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

Good morning. My name is Krista, and I'll be your conference operator today. At this time, I would like to welcome everyone to the KURA Oncology Virtual Investor Event. [Operator Instructions]. I would now like to turn the conference over to Troy Wilson, President and Chief Executive Officer of Oncology. Mr. Wilson, you may begin your conference.

Thank you, Krista, and good morning, everyone, and thank you for joining our call. I want to welcome you to our call to describe the preliminary clinical results from our KOMET-007 study. I'm here with my colleagues, Dr. Mollie Leoni and Dr. Stephen Dale, we're joined by Dr. Amer Zeidan and Dr. Amir Fathi as well to investigators on the study. Each of them will take a turn in walking you through this set of slides. If we turn now to Slide #3. We will be making on this call forward-looking statements, and I'll just want to draw your attention to our website to the SEC website for more information about the risks and uncertainties in an investment in KURA Oncology. With that, now turning to Slide #4. This is an important day. This is a day that we at KURA have been waiting a long time for. When we started this program with ziftomenib, with a Menin Inhibitors, our goal was to transform the treatment of acute leukemias. And today, we want to share with you what we think is a big step forward in that direction. That's an ambitious goal. It's not an unprecedented goal, however, and in the next couple of slides, I want to just walk you through 2 examples that give us optimism as to why we might be able to achieve this goal. The first is here on Slide #4, and that's the example of an immediately adjacent leukemia, namely Acute Promyelocytic Leukemia. This is one that arises from an abnormal fusion protein the PML/RAR? fusion that's quite similar actually to the Menin KMT2A in that it creates a promyelocytes which proliferate uncontrollably and prior to the advent of ATRA and arsenic trioxide this was nearly invariably lethal disease. However, upon the introduction of all-trans retinoic acid and arsenic trioxide, which incidentally, has a very similar mechanism of action to ziftomenib, namely that it differentiates promyelocytes, we've now seen a remarkable transformation in the standard of care for Acute Promyelocytic Leukemia and you see that at the bottom. Today, now we have an 89% overall survival at 10 years in patients with APL. So that gives us optimism. Turning to the next slide, Slide #5. Again, an example in the hematologic malignancies, this one with multiple myeloma. Prior to the 2000s, as many of you know, myeloma was nearly a death sentence very few treatment options and patients were lucky to have a median survival of 2 to 3 years. And then there was a renaissance, we saw the immunomodulatory drugs, the proteasome inhibitors, then the CD38 antibodies and so forth. And now we're at a point, because of these combination therapies where many patients have the hope of actually living with their disease for more than 10 years. And this is an example that we like to use because IMiDs have really become a cornerstone of treatment. They're used in combination with almost everything. They're used throughout the continuum of care. And what these combinations have done is to transform the standard of care in multiple myeloma and by virtue of that transform the market and at peak, the IMiDs were driving peak sales of greater than $15 billion. So it's a tall order, what we're seeking to do with acute leukemia, but we have great optimism and my colleagues and I and our distinguished investigators on the phone are looking forward to walking you through that. With that now, we'll start to get into the data, and I'll turn it over to my colleague, Dr. Stephen Dale.

Thank you, Troy. So just going to the next slide, that's Slide 7. So thinking specifically about ziftomenib, we firmly believe that the drug will have the potential to evoke a paradigm shift in the way that these patients are treated. To date, there has not been a standard of care. Ziftomenib provides these patients with horrendous prognosis in both genetic subtypes to have an effective treatment. The zifto targets foundational mutations at the core of up to 50% of AML. Importantly, our clinical data is compelling I repeat that it is compelling and as such, freely supports combinations with standard of care in frontline disease. And in combinations, both in frontline and relapsed refractory, we see good safety and tolerability and as such, it enables continuous administration of the medicine. One of the areas which I know, understandably, there's been a lot of interest and focus has been on differentiation syndrome and whether this can be effectively mitigated in the KMT2A patients, where we see a higher frequency and severity of extramedullary disease. We are thrilled that our combination data show that the differentiation syndrome is mitigated with our combinations both in KMT2A and NPM1. We do not see any drug-drug interactions. Our clinical activity is highly encouraging. And the enthusiasm of our investigators has been amazing, and I use that word because it really is, and proof of that, of course, is with our enrollment rates just going way over an acceleration over what the target enrollment rates are. Again, just showing that the drug works exceptionally well and therefore investigators are keen to put their patients on certainly for the combination studies to give their patients a chance. And overall, it's important again to understand that this drug is well tolerated. It has clinically meaningful efficacy data, which our investigators will walk you through shortly and it definitely will be best-in-class. So if we move to the next slide, so it is with great pleasure that I can introduce 2 of our esteemed investigators who are also world leaders in hemato-oncology, and we are humbled by the fact that they have been so supportive of the ziftomenib program. And we'll talk to you more around the patient experiences a little bit later on. Dr. Fathi, Program Director for the Center of Leukemia at MGH and also Associate Professor of Medicine at Harvard Medical School. Dr. Amer Zeidan is Interim Chief of Hematologic Malignancies at Yale, and we are delighted that both of these investigators are taking time to join us today. With that said, I'll hand over to Dr. Fathi.

Thank you so much, Dale and Troy for going through the slides and for having me today. It's a pleasure to be here from not so sunny Boston and I was past today to go through some of the data on the monotherapy experience of ziftomenib from the KOMET-007 study. This data was predominantly covered at EHA this past summer at the late-breaking abstract session. So without further ado, let us advance to Slide 10. This slide provides you with a general idea of the schema of the KOMET-001 trial. It started with a Phase 1a Dose Escalation where we started with a pretty low dose of 50 milligrams daily and quickly dose escalated all the way up to 1,000 milligrams daily. Looking at various subpopulations of AML, mainly focusing ultimately on NPM1-mutated KMT2A-altered disease with the goal of assessing safety and tolerability, the pharmacokinetic markers, pharmacodynamic markers and ultimately getting a preliminary sense of activity. It is important to mention that this study was among the first to be designed and applied with the Project Optimus from the FDA in mind where ultimately we wanted to validate certain doses as we were escalating and investigate them to both optimize hence Optimus the tolerability as well as activity of the drug to find doses that were most likely to be active and at the same time safe for patients. Given that, ultimately 2 doses, 200 milligrams daily and 600 milligrams daily, were chosen to further investigate the Phase I goals of the study, namely safety, tolerability as well as correlative science related to these agents, and these cohorts were expanded and further studied. Ultimately, 600 milligrams daily was chosen to be the most pharmacokinetically and pharmacodynamic optimized dose and that was used in the Phase 1b expansion that specifically looked at that dose for specifically NPM1-mutated AML and that has since led to the larger Phase II registration-enabling study with a dose of 600 milligrams daily, again with a primary endpoint of composite remission as well as multiple secondary endpoints with key ones being duration of remission, transfusion independence, MRD assessments and obviously, safety and tolerability again. Next slide, please. This slide just gives you an idea regarding our general observations over the period of dose escalation and key pharmacokinetic profiles of the drug. And as you can see, with an increasing amount of dose, there was a plateauing of the ziftomenib exposure at around 600 milligrams daily based on the mean AUC parameters. And that basically told us that we were pretty good at 600, which was a dose that was safe and well tolerated and led to a very ideal and optimal pharmacokinetics for patients to hopefully achieve the activity which we were hoping to see at the time. And the drug has been very well tolerated considering what we currently have for agents in AML. I want to remind the audience that and I suspect Dr. Zeidan would agree that for -- I think every time I say this, it seems like a decade passes but since the late 1960s, we have not had that many effective regimens or we've had induction chemotherapy and nothing much changed until approximately 6, 7 years ago when there was a flood of targeted therapies and antibody drug conjugates and other approaches, novel approaches to treatment and we've had 8 or 9 approvals sense, including IDH inhibitors, FLT3 inhibitors. And it's been an exciting time because every time, every few years you potentially find something that comes along that potentially has activity in a subset of AML and this Menin seems to have a particular role in patients who have NPM1 and KMT2A alterations as predicted by preclinical efforts in these leukemia subtypes. In terms of the safety and tolerability of the drug, it's certainly much more tolerable than traditional intensive chemotherapies. The one adverse event that we all have heard about that does occur with this class of drug is differentiation syndrome. But there is a differential in terms of its strength and presentation with NPM1 mutated disease versus KMT2A alter disease. With NPN1 in general, it tends to be milder and can be managed with traditional mitigation strategies including steroids, cytoreduction and other efforts. It does tend to be occurring at a higher rate and more severe with a KMT2A altered disease as has been seen also with other Menin inhibitors and seems to be a class phenomenon as has been also been shown with other agents. And it occurs at a higher proportion 38.5% at 200 milligrams and 37.5%, approximately similar at 600 milligrams, so not much different. So it would make sense that a way to potentially mitigate the effect of this drug in promoting differentiation syndrome KMT2A alter disease would be to combine it with traditional chemotherapy or conventional chemotherapy strategies to help bring down this leukemic cell population and decrease the burden of cells that are going into differentiation. It is important to mention that DS is an on-target adverse events and it represents the underlying mechanistic activity of the agent because ultimately, it triggers the differentiation and maturation of cells, which is what we want, but can trigger if it's too robust, a cytokine mediated inflammatory process that can be clinically significant in patients. So thereby, if you decrease the proportion of cells that might be prone to differentiation with concurrent chemotherapy you would in turn decrease the likelihood theoretically of severe differentiation syndrome. So that is an important consideration for this particular subtype of AML. There are other adverse events that were looked for and assessed during the clinical trial, we did not see any substantial evidence or any clinically meaningful QT prolongation that is quite important in our field probably more so than other fields, patients that undergo treatment for AML frequently are many other medications that can prolong the QT interval, including nausea medicines, antifungal agents, antibiotics sometimes psychiatric medicines, all of these can prolong to QT. And when you have that in the background and you have a drug that potentially prolong QT, it can become a problem and in our field of doing clinical trials and drug development, QT prolongation is often a factor that we look at and we worry about, BUT with ziftomenib that has not been a clinically impactful issue on clinical trials. The other important factor when it comes to novel agents and the treatment of AML because AML is a marrow-based disease and because many of the treatments that we have suppressed blood counts, patients who received treatment for AML oftentimes suffer from various degrees of cytopenias and often from severe degrees of cytopenias and by cytopenias, I apologize if I'm speaking in the shop a little bit here cytopenias referred to low blood counts. So if because of the disease or because of the treatment, a patient has a very low platelet count or a very low white blood cell count, they are prone to infectious and bleeding complications, which can impact the safe conduct of the trial, the success of the agent you're trying to develop and ultimately and most importantly, the safety and tolerability that patients have to go through. So it is important to assess also the propensity of individual drugs as they go through development in terms of marrow suppression and promoting cytopenias. In the case of ziftomenib our experience has been at least with the monotherapy study that which is what I'm tasked with presenting today, that once patients achieved the response, meaning that they've achieved their remission, and we know that the drug has achieved its ultimate goal of gaining a marrow response with continuing treatment, these patients did not have substantial decreases in platelets and neutrophils at the doses we were using which was ultimately 600 milligrams daily. And that's important, that means that patients in a state of remission can continue to benefit over time without a worry that we would need to dose adjust that we would need to worry about decreasing the dose and potentially decreasing the impact and efficacy of the drug and allow the patient to have as much benefit for as long as possible. Ultimately, the durability is quite important. Next slide, Slide 13. So this slide provides you some of the data on activity, again, very similar to what I presented at EHA, the same data as presented here. This provides the best overall response for our NPM1 mutated patients. The complete remission rate was 35%. The composite remission rate, which included a patient with CRI was 40% and an overall response rate, which was a patient with MLFS morphologic leukemia-free state, which I believe if they would have recovered their accounts would have also been a remission was 45%. The overall response rate for the KMT2A group is also provided here. The data, and I think this is a small number of patients, but it's for comparative purposes, that on NPM1-mutated patients FLT3 mutated patients and on IDH mutated patients is also provided here to give you a sense in terms of how they may compare historically patients regardless of whether they have 3 mutations or IDA mutations responded at similar rates in terms of complete remission. And it's mentioned here and perhaps it should be mentioned more prominently because it is quite meaningful. The number of prior treatments for our patient population was quite dramatic. So a median number of 3 prior treatments, that's substantial. These are patients that ultimately didn't have many options at that point. We don't have many options for AML historically and if they've already received 2 or 3 prior treatments, oftentimes, there isn't much that you can offer them. So the fact that you could potentially salvage a highly resistant challenging disease at that point is remarkable. So in sum, the high-activity durable responses and favorable safety profile suggests that the potential for ziftomenib to become a backbone in AML in the future is strong. One more slide here, and this circle plot here provides you a general sense of why the investigators associated with this trial as well as the group of leukemia docs in general are excited about Menin Inhibitors. The clinical activity is strong. I mean the data that I just presented here with NPM1-mutated AML in the relapsed/refractory setting and the setting with multiple prior lines of treatment with a remission rate of approximately 40% is remarkable. I would say, if not more important as important is the safety and tolerability. The drug-drug interactions were not a challenge. We didn't have to dose reduce those adjust to these gymnastics during the clinical trial. The QT prolongation wasn't a signal. The differentiation syndrome was there, but it was very manageable with NPM1 mutated disease and ultimately with the KMT2A group, our approach was to try and focus our attention ultimately on combinations. There may very well be, and there is data that is emerging that there could be synergistic potential for Menin Inhibitors as well as other standard treatments for AML. I didn't get into it, but there are a substantial number of our patients achieved molecular residual disease clearance per institutional tests that were performed on study that suggests a depth of response which in general, translates to a durability of response, which is good for our patients. As some in the audience profitably know, resistance to Menin Inhibitors is a phenomenon that has increasingly garnered a lot of attention with various Menin Inhibitors that is an area that is important for us to try and figure out and understand as we explore certainly combinations in the future to ameliorate that risk. And I think all of this put together, the fact that patients don't have to adjust their drugs, the fact that it's generally well tolerated, the fact that a high proportion of patients respond and continue to respond the fact that this then translates to decreasing symptoms, decreasing transfusion needs. All of that impacts quality of life. And as a leukemia doctor, considering the fact that the median age of diagnosis now is around 70. That means that half of our patients are under 70s, 80s and 90s. Many of the patients are not candidates for transplant or intensive therapies and quality of life for as long as possible is quite important. And the last thing I'll say is the pharmacoeconomic benefit and I think over time, if you have less time in the hospital, less complications, that certainly has an impact on the global larger perspective of cost and burden to the health care system. And with that, I will pass the slides along, Amer.

Thank you so much, Amir. For those of you who actually can confuse Amir and myself, I don't feel bad because we actually both trained at Hopkins, and this happened to me all the time where people confuse both of us. So it's really a pleasure to give with Amir on this call. It's also a pleasure to be here on this call because I think this is a very exciting field. I think you heard very eloquently why the Menin Inhibitors and ziftomenib in particular are going to change the way the treatment of AML is being done in the large setting, but importantly, for those patients who have more difficult disease in the refractory relapse setting. But also, we know in hematologic oncology in general, the most important advances in the shape of the disease and in terms of adjusting the natural history of the disease happened when we combine promising drugs with a backbone of standard therapies because this will overcome the multiple and overlapping resistance mechanism that these malignancies will exhibit to therapies. And Stephen outlined a very nice analogy in multiple myeloma with the IMiDs. And because of all of these reasons, and in particular, in this case, because combination therapy also is going to mitigate the risk of differentiation syndrome, having a combination-based approach with Menin Inhibitors with ziftomenib seemed very appealing and many of us were looking forward to starting this trial, which I think is the first and the most advanced as far as I know in terms of combining a Menin Inhibitor in terms of clinical trial in patients with Acute Myeloid Leukemia. It's really also a pleasure to see the rapid approval. There is a lot of excitement about this trial and about these combinations and pace of approval to this trial has been outstanding, and it's really an honor to have the first data, the first look of data in terms of public release. I think many of us were excited and happy to see the data that I'm going to about to show you. Next slide. So many of you are familiar with the design of this study. It's a little bit complex. So we broke it into 2 different slides. Here, you can see that this study which enrolled both frontline and relapsed refractory AML patients. In this slide, you are seeing the frontline treated patients. So those patients who are candidates for intensive chemotherapy which, as many of you know the standard backbone is 7+3, which is cytarabine and daunorubicin. And this has been the backbone for many, many years, more than 40 years in AMA. Most recently, some of the drugs that were very active in the monotherapy setting such as FLT3 inhibitors were combined with this backbone and led to improvement in overall survival, for example, with a FLT3 inhibitors such as gilteritinib or midostaurin those are commonly used now these again basically in combination with chemotherapy and Cytarabine clearly. So I think here, the paradigm is very similar to try to add ziftomenib 7+3 in the specific subset that are more susceptible to ziftomenib which is as you know the NPM1 and the KMT2A rare range leukemias. Those 2 cohorts who were enrolled separately. So they are the cohort for each molecular trusses. It was a dose escalation study in the initial phase as you can see here. We started with the 200-milligram dose, and we treat at least 6 patients in each dose level and then you escalate. The currently enrolling dose for the frontline treated patients is the 200 milligram and you can see that subsequent to the selection of the dose, there will be expansion and validation of this dose level. The drug ziftomenib is being started at day 8 after the intensive chemo part is done with Cytarabine and Daunorubicin. And important to remember that patients who had NPM1 mutation who were enrolled during the dose escalation also had what we classify as adverse risk and those patients basically had to be older than 60 or had to have treatment-related AML or had to have adverse risk cytogenetic per the ELN. And this is important to remember because while frontline treatment of NPM1 disease is generally associated with favorable outcomes. Those patients who have adverse risk like those patients in this category don't do very well and I think this is important when you as a combination when you are thinking about the results that we are going to show you. In the refractory relapse setting, ziftomenib was combined with venetoclax azacitidine as you know venetoclax and azacitidine is a standard of care in all the patients with Acute Myeloid Leukemia who are unfit for intensive chemotherapy. But it's a commonly used salvage therapy as well in the relapsed refractory setting. The design here is very similar to separate cohorts, dose escalation as you can see these cohorts moved a little bit faster in terms of the accrual so we are already at the 400 milligram level. And eventually, this will expand into expansion and validation cohort, as you can see in the associated diagram. This is important because I think eventually, these therapies are going to move to the frontline setting where, again, I think it's going to be the biggest dent on the natural history of the disease. Similar to the intensive chemo, the ziftomenib was started on day 8 after the completion of the azacitidine concurrently with Venetoclax. So here, going to the results in the next slide. You can see here the patient demographics and baseline characteristics. As a reminder, this is the first look of the first 20 patients who were enrolled on the study and these are preliminary data as of January 11, 2024. You can see out of those 20 patients that were enrolled in the trial one of the first thing to note is that most of those patients remain on the trial as of the data cut of the 16 out of the 20%, 80%, which again is encouraging that most patients are still remaining on the trial. You can see a breakdown of the characteristics of patients by cohorts here. The relatively small numbers when you break it down by cohorts, but you get the sense that the median age is older, as you'd expect in patients with AML, the median age was 55%. Most of the patients on this data cut were females 13 of them, 11 of the patients had NPM1 mutations and 9 of them had the KMT2A-r leukemia. Of those patients, you can see that NPM1 mutations were mostly in the relapse setting, 7 out of the 11 were in the relapsed refractory setting and the same thing with the KMT2A where 8 of the patients were in the relapsed setting 8 out of the 9. And then importantly, for those patients who had been in the refractory lapse setting, you can see that those patients who are heavily pretreated you can see the number of prior lines and regimens. Several of those patients had been through transplant, 47%, almost half of them which is those patients are not easy to treat, generally have very poor outcomes. 50% had previous hypomethylating agents and importantly, 67%, 10 of them had previous exposure to venetoclax which is a subset of patients that you do extremely poorly based on evolving clinical literature after failure of venetoclax. So this is clearly in the refractory lab setting a very tough cohort of patients to treat. Next slide, you can see the safety data, again, with using the same cutoff of January 11, 2024. And this is a sick patient population as many of you know so it's very common to see adverse events, treatment emergent adverse events and this is consistent with the underlying disease as well as the backbone therapies. But when you look specifically at the ziftomenib related adverse events, which are grade 3 or higher, you can see again that the drug is very safe. I think most importantly in my mind is the fact that differentiation syndrome was largely mitigated, there were no events reported at this data cut off. There were no QTC prolongation as Dr. Fathi nicely outlined and this is especially when you think that it's very common to use drugs that prolong QTC such as antifungals, et cetera, and the management of those patients, and it's a true headache to try to replace these drugs or adjust them. So it's really nice to have a drug that does not do that because it makes life much easier during the induction treatment. There were no dose-limiting toxicities observed, there does not appear to be a delayed hematologic recovery, allowing continuous administration of the drug. So we were truly pleased to see the safety profile emerging so far. We have been able to kind of enroll patients without thinking too much about the added toxicity which is always a concern when you add drugs to 7+3. But here, I think there is a clear cut since, and this is my own personal sense from treating my own patients on this trial that the additive toxicity seems very minimal. Now talking about the efficacy data in the next slide. We are going to start with the frontline treated patients. As I mentioned, 5 of the 20 patients who were treated in the frontline setting, 4 of them had NPM1 mutation and one patient had the KMT2A-r leukemia and again, 100% small number, early look, but very exciting. It's 100% of those patients, all 5 patients achieved complete remission. Again, remember those NPM1-mutated patients are not your standard young fit patients who have no adverse cytogenetics, those are high-risk adverse cytogenetic older patients therapy-related type of NPM1. And the expected rate of CR/CRi is generally around 1/3 in those patients. So I think, again, this is very promising in my opinion and all of those patients were treated on the 200-milligram starting to. Now going to the refractory lapse cohort in the next slide, we should present it to make the data more easy to understand. We broke it down into patients based on the previous exposure. Why is that? Because we know the efficacy of therapies after ven failure is very different than patients who did not receive Ven and you can see some of the baseline expectations based on the literature. For example, patients who did not receive Venetoclax previously and get treated with Azacitidine generally, the CR rate is 35% to 40% CR/CRi rate. And this is why we tend to use ven in the refractory relapse setting, although it doesn't have a label currently in the U.S. for that indication. On the other hand, for those patients who have KMT2A-r leukemia who are refractory and relapsed the response rate is much worse, some little share coated it at least than 10%. So when you look at those patients, first, by looking at the ones who did not receive a previous Menin Inhibitor, some of those patients in the trial received Menin Inhibitors on other trials, when we look at those who were naive did not receive, there were 9 out of the 15 and out of those 9 the overall response rate was 78%. You can see that for NPM1 was 100% and for KMT2A-r leukemia was 50%. Again, this is patients who are in the refractory relapse setting and important to note that all of those patients were treated in the 200 milligram we are currently rolling in the 400 milligrams. And in the next slide, you will see, and I think, in my opinion, this is among the most impressive data of the trial to date is among patients who are Venetoclax experience or Venetoclax field, as I mentioned, those patients do extremely poorly. We generally don't have good options for them. The response rate has been quoted in the range of 0% to 20%. The survival is very dismal depending on the literature you look at 2 to 3 months and especially in those who have KMT2A-r leukemia after Ven failure. In particular, these patients do very poorly, but when we look at our data, a small number, 10 patients have seen Venetoclax prior to enrolling on the trial. The overall response rate was 40%. When you break it down by NPM1 versus KMT2A it was 60% with NPM1. And most of those were CRHs again, I think this is a pretty compelling data at this early look. So I'm going to go through some case examples of some of the patients who went on the trial to give you a flavor of what we have been seeing in terms of, I think, the impressive activity so far. So in the next slide, you can see one of the patients that was treated, not a young patient. This is a 66-year-old female, so those are older patients, many of them who went on the NPM1 cohort a lot of plate in the bone marrow 77% plus and you can see a number of mutations to not only NPM1, but the patient has also bad mutations such as NRAS and the patient was treated with 7+3 the ziftomenib started on day 8 of the trial, patients quickly achieved complete remission and she was able, by the design of the trial, by the way, to stay throughout during consolidation and post-transplant maintenance with ziftomenib is also allowed on this trial, which I think is very important because we know that most patients with leukemia would still relapse and there is a lot of interest in exploring maintenance options in those patients. So this patient, I think, did very nicely and we continue to follow her on the trial. The second patient here you can see this is an example of this dreadful tab of leukemia the KMT2A-r leukemia. This is a 49-year-old female who was diagnosed with this leukemia and was treated on our study in the frontline setting, she achieved response initially, but then she subsequently relapsed during consolidation and then you were treated on the ziftomenib in the aza cohort in the same trial and she was actually able to achieve remission which was MRD negative and she was able to proceed to transplant. And then lastly, in the next slide, you'll see the last case study that we are going to share with you today is the specific activity of ziftomenib in extramedullary disease which was described by the investigator when ziftomenib was started after azacitidine as you can see in the timeline of the treatment of this patient that the extramedullary disease melted within 2 days of starting ziftomenib, and again, this is particularly impressive when you look at the previous lines of therapy that this patient has seen, this patient has seen intensive chemotherapy venetoclax to allow transplant. So this is, again, I think it's super impressive to see the response of the extramedullary disease but this patient also went on to achieve complete response with partial counter recovery, CRH and then to transplants. So in my opinion, this is an early cut of data, first 20 patients. There are still many more patients to be enrolled in the trial and much longer follow up to be done. But we are extremely pleased to see the safety data and the preliminary efficacy data and we look forward to continue to enroll patients and explore the full potential of ziftomenib as in my opinion, best-in-class Menin Inhibitor that will likely change the way we treat AML in the coming years. Thank you so much.

So much, Dr. Zeidan. If we can proceed to Slide 27, I will walk through the clinical development plan we currently have ongoing for ziftomenib. So based on the safety of the tolerability, the clinical activity and the combined ability we've seen with zifto so far, we want to make sure that zifto is the market leader across combination partners and across lines of therapy. So we're broadly addressing combinations to set the foundation for zifto as the backbone for Menin dependent leukemias. And to that end, we continue to enroll our monotherapy trial that's in the registration-directed portion as described by Dr. Fathi. It is enrolling quickly, and we do expect it to complete enrollment in the middle of this year. Within the same trial, we have opened several sub studies to look at other Menin dependent leukemias, the non-NPM1/non-KMT2A-r leukemias that would also be able to benefit from ziftomenib therapy as well as the KMT2A-r ALL sub-study within the same trial. As Dr. Zeidan described, we have our ongoing combination trials with Ven/Aza currently in the relapsed refractory setting and moving into the frontline setting once we complete the Phase 1a, they're enrolling quickly and again, we are already in the 400 milligram cohort. The combination with 7+3 is also enrolling quite well, and we will be moving out of the adverse risk portion of the cohorts when we complete the Phase 1a as well. Our 008 trial, our combination with gilteritinib, FLAG-IDA or low-dose AraC is currently open and preparing for enrollment and our post-transplant maintenance trial is also planning to initiate and enroll the first patients this year. We have our pediatric programs that have initiated and are enrolling both in the AML and ALL subsets and are also doing well and should be enrolling this year additionally. And with that, I'll pass it back to Troy.

Thank you, Mollie. Just now turning to Slide 29. So as you've heard from the 4 physicians here on the phone, we think there's really tremendous promise for ziftomenib and other Menin Inhibitors to transform the standard of care, not only in acute leukemia but potentially in other serious diseases. We really see it now as a multiplayer, multibillion-dollar market opportunity and here, we're taking 3 approaches simultaneously. The first, of course, is to continue to execute against our monotherapy study, KOMET-001, where we've guided that we should have full enrollment by the middle of the year. That will give ziftomenib access to potentially 30% of the patient population. Beyond that, as you've heard, we're quite excited to continue to move ziftomenib aggressively, both into the frontline and the maintenance. These are much larger patient populations and large commercial opportunity together. They have potential to drive greater than 50% of the worldwide revenue and as you've heard throughout this call, we really think ziftomenib is well positioned. It has the ideal safety, tolerability, absence of drug-drug interactions, combined ability to really position it as the market leader. And then later this year, hopefully, we'll have a chance to share with you some of the work that we're doing and additional opportunities beyond AML that we think also support additional multibillion dollar potential. We have translational data that supports the application of Menin Inhibitors in solid tumors as well as in non-oncology indications. We look forward to sharing that with you in the coming months. Turning finally to Slide 30, just to lay out the upcoming milestones for our acute leukemia program with ziftomenib. As Mollie indicated, they are the first 3 lines, we're intending to dose our first patients in the KOMET-008 study. This is the combination now continuing to expand the footprint for ziftomenib to include combinations with the FLT3 inhibitor gilteritinib, low-dose AraC and FLAG-IDA. We're intending to initiate our post-transplant maintenance program and expand the development of ziftomenib into Acute Lymphoblastic Leukemia. We anticipate that each of these should be achieved this quarter. As I've indicated, we're expecting full enrollment in our KOMET-001 study by the middle of the year. Turning back to KOMET-007, which has been the focus of this call, we're looking forward to determining a recommended Phase II dose for ziftomenib in combination with venetoclax and azacitidine and once we have that, to initiating dose validation or expansion cohorts with ven/aza in frontline AML patients. And then in that context, we're looking forward to providing a next update for the KOMET-007 program. At this point, we haven't decided, it may be a medical meeting, it may be another company update. The next critical value inflection point will be achievement of the RP2D. We look forward to sharing more updates on this program with you. We want to thank the generous support of our investors. We're fortunate to have $570 million now in pro forma cash which gives us runway into 2027 and enables us to invest aggressively in research, development and precommercial activities to maximize not only the value of ziftomenib, but as well as the other assets in our pipeline. So with that, that ends our prepared remarks. Happy to take a moment, and then we'll open it up for Q&A.

[Operator Instructions] Your first question comes from the line of Jonathan Chang from Leerink Partners.

Congrats on the data. First question for the management team. What is your current thinking on how big the opportunity is for this class of drugs following the initial Menin combination data from both you guys and others in the space? Second question for the investigators on the call. What would you say are the key differences between ziftomenib and other minute inhibitors in development, if any? And I guess, if I can just sneak in a clarification question. Can you provide any additional color on the patients with prior Menin Inhibitor experience? Were these patients refractory to the prior minute inhibitor?

Sure. So Jonathan, I'm actually going to take your questions out of order. Understanding that it's enticing to speak to the patients who failed prior Menin Inhibitors, we're going to save that for a future update. That's an evolving story and as Dr. Zeidan indicated, we're continuing to both follow these patients and pursue dose escalation. So we're not going to get into what's beyond the slides. But turning back to the other 2 questions, depending on how you run the models, the opportunity in leukemia alone, we think, could be in excess of $2 billion to $3 billion for ziftomenib and that takes into account up to 50% of patients in the front line, getting a majority of patients back on drug post-transplant, having long-term therapy in the maintenance setting. But as I indicated, I think a number of the players in the Menin Inhibitor space are all kind of coming to a consensus that this is likely to be a multibillion dollar opportunity. How large could it become? One doesn't know. I think the more we continue to see good data good responses, good combinability. That's why I think, as Dr. Zeidan highlighted, the myeloma opportunity is such a telling one because if you look back in history, that's very much what we've seen there with a steady progression of various combinations pushing out the standard of care. There are, Jonathan, just to add to that, other opportunities that we'll talk to. We're just giving you a teaser now, but we'll look forward to sharing as we've said, additional data and development plans and additional indications beyond the acute leukemia later this year. With respect to your question on the differentiation between ziftomenib and other Menin Inhibitors Dr. Zeidan perhaps you could comment on Jonathan's question on that one.

Yes, of course. No, I think I completely agree with you. Clearly, at this point, the data continues to evolve in the combination setting. I mean to me, it's clear that both drugs or the drugs that are being kind of studied several of them to lead to clinical responses and I think it eventually is going to come also both in terms of the efficacy and the safety of these drugs. And I think one major difference, in my opinion, is the QTT issue because I think as Dr. Fathi mentioned during the call, I don't think in setting where we use many other drugs that are QTT prolonging such as or during the management of those patients, this can be a major headache. So I think that is, I think, a major differentiation of ziftomenib over other drugs. I think the other thing in terms of that efficacy in particular in NPM1 mutated disease, I do think that the data seems to favor the ziftomenib. It's really tough to kind of make a big kind of differential statement at this point given where the drug development is in. But in my opinion, it would not be a bad thing for the field to have multiple active drugs because this is, I think, how things generally move in a much more efficient way. So we would be happy to have multiple active agents.

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

Perfect. Appreciate the question and congrats on the data. I wanted to circle back on the responses in the Menin and experienced patients which arguably made up a solid portion of the R cohort. Redosing has kind of been an open question in the field, especially when considering the opportunities and moving say from first line to post-transplant maintenance. I was curious what you thought the current potential look like in terms of responses and do you think the follow-up is it independent of which Menin Inhibitor was initially used?

Jason, it's a good question. I'm going to take this one. Again, probably more to say about that later in the year. It's an evolving story. We have seen patients come in from the Syndax trial, the J&J trial as well as ours. It's early days and as Dr. Zeidan indicated, we're still learning about exactly what's needed in Menin experienced patients as to what to do. So I think it's something to look forward to for a future update. The data thus far is encouraging, but we're going to save that for an update later in the year.

Your next question comes from the line of Roger Song from Jefferies.

Great. Congrats for the data. It's great kind of to see another Menin Inhibitor updates in the field. So a few quick questions from us. One is for the first line. Can you comment on the enrollment seems a bit slower compared to the R&R cohort? Is that due to you exclusively enroll those patient with high risk? And also just the second part of this normal question is how you will move into the come first line for 7+3. I'm curious why FDA requiring you to enroll high-risk first-line only in your first dose escalation? And then I have a follow-up.

Sure, Roger. So I'm going to ask Mollie to speak to your first 2 questions, which are enrollment in the frontline setting and then the requirement for starting in more challenging patients before we move into the broader population. Mollie, if you could.

Sure. Keep in mind that enrollment comes in waves. So while in the first 20 patients, maybe there was a bigger wave of relapsed refractory. That does tend to even out over time, but it is more challenging to enroll the high-risk patients having to narrow down the NPM1 mutants in particular it is difficult having to get patients in the KMT2A setting who have such aggressive disease, it's a challenge to make sure that we get them treated in time within the context of a study, many just start backbone therapies outside of the context of the study. And why high risk, it's such a good therapy, a well-established therapy that FDA always wants to make sure that you are not causing additional harm to patients before opening it up to the broadest patient population. So starting in the adverse risk patients, patients that probably would benefit most from additional therapies from study participation, the FDA tends to push you into testing it there, make sure you're not having additive talk or having any detrimental effect on the efficacy rates that are usually seen. And then you can open it up into a broader patient population. We're pretty confident already that we are not seeing any reason that we won't be able to open it up to that broader patient population in the Phase 1b.

Roger, did you have a third question?

Yes. Just a very quick one for the R&R cohort. So understanding you want to save the save the response or the activity for the patient with prior Menin. And can you comment on these patients, the nature of the response for those patients with prior Venetoclax or ven/aza because maybe we have different expectations for those rechallenging ven/aza due to following the previous ven/aza response.

Sure. Dr. Zeidan, could I ask you to comment on Roger's third question about the nature of the response in Venetoclax experienced patients?

Yes, absolutely. So as I mentioned during the call, there were 10 of those patients out of the 15 who are in the relapsed refractory setting. And out of those, 5 of them were NPM1 mutated and the other 5 were KMT2A-r and the overall response was around 40%. Most of those 60% were in the NPM1 mutated and the 3 out of the 5 basically achieved an overall response rate. And importantly, this is very important to remember that 2 of those have CR or CRH, right? Because when people present in trials, sometimes they make morphologic leukemia-free state or things where you don't have count recovery. But this is 2 out of 5 patients with Ven exposed NPM1-mutated patients who achieved CR or CRH and 1 out of 5 achieved CR/CRH in the KMT2A-r. Now those numbers might look on the lower end for someone who doesn't treat leukemia clinically. But what I can tell you is that it is a ven failure, it is the most horrendous sitting in my opinion in patients with refractory relapse setting. Those patients do extremely poorly with a little -- the survival rate of 2.4 months. The response rate, as we cited on the call is very low. There isn't generally active agents in this setting unless they happen to have an IDH or FLT3 inhibitor or something like that. And even in those settings, the responses are generally not lasting. So I think we need to get larger numbers and longer follow up to understand the rate of response as well as the durability of response and clearly some sense of the overall survival. But what I'm seeing based on my own experience compared to what we used in the kind of standard of care setting where we try whatever we can or in an investigational setting, I think to my eye, the data is very compelling at this early cut off.

Great, thank you. Dr. Fathi, is there anything you want to add on Roger's question about the challenges with ven/aza experienced patients?

I don't really have that much more to add. I think overall, it's very early. I think just broadly speaking, there are certain patient populations that are very challenging and among these is that group that's been previously exposed to Venetoclax in our hands with standard conventional treatments, there isn't much that we can offer them and most of the treatments that follow Venetoclax have not historically been shown to be particularly effective in prolonging durability of response. So if you have a drug or an agent that allows you to salvage patients, I think that is something that will be very welcome in our field.

Your next question comes from the line of Li Watsek from Cantor Fitzgerald.

Congrats from the data. A couple of questions from us. I guess first, can you comment a little bit on myelosuppression, especially in intervene regimen? And since it's a combination and my understanding is the disease may have some contribution here as well. So just curious what are the sort of the key metrics you look at to keep the ziftomenib contribution? And then just curious by your thoughts on whether this may be a class effect or not? And the second question, maybe just make a comment on any dose disruption or reduction during the trial.

Thanks, Li, for the question. So Dr. Fathi, maybe I can start with you. If you could comment on Li's questions around the potential for myelosuppression and what we've seen with ziftomenib and then I'll ask Dr. Zeidan to also add his thoughts. But let's start with you first.

Sure. And as I mentioned earlier, one of the common challenges that we oftentimes have with treatments that we study and employ in AML and other marrow-based malignancies is the effect on the normal healthy progenitors themselves, and treatments that we use in this space can cause substantial cytopenias, whether it's traditional cytotoxic chemotherapy, Venetoclax in combination with Azacitidine or Decitabine. Anything that we've used historically to treat AML at least for the first few weeks of treatment and then subsequently with every cycle leads to substantial marrow suppression and every few weeks, you have to kind of hold your breath as patients drop their counts and hope that you don't get into trouble with infectious and bleeding complications. And with various drugs that have been studied in clinical trials, that has also been a recurring problem, sometimes more so, sometimes less so. So I think if you have agents that over time, especially as patients achieve their ultimate response do not lead to this yo-yo effect of recurrent episodes of cytopenias that cycle and put patients at risk repeatedly. That is something that is very welcome and this is something that we're now seeing with some of the targeted agents that have become available. IDH inhibitors, for example, are an example. Once patients achieve a response, oftentimes on IDH inhibitors, there is not this worry of recurrence of suppression of blood counts over time so that they can tolerate and benefit from it longitudinally in a durable way. And I think the data we have at least so far from the monotherapy experience that I shared earlier is that the patients that achieved a response on that study remained in remission with very good acceptable blood counts that did not suggest a substantial marrow suppressive effect from this Menin Inhibitor. And I think that is an important observation.

Great, thank you. Dr. Zeidan, do you want to add your thoughts on the presence or absence of myelosuppression and if anything, if zifto is contributing at all to that to add to Dr. Fathi's comments?

No, I largely agree with what Amir mentioned, I think myelosuppression clearly is a major headache that we have when we combine many of other drugs with azacitidine or with 7+3, many times it's quite apparent that when you add a drug, it's causing myelosuppression. Here, my sense is that we are not seeing additional myelosuppression. This is a relatively smaller cohort with an early cutoff of 20 patients and different combinations. Ultimately, clearly, you need itemized data to answer this question definitively. But my sense is that we have not been seeing additional myelosuppression as we showed in the data. And we are able to continuously administer the drug through the different phases of the disease induction consolidation. Some patients are proceeding to maintenance. So I think this is certainly a setting where there is no major concern on that area and kind of to actually allude to the earlier question that was asked about moving this to more of the adverse risk and even to the frontline treated patients, I personally think that safety data is very compelling to move this to more like all NPM1 mutated patients. And I think there is no concern on efficacy compromise actually quite effective in my opinion, in the fair-patients treated in the frontline setting. So I do hope we would be able to get the protocol to enroll in the non-adverse risk NPM1-mutated frontline intensive treatment as well as the frontline is even. And I think this is a huge potential for ziftomenib.

Thank you, Dr. Zeidan. And Li, with respect to your third question about discontinuations or reductions, I'm going to ask Mollie, if she could speak to that because she looks across the entire study.

So we are not seeing any patterns of discontinuations or interruptions. We don't have any patients that have required a dose interruption of zifto to allow for count recoveries even if they do have a dose interruption of the backbone therapy, which is a usual practice to allow for account recoveries. So really no need for dose interruptions or discontinuations.

Right. And to Dr. Zeidan's comment, Mollie, can you just speak to the audience about what's needed from an FDA interaction standpoint to be able to go to the front line and relax those initial restrictions?

So fortunately, we negotiated with FDA that we would not need to return to have a discussion with them surrounding the ability to go into a broader patient population within the Phase 1b. We have an independent data monitoring committee as well as a safety monitoring committee that are going to be reviewing the data on a regular basis and at the time it's appropriate to move into the Phase 1b, and they will be able to prove the ability to move into the Phase 1b and into the broader patient populations at that time.

Your next question comes from the line of Peter Lawson from Barclays.

Great. thanks for the update and all the insights from the clinicians. Troy, I've got a couple of questions for the team. Just on the expansion beyond NPM1 and KMT2A in AML. And if you could elaborate on those additional subgroups in heme and kind of what adds to the confidence about search and move? And then second question is around the data that we see later this year in solid tumors and non-oncology indications, is that pre-clinical, clinical, et cetera, would be great.

Sure. Thanks, Peter. Let me ask Mollie if she can speak to our development plans beyond the NPM1 and the KMT2A patient subsets.

So there is data that exists that shows about 50% of patients have some form of Menin dependence to their disease. And that's based upon their HOXA9 MEIS1 expression. We obviously know that about 35% of those are the KMT2A and NPM1 patient populations. And we think we have a good idea of who the additional 15% are. So we're using that knowledge and that additional data that we've generated, and we've gathered from other sources in order to feed into our now non-NPM1, non-KMT2A cohort that is open within the 001 again. And once we are finished doing some additional work around that, making sure that we are able to proactively identify, we'll move those into the combination setting as well and really go for a full Menin dependent leukemia population.