Good morning, everyone, and welcome to Kura's 2023 EHA Investor Event. I'm Troy Wilson, Kura's President and CEO, and I have the pleasure of having a number of our speakers here today who will introduce themselves. If we can go to slide number two. I just want to remind everyone that today we're going to be making forward-looking statements, and I would refer you to our website or to the SEC website for more information about the risks and uncertainties of an investment in Kura Oncology. If we go to the next slide. Here's the agenda for our call. We're going to start with welcome and opening remarks. Stephen's going to introduce our investigators. We're going to give both Dr. Issa and Dr. Fathi an opportunity to walk through the data, and then we'll do a Q&A session with both Drs. Issa and Fathi, as well as our team, Stephen Dale and Mollie Leoni. With that, we'll go to the next slide, and I'll turn it over to slide number four, and I'll turn it over to Dr. Stephen Dale. Stephen? Thank you, Troy. Just to echo the welcome to everybody, I think we're all still excited after the superb EHA event in Frankfurt. I just wanted to say that Kura has a goal, the goal at Kura is to transform the standard of care for AML. If we look across the disease area landscapes, in contrast to lymphoma, to myeloma, and their treatment paradigms, AML and the disease area landscape for AML has certainly lagged behind the other hematological cancers. It presents a significant opportunity for us and for KO-539, for ziftomenib, to address that high unmet medical need. If we look at treatments over the past 10 years, past decade, notwithstanding, the IDH inhibitors coming in, the FLT3 inhibitors coming into play, there is still a high unmet medical need for these patients. With that said, we firmly believe that ziftomenib will transform the standard of care for these patients, and we will evoke a paradigm shift in the way that these patients are treated. To be transformational, obviously, we have to see a positive benefit risk across the spectrum with superior efficacy and superior safety and tolerability. We can achieve that across the spectrum of the disease, from relapse refractory through to frontline treatment, through to maintenance, and really set the gold standard for treatment in these patients. Indeed, we already have emerging data and current data which places us firmly as the best-in-class agent in the menin inhibitor class. You can see on slide four, the four pillars, which are key in this journey to become a best-in-class agent, both being highly differentiated from a competitor point of view, but being superior and early in the treatment paradigm, both in monotherapy but also importantly in combination. Meaningful durability, extremely important, as we look towards maintenance, and a backbone for combinations, and also as a potential to sequence earlier. Data are showing that there will be potential for building on the data so far, so we can sequence ahead of IDH1s, IDH2s, and also FLT3 inhibitors in the treatment paradigm. The 4th pillar, really looking to expand beyond NPM1 and KMT2A patients as we look to build on high clinical activity already seen in our phase I program. Certainly, looking at the SETD2/RUNX1 patient, where we saw a complete remission. With all of that said, I'm therefore delighted that we have two of our esteemed investigators with us today. We have Professor Issa, who's joining us from MD Anderson, and we have Professor Fathi, who joins us from Massachusetts General Hospital. With all of that said, Dr. Issa, I hand over to you. Thank you, Dr. Dale. Today I'll talk to you about the unmet needs. In this case, this is NPM1-mutant AML. NPM1 is the most common genetic alteration in acute myeloid leukemia. It's estimated to be about 6,000 new cases in the United States. When newly diagnosed or in patients that present with leukemia, the first-line treatment, the overall survival is estimated at about 50%. However, during relapsed refractory disease, in fact, the outcome of NPM1-mutant AML is the same as any relapsed refractory acute myeloid leukemia, with really a high unmet need for therapies to improve these outcomes. For the expected survival for second-line therapy in someone with NPM1 relapsed refractory disease is about seven months and drops from third to fourth line to five months to and three months. This is data that we've done at MD Anderson. Despite this high unmet need, there are to date, no FDA-approved therapies or targeted therapies for NPM1, specifically for this subset. In addition, NPM1 frequently co-mutates with multiple other alterations in acute leukemia, therefore, targeting NPM1 could provide a larger opportunity to target multiple mutations since NPM1 is the founding event in development of acute leukemia. Next slide. This is the mechanism of action of ziftomenib, which is a menin inhibitor. Menin inhibition is really targeting the interaction between KMT2A, previously called MLL, and the protein menin. This interaction is critical for multiple subsets of acute leukemia. Most commonly, or the ones that we know best about are KMT2A rearranged leukemias and NPM1 mutant leukemias. Through this interaction, these leukemias have upregulation of an aberrant gene expression program, an abnormal software to this hardware. That's expression of MEIS1 and HOXA9, and this gene expression program leads to development of leukemia, either by blocking differentiation or by increasing proliferation genes. Using this, these small molecule inhibitors like ziftomenib, it blocks the interaction of KMT2A and menin, therefore disrupts this abnormal gene expression program and leads to reversal of this differentiation arrest and an anti-leukemic effect. As you can see also on this cartoon, there are multiple other alterations that are found in acute leukemias, not just AML, that could also depend on this interaction, and therefore, menin inhibition could be a therapeutic opportunity for a larger subset of acute leukemias. Next slide. To take you through the design of this phase I study of ziftomenib. This was a phase I, phase II study in relapsed refractory acute myeloid leukemia. In the phase I-A, we did dose escalation, started with 50 and reached a 1,000-milligram dose. In that case, there was no restriction by genotype. We enrolled NPM1 and KMT2A, including other acute leukemia subtypes, and this is the example that Dr. Dale was referring to with a patient with RUNX1 R52 that responded. Once we reached a maximum tolerated dose or a recommended phase II dose, we moved, or in fact, in here we moved using Project Optimus to the phase I-B to validation cohorts using 200 milligrams, 600 milligrams, and restricted enrollment to NPM1, KMT2A. Afterwards, we did a phase I-B expansion of the 600 milligram daily cohorts in the NPM1-mutant acute leukemias, and we continue enrollment on validation according to the FDA Project Optimus. Dr. Fathi is going to take you through some of the results we found in the NPM1-mutant acute. Next slide. Thank you, Dr. Issa, and my apologies. I'm actually in Berlin, outside of my hotel room, so if you hear any extraneous noises, my apologies, and I hope you can hear my voice well. I just going to go first through some of the safety and tolerability information that I presented a couple of days ago or yesterday, time flies, at EHA, related to this phase I portion of our trial of ziftomenib in relapsed and refractory NPM1-mutated patients treated at a dose of 600 milligrams daily. This data is for both treatment-emergent adverse events as well as treatment-related adverse events in 20% or more patients seen on study. None of the information on either side of these tables here for TEAEs as well as TRAEs are anything new from what has been previously reported. There are no new signals of safety or toxicity concern. I'd like to sort of bring your attention to the more common treatment-related adverse events, which were nausea and differentiation syndrome, and the latter is perhaps of greater interest. In this trial, about 20, actually, 20% of patients had differentiation syndrome. Only one patient had Grade 3 differentiation syndrome, and none had any higher grades of differentiation syndrome. The patient with a Grade 3 differentiation syndrome was managed appropriately with steroids and other measures to sort of mitigate the effects of this condition. Of note, as has been seen with other menin inhibitors, there was no report of drug-induced QTc prolongation. In terms of clinical activity, as of the most recent data cutoff, the complete remission rate is 35%. The composite remission rate, including a CRI, is 40%, and the overall response rate, which includes yet another response MLFS, is 45%. We also looked at co-mutations of FLT3 and IDH. Among the 6 patients who had FLT3 mutations, 2 achieved a remission consistent with a CR of 33%, and among 8 who had IDH mutations, a half of them also achieved complete remission. The median time to response was 51 days. Here's some information regarding the standards of care on the right side of this slide, that we currently have available for IDH and FLT3 inhibitors, in comparison to what was presented earlier, as well as median duration of response. The next slide gives us a general idea of how to assess the timing of response among the patients that have been treated on this trial. As you can see, you have this rise in both platelet count and neutrophil count over time, and people in general achieve a significant rise over the first 3-4 cycles, as can be seen here. The maintained count recovery subsists, continues, and is durable, suggesting that there is no significant drug-induced myelosuppression. The overall safety profile is very encouraging, with no new adverse events or drug-drug interactions. The next slide, I think, hammers home the point of the durability of response. The median duration of response was 8 months. This swimmer plot provides you with all the patients in the phase I-A and phase I-B portion who had NPM1 mutations at both doses of 200 and 600. The 200s are in green, the 600s are in blue or purple. I can't really tell here on this screen. As you can see, the responses are quite durable. The one patient at the top there, I believe, is the patient that we treated at Mass General, who is MRD-negative CR as of the data cutoff all the way into cycle 36. Quite impressive. You have these 2 patients, 9 and 21, who proceeded to stem cell transplant. Patient nine remains on drug, actually, as a post-transplant maintenance. The next slide, the meaningful durability and favorable tolerability of the 600 milligram dose, just to provide some context around what we have here, two patients that we'd like to sort of present. Both of them, I believe, actually are at my institution. We have a 44-year-old female who was dosed at 200 milligrams, achieved MRD-negative CR after one cycle and persisted in that fashion for another 35 cycles, with ongoing response. Their baseline bone marrow blast at time of relapse was 14%, and she had seven prior rounds of treatment, so quite impressive. Another patient, a 22-year-old with an NPM1 mutation AML, was refractory to 7+3. Baseline marrow blasts were very high at 90%. This person was dosed at 600 milligrams and after one cycle, achieved MRD-negative CR, went to transplant and remains following transplant in a deep MRD-negative remission. Just to sort of talk about, you know, some of the analysis that is ongoing on our patients and perhaps provides more rationale to combine this ziftomenib with other targeted therapies or in combination. These are two subjects that I actually treated, that I presented actually at EHA in the spoke. One patient who had a FLT3 TKD mutation and previously treated with midostaurin in a line of treatment. As of, I believe it was four cycles or five cycles, at the end of five cycles, I'm reading here, had no longer any detection of MRD in terms of either FLT3 mutation being picked up or an IDH1 mutation picked up, both of which the patient had at baseline. Another patient with a FLT3- ITD mutation, previously treated with two rounds of FLT3 inhibitor therapy, both midostaurin and gilteritinib, by the end of cycle 4, had marked suppression of NPM1, FLT3- ITD, as well as IDH2, and these analyses are ongoing. In summary, it looks, appears that ziftomenib drives CR and brings co-mutations down along with the molecular markers that are targeted, the foundational targets, including NPM1 and KMT2A, in terms of ongoing response. This appears to be the case, at least on the limited number of patients we've studied, among also patients that have been previously treated with targeted therapies, including the FLT3 inhibitors and IDH inhibitors. This is a segment of the next slide is a segment of this presentation that I did not present, but it provides an additional analysis of patients that have been treated on study. Those patients who actually do not have either NPM1 mutations or KMT2A in the first portion of the study, the 1A portion of the study. One patient, also at our site, had a RUNX1 and a SETD2 mutation, both of which, in theory, could be impacted by the pathway that is downstream of the menin-KMT2A interaction, and this patient actually went into ACR at this relatively low dose of 100 milligrams daily. There is notable evidence of blast reduction in range of off-target patients. The waterfall plot that you see here on the right are a group of patients that have varying degrees of response at different doses and in terms of blast reductions. The patient at the bottom right, I believe all the way to the right there, is the patient that I mentioned. The KOMET-001 study will continue to evaluate additional AML populations over time, and there is a potential to be incorporated into the KOMET-007 and KOMET-008 combination studies. During the presentation at EHA, we also spoke about some of the new emerging data regarding resistance mutations. Given some recent publications regarding specifically 3 resistance mutations to a, to another menin inhibitor that had emerged on therapy, we did some additional analysis in relation to ziftomenib and our patients. When looking at ziftomenib, there are no major in terms of co-crystallography studies, no major conformational changes observed in menin T349M versus wild type, which was one of the mutations that was of concern with other menin inhibitors. The M327 and Y324 side chains adopt new conformations. That appears to be the case, the menin T349 altered protein does not appear to affect ziftomenib binding. The binding affinity of ziftomenib is reduced for the menin M327I, which was also been reported by Dr. Armstrong and his group previously, but is unaffected by T349. Also, ziftomenib appears to retain activity again, shown in recent data against menin G331R. It does appear, again, I think there's ongoing analysis to try to figure that out, but at least when it comes to certain secondary resistance mutations, that this agent remains active. Next slide, please. ziftomenib does appear to be less susceptible to some of these secondary mutations, and following reports of these emerging with other menin inhibitors, there was an analysis of 29 patients that were treated and enrolled and treated on the KOMET-001 study. Among the 29 subjects, one case of M327I mutation was detected in a patient who had evidence of disease progression. This was seen at the end of cycle 4, with a variant allelic fraction of 6%. Of note, this patient also, as I mentioned during the presentation, had a RAS mutation emerging the cycle before, so it is unclear whether the disease progression was due to either of these events, or both, or one or the other. Nevertheless, I think this is interesting data that needs to be looked at further. The MEN1 mutant RNA was not detected after analysis in 13 of 13 other subjects who received two cycles or more of ziftomenib. These were patients who had morphologic evidence of disease, meaning they had persistent disease on treatment or had progressive disease on treatment. This suggests that progression or lack of response in these subjects who had been on ziftomenib for two or more cycles would not be due to the secondary MEN1 mutations. You know, I think a lot needs to be learned in this area, but it is possible that ziftomenib's ability to target the persisting ability of ziftomenib to target resistant mutations G331 or T349, and may have something to do with the lower frequency of MEN1 resistance mutations. In summary, ziftomenib demonstrates significant clinical activity with a 45% overall response rate and a 35% CR rate. There is relatively minimal myelosuppression and maintained count recovery, particularly in patients who are responding. Durable remissions with MRD suppression, particularly of foundational clones like NPM1 and other co-mutations, have been seen in several patients on study, which is encouraging. Resistance mutations have developed, but they have been infrequent, and ziftomenib remains activity against multiple gatekeeper mutations. In total, ziftomenib is well tolerated with no drug-induced QT prolongation. We saw one case of DS among these NPM1-mutated patients that we presented today. The lack of a predicted adverse drug-drug interaction is also notable. I should bring that up because it is supportive of combination therapies. That is, I do hope, as I mentioned also in my presentation over time, will not only enhance efficacy of these agents, and capture efficacy of these patients, but also ameliorate some of that toxicity on differentiation syndrome. It's a bit harder to have differentiation syndromes when you have less cells to differentiate. We think that combinatorial therapy may help in this regard. I thank you so much for your attention. Our enthusiasm to get started into the combinations is really supported by all of the data that Drs. Fathi and Issa were just describing. As you've seen, we've deliberately designed our combination strategy so that there's a place for every NPM1 and KMT2A patient that might enter a physician's office and need treatment from the first line all the way through till their maintenance program, all the way through to relapse refractory disease. Starting at the top, we are, of course, in our registrational directed monotherapy trial, and as Dr. Fathi was referring to, we are excited to get back to our non-NPM1, non-KMT2A disease patient population because we have seen some significant activity in those patients, and we think we are getting better at identifying who is potentially menin-dependent and who could potentially benefit from ziftomenib therapy. We will be beginning our combination strategy with venetoclax and azacytidine, as well as 7+3, and our more relapse refractory focused study with gilteritinib, XOSPATA, and low-dose azacytidine. I want to highlight that while we will be doing the phase I dose escalations in these patients, we will only be carrying forth the combinations that really have the optimal benefit-risk balance and will be most applicable to the most wide variety of patients. We are also initiating our post-transplant maintenance study, and this has actually been converted from initially intended to be an investigator-sponsored study. It will now become a company-sponsored trial with registrational intent. Of course, we are beginning our combination strategies in the pediatric setting. With that, I will hand it back to you, Stephen, for final thoughts. Thank you, Mollie. Before we go into our Q&A session, just to round up what we've been saying, ziftomenib does represent a transformational therapy for AML, and we firmly believe that ziftomenib does have the ideal properties to become a backbone of therapy across the continuum of care for AML patients and moreover, pursuing a broad-based ziftomenib development program, coupled with potential to convert 50% of AML from an acute to a chronic disease. ziftomenib is a significant advancement in the treatment of these AML patients and is firmly in the positive domain of the benefit-risk assessment. With that said, I hand over to Troy. Thank you, Stephen. I should have mentioned at the outset, if you have a question and you want to submit it, there's a box there to submit questions. Quite a few questions have come in. I want to thank all of our speakers, particularly Dr. Fathi, who has a toddler who is sleeping, many time zones away from home. Dr. Fathi, we appreciate you doing this. There's a lot of questions. I'm gonna try to group the questions if I can. Dr. Issa, maybe I'll start with you. Just coming off of what Stephen was saying, the questions come in, do you agree, Dr. Issa, that menin inhibitors are potentially transformational in the treatment of AML? Absolutely, yes. This is the result of years of science that established menin and KMT2A interaction to be critical, and KMT2A-rearranged leukemias, which is, you know, the less common genotype that we're studying. Accounting for NPM1 or other leukemias that have high HOXA and MEIS1, this could represent a large fraction of acute myeloid leukemia, 50%, and possibly acute lymphoblastic leukemia and mixed genotype that have alterations with high HOXA and MEIS1. In addition, because of the co-mutation status of these mutations, you can now think of these alterations as the Achilles heel that we can target with menin inhibition. Therefore, we would expand the reach of targeted therapy to a large subset of leukemia. My favorite part about this is that this is targeting one of the foundational events of leukemia. Instead of targeting a subclone, and later on another subclone would emerge as a mechanism of resistance. In theory or based on lab evidence, we think that by targeting these foundational events, it would lead to durable remissions. Therefore, I think that this is truly gonna be transformational. We still have to wait for the data to see what's gonna happen, but I'm very excited about it. Terrific. Thank you. Dr. Fathi, maybe for you, could you highlight some of the advantages of ziftomenib, both as a monotherapy and as a potential agent in combination? Both you and Dr. Issa talked about your desire to move it, move these drugs into combination. Can you just touch on some of the advantages of ziftomenib that you see, if you would, please? Thanks, Troy, and no problem. I'm always happy to help. I just thought that the street noise in Berlin might be preferable to a toddler screaming, so we went with the street noise. As far as you know, I can't probably directly compare menin inhibitors and probably should not do so, but there are certain features of ziftomenib that are unique, based only from the data that we have. In some fashion, I, you know, I think all of us would agree that the lack of QT prolongation and observed drug-drug interactions is something that would be favorable in any targeted drug. We would be, you know, in terms of combinations and, you know, a lot of patients who have AML are on concurrent therapies of all sorts for infectious and inflammatory issues. I think that is something that is, as I mentioned, favorable. In terms of the drug itself and its properties, you know, I sort of echo what Dr. Issa said. You know, we don't have too many effective targeted therapies in AML. We have IDH1, IDH2, and FLT3 for subsets of AML. FLT3 mutations do occur later in the development of AML. NPM1 mutations, KMT2A, rearranged disease occurs earlier. Therefore, you know, if you get something earlier in the course of the disease, you're therefore less likely to have something potentially bleb off and cause a disease resistance. That, I think, is encouraging. I think the potency and the specificity of this drug are also quite good, and in general, it is quite well tolerated. I think the data is there. There are some cytopenias that have been seen on study, but nothing significant. By the time patients respond, they have really good blood counts, and they continue to respond and do well. At least in NPM1-mutated patients, I did like the fact that differentiation syndrome occurrences were quite minimal. And when they did occur, you know, they could be mitigated. Nevertheless, I think it's something that we need to watch very carefully. Yes, it's something of concern with this class of drug and does require more exploration and publication and dissemination of knowledge. Terrific. Thank you. Thank you, Dr. Fathi. Dr. Issa, we get this question a lot. Can you comment on the unmet need for the NPM1 mutant patients, both in the relapsed refractory setting, and in the frontline and in the earlier lines? Sure. I'll start with the relapsed refractory setting because that's sort of easier to debunk that there's no unmet need. The thought is that NPM1 has favorable prognosis and when newly diagnosed, so that means that when patients have relapsed refractory disease, they should do well. It is not the case. In relapsed refractory AML, the NPM1 mutational status does not affect survival. This is study of hundreds of patients. Therefore, we need therapies for NPM1, just like any other relapsed refractory AML. Menin inhibition would be that solution in that case, for all the reasons that we discussed, because it has excellent mechanism of action that we have studied really well, and it targets a foundational event, it targets transcription, and therefore, could affect multiple transcription programs that are critical for leukemia survival. For the newly diagnosed patients, some may argue, "Well, it's a favorable prognosis. Why do you need more therapy?" That argument, to me, is not very valid because if we went by that logic, breast cancer ER positive would not need therapies, yet we have hormonal therapy as the most successful targeted therapy in breast cancer. By using menin inhibitors in the frontline setting, perhaps we can expand the reach of targeted therapy and target more patients with better therapies that would really mechanistically stop the leukemia and hopefully have less side effects than what we use today. Great. Thank you, Dr. Issa. Mollie, question here for you. It's a two-part question. Does the median DOR include the 200 milligram patient? Yes. Yes, it does. can you tell us, do we know the breakdown in the DOR with and without that patient? With the 200 milligram NPM1 mutant patient, the DOR is 8.2 months. Without the 200 milligram patient, it is 6.9 months. Just continuing to some picking questions off, do we expect that DOR to improve? Well, the DOR we're seeing in a fourth-line plus NPM1 mutant patient population is already extraordinarily clinically meaningful, it's already really sufficient to support the regulatory hurdle of 4-6 months that we would anticipate. That's great. Thank you. Maybe turning, just Mollie, staying with you and turning to the question of mutations. Dr. Fathi, in his presentation, highlighted the data that suggests that ziftomenib is maybe less susceptible to resistance mutations. Why is that? We're just theorizing at this point. One of the ones is one, is something that Dr. Fathi put forward, that yes, we retain activity against at least two of the three known menin mutations, so that could be part of it. Another way that we've been theorizing that we could be avoiding the early onset or the more frequent onset of these menin resistance mutations is what we've discussed in the past, our high level of exposure, our long half-life, our high volume of distribution, our tissue penetrance, accumulation, and ability to hit extramedullary disease. All of these things make it so that we are consistently and constantly, putting pressure on the leukemia, putting pressure on the disease cells so that they have less opportunity to allow these clonal events to happen, to allow these menin mutations to grow out. It's a working hypothesis, but it's one that seems consistent with the data so far. Great. Just a follow-up question to that, Mollie. Did we look in the clinical specimens for the complete set of mutations? We looked for the complete set of reported mutations. In general, we looked for everything. We looked for anything that could be there. Any mutation? Any mutation. Okay. Any abnormality. Great. Thank you. Dr. Fathi, a question for you. If the goal is to get these relapsed refractory patients onto transplant, what difference do resistance mutations make? It depends really on how deep, in my view, at least, your measurable residual disease is. Pardon the wind. You know, if there's still persistence of disease and you pick up a secondary mutation, depending on, you know, how much of it is there, technically, patients can relapse following transplant. That then opens the door, I think, for discussions about, you know, how to manage these patients following transplant and the issue of maintenance therapy. In the session that I presented, Dr. Levis preceded me and provided data on a very impressive data set from the MORPHO study, looking at CLTS maintenance following transplant. I do think that secondary mutations or any mechanism of secondary resistance, even that is not potentially related to these mutations, as was also elaborated on during the meeting, in a prior session, is important because it helps us then manage these patients before they get to transplant, hopefully bridge them to transplant, and then to keep them in remission following transplant. That's terrific. Thank you, Dr. Fathi. I've got to pause for a second and remind everyone, if you want to submit a question, there's a box on the webcast that you can do so. We have a lot of questions we are working through, but we're gonna try to get as many answered as we can in the time we have permitting. Dr. Issa, I'm gonna come to you actually, with this next question. We've heard about the potential for ziftomenib to resensitize patients to venetoclax. Can you comment on this? If so, what does that mean for patients? Sure. venetoclax, which targets apoptosis, in acute leukemia, and it's also used in multiple other leukemias. In acute leukemia, it's now the standard in older, unfit patients, in combination with hypomethylating agents. Because venetoclax is very effective, it's been used in multiple other combinations, including in younger patients. We are ending up, in the majority of cases, having patients exposed to venetoclax before being treated on menin inhibition. Some observation we've seen as investigators is that even though these patients that receive menin inhibition have progressed on venetoclax in the past, they tend to respond to venetoclax after receiving a menin inhibitor. There is some rationale behind that, or at least something I can hypothesize about, but it needs to be tested. This is some preclinical data from Dr. Craig Jordan, Colorado, saying that venetoclax resistance upregulates the menin MLL program. Therefore, by using a menin inhibitor, we are targeting one mechanism of venetoclax resistance. Overall, I think this also indicates that the combination of venetoclax and menin inhibition would be synergistic. There is a few preclinical papers highlighting that this combination would improve survival in the mouse models of either NPM1 or KMT2A rearranged leukemias. Hopefully, soon in patients, we would test this hypothesis. Great. Thank you, Dr. Issa. Mollie, question for you. Mm-hmm. It's actually a three-part question. Have we dosed patients yet in combination? Which combos do we expect to dose first? Can you comment on the starting dose? Sure. We have not yet dosed any of the patients in combination. With the enthusiasm with which sites have been getting on board and getting opening, we expect for that to happen imminently. We do have one site open and about four more that should be opening this month. We do think that the first patient will be on and dosed imminently. As to which combination I think will be dosed first, it's tough to say because as I said a little while ago, we have designed the program so that there's a place for any patient that walks into a physician's office. While NPM1s are more common, KMT2As have such a higher need. It's tough to say if it'll be the venetoclax/azacytidine or 7+3 that'll get a patient first. The third part of your question, Troy? The third part is, can you comment on the starting dose? Starting dose. We are starting 2 dose levels, beneath the monotherapy dose. We're starting at a 200 mg combination with ziftomenib and quickly escalating. Great. Thank you. There's a follow-up question to this, which I'll take. The question is, should we expect combo data this year? Typically, it takes about 12 months to generate phase I-A data. you know, as Mollie indicated, we're starting at a 200 milligram dose. It's our goal. We appreciate people want to see the data in combination, and in particular, to address the question of whether we can mitigate the differentiation syndrome observed in the KMT2A patients. It's our intent to release data as it's available and as it's appropriate, and not necessarily wait for all of it. The typical timeframe is about 12 months for our 1a, but we'll go as quickly as we possibly can. Stephen, just on this theme of combinations, a question here for you. Any tox concerns, any drug-drug interactions that we're watching for as we look to move forward into combinations? Thanks, Troy. In short, the answer is no. We have no concerns whatsoever regarding drug interactions or toxicity moving into combination. I think it's also important to mention that regarding that, we have no evidence of any drug-induced myelosuppression, nor do we have any evidence of QT segment prolongation as well. Both important factors for other menin inhibitors, which may not have that same trend. We have no DDI concerns at all. Terrific. Thanks, Stephen. Mollie, back to you. Can you give an update on the KMT2A portion of this phase I trial? Yeah, sure. Good question. We have had another patient evolve to a complete response since we did our updated ASH back in December. Even though we are still obviously seeing a clear monotherapy activity, we are still quickly moving forward with our combinations as our best approach for handling that particular patient population. Great. Thank you. This will be a question for Dr. Issa and Dr. Fathi. You see these patients day in and day out. What gives you confidence that you will be able to mitigate, potentially mitigate differentiation syndrome in the KMT2A patients through combinations? Dr. Issa, maybe I can start with you. Sure. This would be based on prior experience we've seen in acute promyelocytic leukemia, where differentiation syndrome has been observed, or IDH mutant acute myeloid leukemia, where IDH inhibitors lead to differentiation syndrome. In those settings, when single agents were used, in general, we saw differentiation syndrome. When we started using the agents that lead to differentiation in combination with chemotherapy, and differentiation syndrome incidence was significantly decreased, and the sort of the severity or the degree of differentiation syndrome manifestation decreased with combination. Also, mechanistically, it makes sense that chemo would temper this altered cytokine alteration that happens with differentiation syndrome. I'm hoping soon the combination will address any concerns about differentiation syndrome in KMT2A rearranged leukemias. Great, Dr. Issa. Dr. Fathi, anything you'd like to add on that topic? Well, you know, as I mentioned also in my presentation, I think in a follow-up question, there is these differentiation syndrome episodes that have happened, particularly in patients with extramedullary disease and KMT2A rearrangements, in, with this class of drug, can be quite substantial and problematic. You know, we didn't see it in NPM1 mutated patients as much, certainly, and that was encouraging. In KMT2A, it has been a challenge, and I think, like what Dr. Issa said, the goal of ultimately targeted therapy is to make sure that you can give it safely, and you can maximize and optimize its promise. These drugs have a lot of promise. If you can effectively cytoreduce, hopefully synergistically, and even additively, get something out from the targeted therapy and be able to give it and maintain tolerability in terms of differentiation syndrome, so that patients don't get in trouble the first few weeks of treatment. I really think that is something that is going to maximize the impact of this class of drug. I do look forward to the combination studies for both NPM1, but in particular KMT2A, just because I also think those patients need this class of drug as well. Thank you. Dr. Fathi, I'm gonna stay with you for this next question, and that is: The question is, what makes you excited to evaluate ziftomenib outside of NPM1-mutant and KMT2A rearranged AML? Can you comment on that? Well, because I had a patient who responded very well without those alterations at all, you know, and at a dose of a pretty low dose, at a dose of 100 milligrams. I do think, as I'm sure, you know, I think Gus showed the slide on sort of the pathways. There's multiple pathways and potential targets in AML that sit downstream of the menin-KMT2A interaction on histones. These called FLT3 and DNMT3A and IDH, but also there are interactions with RUNX and with SETD1, and our patient had those two mutations. You know, I think this requires exploration for us to try and figure out what other patient subjects may benefit. I think we do need to do that. We need to go back to that, and see if there is a broader applicability, with this class of agent. Great. Thank you, Dr. Fathi. Mollie, here's a question for you. It's actually a two-part question: How's enrollment going in the NPM1 pivotal trial, and when do you expect to complete enrollment? Maybe you can take the first part of that question. Sure. Well, thanks to the enthusiasm of our investigators, including the two on this phone, we continue to exceed our own internal projections and expectations with regards to enrollment. Enrollment is going extraordinarily well and at an extraordinarily good pace. Great. Then on the question of when we expect to complete enrollment, what we've guided to, just to remind everyone, the KOMET registration-enabling trial is an 85 patient trial. It's 85 patients because we think it's appropriate for FDA to have approximately 100 patients at the RP2D. From a safety perspective, we've guided that we think that enrollment would come around the middle of 2024. As Mollie mentioned, we're doing everything we can. We're seeing significant interest, but at this point, we're guiding to full enrollment middle of next year. As we say, at the moment, things are exceeding our expectations, and we hope that that continues. The next question is: Have you thought about bringing ziftomenib into diabetes, or does Kura have other menin compounds in the preclinical pipeline that might make better candidates for opportunities outside of oncology? Maybe I'll take that question. We've actually evaluated ziftomenib in some of the preclinical models that are used in diabetes. We did see an effect. At that time, you know, we thought the effect was modest. Since that time, you know, there's been the potential to combine menin inhibitors with other agents. What we're doing currently is to take ziftomenib as well as a number of other compounds, both in our portfolio and outside of our portfolio, into preclinical models in diabetes and assess them. We have a next-generation menin inhibitor program underway. we actually have multiple chemical scaffolds, and we do think that if that's a direction we, we're gonna go, we're gonna make it on the basis of a data-driven decision. you know, we'll move that data along as quickly as we can, see if we can make a decision about whether it makes sense to move a next-generation menin inhibitor into diabetes. We also think that's the right thing to do from a development and a regulatory and a commercial standpoint, from the safety perspective on one side to the, you know, the even the impact, potential impact of the Inflation Reduction Act. You'll see us do that. The next question is: When is the appropriate time to partner ziftomenib? Maybe I'll take that one as well. There is significant interest in menin inhibitors among strategics. I think, you know, that interest is growing, thanks in large part to the tremendous efforts of Dr. Issa, Dr. Fathi, the people who are really pioneering this space. Our perspective, as you've heard from, you know, Stephen, starting out this presentation, we really see menin inhibition, and in particular, ziftomenib, having the potential to transform the standard of care in AML. If you do that, you have to be able to move the compound simultaneously in the front line, in the relapsed refractory space, in the maintenance space, we're talking then about running multiple global registration-enabling trials. If you do that, you're gonna need the, frankly, the financial and operational resources of a, you know, of a strategic, of a multinational. We, we wanna make sure that we are well-positioned. I can't really comment more about the specifics or timing, except to say that we are going to do everything necessary to make sure we have the appropriate resources to do what is not only best for the patients here, but also potentially what is best for shareholders. Yeah. Next question, I'll just again, we're coming up to the top of the hour. We have about 5 minutes left. If there are any other questions, you can feel free to submit them. I'm gonna go to the next question. How does the resistance mutation profile affect your decision to select menin inhibitors? How clinically relevant is menin resistance mutations in the combination context with azacytidine and venetoclax, in your opinion? Dr. Issa, maybe I'll direct that question to you to start, and then we can go to Dr. Fathi. Sure. It's a little bit hard to answer the question because these mutations are not yet available in a clinical setting. To be able to identify mutations in patients in real time and act on them, we need testing that's, you know, appropriately validated to be able to use that. Even, even if we had that, I am not sure how it would alter current decisions about menin inhibition. In, in the future, presumably, you know, just thinking about targeted therapies, probably the combination with azacytidine then would reduce the chances of developing resistance just because, you know, just like in HIV, using HAART or acute lymphoblastic leukemia, using combination therapies, by using multiple agents that have non-overlapping mechanisms of action and resistance, the chances of developing resistance would be smaller. To me, right now, these mutations just validate how critical menin-KMT2A interaction is in these leukemias, and we're, you know... For something like KMT2A, it means we finally reached something that works, and this is the interaction that we need to be targeting from now on until the future, until we have something better. It's certainly better than anything we've had in the past. Great. Thank you, Dr. Issa. Dr. Fathi, here's a question for you: Given that these patients are elderly and many of them can't tolerate transplant, can you comment on the clinical relevance of the duration of response with ziftomenib, how do you decide whether to put a patient on transplant? Well, I don't think we have time to answer the second one. It's our speech by itself. In terms of durability of response, that's always welcome. We hope that durability of response is even more enhanced when you combine it with other regimens. In older patients, especially those who are not fit for transplant, that's about the most valuable thing you have, and tolerability. If you have a drug that's well-tolerated, that the response is durable, that the blood counts are not suppressed, that the patient can take orally once a day for a long period of time and benefit from it and have a good quality of life. That's our goal, and a capsule for non-transplant, non-curative, currently approached AML. The question of transplant, you know, who gets transplanted, that's a big question, and difficult to answer and pretty variable, probably in response. At our site, pretty much we have upped the age where we transplant patients up until, honestly, in the early 80s, where some patients who are fit and robust enough, where we think we could potentially tolerate non-myeloablative regimens, sometimes those patients are transplanted. Artificially, the age of transplant has gone from 65 to 70 to 75, and now it's even moved up, down further. It's not really age dependent anymore, within certain limits, but dependent on fitness and organ function and comorbidities. I think all of those together go and go together to make a decision about transplant. Thanks, Dr. Fathi. Mollie, maybe a question for you. Can you remind us how many of the responders had prior venetoclax? Oh, how many of the responders had prior venetoclax? I think approximately 55% of the patients in total had prior venetoclax. I would say that number is a little bit higher in the responders themselves, where most of them are heavily pretreated. I would say it's more around the 75% of the responders had at least seen prior venetoclax. Okay, great. Thank you. I think we have time for maybe one more question. Since you observed a 30%-50% CR rate in either FLT3 or IDH-mutated patients, do you think these co-mutations make the patients more sensitive to menin inhibitors, and would you select patients based on co-mutations? Dr. Issa, maybe I could start with you with that question. Sure. I'd say the numbers are too small to comment on that specifically. I'd say, at least for now, we're not discouraged by having co-mutation with FLT3 or IDH. To me, it looks so far that these mutations at least don't impact negatively the chances of response. It needs to be tested in patients, but at least in the lab setting, we know that it makes sense to use menin inhibition in these subsets because NPM1 precedes development of FLT3 and sometimes IDH. The other point where menin inhibition could affect these is by downregulation of transcription, either for FLT3 or in case of the IDH to epigenetic targeting of the aberrant gene expression. We'll see what more number of patients show us, but if I had a patient who had these co-mutations, I'd take the opportunity of treating with a menin inhibitor, because I think it has the potential of having durable long-term impact. Then hopefully in the future, we could also study menin inhibition in combination with these targeted therapies. That's great. Dr. Fathi, is there anything you'd add to that, or you'd like to add to that? Yeah, I mean, you know, those, I agree, those numbers are small. You have six patients with FLT3 mutations, eight with IDH mutations, I think. I agree it's, you know, it's hard to make heads or tails about it. It's not discouraging, which is good news. I don't know if you can say, just based on those numbers, that the proportion of response is higher or lower. I think we have to wait. We have to get more data from the 85, I think you said, patients that we're trying to enroll on the phase II and see ultimately what we get. Based on that, maybe make some better observations that are better informed. Great. Thank you both. I think we have time for the. This will probably be our last question. How important is it to be first to market? Can you catch Syndax? I guess I'll take that question or those two questions. I would say, you know, we've been encouraged by the data that Syndax has presented. Certainly, you know, we are, as you can tell, excited about the possibility for menin inhibitors to transform AML. We are, as you can tell, we are doing everything we can to complete enrollment in the KOMET-001 study and bring ziftomenib to market in the NPM1 space. We're looking forward to sharing data with you. As Stephen, I think, nicely laid out, right at the beginning of the talk, we think ziftomenib, you know, has multiple pillars that support its best-in-class profile. We're optimistic that as we come to market and as we move ziftomenib into earlier lines of therapy and in combination, ultimately will be potentially a best-in-class option. At the end of the day, that's what's great for patients. You know, we're gonna do everything we can to be best in class and to create value for shareholders. We're very excited by the presentation at EHA and by what we're seeing in the ongoing phase II study. With that, we're now just here at the top of the hour. I want to thank, first of all, Dr. Issa and Dr. Fathi, not only for this, their participation on this, but for both being just tremendous champions and supporters of the trial. They're, you know, they've been terrific to work with and are leaders. I want to thank my colleagues, Dr. Stephen Dale, Dr. Mollie Leoni, for their strategic leadership on this program. Of course, I want to thank all of you who've tuned into this. If you have additional questions, please contact Pete De Spain, or me, and we're happy to follow up with you. Thanks again, everyone, and we wish you all a good rest of the day.