation. And now in the fourth-line, look at this, this is local regional disease. It's been radiated. It's hypoxic, fibrotic. This drug is breaking through and causing local regional regression from 6.8 millimeters to 2.7 millimeters. That is drug activity. That's monotherapy impressive activity with a nice 60% response rate in this case, which is excellent.

So in summary, darlifarnib has demonstrated a manageable safety profile, no new safety signals, excellent tolerability with a q-day or once-daily dosing schedule in weeks on and off alternating. We see encouraging monotherapy activity observed at multiple dose levels in that 3-milligram to 8-milligram range in HRAS mutant solid tumors, which span a number of different hard-to-treat cancer types as well as some more common tumor types like head and neck cancers and mucosal disease.

And we see on-target activity through that broad therapeutic range. These data definitely further support evaluation of this compound and make it an optimal partner for a number of different small molecules. I want to remind people that what's been very challenging with many small molecule inhibitors is that the time when you start combining, you get dose-limiting toxicity. I'll point you to examples of CDK4/6 combinations. You name it with MEK and ATR inhibitors, all of these new glamorous drugs, it's very, very difficult to envision combination intolerance, but this drug is delivering on that account. So it's really exciting to see this drug move forward.

And Mollie is going to talk to us a little bit about some of the emerging data in RCC with cabo.

Yes. Thank you so much. If we want to go to the next slide. So I'm really happy to share our cabo combination data that were actually shared earlier today at ESMO. And I might like to add, received the best poster award in the session. So we're very proud of our FTI-2806 in combination with cabo in renal cell carcinoma. Our data today was presented by affectionally known as Dr. A. So as we and others have been emphasizing, an overactive mTOR pathway signaling drives cell growth, proliferation and survival in RCC tumors. Rapalogs block this pathway and are FDA approved in RCC, but have seen limited use because of tolerability issues as Dr. Hanna was just quoting.

As seen on the right, cabo offers clinical benefit to these RCC patients where you see around 25% to 28% expected ORR in this particular line of therapy and stable disease approaching 60%. However, this is limited activity, and we see reduced activity with subsequent TKIs, which underscores the need to optimize these VEGFR-targeted therapies. KO-2806 inhibits farnesylation of RHEB, which uniquely inactivates mTORC1. Additionally, 2806 enhances cabozantinib's anti-angiogenic activity in both endothelial cells and pericytes in RCC xenografts. Thus, we tested this combination in RCC patients.

Next slide. So this is our FIT-001 trial in addition to the monotherapy that was just described by Dr. Hanna. We are evaluating combinations as well. It is the first-in-human Phase I open-label trial studying 2806 both alone and in combo in advanced solid tumors. The KO-2806 plus cabozantinib combination, we enrolled specifically patients with renal cell carcinoma, either clear cell or non-clear cell. And for the dosing, the KO-2806 was dosed at 3, 5 or 8 milligrams once a day in 1 week on, 1 week off, plus the continuous dose of cabozantinib. We started at 40 milligrams and we're soon able to escalate to 60 milligrams, and this is also given every day in 28-day cycles.

And just as a reminder, this is data as of the 15th of August data cut. We've enrolled over 50, close to 60 patients as of this data cut. And as you can see, clear cell was similarly with the baseline demographics here, there's nothing of great surprise with the types, ages or performance status of patients that were enrolled into this. So I'm just going to draw your attention to a few things.

As you can see, clear cell was the majority of patients that were enrolled. The initial portion of the study was well dominated by patients that were prior cabo exposed, so that's your 40-milligram patient population, while earlier line patients dominated the 60-milligram cohort. And please note that the 3-milligram plus 60 is still enrolling, and thus, that's why you're seeing lower patient numbers in that particular cohort at this time.

Next slide. The combination has been well tolerated to date. No apparent overlapping toxicities have been seen, and we really see the safety profiles of each individual agent as if given alone.

Next slide. As a reminder, in this patient setting, we would expect to see maybe a 25% to 28% response rate with cabo as a monotherapy, and we expect a 0% response rate for 2806 alone. We first filled the 40-milligram cohort and at that dose saw encouraging activities with consistently a 33% response rate overall and activity even in prior cabo failures.

Of the patients that have cleared efficacy evaluation period at the 60-milligram, preliminary data is demonstrating about a 50% response rate in the 5-milligram combination. Again, those patients were enrolled first. The 3-milligram and 8-milligram are currently maturing data and we're not sufficiently mature at the time of this data cut to share, but we look forward to sharing them in the future.

Next slide. We are definitely encouraged by the overall activity we are seeing. Here, the 40-milligram cabo patients are the hash-marked patients and those with prior cabo exposure are marked with stars. Our non-clear cell patients are also included in this particular figure. As you can see, there are consistent decreases in tumor size across doses and subtypes, which is highly encouraging. It appears as we've gone up in the cabo dose, we are seeing increased efficacy, but obviously, we are still evaluating those patients in these combination settings.

Next slide. Just to highlight a patient's experience. This is a 61-year-old male with clear cell. Previous treatment included pembro in the adjuvant setting and the patient came on trial in Stage IV disease. After 8 weeks, the patient had experienced a partial response that actually deepened by week 16, and this patient remains on trial as of this data cut.

Next slide. We've previously shown you preclinical data on RCC xenografts that were nonresponsive to monotherapy TKIs, but that were then responsive to the combination. The results support a potential sensitization to cabo therapy with the use of this combination. So if we move to the next slide.

We are actually also seeing this on study in our patients. This is a 53-year-old with clear cell renal cell carcinoma with 2 prior lines of therapy, the most recent of which included cabo. This patient enrolled at our cabo 40-milligram plus 3 milligrams, the lowest dose of 2806, and the patient quickly obtained a partial response that has been very durable. In fact, this patient is almost going on a year at the time of data cut, again, after just having failed cabozantinib therapy in their most immediate prior line.

Next slide. So what messages should you take away? Well, 2806 and cabozantinib has a manageable safety profile is the most important, and that's across dose levels tested for both drugs as we were able to explore multiple dosing levels of both drugs. The antitumor activity of 2806 and cabo in combination was observed across all doses, including among patients with prior cabo exposure, we were seeing an ORR of 33% to 50% in clear cell. If they had prior cabo, we saw 17% to 50% responses. And a disease control rate was extremely high as one would expect, but maybe even a little bit increased over cabo alone around 80% to 100% in the clear cell renal cell carcinoma.

So the activity of 2806 and cabo combinations really does support the hypothesis that 2806 is able to enhance this anti-angiogenic activity of cabozantinib and supports our further development in this space. With that, I will pass it back to Dr. Hanna.

Yes. So we're going to go a little back and talk about farnesyltransferase inhibition with tipifarnib because the program from the current trial predates the enrollment of the dose escalation and experience with darlifarnib. And this was a combination study, as we'll talk about with a PI3K alpha selective inhibitor in head and neck cancer. So really dual-targeted oral small molecule inhibition or targeted therapy in head and neck.

So this is the current trial in head and neck, tipifarnib and alpelisib in recurrent metastatic head and neck squamous cell cancer, and this was a Phase I study. So just to remind us that the FTI mechanism of action. We talked about this really targets that HRAS and RHEB farnesyltransferase interaction and flagging proteins or carbon chains, I should say, on proteins for localization. But what we learned and as all of you know, is that mechanisms of resistance are significant.

And so one pathway that's upregulated or altered in a co-adaptive mechanism is the PI3K/mTOR AKT pathway. So a number of preclinical experiments and data from different tumor types has shown that blocking one of these pathways can lead to analogous upregulation or sort of adaptive upregulation of the alternative pathway. And we see this a lot in oncology as we've understood resistance mechanisms.

And so the preclinical data supported that we would want to use farnesyltransferase inhibition to suppress that upregulation of MAPKT pathway signaling and mTOR feedback reactivation. And so this was really strong preclinical rationale for combining these 2 small molecule targeting agents.

So that was the basis of the KURRENT Head and Neck study design, which tested both tipifarnib in combination with alpelisib in PI3K-altered or PIK3CA-altered mutated or amplified recurrent metastatic head and neck patients. As it should be familiar, we use tipifarnib in its typical schedule on days 1 through 7 and 15 to 21 with weekly on-off dosing. Alpelisib, however, based on the label and experience from breast cancer was once daily dosing. And together, this was given in monthly cycles.

I have to say the BLRM mechanism to understand safety and tolerability was an important part and an elegant part of this design where we incrementally adjusted the dose step-wise for each of the agents using an algorithm based on safety events observed at the prior dose level. And so this allowed us to understand the contribution of safety and potentially efficacy at different dose levels to combine these drugs safely.

And additional patients were enrolled in the candidate optimally biologically active dose. You can see here, we started at tipifarnib 600 milligrams total dosing daily. Remember, tipi is a twice daily medication, so that would be 300 twice daily plus 200 of alpelisib. And you can see we escalated based on safety and efficacy observation to land on 2 potential dose levels, dose level 2, where we enrolled 16 and dose level 4, 17 patients. And you can see we achieved doses of 1,200 milligrams per day or 600 milligram BID, if you will, of tipi and alpelisib at the 250-milligram daily dose.

In terms of safety and tolerability, this was one of the main focuses of this Phase I trial. Again, demonstrating the important power of an FTI for combinatorial potential given its very predictable and well-tolerated safety profile. And even with alpelisib, a drug that has evidence of some hyperglycemia, some maculopapular rash and some electrolyte disturbances and lipase elevation, we were able to safely get up to 250 milligrams daily and maintain tipifarnib at the 1,200-milligram total daily dose in dose level 4.

So this was very encouraging from an investigator standpoint, again, resonating the point that combinatorial opportunity is highly -- has high potential with the FTIs that Kura Oncology is developing.

So moving forward to activity, we saw encouraging antitumor activity for this combination in patients with alterations or hotspot mutations in PIK3CA. So this is showing you the objective response rate. And really, I think what was most impressive is when we were in the optimal dose range of interest, particularly at dose level 4, where safety wasn't much greater, we saw at the 1,200 milligram and 250 milligram respective dosing of these drugs, almost a 50% response rate.

That's pretty impressive. Keeping in mind, these patients have already been treated with platinum. They've already failed immunotherapy. And in many cases, we were allowing patients in later lines, as I showed you with the darlifarnib experience.

So we have good safety and at an optimal biologic dose. We have a very encouraging ORR. And in a prior study, just a reminder that alpelisib monotherapy has been explored in PI3K-altered patients, and we're talking about response rates approaching 0%. So this is impressive activity proving our hypothesis. Median duration of the objective response, I do want to point out, those numbers are impressive, the high end reaching 20 months in some cases.

So again, we're seeing that durability, patients staying on for long periods of time and very nice disease control rates, particularly at that dose level 4 in complement to our response rates around 47%. Tipifarnib enhances the activity of alpelisib in preclinical models that I believe you've seen before. But we -- it's important to show that we tipi does inhibit mTOR signaling rebound that's observed with alpelisib when dosed alone and that, that combination does allow for deep progression. And we saw that in CDx models, but have now -- are now demonstrating that in patients.

Next slide. So this is just an example of a deep response in a patient treated with the combination. You can see their imaging on the left. This was a 36-year-old HPV-positive never smoker. I do want to point out that PI3K alterations are common in HPV-positive patients, which is the majority of patients we're seeing in practice these days in some instances, given the trends in smoking and the epidemic of HPV. It's about a 30% rate of hotspot alterations in this pathway.

This patient was pretreated with immunotherapy, a novel vaccine and had an R88Q mutation, which is generally sensitive to PI3K and had an 80-plus percent reduction at 4 weeks. So that is rapid disease control in distant metastatic disease with durability exceeding a year, exactly what you want to see in a dual targeted therapy combo.

And these deep responses here is another example. Again, tough to treat local regional disease, heavily pretreated with radiation. We said this is a hypoxic and fibrotic environment, and this combination is doing a nice job to overcome resistance of platinum and immunotherapy in this 75-year-old patient with PI3K-mutated head and neck cancer. This was a rapid regression. This was one of my patients who was immediately able to avoid a feeding tube and get back to swallowing with minimal dysphagia once they were able to start the combination.

This is an impressive response in a difficult-to-treat tumor location for head and neck. So putting this together, in the tipifarnib alpelisib experience for PIK3 mutant patients with head and neck cancer, we see -- I would say, very nice tolerability and a very manageable safety profile where many combinatorial pairs have failed in the past because of overlapping tox. We see robust antitumor activity, fast regression, heavily pretreated patients and nice deep responses with evidence of durability as shown at that 250-milligram daily alpelisib dose and in dose level 4, 1,200 milligrams daily or 600 milligrams BID of tipi.

So these data really do support that. The mechanism has been addressed in this adaptive resistance scenario and really speaks to the power of this drug in combinatorial states going forward. So we are very happy to see this data and happy to share it.

So I think the next steps going forward is probably where we will focus before opening it up to questions.

So obviously, we're very encouraged by all of these data that we have seen thus far. So our next steps for the darlifarnib, the name for 2806 is to obviously complete the escalation of our combination in RCC, so our cabo combination. We're going to be conducting a Phase Ib for 2806 plus cabozantinib and using that combo to determine our optimal biologically active dose and select our recommended Phase II dose.

We will be completing dose escalation for the 2806 plus adagrasib in KRAS G12C mutated patients that either have non-small cell lung cancer, colorectal cancer or pancreatic cancer. And we plan to develop data generation options for darlifarnib plus a PIK3CA inhibitor as well in the future in solid tumors. We're also looking to be able to share additional data, hopefully next year. And that will be updated data, of course, for the RCC, the cabozantinib arm, but also the preliminary data, which we're also very excited about for the 2806 plus adagrasib.

And with that, I'd like to pass it back to Troy.

Thanks, Mollie. If we can just go to the next slide, the large potential opportunity. So as you've heard, one of the pleasant surprises is that the FTIs combine well with each of these targeted agents. While we're not showing you the combination today with adagrasib, we are encouraged there, again, by the ability to combine darlifarnib with a KRAS G12C inhibitor.

Importantly, as we showed you with the preclinical data, if this mechanism works with one drug candidate, it likely works with the entire class. That is both an opportunity and a challenge. The way that we think about darlifarnib and FTIs in general is they're making good drugs better. They're driving better outcomes for patients. And that's what's giving us this large total addressable market here of greater than 200,000 patients across all potential indications.

So there's a lot that we can do. We have to be -- have a thoughtful development strategy. We have to have a thoughtful collaboration and business development strategy, and we'll have much more to say in the months ahead.

With that, we'll conclude the prepared remarks and we're preparing to open it up to questions. I will say, based on the feedback that we got from our last presentation, we're going to do this one a little bit differently. We have a long queue of people who want to ask questions. I would ask those who want to ask a question to please just ask one question. We're going to try to get through everyone. If there's time, please feel free to get back in the queue and you can ask additional questions.

But we want to make sure that everyone gets an opportunity to ask a question. So with that, Dulum, we're happy to turn it over to you for the Q&A session.

[Operator Instructions] And I show our first question comes from the line of Jonathan Chang from Leerink Partners.

On the cabozantinib combination data, can you give us a sense of what the duration of response and/or time on treatment metrics look like? Is there anything you can comment on there? Or is it still too early?

Mollie, would you like to take that?

Sure. Thankfully, it's still a little bit too early, especially because I think we're going to be seeing the selected dose come out of your 60-milligram cohorts, so cabo cohorts. So I'd say stay tuned. We're not disappointed thus far. We've had patients stay on for significant periods of time, but it's still time for some -- to let the data mature. And like I said, we'll present more next year.

And I show our next question in the queue comes from the line of Charles Zhu from LifeSci Capital.

This is Peter Green on for Charles. Congrats on the data. Just a question on patients treated with cabo and darlifarnib. Any color on whether those 4 of 12 responders that had, had prior best response of stable disease, whether they opt cabo due to progressive disease or for some other reason, like toxicity. And then of those 12, did any of them have progressive disease or I guess, how many on cabo?

Mollie?

Yes Sure. So their best response tended to be stable disease and they would come off usually for progression prior to coming on to our treatment. As we said, with that one patient, their best response had been stable disease, and then they were losing control when they came onto the combination. So I can't give you the details on every single patient with prior cabo. We saw some stable disease. We saw at least 2 PRs that looked very good thus far.

Again, I think let's look towards these individual cases and the data we plan to develop even more in the future. But we certainly are seeing, like I said, anywhere from 17% to 50% response rate in prior treated cabo patients that are receiving the combination.

The other point I would just make about that is, you'll notice we were able to go up to 60 milligrams of cabo in combination. So if patients had come off for safety issues, we wouldn't be getting to 60 milligrams. So to Mollie's point, it was a progression issue, not a safety issue.

And I show our next question in the queue comes from the line of Reni Benjamin from Citizens Bank.

Congratulations on the combination data. I guess my one question, maybe it's for Dr. Hanna, is how do you view these combo results when compared to, let's say, the HIF-2 alpha plus cabo combinations? Any sort of color would be great.

Yes. I think the HIF-2 alpha story is still evolving. And certainly, there's a difference in toxicity profile. But I do think seeing combinatorial potential around even that window that Mollie shared was 33-ish to 50% that's impressive. And we're -- from my understanding of the emerging data with HIF alpha or HIF-2 alpha inhibitors, we're not necessarily seeing anything outside that ballpark. This would be equal or better.

Yes. And just to add to that, the HIF-2 alphas are focused, obviously, at least currently on developing in renal. But we do have a firm belief that wherever cabo goes, we can go as a combination. So we think that there is broader opportunity as well.

And I show our next question comes from the line of Salim Syed from Mizuho.

This is Eric on for Salim. Congrats on the data. Just eyeballing the waterfall plot on the cabo plus 2806. It looks like the prior cabo experience are kind of leaning towards lower responses. Just wanted to see if there's any color on that, how we should be thinking about that.

Yes, I think it's tough for you to really be able to interpret because the -- in addition to these patients being prior cabo pretreated, they're much more heavily pretreated, if you look at the baseline characteristics for these patients as well. So they've been through additional lines, and we're still seeing some -- at least some tumor regression in these patients. So you have to wonder, is it a function of having prior cabo exposure? Is it a function of having their disease hit in so many different ways by multiple different lines of therapy.

Tough to interpret at this point, but we hope to gain additional data so that we can answer that question a little bit more clearly. And that is -- will be part of our plans for our next phases of development.

And I show our next question comes from the line of Li Watsek from Cantor Fitzgerald.

Very interesting data. I wonder if you can just comment on neutropenia, whether you have seen any fabrile neutropenia and whether this impacts the dose intensity of cabo? And maybe just more information on the dose modifications in the trial.

Mollie?

I would say I do recall -- I mean I can just speak to this more broadly. But there is the element of anemia that's a little more focused generally in FTI mechanism and then some concern that neutropenia may play in as well. From my recollection of the RCC data, we didn't see any synergistic concerns around cytopenias or cytotoxicity issues that caused dosing problems.

And I'll again turn to the point that we've been able to escalate to the 60-milligram dose of cabo in combination with darli, which -- it speaks to the fact that neutropenia hasn't been a significant issue. We haven't had to turn to growth factor support or long periods of dose interruption. So I can at least say that from the combo.

Yes. And I fully agree. We've seen limited dose reductions in the cabo. I do not think we've actually seen dose reductions in this particular combination in the 2806 as of yet. But overall, I'd say you're really just seeing noncumulative tox.

Thank you. And I show our next question in the queue comes from the line of Phil Nadeau from TD Cowen.

Congrats from us also on the data. Can you discuss in a bit more detail the design of the Phase Ib of 2806 and cabo? And in particular, what cabo patients will you be recruiting to the study? Will they be mostly cabo naive, cabo experienced or a mix of the 2?

Mollie, do you want to take that?

Sure. We haven't really released the details yet. But suffice it to say, this is going to be a very robust Phase Ib so that it allows us to not only select the dose that we think is probably best for this combination, but also to evaluate even more some of these potentials to resensitize patients to cabo.

We're going to more than likely focus on the 60-milligram cabo dose, which means that we're going to see less patients or no patients for the cabo in their treatment paradigm. But we'll be getting more data out on that as the time comes closer.

Thank you. And I show our next question comes from the line of Jason Zemansky from Bank of America.

Congrats on the data. I just wanted to home back to the waterfall plot for the 2806 cabo combination. I appreciate it's still somewhat early, but it looks like the majority of responses here are from the 5-milligram dose and appreciating still dose escalating here. But curious, does that sort of imply that there's a saturation point on what you can get from an FTI in this case? Or do you think if you could increase the dose meaningfully, you could see more responses?

Mollie do you want to take that?

We certainly see a linear dose response curve for the PK, and we're still evaluating. Like I said, the 8 milligrams, especially at the 60 plus 60 is still ongoing. So let's give a little more time for these data to mature, so we can really understand what the 60-milligram efficacy looks like. We understand what the 60-milligram safety looks like, and it doesn't look prohibitive for the dosing of these patients. But let's see what the efficacy turns out as we continue to fill these cohorts.

And I show our next question comes from the line of Roger Song from Jefferies.

Congrats for the data. So maybe just a clarification. In terms of the 60-milligram cabo-combo cohort, since you are enrolling more cabo-naive patient. I think, Mollie, you mentioned earlier, you -- if you pick the 60-milligram, you're more than likely you're going to focus on the cabo naive patient. Just want to confirm that moving forward for the Phase Ib and then the future development, you're focusing on the cabo naive patients.

Absolutely. We obviously haven't absolutely finalized the protocol. But yes, you're correct that we would probably be focusing on the cabo naive. So earlier-stage patients, cabo naive patients.

And I show our next question comes from the line of Peter Lawson from Barclays.

Congrats on all the data. On the dose response relationship for the combination with cabo, that -- do you kind of interpret that kind of flat [indiscernible] is this just still kind of a reflection of limited sample size?

Peter, I think your question relates to the 40-milligram cabo with different doses of 2806, if I'm understanding it correctly.

And around 33%.

I mean, I'll just say, it's too small an end, I think, to draw any kind of conclusion. Interestingly, each of those dose cohorts is better than what you would expect from even cabo monotherapy. As Mollie said, we're not probably going to spend a lot of time optimizing at a 40-milligram dose. I think it's encouraging. But Mollie, you should add your thoughts.

No, that's exactly right. We're not going to spend too much time optimizing the 40 milligrams. And when we refer to that 25% to 28% response rate of cabo monotherapy, we're referring to the 60-milligram dose. So the fact that we're seeing these 33% in previous cabo failures, it implies that things are certainly going in a better direction than one would expect for either therapy alone. Still think it's small numbers, but we will continue to update the data.

Yes. Maybe I'll just add before we prompt the next question. One of the things that gives us confidence, again, as we look across these different tumor types is -- this goes back to the way that Dr. Hanna laid it out is TORC1 pathway reactivation, the key mechanism of action. And as you look at both the RCC data and the PIK3CA mutant data, and of course, you're not seeing the KRAS data, but hopefully, you will next year, that's what gives us confidence that we're on to something significant here.

That we've known as the TORC1 is a validated clinical target. This may just be a much better way to inhibit its activity. I will say, before we take the last question, if anyone else would like to ask another question, please get back in the queue. And we have time for just a few more questions. But Dulum, over to you for the next question or 2.

[Operator Instructions] And I show our next question in the queue comes from the line of David Dye from UBS.

Congrats on the data. So for the cabo combo, we did see pretty good safety with no overlapping toxicity. But we did see slightly higher levels of diarrhea at 60 milligrams cabo dose. So maybe a question for Dr. Hanna. From a clinician's point of view, what do you think about the rate of diarrhea in this combo? And how do you typically manage them?

Yes. I mean I think as Mollie sort of or Dr. Leon alluded, we're not seeing an uptick in these types of side effects. It's on par with what you would expect. We don't generally see a lot of GI toxicity by partnering with darlifarnib. So whatever we are seeing in the RCC cohort at 60, which is small numbers at present is going to be from the cabo alone, just given its mechanism of action.

But because these drugs have been around for some time, these are generally manageable and predictable side effects. You would give someone Imodium or Lomotil, encourage them to take magnesium and hydrate. So I can't say that having seen the data that I've been to date that there's been any concern that there's enhanced GI tox. That has not been my observation.

And just to keep in mind, a lot of the data you're seeing is from the dose limiting toxicity period where you don't necessarily prophylactically treat for a lot of these things. that we would be able to treat for in "normal life" or in later lines of our development program. So I think that there's a lot of room for improvement in how we approach pretreating and prophylactically treating these patients once we're through this particular phase.

And I show our next question in the queue comes from the line of Jonathan Chang from Leerink Partners.

Maybe for Dr. Hanna, how would you compare your experience with darlifarnib versus tipifarnib? I know it's not apples-to-apples here given the differences in the settings, but it would be great to hear your thoughts here.

Yes. There's -- I think I highlighted in the earlier presentation of the escalation monotherapy data that they're both very well-tolerated molecules. I think the properties that were outlined by Troy initially and then the preclinical work and now in patient dosing exhibits that very nice activity level at low -- a broad therapeutic range, but at low dosing levels and allows for a more predictable PK profile in PD that give us a once-daily dosing option.

So I think that's very important. I think another point to make is that in our experience with salivary gland cancer, where we're seeing some patients, as I showed you, with durable and impressive partial response rates. I actually put together the tipifarnib salivary cancer population data a number of years ago, and we weren't actually seeing. I think there was only one short-lived PR in that cohort.

So we're seeing more evidence of antitumor activity in comparable diseases with the darlifarnib sort of more modern STI. So I think for that reason, it's starting to become appealing as sort of the preferred agent, not just a metoo.

Thank you. I'm showing no further questions in the queue at this time. This concludes our Q&A. At this time, I would like to hand the conference back over to Troy Wilson, President and CEO, for closing remarks.

Thank you, Dulum. I want to thank, in particular, Dr. Hanna for being generous with his time and his experience. He's been an incredibly valued partner from the very first days of our FTI program, and we're at an exciting inflection point. I want to thank all of you for your attention and your questions. Glad we were able to get at least one question from everyone.

We will be available for follow-up. If people would like, you can contact Greg or me. And we'll look forward to talking to you next time, at least at our next earnings call, which is for early November. But we appreciate it. We hope everyone has a very productive and successful ESMO. And with that, we'll conclude the call. Thanks very much.

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

Hi, everyone. I'm David Dai. I'm one of the biotech analysts here at UBS. Thank you for joining our inaugural Virtual Oncology Day today. We continue our session with Kura Oncology. It's our great pleasure to have Troy Wilson, President and CEO of Kura Oncology with us. Troy welcome.

Thank you, David, and thanks for the invitation to participate in the inaugural Oncology Day conference.

Excellent, excellent. Great. Always a pleasure speaking with you, Troy. So maybe just for the audience here who are new to the Kura story, could you maybe provide a quick overview of Kura, and then we can dive into some of the latest and greatest over the next 12 months.

Sure. Thanks. I'd be happy to. Maybe let's start with ziftomenib in AML. So we are -- we have our first PDUFA date on November 30, we think we're in a good spot for the FDA approval and getting a label that is competitive in the relapsed/refractory setting for NPM1-mutant AML. We're encouraged by the KOL feedback that highlight the efficacy, the simplicity, the compatibility and the safety of zifto relative to competitors. Our commercial team is in place, and it's ready to go. We've done everything we need to do in terms of hiring, market access, preapproval information exchanges.

If we move beyond that initial indication, David, and think about frontline combinations, we are excited to be advancing ziftomenib in combination with the standards of care in the frontline setting. We reported promising data in combination with intensive chemo at EHA. We look forward to reporting similar data with venetoclax and azacitidine later this year, potentially at ASH. We think zifto shows promise as an early intervention in both the intensive and non-intensive setting.

Your participants might have seen, we announced this morning the launch of a trial to evaluate quizartinib and 7+3 in combination with ziftomenib this morning. And then building on all of that momentum in the frontline, on Monday of this week, we announced we had initiated registration-enabling trials for ziftomenib in both intensive and non-intensive.

So if we look at those settings, intensive, non-intensive and FLT3, we have the potential to impact up to 50% of patients with AML, drive meaningful value.

If we move from AML to GIST, we're evaluating ziftomenib in combination with imatinib in patients with advanced GIST, that trial, which we call KOMET-015, is in dose escalation and going well. Our Kyowa Kirin partnership is going well, really bolsters our global development and commercialization of ziftomenib. We're moving aggressively into the frontline, supported by our collaboration with Kyowa Kirin, and we're keen to work with them on the launch and build on the excitement for menin inhibitors.

And then finally, our FTI program, we've been making excellent progress there. including with our new FTI, a compound called K0-2806 or darlifarnib. That program is addressing resistance to targeted therapies, enabling deep and more durable responses. And we will have a data update there at ESMO here in just a few short weeks.

So hopefully, that -- and then from a cash perspective, we had $630.2 million as of the end of the quarter. We're anticipating receiving substantial milestones in connection with the progress of the ziftomenib program, David, that should leave us in a very strong cash position. So there's a lot going on. We're ready to go, and we're well funded in this environment.

Excellent. Thanks for that overview, Troy. So let's dive into some of the programs you mentioned, many different developments in the space right now. So focus on ziftomenib, especially in the relapsed/refractory AML. The PDUFA will be on November 30, so very soon actually. So we should be expecting potential approval. So could you help us understand some of the key engagement with the FDA so far? Have they performed any site inspections? Have you discussing -- the label discussion so far, what's the latest development on the FDA engagement with zifto ahead of the PDUFA date?

Yes. I mean we haven't really given granular details, David, as we go. What I can tell you is if you look at the FDA guidance, typically, any inspections have to be completed, at least 60 days prior to the PDUFA date. That was yesterday. So you can kind of interpret from that where we might be in terms of your question around inspections and inspection readiness.

As far -- we're now late into the review. And our engagement with FDA has been very constructive. The shutdown, notwithstanding the latest drama, we've been impressed by their timeliness, by their engagement through the review process. They continue to be very constructive. We will -- we're looking forward to that November 30 PDUFA, and we will be ready to hit the ground running, if and when we receive approval.

Yes. As you mentioned, given all the things happening at the FDA, have you had any kind of changes in terms of interaction with the FDA so far? Has that just been like things as usual, business as usual? Any updates here?

Yes. So I mean, I can only comment on our specific interactions. We're working with the hematology oncology group within the oncology division. I think, David, that, that group has been relatively insulated from a lot of the change and the drama that's gone on.

The reviewers that we have on the ziftomenib NDA are the same folks with whom we've been interacting on the various combination studies, the front-line registrational studies. So there's been a good continuity of experience and we've not experienced any disruptions to this point.

Got it. Okay. That's really helpful. And then so on the label discussion so far, we saw that FDA would ask for their own or perform their own adjudication of complete response assessment for AML. So can you just help us understand what are some of the differences between your assessment versus FDA's assessment? And do you think this might lead to some differences in terms of CR, CRh rates?

Yes. I mean -- so it is true. I mean, it's not just the efficacy data, right? The FDA goes in and performs its own analysis on everything you give them. So safety, PK exposure, drug-drug interactions, efficacy, they really do an independent review, David. I can't comment on the specifics of where I think we'll end up. But that's well known, right? So we were prepared for that. That's part of the information requests and answers that go back and forth between sponsors and the agency. We'll look forward to sharing the label with you again, if and when.

We're optimistic. I just want to caveat it that it's never over until it's over. But hopefully, you'll see an approval here shortly, and then we can talk specifically to the label.

On that front, I'm just curious, is there any difference in terms of the CR assessment between the FDA's adjudication versus yours?

There shouldn't be. No, because we're using the same guidance, the guidance that they've put forward. But the -- let's see where everything ends up in terms of the label.

Where could difference come from, though? I mean we did see a difference between your competitor, right, their assessment versus FDA label seems to be a little bit off. What do you think that could be?

I don't know. We'd have to ask them. I don't actually -- it's hard enough, David, to have visibility into your own engagement with the agency. I'd be speculating if I talked about anybody else's. I think ours is going to be, again, very strong, very competitive in terms of safety, combinability, convenience and efficacy.

And at the end of the day, I mean, let's step back and look at the bigger picture, right? This -- for both us and any potential competitor, this is your first approval. If you really want to maximize the value for patients, you need to get into combinations, you need to get to the frontline as fast as possible.

We are now, I think, in a position to get ahead of everybody else in those frontline settings. The 017 study, I know maybe we'll talk about it in a subsequent question, but that is designed to really begin to outpace the competition and get us potentially to registrational data sets in the frontline. You'll also see us publishing additional data on combinations of ziftomenib with various standards of care in the relapsed/refractory setting.

So that's -- it's less, I think, about the little differences in the labels between the two drugs and more about how do you capture that very significant opportunity throughout the continuum of care in AML.

Got it. Yes. That's helpful. And so then ahead of the PDUFA date, you mentioned that you're currently preparing the launch activities, especially getting market access, hiring commercial team. Maybe just tell a little more -- provide a little more granular detail around what things you're doing right now to make sure that it's going to be off to a good start once its -- launch will be off to a good start once it's approved in November.

Yes. So we're doing this in the context of the collaboration. November of last year, about a year ago, we signed this collaboration with Kyowa Kirin to develop and commercialize ziftomenib globally. The funding that's coming, really helps to support this broad development strategy. We and Kyowa Kirin are working together to commercialize ziftomenib in the U.S., which will hopefully be the first approval. Importantly, under that collaboration, Kura leads global development, Kura leads U.S. commercial strategy and Kura books all U.S. sales.

We have -- David, as you said, we have -- we call them now oncology account managers, in the old days, we used to call them sales reps. We have the sales organization, marketing, market access and medical affairs, all in place. We have the agreements in place with the specialty pharmacies, the specialty distributors will be ready to go.

The way we're going to do it, David, is our sales organization and Kyowa Kirin's will actually sit on top of each other. So rather than trying to divide up territories, what we're going to do is call on more sites in a given territory and call on them more frequently. Our organization will look very similar probably to our competitors. But on top of that, we'll have a similarly sized organization from Kyowa Kirin where they are allocating at least 30% of their time to promoting ziftomenib in this initial indication.

That should give us, David, the ability to work from the Tier 1 sites all the way down into the stack, to get out to as many sites, both in the academic and the community, as possible. And we're going to compete -- I definitely don't think the NPM1 relapsed/refractory market is a winner take all. We're going to be competing very aggressively for every patient out there and looking to get share of voice with ziftomenib.

Our medical affairs team will be educating physicians, nurses, study teams on the opportunities to combine ziftomenib with other standards of care, both in the relapsed/refractory and eventually in the frontline setting. So that's how we're going to handle it.

Yes. I think that's sort of my next question, which is your competitor will launch their drug in the NPM1 setting a month before, right? So -- and they've already seen some off-label use in NPM1 anecdotally. So I'm curious just in terms of your strategy to kind of gain market share while you're a little bit later to the market, but your safety or your ability to combine with others might be able to offset that lateness to the game. So help us understand the overall commercial strategy there?

Yes. And I would say this, even if we were a few weeks ahead of them in terms of our PDUFA dates, I don't think a few weeks makes any difference, David, in this setting. And the reason it is, unfortunately, in relapsed/refractory AML, there's not a large body of patients that are sitting around waiting for therapy. If you don't treat them within a matter of a few days to weeks, they're going to expire from the disease. So it's not like there's a big pent-up pool of patients that somebody is going to capture in a few short weeks.

You said it exactly right. And that is you started in the labeled indication of NPM1-mutant AML, there's as much competition, David, between the menin inhibitors as well as with other standards of care like gilteritinib, venetoclax. Half of the NPM1 population is FLT3 mutant in the relapsed/refractory setting. That's why I'm putting such a strong emphasis on the upcoming data that you'll see next year of ziftomenib combination with gilteritinib. You need to get to combinations as quickly as possible.

That also allows you, David, to get to earlier lines of therapy. Ideally, you'd like to get these patients when they're second line because obviously, there are more of them, and they do better on therapy when you treat them earlier. If you have to wait until third, fourth or later lines, then it's harder to help these patients with their disease.

So you're going to see us competing very aggressively, both on the ground with our oncology account managers and again, we -- part of the reason we did the partnership with Kyowa Kirin is it gives us the operational and the financial firepower to be able to do the broadest, deepest development strategy of any menin inhibitor out there. And between intensive, non-intensive FLT3, there really isn't any standard of care we're not currently combining with.

So all of that data is going to be out there. And the physicians will tell you, they want to use these drugs in combination, they want to use them earlier in lines of therapy. The first few quarters, we're both going to kind of find our rhythm, David. Again, I think it's good to have options for patients. And eventually, you're going to see all these drugs trying to move into combination and into earlier lines. That's very much part of our near-term and then longer-term strategy to really become the market leader.

So you're saying that with combination with zifto -- or with combining 7+3 or ven-aza right now, is it possible to move into off-label use in frontline setting?

So I have to answer this very carefully, right? Because you always -- we will only be able to promote within the four corners of our label. That is clear, right? So the oncology account managers will speak to the label. Medical affairs, the physicians, if you ask them, how do they want to use menin inhibitors. They will tell you, well, we want to use them in combination.

We have to be very careful how we walk that line, and we will. I mean other companies do this all the time. I would expect, David, there will be some off-label use, particularly in combination. We are going to show you data at ASH, hopefully this year of ziftomenib with venetoclax and azacitidine, both in the frontline setting and in the relapsed/refractory setting.

And part of the reason for us doing that is we've heard very clearly from the physicians you need to show data of zifto in combination with ven-aza because that's how we'd like to use it. And let us -- whether it's through the NCCN guidelines or other mechanisms, let us work with you to make other physicians aware of the potential of using these drugs in combination.

I think we'll be able to do it all. We are going to keep our oncology account managers very focused on promoting on-label. And then with this ever-expanding data set, and we're talking now, David, about hundreds of patients being treated with ziftomenib in these various combinations. That's going to provide a good body of data, body of evidence to help both support the ongoing registrational studies and to give physicians comfort that they can safely combine these agents together and potentially drive better activity.

Okay. One last question just on zifto in elapsed/refractory NPM1. So you just published the KOMET-001 data in Journal of Clinical Oncology last week. So then that also gives you a fast track to potentially include zifto in NPM1 in NCCN guidelines. So any thoughts around potential time line as to when this will be included in NCCN guideline?

Yes. I'm glad you asked. So in order to be included in the guidelines, David, a drug has to first be approved. So we will -- if and when, ziftomenib is approved on or around its PDUFA date, you'll see us immediately turn around and submit to NCCN. Now that we have that JCO paper out there, but a condition precedent is the drug has to first be approved before it can be included in the guidelines.

For subsequent conclusions, David, we'll be ready to go. But those will be very close in time. The NDA approval and the submission to NCCN, expect that those are going to happen contemporaneously. The NCCN committee meets, my understanding is about every 6 months or on an ad hoc basis. And we'll do whatever we have to do to support them as they review the data. The timing of that, David, that I can't forecast yet.

Got it. Okay. It makes sense, Troy. So let's switch gears and talk about the frontline opportunity here, which is a big focus, right, especially focusing on the KOMET-017 trial in frontline AML. One thing we noticed a couple of days ago was that you just initiated -- or first person was dosed into this trial, I believe, or enrolled into this trial. And so the one thing we're just wondering is, Troy, can you provide some additional kind of color around like when are you going to be providing details around this trial, enrollment targets, powering assumptions, any kind of planning term analysis?

Yes. Let's -- so there's a lot in that question. So as you said, I mean, we announced the first patients into KOMET-017. Just for everybody's benefit, this is two parallel Phase III trials, one in intensive, one in non-intensive, each with their own co-primary or dual primary endpoints. So in intensive, you have a potential for accelerated approval off of an MRD-negative CR endpoint with a survival-based endpoint of event-free survival. For venetoclax and azacitidine, it's the CR endpoint with an OS survival-based endpoint.

All in, David, it's about 1,200 patients, more toward the intensive trial because that's a three-arm trial, designed to try and get a continuation label for ziftomenib. So think of it as maybe 700 in that trial and about 500-ish in the ven-aza trial. There really, David, isn't an interim to your question there. There is the potential for an accelerated review. We did that in consultation with FDA.

What's triggering the timing of that, and we've guided that we think the first top line result for an accelerated endpoint could come in 2028. We haven't yet been more specific about where in 2028. But that, David, is driven by enrollment. That's the MRD-negative CR accelerated endpoint in the intensive trial. In our mind, that's half the market, van-aza is the other half. But the reason that's in 2028 is FDA guidance requires that you have the trial very nearly enrolled. But at the time at which you would unblind it essentially on an accelerated endpoint. So that's what's driving the timing of these accelerated reviews. It's enrollment. It's not events.

In terms of putting the two trials together, why we think we're so well positioned, it really streamlines it with the sites. They have one -- a single budget, a single trial agreement, a single either IRB or ethics board review. The sites have said to us, this is what would make us prioritize your trial over any competitor. And I think we'll very quickly catch up and overtake our competition.

We've seen the number of patients that have been enrolled in our competitors' trial. And I would expect that we will overcome that and out-enroll them relatively quickly. And just look at the number of patients we've enrolled in the 007 trial, the Phase I trials, David, more than 100 in both intensive and non-intensive to this point with just a handful of sites. In 017, it's going to be nearly 200 sites globally. So I think it will go -- it will go quite quickly.

Got it. And what are some of the initial feedback from the physicians so far on using zifto in frontline setting. Maybe you can share some of the feedback, especially in those open sites on the enrollment for frontline.

Yes. I mean -- again, this is -- one has to take a holistic view of this, David. We talk about like what are the oncology account managers going to do, right? Your earlier questions about how do you sell in that initial setting. We are going to be at nearly every major medical center in the U.S. and most of Europe. I mean 200 sites globally. We -- if you ask the physicians, we are the most attractive trial because it's a one-stop shop. They can do almost any patient who walks in the door in their clinic. They can put them into 017.

The reason we did that, David, we made a very deliberate decision, if that site is already working with zifto, whether it's a frontline trial or a relapsed/refractory trial for 007 or 008, they're going to have familiarity with it. They're going -- these physicians all talk to each other. They're going to want to recommend it to their patients in a commercial setting.

We've gotten very, very positive, very strong feedback, both for the 7+3 data, which we've shared with you. We'll give you an update likely next year on 7+3. As well as ven-aza, which you haven't yet seen kind of the frontline data. You'll be seeing that at ASH. The docs are -- what the drug is doing is it's you're not really going to increase CR rate in the intensive setting, you're going to increase MRD negativity. That's what we're seeing, right? We're seeing great durability, patients staying on, not needing to go to transplant.

With ven-aza, you do have the prospect of actually meaningfully increasing the CR rate. And that's what we expect to see, David. And we're looking forward to sharing that data with you and with your audience hopefully at ASH, if those submissions are accepted.

Very interesting actually. And on the CR rate, MRD-negative CR for accelerated endpoint or accelerated approval, surrogate endpoints. I'm curious, any kind of updates on the level of CR -- MRD-negative CR will be considered meaningful for the FDA and also for the clinicians?

Yes. So one has to be careful about where are you assessing MRD. And we're doing it in bone marrow. We're doing it at the end of the second cycle. The -- for 7+3, David, the standard is about 45% MRD negativity among the CRs, just for 7+3. If you look at what we've published at EHA, you're seeing sort of 60% to 70%, and that number is evolving. It's actually getting higher as time goes on. It needs to be clinically meaningful, David. That's usually 15% above kind of baseline, we think we're well within that range.

The other thing that we've shown is in the Phase I trial, those numbers are assessed at the site level, but we've done the work now to test the concordance with a central review because that's the way you're going to show the -- demonstrate to the regulators that you've actually achieved the goal. And we're seeing very good concordance between the central review and the site review.

So again, that data is going to evolve over time. But I think you're -- and you say, David, is it working? Well, these patients are staying on without having to go to transplant, right? That's the problem with intensive chemo. You have very high CR rates, but also very high recurrence. 60% of patients recur, and then they're relapsed/refractory and they go rapidly downhill. If we're able to keep them on zifto, they can delay or perhaps even avoid going to a transplant, that tells you clinically you're having the effect that you desire, you're keeping that disease at bay.

So I think that's going to be a very good story over the next year or 2 as we're now running the 017 study on top of it in a registrational context.

Great. That's really helpful, Troy. So a couple of minutes left. Just wanted to focus on -- switch gears and focus on the FTI program, especially the most near-term update will be at ESMO, right, for darlifarnib. And so I'm curious, for darlifarnib, you're going to be showing some data in RCC. Maybe just help us understand some expectations heading into this data set, and what should we be looking for, for this data set here?

Yes. So big -- to help people understand big picture, an FTI has the potential to take good drugs and make them better by addressing innate and adaptive resistance, TKIs, PI3 kinase inhibitors, KRAS inhibitors. You focused in on RCC. I think that's appropriate. We're going to show you a combination data with cabozantinib at 2 different doses of cabo, 40 milligrams, 60 milligrams. The 40-milligram dose, David in combination are going to be heavily pretreated patients, many who have already seen cabo. The 60-milligram will be largely cabo naive.

We did that because actually, we were able to combine much better than we ever expected. We can combine at a full dose of cabo with a full dose of 2806. The way to think about it, David, is cabo monotherapy gives you a response rate of 25% to 28%. With the HIF2 alpha inhibitors, we've seen 31% to maybe 45%. And you're going to see combo data. You want to see activity of the combo in that range.

You also, David, want to see examples where we can take a patient who is progressing on cabo and actually put them back into a response. If we could show you that with good safety and tolerability, we think we have a very competitive play. The difference from this and HIF2 alpha is, we can go anywhere cabo can go. So we can go, for example, to neuroendocrine, we can go to other tumor types as well as KRAS and PI3 kinase.

If we're right, the FTIs have a total addressable market of greater than 200,000 patients in the U.S. It will be a very significant drug. And I think a nice complement to what we've been talking about with zifto.

Great. This is really, really helpful, Troy. We're at the top of the hour, and I think we'd just wrap up here. I really, really appreciate you taking the time to speak with us, and hopefully, you all have a good time here at our Virtual Oncology Day.

Thanks very much again, David, for the opportunity to participate and thank you for all the questions.

Great. Thank you so much, Troy. Have a good one.

You too.

Thank you for standing by and welcome to Kura Oncology's FT Pre-clinical Program Review: Synergistic Combinations with Targeted Therapies. [Operator Instructions]

I would now like to hand the call over to Troy Wilson, CEO. Please go ahead.

Thank you very much, and welcome, everyone, to our Farnesyl Transferase preclinical program review. I'm Troy Wilson, Kura's President and CEO. And it's a pleasure to have all of you with us today. We could go to the next slide.

In connection with today's presentation, we're going to be making certain forward-looking statements. We would refer you either to the SEC's website or to the Kura Oncology website for more information about Kura oncology and about the risks and uncertainties in an investment in Kura. If we could go to the next slide, please, Slide 3.

Joining me today on today's call are Francis Burrows, Kura's Chief Scientific Officer; and Mollie Leoni, Kura's Chief Medical Officer. As you'll see, I'm going to give a few introductory remarks, and then I'm going to turn it over to Francis to walk you through a lot of the preclinical data. He'll then turn it over to Mollie to connect that to the clinical trials and what you might expect at the upcoming ESMO presentation in October. Next slide, please.

So it's an exciting time at Kura. We are really, I think, well positioned to build on the success with ziftomenib and to develop a robust pipeline of targeted therapies for the treatment of cancer. Ziftomenib has really been much of the focus at Kura over the last couple of years, and that we continue to be both very excited and very well prepared. Our -- we are currently under review with FDA for our first potential approval in NPM1 mutant relapsed/refractory AML. We think ultimately that if successful in both the relapsed/refractory and the frontline settings, the menin inhibitor class could be a $5 billion to $10 billion class. We think we could take meaningful share of that. Our commercial team is -- has been hired, is trained, is out in the field engaging with physicians and we're very grateful to the collaboration with Kyowa Kirin, who have been our partners both in the development and commercialization of ziftomenib. We look forward to positively impacting the lives of patients worldwide.

Today, we're going to actually now talk about something that has been years in the making, and that's our Farnesyl Transferase inhibitor program, which is in the center of Slide 4. And as I think you'll see, FTIs really represent a compelling therapeutic target in their ability to address innate and adaptive resistance to multiple large classes of targeted therapies. Today, we're going to walk you through the preclinical data. This is Chapter 1, if you will. Chapter 2 will be from ESMO, where we'll share with you the first preliminary clinical results. As you'll see, the breadth of potential indications is vast and includes head and neck, lung, colorectal, breast as well as endometrial and neuroendocrine and we're very excited to bring both the pre-clinical and the clinical data to you.

This is really the next installments in our pipeline. But even behind that, we have additional therapeutic opportunities. These are familiar to many of you. We're progressing ziftomenib in combination with imatinib for treatment of patients with advanced gastrointestinal stromal tumors. That study is currently in dose escalation. Hopefully, we'll be in a position to share data with you next year. And we've also, just in the last quarter, nominated our first development candidate menin inhibitor for the treatment of diabetes and other cardiometabolic indications, and we'll have more to say about the development plans, the time lines and what to expect in a future call. Next slide.

So as I mentioned, today, we're going to focus really on the Farnesyl Transferase inhibitor program, and in particular, the rationale for how do we use FTIs in combination with other targeted therapies to overcome drug resistance. Next slide, please.

The industry has really been incredibly productive and successful with developing small molecule targeted therapies against a range of different targets. Many of those therapies are successful. They are able to drive tumor regressions, but they're not the whole story. Unfortunately, despite the fact that they may show monotherapy activity in the clinic, they're often insufficient as monotherapy to really give patients the full benefit. As such, there's really a premium on developing rational combinations and for example, the combination of KRAS inhibitors with EGFR inhibitors, but this is a long-standing problem with targeted therapies and it really motivates the need to identify and develop companion therapeutics that can address innate and adaptive resistance. Next slide.

What we have at Kura is the Farnesyl Transferase inhibitor program. We are the pioneers, we've been working on this target for a number of years. And today, we'll talk to you about, in particular, one of the farnesylated targets. A protein called REB and its relationship to a central target, namely the mammalian target of Rapamycin. mTOR, you'll hear mTOR, and in specifically TOR-1 through Francis's slides, is a central actor in both the MAPK-kinase and the PI3-kinase pathways. And what we'll show you is that simultaneous inhibition of RHEB and mTOR through defarnesylation of RHEB has the potential to address resistance again, to multiple large classes of targeted therapies. Please, if we can go to the next slide.

And that's really shown here on Slide 8. You can see the canonical signaling diagram. This is the signal transduction pathway, KRAS on the left, PI3-kinase alpha pathway on the right. This is, of course, an oversimplification of the pathway, but it makes an important point, namely these pathways work in concert to drive cell signaling, and they are relevant to these three large classes of targeted therapies. RAS inhibitors on the left, VEGF receptor tyrosine kinase inhibitors at the top and PI3-kinase alpha inhibitors on the far right-hand side. As you'll see, 2806 blocks farnesylation of RHEB and in so doing blocks the activity of mTORC-1. Francis is going to show you the preclinical data and help set the stage for the translation into the clinic.

If we go to the next slide, today's presentation is primarily going to focus on several examples. We show you here, this is not an exhaustive list. But of course, these are therapeutic targets where there's tremendous interest, tremendous activity. The point we want to make to you with this preclinical data, as you'll see is if you're seeing good activity with, for example, adagrasib. It's our view, at least preclinically, that should read through very positively to the entire class, both mutant selective and pan-RAS inhibitors. Similarly, in the case of the VEGF receptor TKIs and the PI3- kinase alpha inhibitors, although we won't show you every combination, we think there's good reason to believe that if you're seeing additivity or synergy with one, it's reasonable to think about how do you translate that across the entire class. That's why FTIs are potentially so impactful as this mechanism.

So with that, I'll turn it to the next slide, Slide 10, and I'm going to turn it over to my colleague, Dr. Francis Burrows, to introduce to you KO-2806 and to walk you through the preclinical data.

Thank you, Troy. At Kura's inception in 2014, we in-licensed the J&J Farnesyl Transferase inhibitor tipifarnib, with a view to developing it in HRAS mutant head and neck cancer. It was appealing because it had shown clinical activity and the safety profile was very well characterized and it duly performed very well in the clinic, delivering excellent antitumor activity in HRAS mutant head and neck patients and combining quite well in various trials with challenging drugs such as erlotinib and alpelisib. On the downside, the pill burden was high with patients receiving 1.2 grams per day due to its extensive first-pass metabolism. There's little doubt in my mind that tipifarnib was the best in its class. But since that class graduated some time ago, its IP protection is now limited.

Using tipifarnib as a solid platform, we evolved the next-gen FTI recently dubbed, darlifarnib for optimized for use in combination regimens. This drug is significantly more potent than [indiscernible] and demonstrated good combinability with a laundry list of PI3K-RAS inhibitors and TKIs in vivo. Darlifarnib is administered QD at substantially lower doses than Tipi due to its reduced clearance and optimized metabolism and also, of course, has extended protection as a new chemical entity. Initial clinical testing of darlifarnib in the FIT-001 trial is in progress. And today, we'll summarize the preclinical data supporting the use of the new FTI in combination with several classes of targeted therapies in solid tumor models.

Our first example is renal cell carcinoma where TKIs that inhibit VEGF receptor signaling are a prominent therapeutic class. As you see the pathway diagram coming back here, in this case, it's playing out in the tumor endothelial cells where the anti-angiogenic activity of TKIs, such as axitinib, lenvatinib, and cabozantinib is limited by mTOR activation. FTI co-therapy silences mTOR, deepening the anti-antigenic effect of the TKI. And this, of course, is the real Achilles heel of RCC. Indeed, the mTOR pathway is hyperactivated in RCC. And several mTOR inhibitors of the rapalog class are approved in the indication. Although uptake has been poor due to tolerability issues with high rates of dose reductions and discontinuations associated with high-grade AEs have been frequently reported.

FTIs silence mTOR signaling by displacement of the farnesylation-dependent mTOR co-activator, RHEB from lysosomal membranes, preventing correct mTOR localization. So mTOR does all of its business from the lysosomal membrane. If it cannot insert into there, it is essentially switched off. And this is how FTIs shut down the mTORC1 node.

Anti-angiogenesis is a key component of all therapeutic strategies in clear cell RCC. With VEGF pathway TKIs and HIF-2 inhibitors validating the particular dependence of this tumor type on its neovasculature. I'll spare you the blocks showing that cabo only partially inhibits VEGF-dependent mTORC1 signaling in tumor endothelium but sufficient to say that the KO-2806 finishes a job, which really puts the brakes on angiogenesis. So as you can see in the IHC here, while both cabo and 2806 monotherapies do reduce vascular density, the combination of the two agents is synergistic in this particular PDX model. And indeed, we saw similar effects with the first-line anti-angiogenic TKIs. As expected, given the angiogenesis dependence of RCC, the improvement offered by addition of KO-2806 TKI monotherapy was both class wide and highly consistent.

As you see on the left, in the TKI-resistant VHL wild-type KACI-1 model, addition of 2806 made all three TKIs highly effective. These composite waterfalls can be a little hard look at sometimes. But essentially, the gray here is showing you the TKI monotherapy activity. So you can see the tumors are progressively growing, whereas the orange captures the combo activity where all of the waterfalls fall below the line indicating everyone was experiencing regressions. And that was also seen in the wider panel of RCC models where we see that the FTI enhanced the activity of cabo in both resistant models towards the left of that chart or more sensitive models, irrespective importantly, of the VHL genotype.

Anti-angiogenic TKIs are prominent components of early line regimens for metastatic RCC. So, we wondered whether prior exposure to VEGF pathway directed therapy would render mTOR-driven resistance irrelevant. In animals bearing RCC tumors that were progressing on first-line TKI therapy, switching to cabozantinib did indeed slow tumor growth. But switching to the cabo FTI combo induced consistent regressions even in animals progressing on cabo monotherapy.

So summarizing what we've seen in RCC models, we see a composite effect of inhibiting both VEGF receptor signaling and the adaptive mTOR signaling that comes up in response to that, improves and lengthens the anti-antigenic activity and that this is effective with both first and second-line TKIs and is active even in tumors that are progressing on the first-line therapy.

Although our RCC program is the most advanced with KO-2806, the first place where we found a role for FTI-dependent mTOR activation and drug resistance was actually in the context of PI3K inhibition. PI3 kinase alpha or PIK3CA is one of the most commonly mutated genes in solid cancers. Prevalence in several large indications, including breast, colorectal, bladder and endometrial cancers. PI3K inhibitors, if you look at back at the pathway diagram there, Unsurprisingly, effectively block the right-hand side of the pathway that collateral signaling through the MAPK kinase signal -- through the MAPK kinase pathway, reactivates mTOR and undermines their effectiveness. FTIs blunt this resistance pathway by blocking farnesylation of RHEB, leading to more effective reduction of mTORC1 signaling, while importantly sparing mTORC2. This is quite significant clinically because blockade of mTORC2 can cause insulin resistance in type 2 diabetes can lead to increased susceptibility to infection and have significant lung complications, particularly pneumonitis.

So building on the clinical activity, we achieved with tipifarnib in HRAS mutant head and neck squamous cell carcinoma, we sought to extend the clinical benefit of Farnesyl Transferase inhibition to the larger population of PIK3CA mutant head and neck cancer patients by combining tipifarnib with alpelisib and approved PI3K alpha inhibitor. In preclinical models, we saw that the alpelisib rapidly induced a down regulation of mTOR activation close to baseline, but this did not persist and quite rapidly, we saw a rebound that was complete within 24 hours. By contrast, when KO-2806 was added to the mix, mTOR activity was suppressed throughout the dosing interval. And this translated into a significant improvement in antitumor activity in this PIK3CA mutant head and neck squamous cell carcinoma CDx model.

So as you see on the right, the alpelisib monotherapy gave a mixed response with some progression and some regression whereas all animals treated with the combo exhibited deep regressions. We subsequently expanded this to a panel of a dozen or so CDX and PDX models with similar results. And this formed the basis of our current HN trial combining tipifarnib and alpelisib in PIK3CA mutant head and neck cancer, upon which we will report at the forthcoming ESMO meeting.

As far as KO-2806 is concerned, we're digging into the role of nor dependent resistance across the range of tumor types with prevalent PIK3CA mutations. It's early days, but so far, the pattern that we saw in the RCC model seems to be maintained in that addition of KO-2806 enhances the antitumor activity of both of the mutant selective next-gen PI3K inhibitors tested and displayed this property across the full activity range of those PI3K inhibitors, slowing or stopping tumor growth and inducing regressions in more sensitive models, including, as shown on the right, some encouraging preliminary activity in breast, bladder and cervical models.

So how about RAS inhibitors? Just to remind you, the reason why RAS is so important in cancer is because it's the only non RTK that drives both MAPK kinase and PI3 Kinase pathway signaling. But its control of the MAPK kinase pathway is stronger. The rationale for using 2806 as a partner for RAS inhibitors, therefore, mirrors the issue for PI3K inhibitors. In this case, RAS inhibition takes out the MAPK kinase pathway very nicely, but residual PI3K pathway activation drives mTOR-mediated resistance. Once again, RAS inhibitor monotherapy fails to persistently block mTOR signaling, but the combination is effective across the class.

For example, as shown on the right, while adagrasib only partially blocks mTOR activity with full rebound observed, the combo flatlines, it's for days. The RMC pan-RAS inhibitor does a better job but the activity still decays and can still be rescued with KO-2806.

KRAS inhibitor development has been focused on non-small cell lung cancer and colorectal cancer with mutant selective inhibitors of KRAS G12C and G12D and pan-RAS-ARM inhibitors, such as the RMC compound. Darlifarnib enhances the activity of both classes of RAS inhibitors across their full activity range in both lung and colorectal xenograph. In the lung cancer panel, shown on the left, for instance, KO-2806 improve responses to adagrasib and refractory models by slowing tumor growth and deepened regressions in sensitive models but most excitingly, also converted some tumors from resistant to sensitive. We also saw this with MRTX1133, the G12D inhibitor in colorectal models and with the RMC pan-RAS inhibitor in the colorectal panel also.

Now I'm sure you all appreciate that KRAS inhibitor development is a highly active field. And so it's likely that many patients accruing to our trials will have had prior exposure to one or more drugs in the class. So we modeled switching to the combo after failure on KRAS inhibitor monotherapy.

In this lung cancer model, KRAS monotherapy was temporarily effective and switching within class didn't help, as you see on the upper right going from sotorasib to adagrasib. Switching from [indiscernible] to the pan-RAS inhibitor provided some benefit. But by contrast, the FTI RAS inhibitor combo induced regressions in all cases. To model the KRAS inhibitor naive situation, we also looked at the upfront combination and either with adagrasib or RMC, as you can see here, the upfront combinations did not disappoint. In the KRAS G12D mutant CRC model, mutant selective and pan-RAS inhibitors are highly effective for three to four weeks, inducing nice regressions, but then they consistently fail. In this case, switching from mutant selective to pan-RAS inhibition does not flow to tumor growth, perhaps due to the PIK3CA co mutation in this particular model. But once again, combination with KO-2806 drives long-lasting regressions in all of the animals. As before, combination treatment was rapidly active and maintain deeper regressions in KRAS inhibitor naive animals.

So the big take-homes from the KRAS models are that the FTI enhances activity of all the classes of RAS inhibitors across their full activity range in both tumor types we looked at and the darlifarnib combination therapy can deliver regressions in animals bearing tumors that have failed RAS inhibitor monotherapy.

So in conclusion then, from the preclinical session, we've shown you, I hope that FTIs address a resistance pathway common to many targeted therapies across a range of large indications and that the targeting of this innate and adaptive resistance via FTIs in combination with highly active targeted therapies has demonstrated the potential to drive deep responses in preclinical models. FTIs have been successfully combined in the preclinical setting with multiple drug classes, including PI3K alpha inhibitors, KRAS inhibitors and anti-angiogenic tyrosine kinase inhibitors. KO-2806 or darlifarnib is our next-generation FTI optimized for collaboration approaches with improved pharmaceutical properties. So hopefully, we've convinced you that these preclinical data robustly support combination therapy using darlifarnib to address resistance and provide more durable activity.

With that, I'm going to hand you over to our CMO, Mollie Leoni, to briefly preview the upcoming clinical data reveal at ESMO.