Welcome to the quarter one 2021 Kura 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 answer session. During the question and answer session, if you have a question, please press star then one on your touch-tone phone. I will now turn the call over to Pete De Spain. You may begin.
Thank you, Jenny. Good afternoon and welcome to Kura Oncology's first quarter 2021 conference call. Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer, and Dr. Marc Grasso, our Chief Financial Officer and Chief Business Officer. James Basta, our Chief Legal Officer, Dr. Stephen Dale, our Chief Medical Officer, Kirsten Flowers, our Chief Commercial Officer, and Kathleen Ford, our Chief Operating Officer, are 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 will now turn the call over to Dr. Troy Wilson, President and CEO of Kura Oncology.
Thank you, Pete, and thank you everyone for joining us this 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-539, 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 two 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-539 is well-positioned as a potentially best-in-class and first-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-539, both as a monotherapy and in combination, aimed at providing the greatest benefit to patients with acute leukemia. A critical component of our development plan is the determination of an phase II dose. In order to better inform a phase II dose and beyond, we've amended our KOMET-001 trial of KO-539 to include two phase IB expansion cohorts, one at a higher dose and one 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-539 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 two phase Ib expansion cohorts and assess those patients for safety and tolerability, PK and PD, and efficacy in order to determine the phase II dose. In addition, the amended phase IB 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 phase II dose have the potential to be included in the subsequent registration-directed portion of the KOMET-001 trial.
The amended protocol has been submitted to sites for IRB approval, and we will shortly begin enrolling patients in the phase IB 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 KO-539. 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 I data from KOMET-001 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.
We remain just as excited about the opportunity for farnesyltransferase inhibition in oncology, an evolving story best told in three chapters. For those newer to our story, as a prelude, we in-licensed tipifarnib, our first-generation farnesyltransferase inhibitor from Janssen in December 2014. Previously, it had been studied in more than 5,000 patients and demonstrated compelling and durable anti-cancer 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%-8% of HNSCC patients have HRAS mutations. This is chapter one.
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 phase II 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 HNSCC 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 first 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 a 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 alpha 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 two of our story.
We're currently preparing a phase I/II proof-of-concept study of tipifarnib in combination with a PI3Kα inhibitor in patients who have HRAS overexpressing and/or PIK3CA-dependent HNSCC. We expect to initiate this study in the second half of 2021. 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. 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 three 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 physicochemical properties relative to tipifarnib.
We've already identified a number of advanced lead compounds. We anticipate nomination of a development candidate for IND-enabling studies later this year. None of this would've been possible without the pioneering work our team has done over the last five 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 Marc Grasso for a discussion of our financial results for the first quarter 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 file today for more detailed discussion. Research and development expenses for the first quarter of 2021 were $20.3 million, compared to $12.6 million for the first quarter of 2020. The increase in R&D expenses was primarily due to increases in companion diagnostic development activities and clinical trial costs related to our registration-directed tipifarnib trial, clinical development and manufacturing activities related to our KO-539 program, personnel costs, and other expenses. General and administrative expenses for the first quarter of 2021 were $10.6 million, compared to $7.6 million for the first quarter of 2020. The increase in G&A expenses was primarily due to increases in personnel costs and non-cash share-based compensation.
Net loss for the first quarter of 2021 was $30.7 million, or $0.46 per share, compared to a net loss of $19.2 million or $0.42 per share for the first quarter of 2020. As of March 31st, 2021, we had cash equivalents, and short-term investments of $603.9 million, compared with $633.3 million as of December 31st, 2020. Based on our current plans, we continue to believe that our 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, Marc. Before we jump into the question and answer session, let me lay out our anticipated milestones for the remainder of this year. For KO-539, initiation of genetically enriched phase IB expansion cohorts in mid-2021 and additional phase I data from KOMET-001 in the second half of 2021. For tipifarnib, initiation of a phase I/II proof-of-concept study in combination with a PI3Kα inhibitor in the second half of 2021. For our next-generation farnesyltransferase inhibitor program, nomination of a development candidate in mid-2021. With that, operator, we're now ready for questions.
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 own efforts to determine a minimum safe and biologically effective 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 eight 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 phase II dose. There was a fair amount of discussion around that. What we've seen, and let's take the FLT3 inhibitor, gilteritinib, 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. 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 and clinical activity.
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 FDA that given we have multiple doses potentially at which we could move forward, we made a proposal to FDA that we do the gold standard and do a phase IB 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? Of course, efficacy. I think it was a little bit coincidental FDA was very much in agreement with that approach.
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. 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 zero in on the lowest dose with maximum pharmacologic and clinical activity. 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. I think it's our view that this is going to be an increasing trend for companies doing work early on to really zero in on the right dose. In our case, it's exactly the right thing to do. We've got two good doses.
We think we'll come out of this phase IB expansion with really the best answer moving forward into the registrational study and beyond. Sorry for the long answer, I think it's important to provide that context.
Great. That's helpful. Second question, with the recent data disclosure from the competitor's menin-MLL inhibitor program, what are the reasons for confidence that KO-539 could do better?
That's a really good question. Let's break it down because there's sort of several elements there. I think first 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 number of patients that were converted to MRD negative, right? Zero measurable residual disease. The challenge that that competing program has is they're trying to navigate the straits between two cliffs. On the one hand, 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 well known to be inhibitors of 3A4. It doesn't mean there isn't a path forward, it just means it's more complicated, both as a monotherapy and in combination. In contrast, the Kura 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 phase II dose.
We don't require the addition of exogenous agents to address that CYP3A4 liability, as you see with the competing program. 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 IB portion, we think we can also be first in class. We're really going to work hard toward achieving both of those goals.
Got it. Thanks for taking the questions.
Thank you.
Our next question comes from Peter Lawson from Barclays. Please go ahead.
Hey, Troy. Thanks so much for taking our questions. Just on the data readouts this year, just wonder if you could talk to the extent of the data that we could see in the second half of the menin inhibitor. I assume that that's mostly escalation data.
Yeah, Peter. It's a good question. We've guided toward providing a data update in the second half of the year. 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 IB 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 phase II dose. 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. In terms of will it include any of the phase IB data, I think we'll continue to give qualitative updates on how the program's going, in terms of what we're seeing.
We are looking toward an update later this year. Of course, we haven't even dosed the first patient yet in the phase IB. I would expect that when that data's ready, and we've determined the phase II 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 IB. 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.
Thank you. Just from the press release, you talk about expansion opportunities for the menin inhibitor into.
Yes.
Other genetic subtypes, what are those?
Yeah.
MDS patients, I'm just curious what percentage of MDS patients could benefit from a menin inhibitor.
Yeah. Let's take those two separately. As far as the other genetic subtype, people on the call will recall that at ASH in December, we showed that KO-539 was able to drive complete remission in a patient with CEBPA RUNX1 co-mutant AML. 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 MLL-R. The challenge we have, Peter, just to be candid, is I don't think we fully understand the selection rules. We know that menin and MLL pathway's 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 third potential cohort. The phase IB, really the goal there is to select, going forward, a phase II dose.
In doing that, we're going to enrich in KMT2A and NPM1. 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, we've determined a phase II dose. Using that phase II dose, we can look toward expanding the application of KO-539 to other genetic subtypes. When you're trying to both understand the biology and the dose at the same time, it's complicated. If you do them serially, it makes much more sense. 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. There's both preclinical work going on and, of course then, looking at the work we're doing in AML. 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 phase II dose, it will be an opportunity to explore.
Our next question comes from Reni Benjamin from JMP Securities.
Hey, good afternoon, guys. Thanks for taking the questions. Troy, I'd love to maybe just expand a little bit more 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 one and the other? Why not explore some granular doses as well? Maybe something between the 50 and 100, right? Maybe even change the dosing schedule.
Yeah. It's a good question, Ren. It's a really good question. 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. That's the first thing you need to look at. The question is exposure. We've said, although we are seeing increases in exposure at increasing doses, eventually you'll reach a plateau. That's part of the answer to the earlier question from Jonathan. FDA is saying, why be on the, if you think of the dose exposure curve as looking like a knee, right? You want to be up on top of it, but you don't want to be all the way up on the thigh. You want to give as much drug as you need to give and not a lot more.
The final, probably most important, is clinical efficacy. 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 two doses, we can define whether there's an advantage of the higher dose. The lower dose, the dose of 200 mg, you'll recall we saw two responses, or I should say, an MRD negative CR in one NPM1 mutant patient and a morphologic leukemia-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, we're trying to say, let's get to the right answer without necessarily the perfect answer.
We do recognize this is a competitive space, both with the existing competition and new entrants in the field. We're trying to really, Ren, strike that balance between getting the right phase II dose and moving as quickly as we can to registration. I think the phase IB 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. 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.
Yeah.
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? Also, just in terms of timing, 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 total once this is up and running. Can you maybe help fine-tune those assumptions?
Sure. There's a few things packed into that question. Let's start with number of sites, because that's our current focus, right? Is getting the protocol through IRBs, getting new sites booted up, and getting the existing sites able to enroll under the phase IB portion of the protocol. We're at seven or eight 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 have projections based on different data sources. Until you're really in there, actually at steady state, no one really knows what the rate of bringing patients on study. If 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. Right now, Ren, our goal is to determine a phase II 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. I think we're in good shape. You asked about the alignment with the registrational study and how to think about that.
One of the advantages of doing it this way is we've now aligned the endpoints of the phase IB with those that will be used in the registrational portion. We're looking at CR, CRh with transfusion independence as a key secondary endpoint. That'll be important. That was actually a recommendation from FDA to allow us to count patients 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 and KOLs is 20%-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.
If you are looking at a 20%-30% response rate, you're talking about a registrational study, Ren, of 50-100 patients per cohort, just depending on the response rate. We haven't really talked about the registrational study. We will as we get into that next phase, but it's going to look like the design of other targeted therapies. With an important distinction. The phase IB 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 phase II dose is selected, it's our belief we can take the patients from the selected cohort, the phase IB selected cohort, and then we will separate the patients by genetic subtype.
We'll have a KMT2A arm, we'll have an NPM1 arm, and we're anticipating having a third arm, which was the question I was addressing from Peter earlier in the call. 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%-30% response rate. Does that give you sufficient color on your question?
Yes, it does. Thank you very much for taking the questions.
Our pleasure. Thank you.
Our next question comes from Joseph Pantginis from H.C. Wainwright. Please go ahead.
Hey, guys. Good afternoon. My first question might be for Marc. 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&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.
Yeah. Thanks, Joe. To answer the question, there are some one-offs in the first quarter that would potentially make the first quarter more outsized. In particular, there was 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. 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. I think you should continue to see an increase in R&D spend over the course of the year.
No, that's helpful. Thanks. Just switching to sort of some of the back-end prepared comments, Troy, you gave a lot of different kinds of properties with regard to the next generation farnesyltransferase inhibitor . I 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?
Joe, thanks. It's a good question. Tipi's a very good drug. However, as we've seen with a number of other drugs, EGFR inhibitors as kind of the most notable, you can generally improve upon first 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 mg twice daily. That's a lot of drug for a head and neck patient. 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. Give all the therapeutic punch that you see with tipifarnib.
We want to make sure we maintain the good safety profile of Tipi, but we do think both in terms of the physicochemical and the pharmacokinetic properties, that we might be able to improve on it. The early compounds suggest that's possible.
Got it. My last question, I guess, is sort of my mandatory have to ask regarding the status of the AIM study. It's more of not like, do you have any timelines to provide?
Yeah.
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 and along those lines?
Yeah. It's a good question, Joe. 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. The countries 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 going to try to pursue other options. 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. It's usually either a trial like this or hospice.
COVID definitely makes that worse, but I think the other thing is 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. 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 make it easier for patients to come on study. Those changes do appear to be yielding some benefit. We can't move fast enough to have our next study, the PI3Kα combo study online, because you really need physicians, study teams, sites, patients thinking about genetic screening. Genetic screening is key to this puzzle. If they're screening for PI3K mutations or amplifications in addition to HRAS, we think that ultimately we'll be better off.
We're really looking at HRAS mutant head and neck as a beachhead to potentially a much larger opportunity with the combo. That's borne out by the pre-clinical data, Joe, as well as just 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 alpha 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 IB expansion cohorts. You mentioned in particular that one of the goals is PK/PD in those cohorts. I'm curious if you'd be willing to share with us what maybe some of the pharmacokinetic or pharmacodynamical 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. Not really, no. That's in contrast to our competitor's program. It's not that we're looking for a particular plasma concentration or time above IC90. Rather, 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. We'd like to understand that better. 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.
How do you optimize that in terms of driving the greatest efficacy? It'll 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 competitor showed, I think, some nice data. In the genetically selected populations, you would expect to see knockdown of the target genes, MEIS1 and HOXA9. Are you seeing that consistently, right? Are the arrows lining up with the clinical activity and exposure? It's part of the overall package. We firmly believe we've got two good doses, both the higher and the lower.
We want to do what I think is increasingly going to be the gold standard, that is which of those two is the phase II dose going forward. We'll go as fast as we can to get that answer, and I think that'll put us in a very good position as we're then segueing into the registration portion.
One question on the biomarkers. Your competitors showed really good knockdown of MEIS1. HOXA9 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 HOXA9?
MEIS1, our pre-clinical data suggests that MEIS1 is the better biomarker from a PD perspective relative to HOXA9. Sorry, HOXA9. You can knock down MEIS1 nearly completely and consistently. HOXA9 appears to be more variable. We would prefer to use MEIS1 as a marker of activity. In our view, you get better signal to noise. For the investors that are wondering, we think it's probably more the biology of HOXA9 relative to MEIS1, and they should really focus on MEIS1.
Great. 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 two approaches in Menin?
Yeah. I think we've mentioned in the past, when we were developing KO-539 as part of a collaboration with the University of Michigan, this is 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 six hours, and we made a very data-driven decision, and that was we could dissociate 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.
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. 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 in your target protein. That toxicity often doesn't manifest itself until you're in patients, because animals, preclinical models, are not predictive of it. Phil, both from not really needing it to drive activity, you've got Kura and Syndax both showing CRs at the first or second dose. It's not clear what a covalent inhibitor's going to do better than that.
You want to have as squeaky clean a compound as you can. We made a data-driven decision to go with the reversible inhibitor, with 539. Ultimately, I think that was the right decision.
That's very helpful. Thanks so much for taking our questions.
My pleasure. Thank you.
Our next question comes from Tiago Fauth from Peritus. Please go ahead.
Thanks for taking the question. Just a quick one on NPM1. With specific questions on the relative merits of targeting either MLL-R versus NPM1 population, given that the frontline outlook is fairly different across those two populations. To the extent that you've seen some data, but not as much as MLL-R, but we've seen some data in NPM1 from you guys and from competitors. How consistent is the data we've seen to date with perhaps a worse prognosis once you reach that relapsed refractory stage? What's the actual attractiveness of the class within that patient population? What's sort of the bar for that? Again, that 20-30 seems about right, but I'm curious if you could break down for subsets, you may have a different answer necessarily. Thanks.
Sure, Tiago. It's a good question. In the relapsed refractory setting, NPM1 commonly appears with other co-mutations, DNMT3A, IDH, FLT3, and has a very negative prognosis. Those patients do not do well on existing therapies. I think both we and Syndax have shown encouraging early signals of activity in that population. What is meaningful there is the ability to drive to MRD negativity, right? That will increasingly be the gold standard in AML. 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 MLL-R 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 phase III study.
The response rate's about, I think, 60%, about a 20% MRD negativity rate with 2025, and 15 months of overall survival. 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 patients with MRD negative responses have better survival. That's why FDA gave the green light to Kronos 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. This mechanism of action is 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.
Although you may increase the response rate, the hope is that you will make those responses deeper, more durable, and that'll be a benefit to patients, both in the non-intense chemo as well as in the intense chemo populations.
Yeah, understood. Appreciate the answer. All right, thanks.
Thanks, Tiago.
As a reminder, if you have a question, please press star then one on your touch-tone phone. Our next question comes from Jonathan Chang from SVB Leerink. Please go ahead.
Hi, guys. Thanks for taking the follow-up. What is cobicistat, 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. Cobicistat is a strong CYP3A4 inhibitor. For those who may not be aware, I think Jonathan's referring to an update on clinicaltrials.gov from one of our competitors. As far as we know, the cobicistat is used to increase the drug levels of sensitive CYP3A4 substrates. The thought is that our competitor is dosing their compound with cobicistat as a way of trying to increase the exposure of their menin inhibitor and reduce the sensitivity to azoles. They're trying to increase the exposure at lower doses by effectively giving all of the patients cobicistat. If you can do that, then potentially, you could remove the requirement of having two doses, one for the azole and one for the non-azole.
The complication, of course, is it makes it much more difficult to then use that in combination with other drugs. You can just go into the package insert for cobicistat and look at the drugs that are contraindicated, and you'll see it includes azoles, because of the CYP3A4 interactions. 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. In contrast, of course, 539 needs none of that, right? Our exposures are independent of whether patients are on no azole, moderate azole, or strong azole. We don't have to dose with cobicistat or another compound that's commonly used is ritonavir. It's just a much better setup both for the monotherapy and in 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. Thank you all once again for participating in the call today. We'll be at the JMP Securities Life Sciences 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 De Spain, Marc Grasso, 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.