Hello, everyone. Welcome to our Fireside Chat with Kura Oncology. I'm Li Watsek, a Biotech Analyst at Cantor. I'm very pleased to have CEO Troy Wilson with us today. Really looking forward to the discussion. Troy, I thought to start us off, maybe just talk a little bit about, you know, what you're focusing on right now, and what's coming up that's exciting. Sure. Thank you to you, to the whole Cantor team for the invitation to come. You guys have been doing a tremendous job, so fun to be a part of. At Kura, we have two pillars to the business. We'll probably spend most of our time on the first one, which is our Menin inhibitor program. We also have a farnesyltransferase inhibitor program, which I think we'll touch on if we have time. With respect to Menin, we're now at a point where we are pursuing the lead program, Ziftomenib, both as monotherapy and in combination in genetically defined AML. The goal is ultimately to be able to treat up to 50% of patients throughout the continuum of care, from the frontline, you know, through maintenance. We'll start, of course, in the relapsed refractory setting, but that program has a tremendous amount of momentum. We'll have a data update, we hope, at ASH, provided that we get accepted. We can talk through that, as well as the upcoming monotherapy pivotal data, which we've guided to early next year. The second chapter in that three-part series is Menin in solid tumors. We've actually been sitting on this. We have the luxury now that, you know, we have enough going on, that we can take our time. So we have announced that we intend to start dosing patients, who have GIST, gastrointestinal stromal tumors, in combination with Imatinib. The goal there would be to restore sensitivity of those tumors to Imatinib. There may be additional liquid and solid tumor indications. We'll, you know, I would say, stay tuned on that. We're pursuing them. To the extent that there are solid tumor indications, we'd expect they would be in combination, but we'll start with GIST. GIST is an interesting opportunity because if it works, it could be as large as some of the frontline AML indications. Then the third chapter in that series is Menin in diabetes. We showed some encouraging preliminary data, again, for Ziftomenib, in this case, as a tool compound in rodent models of diabetes. We saw glucose lowering, insulin production, restoration of insulin sensitivity, and expansion of pancreatic beta islet cells. We will take a next-generation Menin inhibitor forward in that indication, and we've guided we should have a development candidate early next year. Potentially, that works in both Type 1 and Type 2 diabetes, so there's a lot to like there. I'll put a plug in for the FTIs, 'cause I don't know if we're gonna get back to them. We've shown. I ultimately think this is gonna end up being a very important therapeutic target. We've shown we can drive monotherapy activity in HRAS mutant head and neck. We've guided that we'll show preliminary data with Alpelisib and Tipifarnib in PIK3CA mutant head and neck. Neither of those agents really drive responses as a monotherapy, so you're looking for an example of one plus one equals three. That's sort of a transition or a segue into our next generation FTI, a compound called 2806, that is a new and improved farnesyltransferase inhibitor. There, we're evaluating that as a monotherapy in combination with Cabozantinib in renal cell carcinoma, and in combination with Adagrasib in KRAS-driven, KRAS G12C-driven non-small cell lung. The idea is, you know, both Menin and farnesyltransferase are meta targets. Neither one of those is an oncogene, but if you drug them, you have the potential to combine with other agents to be able to drive better activity, to delay innate and adaptive resistance, and ultimately to provide better clinical benefits. So there is a cohesive theme here. To your point, I think we're gonna see a number of clinical data sets and important catalysts over the next kinda 12 to 24 months. Great, and I thought it was fun for me to cover Menin space because I, I remember maybe one or two years ago, we mostly thought Menin inhibitors are for leukemia, but now we're start to see, well, you can move into GIST, solid tumors, and even diabetes, so I thought that was really interesting. Yeah. Maybe let's start with AML first, right? So I think the space, if you're looking at the landscape, probably we're looking at maybe three players. Mm-hmm. So maybe talk a little bit about, you know, differentiation, not differentiation syndrome- Right but differentiation for Ziftomenib, and what do you think it sets it apart from your competitors, and do you think the degree of differentiations may be greater in combination? Yeah. So I often find when I talk to, you know, others in this business, that people jump to activity. They measure this response rate against that response rate in two completely unrelated trials, and, you know, they squint, and they try to draw some comparison. This is now a world in oncology where it is all about combinations. By and large, it's all about combinations, and so you put a premium on safety, tolerability, combinability, absence of drug-drug interactions, and ability to keep patients on drug for prolonged periods of time. If you can do that, you're gonna provide a greater clinical benefit, you're gonna provide a greater commercial case. I think that is Ziftomenib's strength. It has exceptional safety and tolerability. We have other than differentiation syndrome, which I think is now mitigated in combination, there really isn't any toxicity that we see on a chronic basis. That's important for diabetes, for example. It's why I think Menin inhibitors will only be active in solid tumors in combination. If it was more active, they would be active as monotherapy in solid tumors. Menin inhibitors are very safe and well-tolerated, but Zifto is even a cut above. It has no drug-drug interactions. It has no QT prolongation, it has no myelosuppression, it has no thrombocytopenia. Those characteristics that I think characterize some of our competitors ultimately will play themselves out in combination. If you have to interrupt therapy, if you have to dose reduce, if you have patients peeling off due to cardiac tox or thrombocytopenia, that's gonna affect their time on therapy. We don't have that with Zifto, and so Li, to your point, I think the farther we go into combinations, the more profound Zifto's advantages become. I'll leave you with two other things, and this is just to pick up on your comment about GIST. So we looked at multiple Menin inhibitors. We looked at multiple KIT inhibitors in various models of GIST, and they by and large, they're almost all active, with one exception. But Zifto is unusual because of its tissue penetration and because of its profound exposure. It's not more potent on an IC50 basis, but it's much more tissue penetrant. You can drive better activity in solid tumors with Zifto than you can with some of the competitor Menin inhibitors. I think that's gonna play out in the combos as well, and we'll talk about it, but the next installment will, of course, hopefully be at ASH. Okay, great. We'll talk about combinations later, but I wanted to sort of get your thoughts on some of the monotherapy data that's gonna come out. I think one from your competitor, Evotec study data coming later this year, and your own monotherapy data come next year. So maybe just set the stage for us, what do you hope to see? And I obviously understand the combinations sort of are the key here, but just from the monotherapy standpoint, what do you hope to... Yeah. So I think both we and our competitor have been consistent in that a CR/CRh rate of 20% to 30% and a median duration of response of 4 to 6 months is probably sufficient to support approval, full approval in the monotherapy setting. And the reason for that is that actually exceeds the overall survival in, you know, third and fourth line AML in those genetically selected populations. That's what we're hoping for. I don't have any expectation that we're gonna see the 35% CR rate that we reported in phase 1b. There's always some degradation of signal as you go to larger studies and more sites and more investigators, but I think if you're in that 20% to 30% window, you're in good shape. And to your point, I think that will support registration in the U.S. and should support use. The relapsed refractory setting is. It's still, you know, it's a relatively niche market. Patients don't stay on therapy for very long, typically because they're so advanced. That's part of why, just as it was in myeloma, in lymphoma, you wanna move as quickly as you can and bring these agents to the frontline in combination. But it's an important foundational step to getting it out there and with the major medical centers and ultimately out in the community. Great. So let's talk about combinations. Obviously, that's the focus for a lot of investors and you as well. So maybe just give us sort of an overview of different combinations that you're doing. So there are, if you think of it as three big pie slices. There is the so-called fit population, who are typically treated with intensive chemotherapy, otherwise known as seven plus three. There is the unfit population, who are typically treated with Venetoclax and Azacitidine, and then there is the FLT3 population. And the FLT3 population is overlapping with the other two, but given that you now have Quizartinib approved in the frontline population, you have to think about your trial design carefully. I think one of the advantages, Li, that we have is, I don't see a reason why we won't be able to ultimately move into each of those three segments. FLT3 is complicated for our competitors because there are three approved FLT3 agents: Midostaurin, Gilteritinib, and Quizartinib. At least two of those three have QT prolongation, as a dose-limiting toxicity becomes challenging to combine with other agents that might be characterized as having QT prolongation, as in the case of one of our competitors. But FLT3 is a significant population. It's 25% of all of AML. It's up to half of NPM1, so you need to find a way to get there. The preclinical data with FLT3 is some of the strongest that exists of any combination. We are... And I'm jumping around a little bit, but we are currently enrolling in our zero zero eight protocol, Gilteritinib plus Ziftomenib in relapsed refractory NPM1 mutant patients. I think we will move into a combination with Quizartinib probably sometime next year. And the reason for that is Gilteritinib is approved in the relapsed refractory setting, Quiz is approved in the frontline and post-transplant maintenance setting. You need to be able to play with both, ideally, to cover all of those patients. Coming back to the fit and unfit, that's the foundation for the zero zero seven protocol. Depending on who you ask, those two populations are roughly of equal weight. And collectively, if you look at fit, unfit, and FLT3, you're talking about, at that point, more than 50% of all AML patients, in the U.S. per year. So let's talk about the KOMET-007 study. Obviously, you have shown some pretty nice data early in the year, and that's at the lowest dose, 200 mg, right? So as you move into, you know, 400 and 600, these higher doses, maybe just set the expectations for us in... And I understand there are some nuances in terms of, you know, different cohorts, risk averse or not. So maybe just walk us through the trial design and the expectation. Sure. So let's start with the trial design. The phase IA portion is a dose escalation portion. We started, as you said, in patients who are higher risk. So in the case of fit or intensive chemo, it's patients who have adverse risk. In Venaza, it's relapsed refractory. We are dosing KMT2A and NPM1 patients in separate cohorts, so the simplest way to think about it is there are four parallel cohorts, three doses, at least six patients per dose. So at a minimum, you have 72 patients if you take all four cohorts to 600 milligrams. We said on our last earnings call, we had more than 100 patients had been enrolled in the 007 protocol. That's largely due to over-enrollment, although not exclusively. And over-enrollment comes from the fact that if you have patients in screening and you haven't and the safety monitoring committee hasn't cleared the next dose, they have to go somewhere ethically. So we have seen over-enrollment in those cohorts. That you saw the first installment of that data back in January, and you were kind to characterize it as encouraging. I think we were as well. We were encouraged. First, probably, you know, the reason we put that data out was it put to rest the question of differentiation syndrome. So in the KMT2A, we went from 30% to 40% grade three and above in KMT2A, to we saw no instances of DS of any grade among the first 20 patients. I said at the time, "Don't get emotionally attached to zero. It's not gonna be zero, but it's gonna be relatively infrequent, moderate, manageable. Ideally, you don't interrupt therapy. That's what we've seen to this point. The other thing we saw was in the intensive, in the fit population, we saw five out of five CRs. The background there or the benchmark is the control arm to the study that got Vyxeos approved. That's the frontline adverse risk population. The number you'd expect is 35%. You know, we saw five out of five. Hooray! I said to people, "Again, don't get emotionally attached to a 100%. There's nowhere to go, but down," but you want to see, ideally, a consistent level of activity as you're climbing. We know from the monotherapy, 600 milligrams is the optimum dose. The critical question, what we have no predicted drug-drug interactions, we have no observed drug-drug interactions, but until you run the experiment, you don't know. The fact that three of the four cohorts have now moved into the expansion phase, and I'll talk about that in a second, at 600 milligrams, gives you confidence that that's the dose you want to use. You know, I, we got a question earlier this morning, will you be able to tell the difference between 200 and 600? Probably not in a dose escalation. It's not really powered to answer that question. What we can tell you is, everything, you know, if your goal is, again, you know, maintain a response, pre or post-transplant, keep patients on therapy, keep them in response, more drug is better. More whole body exposure is better. So we want, in every combination, whether it's these three or the three we're doing in zero zero eight, FLAG-Ida, Gilteritinib, and LDAC, you want to ideally drive 600 milligrams of Zifto. You, investors, when they look, will, I think the ASH abstracts are scheduled to be released on Election Day. In case there isn't enough drama, we'll have the ASH abstracts. At that time, that's as of a June data cutoff. You'll see 200 milligram data, somewhat less mature 400 milligram data, and a nod to 600. It's really intended for us to get a spot at ASH, either as a poster or an oral. By the time we get to ASH, you'll have the full data set, 200, 400, 600. So I would tell people, "Don't overinterpret the ASH abstract." It's, you know, that data will be six months old, nearly by the time you see it. You'll get an update just a few weeks later at the main event. In terms of the expansion, let me just speak to that, and then I'll stop. We got agreement from the FDA that once we defined, or once we identified the recommended phase II dose, the study could turn from escalation to expansion. So in seven plus three, you lose the requirement of adverse risk. You can go into any frontline intensive or any frontline fit population. In the unfit population, we will do parallel expansions in the relapsed refractory at the 600 milligram dose, in the frontline at 600 milligrams, and then a cohort of Venetoclax plus Ziftomenib in NPM1 mutant relapsed refractory. That's really to answer the question of: do you need Azacitidine? There's a hypothesis that you may not need aza, given you have a Menin inhibitor on board. We'll test that concept. The goal, ultimately, as you think about now that moving into a registrational study, which we would look to start probably the middle of next year, would be, on the one hand, frontline intensive, seven plus three, so seven plus three plus Zifto in both KMT2A and NPM1, and the other is Venetoclax plus Azacitidine plus Zifto, again, NPM1 and KMT2A in the frontline population. That's where we're going. We're already designing those studies at risk. So you sort of identify six hundred as sort of the going forward dose. Yep. And how confident that the FDA will not give you any back? Or do you have to clear this dose with FDA, or? Yeah. Well, you have to clear it in the sense... So the next time- Yeah one has a discussion with the agency about dose is, is when you submit the phase III protocol for review. And as part of that, you do a dose justification for Zifto. And we've deliberately done a very robust, very muscular dose escalation, dose expansion. Project Optimus says, "Go with the lowest dose that drives maximal activity." And we believe that near term and longer term, 600 milligrams is that dose. We believe we're generating the data that will substantiate that. It's not over until the FDA says, "Yes, here's your safe to proceed letter for your phase III," but that's when you have that discussion. They certainly didn't have any concerns. They were able to let the safety monitoring committee approve us moving from escalation to expansion. We didn't have to go back and check in with the agency, so I think that's a good sign. But they want, you know, and we're, we're not, we're not unique. They want sponsors to do the work around dose optimization and really show. And it, it comes down to safety and tolerability. Show that that dose is going to drive the best clinical benefit or benefit risk for patients. I think we, I think we're doing that, and we should, it should position us well to start those studies, you know, middle of next year. So for the data update later this year, presumably at ASH, so we'll see data in over 100 patients? Yep. That's mostly from dose escalation, or will we see any patients from expansion as well? Yeah, I would say it's probably gonna exclusively be from the escalation. The expansions are enrolling now, and I'm just gonna get this out here because, you know, we didn't get a chance on our earnings call to say it, so three of the four cohorts have moved into expansion. That is NPM1 seven plus three, NPM1 Venaza, and KMT2A Venaza. The only one that's lagged a little bit behind is KMT2A seven plus three. That is, it's a slightly smaller population, and it's just sort of the stochastic nature of how these trials go, but you will see. You know, the focus is really gonna be on the escalation data. The expansion data, Li, although Mm-hmm those three expansion cohorts are now enrolling. I don't know that the data is gonna be sufficiently mature. That's probably middle of next year when you get to see the true, you know, frontline populations. I think the escalation data will be meaningful. It will be very instructive of how to think about those combinations. And as I said, a big question is: do you have to interrupt dosing? Do you have to dose reduce? Can you keep patients on therapy, right? How does it start to come together? We're looking forward to sharing that data with the financial as well as the clinical communities. Okay, Troy. So you mentioned you may move into pivotal study next year. Yep. So how should we think about the trial design here? Yeah. So the trial designs here, because of the high rates of CRs with the standard of care, you need to power those studies appropriately. And these are big studies, you know, hundreds of patients. There may be an opportunity for an accelerated endpoint in the form of MRD negative CR in one or both of those populations. But unless and until we have agreement from both FDA and EMA, I don't wanna sit here and tell you that I know for certain what the design is. There's a good rationale for using MRD negativity as an accelerated endpoint, with a survival endpoint then to support full approval. But we are, and I'm sure others in this space, are doing the work now to gain alignment with the health authorities. But that, in an ideal world, that's what you would look for, is an accelerated endpoint around MRD negativity. The reason we say that is there's increasing evidence that that's a good correlate to survival. And then, as part of the same protocol, ultimately, you'd follow the patients, and you look for a survival endpoint for full approval. But we need to... You know, we are right in the midst to set expectations, it typically takes nine months from when you have the dose until, and the protocol, until you can actually start a registrational trial in terms of working it through the system. So we're right in the middle of that right now. Okay. Maybe just last question on Menin, AML is the maintenance setting, right? Yep. So what needs to be done to get used here? Yeah. So when we talk about maintenance, we're talking about post-transplant maintenance. Our thought is, ideally, again, you're gonna go for NPM1 or KMT2A patients, but they can find their way to you no matter how they got there. So if they're NPM1, but they are a FLT3 mutant, NPM1 co-mutant, if they've come off of one of our competitors' compounds, those could all be patients eligible for a maintenance protocol. We have, Li. There is an investigator-sponsored study that is enrolling now that will provide a safety and tolerability foundation in about 20 to 30 patients, that will allow us to then have a discussion with the health authorities about the dose, the safety, the tolerability to do a post-transplant maintenance study. Our thought would be, you know, your control arm is placebo, and we're just gathering that data now. I would expect that you're gonna see us stand up the registration-enabling studies in the frontline combinations first, and then the post-transplant maintenance as a second step, while we're elaborating the dose around the FLT3 inhibitors. That'll, you know, that's coming along as well. I wanna switch gears to just so you mentioned in the beginning this very interesting solid tumor. Obviously, you've seen some nice preclinical data supporting that. So maybe just talk a little bit about your clinical plan and the cadence of the clinical data. Yeah. So, again, we've been sitting on this data now for about eighteen months. One uses these compounds in combination. In just tumors that have developed resistance to Imatinib, neither Imatinib nor Zifto are effective at, you know, driving responses as monotherapies. But together, they are highly synergistic, and the reason for that is Menin appears to control the overexpression of KIT, which is essential for the survival of GIST-driven tumors. So the beauty of it is, it works with multiple KIT inhibitors. It's mutationally agnostic. We are starting with Imatinib because Imatinib is the accepted frontline standard of care. We're starting in patients who've progressed on Imatinib because, if we can, you know, drive clinical benefit there, then you would go to a frontline Imatinib, Zifto combo, and, you know, we would look for, sort of a similar pricing as AML, and that could be a pretty attractive opportunity. And it would essentially cut off any of the subsequent KIT inhibitors. We're now in the process of standing that trial up, site selection, investigators. I would expect we'd dose patients in the first half of next year. We will step down the dose initially, just to confirm that, you know, there's nothing unanticipated, combining Imatinib and Zifto, but ideally, you're driving, you know, you're driving that trial at 600 milligrams, or potentially even higher if it made sense. This is where you know, the pharmaceutical properties of Zifto are really ideal. Its exposure, its tissue penetrance, that becomes even more important in solid tumors than in liquid tumors. We are doing work on additional solid tumor indications. If we have more to say, we'll come back to you and give you an update. I do think you're gonna get to see the GIST data probably within the next month or so. It's been accepted for a poster at an upcoming scientific conference. So that's the preclinical? That's the preclinical data, correct? Okay. Of Zifto, Menin, and Imatinib. And it's again, there is a reference in the literature out there, but this is, we've really. Our translational research team and Francis Burrows and his colleagues have done a really nice job of annotating that whole opportunity. And any subsequent solid tumor opportunities, Li, will also, I think, be in combination. But let's stay tuned on those. I think, Troy, you mentioned maybe there is some possibility in combining KAT6A. Is that something on the table as well? Yeah, so there is a. I have to, you know, give a nod to Professor Scott Armstrong. He not only the one who elucidated the connection to NPM1, but also one of his colleagues did the GIST data, and as you said, recently showed very interesting synergy of Menin and KAT6A in breast cancer. That's a potential opportunity. Let me just put a plug in here. If one goes into additional solid tumors, you may wanna use a different Menin inhibitor, for safety, for tolerability, for IP, for pricing, for IRA, and that goes back to why we're doing a next gen. You know, we talked about diabetes, but we also have a next gen inhibitor in oncology as well, because you need to think about it on a franchise basis, and the pipeline on a pill worked really well, but recent events have made that strategy a little bit more complicated. Okay, maybe just last question, just quickly on diabetes. Sure. Talk to us a little bit about, you know, what is the plan and how do you, I guess, what is the strategy for you to move into an entirely different set of indication other than, you know, oncology? Yeah. So, the preclinical data that we showed at the American Diabetes Association meeting, as I said, shows glucose lowering, insulin production, restoration of insulin sensitivity, and expansion of pancreatic beta islet cells, but not the alpha cells, right? So, DYRK1A inhibitors, for example, work on expanding pancreatic beta islet cells, but they're, you know, the risk is tumorigenesis because they expand other cell types as well. Menin inhibitors don't do that, and in fact, in that assay, which is done by a company called InSphero, Ziftomenib was the most potent compound they've ever tested, including the control. So there's a really interesting opportunity. It's potentially relevant to both Type Two and Type One. It could be the first novel, you know, oral agent to come along, or first novel agent since GLP-1. We will do it with a next-gen compound. One does not want to put Zifto at risk, you know, in a different indication for a whole bunch of reasons. We have a next generation compound. We are also getting input from KOLs as well as strategic players who know the diabetes space well. You would likely give a Menin inhibitor on an intermittent basis. You'd look to expand the pancreatic beta cell repertoire and then you know, take it off. But for everything from, you know, refractory type 2 to potentially type 1, beta cell implants, there's an interesting thing to do. I think we could potentially lead, do some early clinical development. I do not see us doing, you know, the twenty-five thousand patient phase IIIs that are required. It will probably always be Kura Oncology, but I think we can potentially create a lot of value for our shareholders, with a, you know, a novel mechanism of action in diabetes. So more to come probably next year. Okay, great. Thank you so much, Troy. Oh, my pleasure.