Earnings Call: Q1 2021

May 6, 2021

Welcome to the Quarter 1, 2021 Cara Oncology, Inc. Earnings Conference Call. My name is Jenny. I'll be your operator for today's call. At this time, all participants are in a listen only mode. Later, we will conduct a question and I will now turn the call over to Peter Despain. You may begin. Thank you, Jenny. Good afternoon, and welcome to Kura Oncology's Q1 2021 conference call. Joining me on the call are Doctor. Troy Wilson, our President and Chief Executive Officer and Doctor. Mark Grasso, our Chief Financial Officer and Chief Business Officer Jim Bosta, our Chief Legal Officer Doctor. Steven Dale, our Chief Medical Officer Kirsten Flowers, our Chief Commercial Officer and Kathy Ford, our Chief Operating Officer are also with us and available to answer questions. Before I turn the call over to Doctor. 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 will now turn the call over to Doctor. Troy Wilson, President and CEO of Kura Oncology. Thank you, Pete, and thank you, everyone, for joining us afternoon. Over the past quarter, we've continued to make significant progress as a company, and we believe the relative positioning of our menin inhibitor program, KO-five thirty nine has improved meaningfully. We've also witnessed a number of new developments in the space, including updated clinical data from a competitor program that further validated menin MLL as a therapeutic target in AML, as well as the emergence of 2 additional clinical stage programs. This heightened activity speaks to the mounting excitement surrounding the menin inhibitor space and the significance of driving meaningful clinical activity in genetically defined subsets of AML. It's also served to highlight our leadership position, while underscoring the value of an aggressive clinical development strategy and the importance of operational execution. We believe KO-five thirty nine is well positioned as a potentially best in class and 1st in class menin inhibitor. This confidence is supported by a growing body of clinical data, including compelling activity, a favorable safety and tolerability profile and a wide therapeutic window. As such, we intend to conduct a comprehensive clinical development plan for KO-five thirty nine both as a monotherapy and in combination aimed at providing the greatest benefit to patients with acute leukemia. The critical component of our development plan is the determination of an optimal Phase 2 dose. In order to better inform a recommended Phase 2 dose and beyond, we've amended our COMET-one trial of KO-five thirty nine to include 2 Phase 1b expansion cohorts, 1 at a higher dose and 1 at a lower dose, each enriched with NPM1 mutant and KMT2A rearranged relapsed and or refractory AML patients. These expansion cohorts should enable us to maximize the benefit risk for KO-five thirty nine in our target patient populations, similar to what has been done previously with other targeted therapies in AML. We expect to enroll at least 12 patients in each of our 2 Phase 1b expansion cohorts and assess those patients for safety and tolerability, PK and PD and efficacy in order to determine the recommended Phase 2 dose. In addition, the amended Phase 1b protocol gives us flexibility to enroll up to an additional 18 patients per cohort as appropriate. Importantly, we believe patients enrolled in the cohort selected as the recommended Phase 2 dose have the potential to be included in the subsequent registration directed portion of the COMET-one trial. The amended protocol has been submitted to sites for IRB approval and we will begin we will shortly begin enrolling patients in the Phase 1b expansion cohorts at both existing and new clinical sites. Meanwhile, we continue to engage with our key opinion leaders and global steering committee to further define a comprehensive clinical development plan for KL-five thirty nine. Additional opportunities include frontline combination studies, additional genetic subtypes, a pediatric development strategy and other indications such as acute lymphocytic leukemia and myelodysplastic syndrome. We intend to move these efforts forward aggressively pending determination of an optimal dose. We look forward to providing an update, including additional Phase 1 data from COMET-one later in the year. Given the excitement around our menin program, it's easy to understand why it's captured Wall Street's attention over the past year. However, we remain just as excited about the opportunity for farnesyltransferase inhibition in oncology, an evolving story that's told in 3 chapters. For those newer to our story, as a prelude, we in licensed Tipifarnath, our 1st generation farnesyltransferase inhibitor from Janssen in December 2014. Previously, it had been studied in more than 5,000 patients and demonstrated compelling and durable anticancer activity in certain unselected patients. Using advancements in cancer genetics and tools such as next generation sequencing, we identified multiple genetically defined subsets of patients most likely to respond to Tipifarnib. The most advanced of these initiatives is focused on patients with head and neck squamous cell carcinoma or HNSCC that carry mutations in the HRAS gene. We estimate 4% to 8% of HNSCC patients have HRAS mutations. This is Chapter 1. Earlier this year, Tipifarnib was granted breakthrough therapy designation from FDA for the treatment of patients with recurrent or metastatic HRAS mutant HNSCC. The breakthrough therapy designation was based on data from our Phase 2 RUN HN trial, which was recently published in the Journal of Clinical Oncology. Development of targeted therapies in HNSCC has lagged behind other cancer indications. Thus, we were very gratified by FDA's award of Breakthrough therapy designation, which acknowledges both the dire unmet need for patients with recurrent or metastatic HRAS mutant hNACC and the promise of tipifarnib to provide clinical benefit to patients. We're motivated by our data and the potential that tipifarnib could represent the 1st approved small molecule targeted therapy in HNSCC. We remain focused on conducting our AIM HN registration directed trial and bringing Tipifarnib to market as quickly and as efficiently as possible, providing a beachhead to the development of rational combinations and expansion to larger genetic subtypes. Among these potential combinations, we've prioritized the combination of tipifarnib and PI3 kinase alpha inhibitor. Our preclinical data suggest that HRAS and PI3 kinase alpha are codependent oncogenes in HNSCC and that combining tipifarnib with a PI3 kinase alfa inhibitor has potential to provide meaningfully better antitumor activity than inhibiting either target alone. We believe this has the potential to increase the total addressable population for tipifarnib to as high as 50% of HNSCC. Building on the promise of tipifarnib as a monotherapy, this combination represents Chapter 2 of our story. We're currently preparing a Phase onetwo proof of concept study of tipifarnib in combination with a PIADR kinase alp inhibitor in patients who have HRAS overexpressing and or PIK3CA dependent HNSCC. We expect to initiate this study in the second half of twenty twenty one. Meanwhile, through internal efforts and our network of academic collaborations, we've uncovered some compelling opportunities for farnesyltransferase inhibitors in combination with other targeted therapies. This biology is totally novel and we believe it warrants a greater investment in the therapeutic class. From this investment, we're advancing a discovery stage program to develop a next generation farnesyltransferase inhibitor, designed to target innovative biology and address large oncology indications of high unmet need through rational combinations. This represents Chapter 3 of our story and potentially the largest opportunity. Our goal for this program is to deliver a drug candidate that has comparable potency and selectivity and improved pharmacokinetic and physical chemical properties relative to Tipifarnib. We've already identified a number of advanced lead compounds and we anticipate nomination of a development candidate for IND enabling studies later this year. None of this would have been possible without the pioneering work our team has done over the last 5 years. While we continue to focus on the opportunity with HRAS mutant HNSCC, we view farnesyltransferase inhibition in oncology as a potentially broader and more valuable therapeutic and commercial franchise and one that has potential to deliver multiple opportunities for additional indications. We look forward to sharing an update with you as the story continues to evolve. With that, I'll now turn the call over to Mark Grasso for a discussion of our financial results for the Q1 2021. Thank you, Troy, and good afternoon, everyone. I'll provide a brief overview of our financial results here on the call and invite you to review our 10 Q filed today for a more detailed discussion. Research and development expenses for the Q1 of 2021 were $20,300,000 compared to $12,600,000 for the Q1 of 2020. The increase in R and D expenses was primarily due to increases in companion diagnostic development activities and clinical trial costs related to our registration directed to be far enough trial, clinical development and manufacturing activities related to our KO-five thirty nine program, personnel costs and other expenses. General and administrative expenses for the Q1 of 2021 were $10,600,000 compared to $7,600,000 for the Q1 of 2020. The increase in G and A expenses was primarily due to increases in personnel costs and non cash share based compensation. Net loss for the Q1 2021 was $30,700,000 or $0.46 per share compared to a net loss of $19,200,000 or $0.42 per share for the Q1 of 2020. As of March 31, 2021, we had cash, cash equivalents and short term investments of $603,900,000 compared with $633,300,000 as of December 31, 2020. Based on our current plans, we continue to believe that our cash, cash equivalents and short term investments will be sufficient to fund our operations into 2024. With that, I will now turn the call back over to Troy. Thank you, Mark. Before we jump into the question and answer session, let me lay out our anticipated milestones for the remainder of this year. For KO-five thirty nine, initiation of genetically enriched Phase 1b expansion cohorts in mid-twenty 21 and additional Phase 1 data from COMET-one in the second half of twenty twenty one. Certipifarnib initiation of a Phase onetwo proof of concept study in combination with a PI3 kinase alpha inhibitor in the second half of twenty twenty one and for our next generation farnesyltransferase inhibitor program, nomination of a development candidate in mid-twenty 21. With that, operator, we're now ready for questions. Thank And our first question comes from Jonathan Chang from SVB Leerink. Please go ahead. Hi, guys. Thanks for taking my questions. First question, I'd love to get your thoughts on the recent Amgen disclosures on their KRAS G12C inhibitor and their efforts to evaluate whether a lower dose is also safe and efficacious. That seems to have parallels to your efforts to determine a minimum safe and biologically affected dose. How should investors be thinking about this? Hi, Jonathan. Thanks for the question. When we communicated the feedback that we received from FDA just about 8 weeks ago at our last quarterly call, we put that feedback in the context that it was our understanding this is an initiative at FDA to ask sponsors to really do the work to define the optimum Phase 2 dose. And that optimum and there was a fair amount of discussion around that. What we've seen and let's take the FLT3 inhibitor giltolitinib as an example is with these targeted therapies, one has the potential because of the wide therapeutic window to saturate the target and then continue dose escalating. So, FDA, it's our understanding and it was part of the discussion we had around our trial. FDA is really asking sponsors to define the lowest dose with maximum pharmacologic in clinical activity. Now in the Amgen case, they have essentially a completed registrational study. They're going to go back and do some work to bridge potentially to a lower dose. In our situation, it was actually not a request from FDA. It was a recommendation that we made to a request from FDA. It was a recommendation that we made to FDA that given we have multiple doses potentially at which we could move forward, if we made a proposal to FDA that we do the gold standard and do a Phase 1b expansion with a lower dose and a higher dose and ask the question, between those two doses, is there a difference in PK and exposure? Is there a difference in PD, safety and tolerability and of course efficacy. And FDA, I think it was a little bit coincidental. FDA was very much in agreement with that approach. So we're earlier in the development paradigm, Jonathan, if you want to sort of make a direct comparison between our efforts and those of Amgen. But the rationale is the same. And that is with these targeted therapies, particularly as one is thinking about polypharmacy and combinations, you really want to do the work needed to 0 in on the lowest dose with maximum pharmacologic and clinical activity. And that's particularly important in AML because as you go to earlier lines, you have patients on 7+3, Azoles, venetoclax, as well as potentially PPIs, antidepressants. So I think it's our view that this is going to be an increasing trend for companies doing work early on to really 0 in on the right dose. In our case, it's exactly the right thing to do. We've got 2 good doses. Think we'll come out of this Phase 1b expansion with really the best answer moving forward into the registrational study and beyond. Sorry for the long answer, but I think it's important to provide that context. Great. That's helpful. And second question, with the recent data disclosure from the competitors menin MLL inhibitor program, what are the reasons for confidence that KL-five thirty nine could do better? Yes. That's a really good question. So let's break it down because there's sort of several elements there. I think 1st and foremost, the competitor data underscores the importance of the menin MLL pathway as a therapeutic target. We're a competing program, we play to win, but you have to be impressed by the level of clinical benefit in terms of both response rate and the ability the number of patients that were converted to MRD negative, right, 0 measurable residual disease. The challenge that that competing program has is they're trying to navigate the straits between 2 cliffs. On the one hand, they have their compound is a very sensitive CYP3A4 substrate, which makes it difficult potentially if they're in an environment where they have inhibitors of CYP3A4. They also have dose limiting toxicity in the form of QTC prolongation. The CYP sensitivity is an issue in that the exposure of their compound can vary depending on the other agents that the patient is taking. Those can be things like antifungals, azoles, as well as grapefruit juice, St. John's wort, right. All of these are known well known to be inhibitors of 3A4. Doesn't mean there isn't a path forward, it just means it's more complicated both as a monotherapy ending combination. In contrast, the Cura program, we show no dependence on Azoles. We've said that repeatedly. Our compound has a very wide therapeutic window, good safety and tolerability. There is increases in exposure with increasing dose. We need to do the rest of the work to decide which dose is the right one to move forward as a recommended Phase 2 dose. But we don't require the addition of exogenous agents to address that CYP-three eighty four liability as you see with the competing program. And I think we don't have the QTC prolongation. We've seen no evidence of cardiac tox. It's early days for both programs. I think we believe that 539 has the potential to be both best in class. And given that we're now just about ready to transition into the Phase 1b portion, we think we can also be 1st in class. And we're really going to work hard toward achieving both of those goals. Got it. Thanks for taking the questions. Thank you. And our next question comes from Peter Lawson from Barclays. Please go ahead. Troy, thanks so much for taking my questions. Just on the data readouts this year, so just wonder if you could talk to the extent the data that we could see in the second half in melanin inhibitor, and I assume that that's mostly escalation data? Yes, Peter. So it's a good question. We've guided toward providing a data update in the second half of the year. I don't our focus just so we're clear for you and everyone else on the call, our focus is to get into and then through those Phase 1b expansions as quickly as possible because we know we have good safety and tolerability. We know we have compelling evidence of activity. We need a dose, a recommended Phase 2 dose. And that's really what we're looking to achieve and then looking to share as quickly as we can. We'd like to provide an update later in the year. I don't know yet exactly what that's going to look like. But in terms of will it include any of the Phase 1b data, I think we'll continue to give kind of qualitative updates on how the program is going in terms of what we're seeing. But we are looking toward an update later this year. And then of course, we haven't even dosed the 1st patient yet in the Phase Ib. I would expect that when that data is ready, and we've determined the recommended Phase 2 dose and are then moving into the registration enabling portion, we'll then provide another update to you, the other analysts and of course to The Street to help understand what was the output of the Phase 1b. We just at this point, we don't have any clarity yet on the timing of that. We have goals, but until we're really enrolling steady state in those Phase Ib cohorts, it's a little bit hard to be more concrete. And then just from the press release, you talk about expansion opportunities for the menin inhibitor into other genetic subtypes and so what are those? And you also mentioned MDS patients. So I'm just curious what percentage of MDS patients could benefit from it. Yes. So this is so let's take those 2 separately. So as far as the other genetic subtype, people on the call will recall that at ASH in December, we showed that 539 was able to drive complete remission in a patient with SETI2 RUNX1 co mutant AML. And we were pleasantly surprised by that. We weren't completely thunderstruck, but we were surprised. We've continued to see evidence of biologic and clinical activity outside of the genetic subtypes of the NPM1 and MLLr. The challenge we have, Peter, just to be candid is, I don't think we fully understand the selection rules. We know that menin MLL pathway is important. We know that it interacts with other targets. We're still trying to define those selection rules that would help us to enroll a 3rd potential cohort. The Phase Ib, really the goal there is to select a going forward a recommended Phase II dose. And in doing that, we're going to enrich in KMT2A and NPM1. And we're trying by doing that, we're trying to enroll in a population where we have the highest likelihood of seeing clinical benefit and as few variables as possible, so that we can really say between these two dose cohorts, are we seeing a meaningful difference in one versus the other? When we're on the other side of that, and we've determined a recommended Phase 2 dose, Using that recommended Phase 2 dose, then we can look toward expanding the application of KO-five thirty nine to other genetic subtypes. When you're trying to both understand the biology and the dose at the same time, it's complicated. But if you do them serially, it makes much more sense. And this is consistent with what's been done with other targeted therapies. As for your question around MDS, yes, there is a percentage of patients with MDS, they're pre AML, who have NPM1 mutations. There's some very interesting work going on in academic labs looking at the sequencing of mutations in these myeloproliferative and myelodysplastic diseases. We're intrigued that there might be a possibility there to intervene before a patient ever develops full blown AML. And there's both preclinical work going on and of course then looking at the work we're doing in AML. But that's if one could prevent the onset of AML, that would, of course, be the ideal situation. Don't know whether that's possible, but certainly something that when the time is right and we have a recommended Phase 2 dose, it will be an opportunity to explore. And our next question comes from JMP Securities. Troy, I'd love to just maybe just expand a little bit more on these on the Phase Ib. You mentioned a lower dose cohort, a higher dose cohort. Have you guys picked what those doses will be? And why pick between 1 and the other? Why not explore some granular doses as well? Maybe something between the 50 100, right? Or maybe even change the dosing schedule a little? Yes. So it's a good question, Ren. It's a really good question. So again, you're looking at a number of variables, right? Number 1 is safety and tolerability. It's our belief that both doses will have passed the safety threshold for the escalation. But that's the first thing you need to look at. Then the question is exposure. And we've said, although we are seeing increases in exposure at increasing doses, eventually you'll reach a plateau. And that's part of the in the answer to the earlier question from Jonathan, FDA is saying why beyond the if you think of the dose exposure curve is looking like a knee, right, you want to be up on top of it, but you don't want to be up all the way up on the thigh. You want to give as much drug as you need to give and not a lot more. Then the final and probably most important is clinical efficacy. And we just to date, we haven't had enough enrichment to be able to say whether one is different than another. It's our belief that with 2 doses, we can define whether there's an advantage of the higher dose. The lower dose, the dose of 200 milligrams, you'll recall we saw 2 responses or I should say, an MRD negative CR in 1 NPM1 mutant patient and a morphologic leukemic free state in the other. The question is, are you getting any incremental benefit as you go higher? One can be as granular as you want to your question. There's nothing that says you couldn't explore more doses, but we're trying to balance we're trying to say, let's get to the right answer without necessarily the perfect answer. And we do recognize this is a competitive space, both with the existing competition and new entrants in the field. So we're trying to really strike that balance between getting the right recommended Phase 2 dose and moving as quickly as we can to registration. And I think the Phase 1b is nicely set up for that. As with every study, we're data driven. If there's a reason to explore something a little different, we'll do that. But we're trying to keep it fairly simple. Okay. And then just as a follow-up, you're mentioning the registrational study, the fact that you might be able to utilize patients from either dose that you wind up choosing for the registrational study. Can you talk a little bit about what you think a registrational study could look like? And then also just in terms of timing, and I'm not trying to pin you guys to anything, but I would think that maybe those 12 patients could get enrolled even if you start the study by the middle of this year, that it could be done this year, just given the fact I think you've mentioned in the past that you hope to be at about 20 sites or so so, total once this is up and running. Can you maybe help fine tune those assumptions? Sure. So there's a few things packed into that question. We are let's start with number of sites because that's our current focus, right? It's getting the protocol through IRBs, getting new sites booted up and getting the existing sites able to enroll under the Phase 1b portion of the protocol. We're at 7 or 8 sites now, I want to say. We're anticipating tripling that over the next several months as we bring new sites online to the sites currently enrolling. We don't we have projections based on different data sources until you're really in there actually at sort of at steady state. No one really knows like what the rate of bringing patients on study. Anything, we're trying to power it appropriately with enough sites to help drive enrollment, both in the Phase Ib and ultimately in the pivotal. But we just right now, Ren, our goal is to determine a recommended Phase 2 dose this year. It's hard to be a lot more granular than that, until you both get the sites open and you get some experience with how many patients they're seeing. Not every patient that we identify, for example, is eligible to come on the study. There's a fair number of screen failures that you have to account for and so forth. But I think we're in good shape. As far as the you asked about the alignment with the registrational study and how to think about that. So one of the advantages of doing it this way is we've now aligned the endpoints of the Phase 1b with those that will be used in the registrational portion. So we're looking at CR, CRH with transfusion independence as a key secondary endpoint. That will be important. That was actually a recommendation from FDA to allow us to count patients toward it, toward the totals. In terms of what we think is needed, sorry, there's a little bit of background noise. In terms of what we think is needed, what we're hearing from investigators in KOLs is 20% to 30% response rate, I. E. CR rate in this population is likely registrational. These are populations of very high unmet need. These patients do not do well on any available therapy. And if you are looking at a 20% to 30% response rate, you're talking about a registrational study ran of 50 to 100 patients per cohort, just depending on the response rate. Our study will we haven't really talked about the registrational study. We will as we get into that phase, that next phase, but it's going to look like the design of other targeted therapies with an important distinction. The Phase 1b is enrolling both NPM1 and KMT2A in each dosing cohort. The goal is just to select dose. So you're going for the patients most likely to respond. Once the recommended Phase 2 dose is selected, it's our belief we can take the patients from the selected cohort, the Phase 1b selected cohort, and then we will separate the patients by genetic subtype. So we'll have a KMT2A arm, we'll have an NPM1 arm and we're anticipating having a 3rd arm, which was the question I was addressing from Peter, earlier in the call. And those will look fairly typical with what you've seen with other small molecule targeted therapies, given that you want to meet or exceed that 20% to 30% response rate. I hope does that give you sufficient color on your question? Yes, yes, it does. Thank you very much for taking the questions. Our pleasure. Thank you. And our next question comes from Joe Pantginis from H. C. Wainwright. Please go ahead. Hey, guys. Good afternoon. My first question might be for Mark. I know you guys don't usually give granular financial guidance, but when you look at OpEx for the rest of the year, I guess from an R and D standpoint, I'll ask specifically though, can we look at this as a bit of a baseline? Are there sort of one offs with regard to say manufacturing that took place to have drug supply for clinical studies? I just wanted to get some sort of read. Thanks. Yes. Thanks, Joe. So to answer the question, there are some one offs in the Q1 that would potentially make the Q1 more outsized. In particular, there is some spend on the companion diagnostic front. That said, we do anticipate the spend to be continuing to increase over the course of the year. And while we haven't given specific OpEx guidance for the year, that may be something that we're going to do in the short term. And I think you should continue to an increase in R and D spend over the course of the year. That's helpful. Thanks. And then when you just switching to sort of some of the back end prepared comments. And Troy, you gave a lot of properties with regard to the next generation farnesyltransferase inhibitor. Was just curious with some of your lead candidates, any of those properties that are sort of rising to the top that you really wanted to see as part of your rational design? Yes, Joe. Thanks. It's a good question. Tipi is a really it's a very good drug. However, as we've seen with a number of other drugs, EGFR inhibitors and as kind of the most notable, you can generally improve kind of upon 1st generation technology. One of the things we'd love to be able to do that's very simple is to lower the dose and to be able to have the drug given once a day as opposed to twice a day. For the head and neck patients, we're dosing patients at 600 milligrams twice daily. That's a lot of drug for a head and neck patient. And based on what we know, we think there's the potential to come in with a development candidate that's more potent, potentially has less inter patient variability and better bioavailability such that you could basically have a smaller pill, but give all the therapeutic punch that you see with Tipifarnib. So those are we want to make sure we maintain the good safety profile of Tipi, but we do think both in terms of the physical chemical and the pharmacokinetic properties, that we might be able to improve on. The early compounds suggest that's possible. Got it. And then my last question, I guess, is sort of my mandatory have to ask regarding the status of the AIM study. And it's more of like not like do you have any time lines to provide, but maybe some sort of anecdotes as to are you seeing some sites getting ready to open again post COVID, where you're seeing some activities in particular regions, something maybe more benign along those lines? Yes. It's a good question, Joe. And it's an important study. It's potentially the first approval of a targeted therapy in head and neck. You do see country specific effects and it's not entirely clear whether they're due to COVID, to be honest. It's the country is sort of wax and wane. Europe has largely been locked down. And what we have found with head and neck patients generally is they're reluctant to travel. If you don't get very close to them, in terms of their ability to get therapy, they're just they're going to try to pursue other options. And that's partly because by the time we're getting them, they're so far down the disease path that it's tough for them, right? It's usually either a trial like this or hospice. So COVID definitely makes that worse. But I think the other thing is, we're seeing where we seem to get the best traction is where patients are newly identified. If you go into databases, for example, you'll find HRAS mutant patients, but often those patients have passed on. So that's why we have such an active screening campaign to find these patients. As we've indicated in the past, we've made changes to the protocol to allow make it easier for patients to come on study. Those changes do appear to be yielding some benefit. We're also looking we can't move fast enough to come to have our next study, the PI3 kinase alpha combo study online because you really need physicians, study teams, sites, patients thinking about genetic screening. Genetic screening is key to this puzzle. And so if they're screening for PIATTRK kinase mutations or amplifications in addition to HRAS, we think that ultimately will be better off. We're really sort of looking at HRAS mutant head and neck as a beachhead to potentially a much larger opportunity with the combo. And that's borne out by the preclinical data, Joe, as well as just the what we're hearing from the investigators and the study teams as we're preparing for the current study, which will be the combo study of tipifarnib plus a PI3 kinase half inhibitor due to start here in the second half of the year. Got it. Thank you very much. Our pleasure. Thank you. Our next question comes from Phil Nadeau from Cowen and Company. Please go ahead. Good afternoon. Thanks for taking my questions. A couple on the Phase 1b expansion cohorts. You mentioned in particular that one of the goals is PKPD in those cohorts. I'm curious, sorry, if you'd be willing to share with us what maybe some of the pharmacokinetic or pharmacodynamic goals are. In particular, is there like an AUC that you're going for a time above IC90 or other markers? Thanks, Phil, for the question. No, not really, no. And that's in contrast to our competitors' program. It's not that we're looking for a particular plasma concentration or time above IC90. Rather, and this was suggested, we showed kind of an early cut of the cycle 1 day 1 data at ASH. You do see inter patient variability in exposure. Now that variability in exposure doesn't appear to be associated with toxicity. It's not clear that it's associated with efficacy. It's not like the outliers are the patients that are seeing the responses, but we'd like to understand that better. And it's easier when you're in an enriched population of being able to say, okay, what's the basis for the inter patient variability? Is it, for example, the PKA of the compound? Is there a food effect? The sort of standard stuff you do in drug development. And then how do you optimize that in terms of driving the greatest efficacy. So it will be an element of the data set that we look at from the Phase Ib. But ultimately, what we think will be the greatest determinant between the two doses is going to be pharmacologic and clinical activity. The biomarkers, Phil, are and again, our competitors showed, I think, some nice data. In the genetically selected populations, you would expect to see knockdown of the target genes, MEIS-one and HoxA9. Are you seeing that consistently, right? Is that are the arrows lining up with the clinical activity and exposure? It's part of the overall package. But we firmly believe we've got 2 good doses, both the higher and the lower. We want to do what I think is increasingly going to be the gold standard and that is which of those 2 is the optimum Phase 2 dose going forward. And we'll go as fast as we can to get that answer. And I think that will put us in a very good position as we're then segueing into the registrational portion. One question on the biomarkers. Your competitors showed really good knockdown of MEIS-one. HOX-nine was knocked down, although not completely suppressed. And I guess investors have been debating whether that's a function of HoxA9 or that specific compound. Do you have an opinion on whether it's possible to totally suppress HOX-nine? So MEAS-one, our preclinical data suggests that MEAS-one is the better biomarker from a PD perspective relative to HOXA-nine. You can knock down MACE1 nearly completely and consistently. HoxA9 appears to be more variable. We would prefer to use MEAS1 as a marker of activity. You just get a in our view, you get better signal to noise. So for the investors that are wondering, I think we think it's probably more the biology of HOX A9 relative to MEIS-one, and they should really focus on MACE-one. Great. And then last question from us, another question we get all the time is comparing and contrasting covalent versus non covalent inhibitors. Do you have a perspective on the pluses and minuses of the 2 approaches in Meninitis? Yes. So, we as I think we've mentioned in the past, when we were developing KO-five thirty nine as part of a collaboration with the University of Michigan business back in the early days before there was much interest. We actually pursued both covalent and non covalent approaches. We had hits that we were evaluating using both approaches. Menin turnover in cells is about 6 hours. And we made a very data driven decision and that was we could knock down we could disassociate menin from MLL and chromatin completely. We could induce differentiation with a reversible inhibitor. An irreversible or a covalent inhibitor didn't really seem to get us anything. As far as being able to drive dissociation of menin from MLL. The flip side of course is covalent inhibitors are not without cost. And just to remind everyone for those who are newer to the Kura story, the chemistry team that developed our menin inhibitor did all of the pioneering work on the KRAS G12C inhibitors. You can follow the publications and the patents. So they come from great knowledge of covalent inhibitors. We've even seen not only with KRAS, but with other targets as well, you can get idiosyncratic off target toxicity due to the fact that the electrophile in the covalent inhibitor is binding cysteines other than your target cysteine and your target protein. And that toxicity often doesn't manifest itself until you're in patients, because animals preclinical models are not predictive of it. So Phil, both from a not really needing it to drive activity, I mean you've got Cura and Syndax both showing CRs at the 1st or second dose. It's not clear what a covalent inhibitor is going to do better than that. And you want to avoid any you want to have as squeaky clean a compound as you can. So we made a data driven decision to go with the reversible inhibitor with 539. And ultimately, I think that was the right decision. That's very helpful. Thanks so much for taking our questions. My pleasure. Thank you. And our next question comes from Thiago Fauch from Paradis. Please go ahead. Thanks for taking the question. So just a quick one on NTM-one. So with specific questions on the relative merit of targeting either the MLR versus NPM1 population given that the frontline outlook is fairly different across those 2 populations. So to the extent that you've seen some data, but not as much as MLLr, but you've seen some data in NPM1 from you guys and from competitors, how consistent is the data would seem to the class within that patient population? What's sort of the bar for that? And again, that 20 to 30 seems about right, but I'm curious if you break down for subsets, you may have a different answer necessarily. Thanks. Sure, Thiago. So it's a good question. So in the relapsedrefractory setting, NPM1 commonly appears with other co mutations, DNMT IIIA, IDH, FLT3 and has a very negative prognosis. Those patients do not do well on existing therapies. And I think both we and Syndax have shown encouraging early signals of activity in that population. And what is meaningful there is the ability to drive to MRD negativity, right. That will increasingly be the gold standard in AML. And I think we've shown one anecdotal example as of the ASH update, Syndax had I think a second one in NPM1 and then some MRD negative patients in the MLLr patient population. That's all encouraging. As you transition to frontline, particularly in the patients who cannot tolerate intensive chemo, if you look at the response rate and the rate of MRD negativity with venetoclax and azacitidine, there's a landmark Phase 3 study. The response rate is about, I think, 60%, about a 20% MRD negativity rate, 20, 25, and 15 months of overall survival. You'd really liked there's clear literature and it's available if people want they can ask Pete, we can give you the citations. There's clear literature that says if patients with MRD negative responses have better survival. And that's why FDA gave the green light to Cronos for their trial with the SYK inhibitor. The potential, Tiago, of a menin inhibitor to drive an MRD negative response in that frontline, a durable response, that's really what you're going for. And this mechanism of action is like it's the perfect tool for that problem, because the NPM1 is directly related to the menin MLL pathway. And by virtue of the mechanism that you're inducing differentiation and driving these MRD negative responses, we're keen to get to that frontline setting because although you may increase the response rate, the hope is that you will make those responses deeper, more durable and that will be a benefit to patients both in the non intense chemo as well as in the intense chemo population. Understood. I appreciate the answer. Thanks. Thanks, Tiago. Our next question comes from Jonathan Chang from SVB Leerink. Please go ahead. Hi, guys. Thanks for taking the follow-up. What is cobisastat and what impact could this have in combination with a menin MLL inhibitor and future development strategy? Jonathan, kudos for you for getting back in the queue. Sure. So covisostat is a strong CYP-three eighty four inhibitor. And for those who may not be aware, I think Jonathan is referring to an update on clinicaltrials dot gov from one of our competitors. As far as we know, cabistastat is used to increase the drug levels of sensitive CYP3A4 substrates. And the thought is that our competitor is dosing their compound with cabistat as a way of trying to increase the exposure of their menin inhibitor and make reduce the sensitivity to Azoles. So they're trying to increase the exposure at lower doses by effectively giving all of the patients cobisostat. Now if you can do that, then potentially you could remove the requirement of having 2 doses, one for the azole and one for the nonazole. The liability the complication, of course, is it makes it much more difficult to then use that in combination with other drugs. And you can just go into the package insert for cabizostat and look at the contra the drugs that are contraindicated and you'll see it includes Azoles, right, because of the CYP-three eighty four interactions. So it may ultimately help in the near term with increasing plasma exposures at lower doses. In the long term, it's going to make combinations, we think, much more complicated. And in contrast, of course, 539 needs none of that, right? Our exposures are independent of whether patients are on noazole, moderateazole or strongazole. We don't have to dose with cabicastat or another compound that's commonly used is ritonavir. So it's just a much better setup both for the monotherapy and the combination. Got it. Thanks for taking the follow-up. Sure. Appreciate the question. We have no further questions at this time. Great. Thank you, operator. And thank you all once again for participating in the call today. We'll be at the JMP Securities Life Science Conference next month. Look forward to speaking with many of you then. In the meantime, if you have any questions, please feel free to contact Pete, Mark or myself. Thank you again and have a good evening everyone. Thank you, ladies and gentlemen. This concludes today's conference. Thank you for participating. You may now disconnect.