Good morning, ladies and gentlemen. Thank you for standing by, and welcome to Kura Oncology Clinical Update Conference Call and Webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you will need to press the star then the one key on your touchtone telephone. If you require operator assistance, please press star then zero. I would now like to hand the conference over to your speaker host today, Pete DeSpain, Vice President of Investor Relations. Thank you, Livia. Good morning and welcome to Kura Oncology's KO-539 Clinical Update Conference Call. I'm joined on the call by Dr. Troy Wilson, our President and CEO. Dr. Marc Grasso, our CFO and CBO, is also with us and available to answer questions. Before I turn the call over to Dr. Wilson, I would like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company. With that, I'll now turn the call over to Troy. Thank you, Pete. Thank you all for joining us this morning. Earlier today, we announced FDA has placed our KOMET-001 phase I-B study of KO-539 in patients with relapsed or refractory acute myeloid leukemia on a partial clinical hold. This partial clinical hold was initiated following our recent report to FDA of a Grade 5 serious adverse event, a patient death, in the lower 200 mg dose cohort, a dose that was determined to be safe and efficacious in the phase I-A dose- escalation portion of the study. The event has been potentially associated with differentiation syndrome, a known adverse event related to differentiating agents in the treatment of AML. We share the FDA's commitment to patient safety. We're working closely with them, with the agency and our site investigators on our mitigation strategy for differentiation syndrome and to resolve the partial clinical hold as quickly as possible. Differentiation syndrome is known to be an on-target effect associated with therapeutic agents that induce differentiation, and we want to ensure that physicians are fully informed and prepared to address these events if they occur. Importantly, patients currently enrolled in the phase I-B study may continue to receive KO-539, although no additional patients may be enrolled until the partial clinical hold is resolved. Until we have more clarity regarding the impact on timing, we're suspending guidance on the completion of enrollment in the KOMET-001 phase I-B study and determination of the recommended phase II dose of KO-539. We appreciate our ongoing dialogue with FDA, and we're working diligently to address their request for information. We look forward to providing an update as soon as we have additional information to share. Based on the totality of data, including the overall safety and evidence of clinical activity, we continue to believe that KO-539 has the potential to address the significant unmet medical need of AML patients, including those with NPM1 mutations and KMT2 rearrangements. With that operator, we're now ready for questions. Ladies and gentlemen, to ask a question on the phone line, you will need to press the star then the one key on your touchtone telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question coming from the line of Jonathan Chang with SVB Leerink. Your line is open. Hi, guys. Thanks for taking my questions. First question, I guess beyond this one Grade 5 event, can you speak to the experience with differentiation syndrome broadly in the study? Yeah, sure, Jonathan. We have seen, you know, fewer than a handful of cases of differentiation syndrome across all the patients that have been treated with KO-539. The other cases were manageable and resolved with treatment of steroids. This case in particular, you know, was more complicated and was confounded, and, you know, what unfortunately resulted of course in the Grade 5 SAE. We have seen relatively few examples of differentiation syndrome, and in our experience in general it's been manageable with steroids, provided that the physicians get on top of it quickly, and if necessary, you know, escalate the mitigation strategies which are well known and well sort of have been well developed through, you know, APL, through the IDH inhibitors. What really the point of this hold, I think, is to ensure that, you know, all of the physicians on the study are doing proper surveillance and have, you know, a very well-developed and well- understood strategy, if needed, to address differentiation syndrome. It's been a relatively rare event in our experience. Understood. Second question, I guess this is just a broader catch-all question. Mm-hmm. Is there additional color here you can provide in terms of patient background, pharmacology and exposure level, time to onset, et cetera? Yeah. All good questions. As I mentioned in the prepared remarks, this patient was on study at the 200 mg starting dose. What we have observed with KO-539 in certain patients, not in all patients, but in certain patients, is that you see initially a rise in the counts in the periphery. That seems to be, you know, related to trafficking out of the viscera and the bone marrow as the blasts are maturing. That was what was seen in this case. That's typically happens in around, you know, the end of the first week. This patient actually was pretty heavily confounded, had, you know, failed four prior lines of therapy, had really not responded to anything. It was a KMT2A patient, actually, you know, initially we saw this elevation in counts. There was a concern that perhaps the patient was progressing. But, you know, and there was a request to, you know, potentially to escalate the dose. The dose was not escalated, and actually, the counts began to come back down, again, which is consistent with our observation of this mechanism of action. But some of the symptoms of differentiation syndrome continued, shortness of breath and so forth. Ultimately, you know, several weeks into therapy, you know, the patient had a cardiac tamponade, which is a fluid surrounding the heart. It's not typically associated with differentiation syndrome, but it, the patient clearly had differentiation syndrome, and the patient passed away. That's what we know. The other cases, as I've mentioned, have been relatively, you know, readily managed with count elevation, which you could manage by treatment with steroids. Got it. Maybe just one last one, if I may. Sure. And that is- Yeah. How should we be thinking about next steps and timelines for enrollment and data from here? Thank you. Yeah. Let's start with next steps and then talk about timelines for data. The FDA has asked us for, really for three pieces of information. The first is to review the safety database, and in particular, to look at the changes in the counts as a function of time and of dose. Just to be clear to everybody on the call, in our trial, if there's ever even a hint of anything that looks like differentiation syndrome, our clinical team, you know, raises it with the investigator and escalates it to the safety review committee. We're not expecting to find, you know, any other instances of this. Just for the sake of completeness, we'll provide that safety database to the FDA, you know, with particular attention to what the various counts are doing as a function of time. That's number one. Number two is a very clear, you know, articulated mitigation strategy. I wanna emphasize we have and have had a mitigation strategy for differentiation syndrome in our investigator's brochure. This is something that is fully expected with this mechanism of action. But as I've said, one needs to be vigilant. And there is a series of sort of steps of increasing intervention. You start with steroids. If necessary, withdraw the drug. If needed, if that doesn't work, you can induce either hydroxyurea or leukapheresis to reduce the counts and again, potentially withdraw the drug. If that doesn't work, then you can work on cytoreductive therapies. And that's again well-known. It's well-established. In fact, Dr. Montesinos, who developed the Montesinos criteria for differentiation syndrome, is one of the investigators on our study. We have some of the leading experts in differentiation syndrome. What I think we really have to make sure we do is that everyone is being very vigilant, and if you see any hint of it, jump on it and make sure that it's well managed. That's the second piece. The third piece is, in that context, to reaffirm the rationale for dose selection of the 200-mg and 600-mg dose. I can tell you know, from our experience, both from the safety and tolerability and the evidence of clinical efficacy, we feel those are the right doses. You know, the FDA, I think, is doing the right things and looking at the data, looking at the mitigation strategy, and then saying, "Okay, are we using the right dose going forward?" We expect, you know, this is an information request. We expect to have this back to them in very, very short order. We began working on this as soon as we learned of the Grade 5 event. We had actually put ourselves. We'd paused enrollment, which is effectively what the FDA has done. We'll be well prepared to respond to the FDA quickly. What we, of course, can't control is the timing of the FDA responding to us, once they have that information in hand. As for the second part of your question around the timing to full enrollment and data, you know, unfortunately, we had a number of patients in screening sort of ready to go on study this week and next week. We've now had to pause that. At this point, Jonathan, we can't really give guidance on that until we know how long it's gonna take the agency to respond to us. We're clearly in control of our timing, and that's gonna be very quick. But you know, I can't speak for the FDA. We are optimistic that this will be a relatively short partial clinical hold. The FDA's request is not complicated. You know, everyone, the investigators are all, you know, working with us and very supportive of moving forward, but we just need to get through these steps. Once we're through it and the hold's lifted, I think we'll be able to then provide more clarity on the timing for full enrollment of the phase I- Bs and ultimately for data on the other side of that. Got it. Thanks for taking my questions. Sure. Our next question coming from the line of Peter Lawson with Barclays. Your line is open. Hey, Troy. Thanks for the call today. Just on your thoughts just around the effect, do you think it's a class effect, or is there anything particular to your molecule versus others? Are there any parallels here with other drugs in AML or leukemia we should be thinking about, such as the IDH1/2s that have a differentiation syndrome? There's three parts to that question, Peter. It's absolutely a class effect. There's no question. If you have a potent menin inhibitor, you will see differentiation syndrome, and you will need to manage it. In fact, one of our competitors, who everyone on this call knows well, has reported, you know, differentiation syndrome. I don't think that should surprise anyone. That is part and parcel of this mechanism of action. That is in fact what this drug is designed to do, is to differentiate leukemic blasts. The issue is if patients have such high tumor burden, you know, that can induce you know a more rapid differentiation syndrome or a more severe one, and I think you have to watch out for it. In our opinion, it's absolutely a class effect. There are parallels to the IDH inhibitors, as well as to you know arsenic in the treatment of APL, or I should say, you know, retinoic acid, agents that are known to induce or be associated with differentiation. There does seem to be. I don't wanna speak for the FDA, but there does seem to be sort of a heightened awareness of differentiation syndrome you know out there, and I think the FDA is you know being careful and putting patient safety first, as are we. Again, you know, this is manageable. It's now well-managed with the IDH inhibitors. This is an unfortunate reality of drug development. You learn as you go. You asked, is there a difference. What I can tell you, in our experience, is KO-539 is a very potent menin inhibitor. It's very, very active, and as a consequence of that, you know, I think there's sort of two sides to this coin, right? I think we have to be vigilant and watch for differentiation syndrome. That's going to, that will, at some level, you know, be something that you have to watch for as a potential adverse event when you have an agent that's, you know, that's designed to, you know, induce the differentiation of leukemic blasts. I think I've answered all your questions, but let me know. Perfect. Thank you. I'll get back in touch with you. Sure. Our next question coming from the line of Reni Benjamin, JMP Securities. Your line is open. Hey, good morning, guys. Thanks for taking the questions. Troy, you mentioned that, you know, you already had a mitigation strategy in place, and so I'm kind of curious, you know, how different can a new mitigation strategy be? You know, how are you thinking about that? Yeah. You also mentioned that this did occur before. Did this occur across kind of all doses, or was it kind of, you know, grouped a little bit more? Mm-hmm. Did it occur in responders, or was it just kind of more broad? Ren, they're all good questions. Let's take them actually in reverse order. As a knowledgeable MD said to me yesterday, you know, a drug that isn't working doesn't do this. This is, you know, part and parcel again of the mechanism of action. You see this in situations where you're inducing differentiation. Now, you know, are those responders? That depends, right? Are you clearing blast counts, and are you seeing a recovery of normal counts? That's a technical definition, but this is what you see in a leukemia patient when the drug is doing what it's designed to do. Interestingly, it doesn't happen in all patients. It doesn't actually happen that often. It can happen. I think as to your other questions, we've seen it again in fewer than a handful. I mean, it's, you know, several isolated cases. The others were, you know, relatively benign, so it's hard to say. It doesn't appear at this point to be dependent on dose, but, you know, to be frank and to be fair, I don't think we have enough data to say that for certain. I think it's more a reflection of the underlying disease, and potentially, you know, patients with higher blast counts might be more susceptible to it. You do see, as I mentioned in the response to Jonathan's question earlier on, it's not uncommon for us to see an elevation in the counts in the periphery in the first week. That's actually in our experience been a biomarker that things are going in the right direction. That's, you know, paradoxically, that's actually a good thing, right? Where you have to be careful is that that doesn't then tip over into the complications of differentiation syndrome, which are the edema, the shortness of breath, you know, that can very get out of control. You're walking a fine line. In most cases, steroids are sufficient. If necessary, you know, you can go to more, you know, to measures, as I mentioned, treatment with hydroxyurea, leukapheresis, potentially cytoreductive agents. Those are available if needed. When I talk about to your first question, I'm taking them in reverse order. Yes, you know, our mitigation strategy now doesn't look a lot different than it did before. It's just reinforced that, you know, we, the physicians and we, as the sponsor, need to be monitoring for this closely. Where you get into trouble is if you're, you know, you don't get on top of this and treat quickly. The most immediate and obvious thing to do is to put the patient on steroids, and if necessary, withdraw KO-539. It's more, Ren, I would say, an education and an awareness that this, I've said consistently in response to questions, 539 has a very attractive safety and tolerability profile. The one potential adverse event that I've commented on in the past is the potential for differentiation syndrome because it's part of the mechanism of action. You know, that is something I think that we're gonna need to continue to be vigilant about. Our investigators have all signed off on the guidance, again, a number of the leading investigators in differentiation syndrome. From their perspective, I think as soon as the FDA gives us the green light, we're good to go. Our investigators are good to go, and they're actually quite enthusiastic about putting additional patients on study. We'll work through this, not unlike the IDH inhibitors, not unlike venetoclax. You know, this is the reality of drug development, but it is, it's something we were expecting. We feel terrible for the patient and the patient's family, but you know, we'll learn from this and, you know, continue to put patient safety first. Got it. Just, you know, you mentioned cardiac tamponade, and it's not necessarily something that you would see with differentiation syndrome. Yeah. You talked about, you know, kind of the next three pieces of information or the next steps that are required. I would have thought, you know, kind of really pinpointing exactly what's happened to those patients would also be a, you know, a key gating item. I guess, you know, I'm kind of curious, how do you kind of solidify whether this, you know, this was due to the drug, this was- Yeah. differentiation syndrome or something else? Yeah. This is where theory meets reality. In theory, all patients are available at all points in time for blood draws, you know, sampling, for autopsies. In reality, that's not the case. This patient's family unfortunately didn't consent to an autopsy, so we may never know for certain what was involved. As with many AML patients, you know, this patient had extensive disease. I mentioned had failed four prior lines of therapy, had a number of confounding factors. What I think we can say for sure is there was evidence of differentiation syndrome, and that's why the investigator and we are characterizing it as potentially related to differentiation syndrome. I don't wanna minimize that in any way, right? We do need to be vigilant for that. Was that ultimately the cause of death? Not sure that we'll ever know. It likely contributed. It's certainly something that we wanna make sure that we mitigate. The reality, Ren, is, you know, when reality butts up against theory, if you can't get an autopsy, it's hard. Even with the autopsy, I'm not sure we'd know, but it'll be hard to know. It's sufficient, though, to say that we need to make sure that we're being vigilant about differentiation syndrome. I think it was the combination of the Grade 5 event and the differentiation syndrome that, you know, ultimately was what sparked the FDA to place us on a partial clinical hold. That's why I think we're, you know, we see a path forward. We know what we need to do. I think we're, you know, we're hopeful that this partial clinical hold will be resolved relatively quickly, because, you know, it's this is just the reality of treating patients with AML. Great. Thanks for taking the questions. My pleasure. Our next question coming from the line of Joe Pantginis with HC Wainwright. Your line is open. Hi, guys. Good morning, and thanks for all the added details today. Hopefully, I'm not gonna sound like I'm parroting back, but I just wanna, you know, what appears to me is that, you know, you've taken the responsible steps for something that's very well known and mitigation strategies are all in place. It really almost just sounds like, you know, even though it's unfortunate, you know, a housekeeping issue at this point because you have to report these. You're taking the responsible moves, the FDA is taking the responsible move, and you appear to have the right strategy in place. I guess what I wanna ask then is even though it appears that this should be resolved pretty quickly, I guess I wanna see if there's any difference from a comment you made on your recent third quarter call, and not to take away from the menin pathway, but I guess when you look at the overall corporate strategy of the company, you obviously have an oral presentation upcoming for tipifarnib in PTCL, especially the AITL patients. I was just curious, you know, do news events like this have you reevaluate any of your, you know, strategy to say maybe we'll also look to, you know, bring forward the PTCL study into more advanced studies? Yeah. It's a good question, Joe, and I understand why you're asking it. The short answer is no. I think, as a strategy, you know, we have to look at the integrated whole, but we also have to compartmentalize. With regard to menin, you know, this doesn't really put us off in any way from the promise of this drug. I know it's, you know, it's distressing to us, it's distressing to investors. You know, no one likes to have setbacks, but drug development is a business of working through setbacks. We continue to believe we have the potential for a best-in-class menin inhibitor. As I've mentioned, you know, we've seen encouraging signs of activity. This is a very potent compound. You know, we're learning how to use it, and that is what you do with a new mechanism of action in a disease that has been as challenging as AML. We have investigators that wanna put patients on the KOMET study. We have investigators that wanna do a whole litany of other studies, including combinations. We're all working together, our team, the investigators, to work through this partial clinical hold as quickly as we can. I don't think this puts us off of menin at all. We will work through this relatively quickly and be back on track. With regard to a potential opportunity for tipifarnib in AITL, that is potentially interesting. I think as we indicated on the Q3 call, we need to understand potential next steps and possibly get some regulatory input before we can say, you know, what the next steps there would be. No one on this call should take from this a shift away from menin at all. I would say, you know, it quite the opposite. This is a, you know, as far as toxicities go, this is a toxicity or an adverse event that's spot on the mechanism. We just have to make sure that our physicians are extremely well prepared to manage it if it occurs. You know, we'll do that, and we'll work through this just as quickly as we can. Got it. Thank you, Troy. Sure. Ladies and gentlemen, as a reminder, to ask a question, please press star one. Our next question coming from the line of Phil Nadeau with Cowen. Your line is open. Hi. Good morning. Thanks for taking our questions. Troy, one question on the drug levels. You mentioned that this doesn't seem to be dose related. Do you have a sense for what the drug levels were in this patient? Is there any evidence of accumulation? There is accumulation, Phil. There's accumulation in every patient. The half-life of KO-539 is beyond 24 hours, so the drug accumulates, you know, over the first couple of weeks and then reaches a steady state. As far as we can tell, there's nothing unusual about the exposure in this patient versus any other patient. At this point, what it appears to us, and we may learn more, you know, we're obviously going to be interrogating this as we go. As I mentioned, it seems to be more in the nature of the biology than it is anything relating to the dose level. If you're inducing differentiation, you're inducing it. We have evidence that both the 200 mg and 600 mg doses are sufficient to drive biological activity. This patient was actually responding to therapy, you know, which is great. The differentiation syndrome is unfortunate, but I don't think there's anything. I don't think the, at least on the basis of the information we have now, it doesn't appear that, you know, there's some sort of super exposure or anything like that. It's more, you know, this is, as with the IDH inhibitors and other things, this is just something you have to watch out for. Maybe more relevant in patients that have really a lot of extensive disease. One thing just that you might appreciate, Phil, is one way to treat this, of course, would be to give KO-539 in combination with a cytoreductive agent, right? So that you're keeping the counts down with a cytoreductive agent while you're differentiating the leukemia. That's, of course, one of the next things that we'll do once we move through this and move to the recommended phase II dose and then on into the combinations. Actually, you know, the menin inhibitors, they'll ultimately be registered likely as a monotherapy, but they'll probably, in the real world, won't be used as a monotherapy. That will help to further mitigate across, you know, the class, any risk of differentiation syndrome. Perfect. I guess second question also on dose. In light of this adverse event, is there any contemplation of looking at lower doses or eliminating the 600 mg dose from the trial, or is this, as you said, something that would be generally anticipated from an AML drug, so no reason to change the protocol in any way affecting the doses being investigated. At this point, I mean, I can't speak for the FDA. What I can tell you is that we will be addressing the FDA's questions, and we will be recommending that we restart enrollment at the 200-mg and 600-mg doses. Our investigators are on board with that and actually have patients, you know, waiting for a green light from FDA. I don't see us changing. Now, could FDA have a different view? They could. I think that would surprise us. Again, unless and until the partial clinical hold has been lifted, you know, we're not adding any additional patients, but it'll be our recommendation just to restart and to make sure that, you know, the physicians and we, the sponsor, are being vigilant to watch out for differentiation syndrome. We think we have the right doses. This is just, you know, an unfortunate case and something that I think we need to really make sure that we're watching for. As far as we can tell, you know, it's really the only toxicity that we've seen thus far with the drug or the only, you know, really drug-related adverse event that I think we have to keep an eye on is this potential for differentiation syndrome, which is, again, as I mentioned, likely a class effect. Great. Last question from us. In terms of that vigilance, guess we're a bit unclear if there are any changes to the brochure or- Yeah. Long-term requirements. Are there any? There will be some minor tweaks. We're gonna beef up the section on differentiation syndrome, you know, just a bit more to make sure that it, you know, it is overkill, if you will, to bring it, you know, in line with IDH and everything else. You know, substantively, it really won't change anything, but it's laid out very specifically to say, you know, "If you get this, then this. If you get that, then that." So we're already in the process of working through that, and we'll revise the investigator brochure and ultimately kind of work this into a future amendment to the protocol. Perfect. Thanks for taking our questions. Our pleasure. We have a follow-up question from Peter Lawson with Barclays. Your line is open. Okay. Great. Thanks for the follow-up. Just as you think about restarting, will there be any requirement to go back to preclinical data or do further preclinical work to start the trial? Sorry, Peter, say that again. Preclinical data? Yeah. Is there any requirement from the FDA that you would have to go back to any preclinical data to- Oh, I see. I see what you're asking. No. Yeah, in the written notification that we received from FDA relating to the partial clinical hold, they didn't indicate any preclinical data. Really what they're looking for, Peter, is, you know, for us to analyze the safety database from the ongoing study, to, you know, fully articulate the mitigation strategy, which, you know, is straightforward. Then, to, you know, make a recommendation on benefit risk around the two doses. This isn't. I can't even think of preclinical data that would help to inform this. This is really at this point, you know, firmly within clinical development. I think in fairly short order, we'll have all of that information back to the FDA. I don't expect any additional preclinical studies, and they haven't asked for any. Okay. Thank you. Does the differentiation syndrome limit any potential combination therapies? No. In fact, as I was saying to, I believe it was Phil, it's. There's been a lot of questions. As I was saying earlier, no, in fact, it actually argues in favor of combination because you know, by combining with, for example, FLAG-IDA, you know. That's a way of mitigating differentiation syndrome, giving a menin inhibitor in combination with a potent cytoreductive agent. There's nothing that we've seen that would limit our ability to combine with, you know, with anything else out there that would be a potential combination partner for menin. And in fact, there's a good rationale for moving to combinations even, you know, with all due urgency. We indicated on our last quarterly call that that's our intent. Once we have the recommended phase II dose, we're looking to get into combinations in the front line in the first relapse, or early, I should say early relapse, as quickly as we can. Gotcha. Thank you. Would managing differentiation mean you would potentially start at a lower dose with patients with high disease burden? No, not initially. The risk there, Peter, is, you know, this is often, you know, rapidly proliferating leukemia, right? You have to be careful. I know where you're going. You have to be careful with dose escalating because the leukemia can get away from you. More likely is monitor the patients, you know, a bit more intensively in that first couple of weeks to make sure that they're not showing, you know, symptoms of differentiation syndrome. You can do that both quantitatively by looking at counts, and you can do it qualitatively by looking at things like, do they have shortness of breath? Do they have unexplained weight gain or fever? You know, a number of the symptoms that are associated with differentiation syndrome. The physicians will do both. I think it's better to give them a dose that we believe is gonna drive maximal efficacy, monitor them for the first couple of weeks, few weeks, and then, you know, if you're seeing elevated counts, then, you know, consider steroids prophylactically, you know, if a physician wanted to do that. In our view, that makes more sense than doing a dose escalation or, you know, titrating the dose up, I guess, is a better way of saying it. That's probably not gonna be as effective with a rapidly proliferating disease such as AML. Great. Thank you. Thanks for the follow-up. Sure. I'm showing all further questions at this time. I would now like to turn the call back over to Dr. Wilson for any closing remarks. Thank you, operator. We appreciate everyone's participation on the call today. We'll be participating in the Evercore ISI conference and the JMP Securities Hematology and Oncology Summit over the next couple of weeks, and we look forward to seeing many of you there. In the meantime, if you have any questions, please reach out to Pete, Marc, or myself. Thank you all for participating, and have a good rest of the day and Happy Thanksgiving. Thank you. Ladies and gentlemen, that does end our conference call today. Thank you for your participation. You may now disconnect.