Perfect. Thank you so much. Good morning. My name's Pete Lawson. I'm one of the biotech analysts at Barclays. Welcome to Barclays Global Healthcare Conference in Miami. I'm really pleased to have up on stage with me management from Kura, so Troy Wilson, CEO. I guess clearly the focus is gonna initially be around menin inhibitors and combination data, pivotal, and their expansion opportunities. I guess kind of first question is around the updates that we're gonna see in the combination therapy.
Mm-hmm.
Kind of what we should expect to see in that kind of mid-2024 update, in combinations in the combination 07 trial.
Sure. Yeah. So thank you, Peter, and to you and Barclays for the invitation. It's always nice to come to Miami, particularly in the spring. So you asked about the KOMET-007 data and how to think about updates. We are now evaluating ziftomenib in that study at 400 mg in all four cohorts. So as a reminder to everyone, the KOMET-007 study is intended to evaluate ziftomenib, which is our menin-MLL inhibitor, with two different backbones, venetoclax and azacitidine in the unfit patients and 7+3 in fit patients. The dose escalation portion of the study is being conducted in higher-risk patients. So in the case of venetoclax/azacitidine, we're actually in the relapse refractory setting. In the 7+3 context, we are in patients who have adverse risk.
and the thinking there and actually the agreement with the agency is that at the time we reach a recommended phase II dose, our safety monitoring committee can relax the restrictions and expand the patient population. And what that means is in the venetoclax-azacitidine population, we will pivot from the relapse refractory to frontline, untreated. And in the 7+3, we will remove the adverse risk restriction. The reason I lay that out is because that informs sort of how to think about data updates. So as I said, I think in our earnings call a couple of weeks ago, we disclosed that we were at 400 mg in 3 of the dose escalation cohorts, and we were still at 200 mg in the fourth. Now we're at 400 mg in all the cohorts.
Those cohorts are NPM1 mutant and KMT2A rearranged in each of the backbones. And they're, you know, the dose escalation study is six patients, at least six patients per dose starting at 200 milligrams, potentially up to 600 milligrams. So if every cohort enrolls to a full dose of 600 milligrams, you would have six patients times four cohorts times three doses, or 72 patients minimum in the dose escalation portion. The dose expansion and validation would probably be approximately another 15 patients or so. So that's the way the trial's designed. The reason for that is initially, you know, it's obviously it's a safety study. Everybody's always keenly looking at activity, and that's understandable. We are escalating to get a, you know, a view on safety, and then you expand in your target population.
We would, of course, you know, look to do a registration-enabling trial in the frontline with venetoclax, potentially in the frontline with, with 7+3. So that's the rationale for the trial. I give you that introduction to then say, "What are the two most important updates?" Well, the first one is one we'll probably disclose, you know, either via press release or, or a forum like this, and that is, "At what dose are we expanding?" you know, is it two is it is it 200, 400, 600? I can tell you it's probably not 200. So far, 400 seems to be going well across all four cohorts. If you look back to the monotherapy data, I think that's instructive of what to expect. There's no difference in safety between 200 and 600. There's no difference in DS between those two doses.
There's a clear difference in clinical activity between 200 and 600 in favor of 600. So if we can escalate to 600, we'll do that. But that's the first question people should ask, is, "At what dose are you expanding?" The second question then is, "What are we gonna see?" And what we'd like to show people is, I think, the expansion cohort data at the recommended phase II dose because that really helps you to understand, "How do I think about a potential pivotal? How do I think about how this drug compares to others in the field?" You know, we may provide an update along the way as we continue to dose escalate, but the main event is gonna be the expansion cohort at the recommended phase II dose. We have guided we should have a candidate RP2D by the middle of the year.
I think we're on track for that given that we're at 400, you know, in all four cohorts. And then it's a matter of the, you know, enrolling the expansion and letting that data mature long enough that we can we can show something. We haven't yet made a decision on how we would show the data. Would it be a company, you know, an investor event like what we did in late January? Would it be at a medical meeting? Would it be some combination of the two? We're sort of keeping all the options open. We, we know what people want to see. The January update was primarily, you know, safety, tolerability, ability to mitigate differentiation syndrome. I think that was well understood and well received. Now the next update is safety, tolerability, and of course, you know, people will look at clinical activity at the RP2D.
So I think it's, you know, could be mid-year, could be sort of in the second half. What we're trying to do is be very transparent about how the trial's going and what our goals are to share with folks. And I can tell you enrollment continues to be very robust. I'm gonna just go back and underline something. By the time this dose escalation cohort is fully enrolled at 6 patients per cohort, that's 72 patients. Now, some of the cohorts are over-enrolling because if you have a cohort, if you're screening patients and the next cohort isn't available, you may put 7, 8, 9 patients into a cohort. But just contrast that with, you know, other trials that are running. 72 patients in 7 months is pretty remarkable as a rate of enrollment.
I think it really speaks to the demand for ziftomenib, and in particular—and this is what we're gonna see, I think, in the real world—the willingness to use these drugs, menin inhibitors in combination with standards of care. That was always kind of the vision and the goal. The monotherapy is a big step in that direction, but we're seeing it even early on in dose escalation. These cohorts are just enrolling incredibly well and incredibly rapidly. It's a long answer to your question.
Perfect.
That's a great help.
I think that you've been reading my questions.
Yeah.
that pivot.
Yep.
To, like, frontline or remove the restrictions, how smooth would that be? Do you have to go back to the FDA or is that?
We don't. Yeah. Well, it's yeah. Sorry. I didn't mean to step on your question. No. And that's an important point of agreement with the agency. The safety monitoring committee can make the decision. So, obviously, the safety monitoring committee meets every time you complete a dose and determines is it safe to then, you know, escalate to the next higher dose. Once there's a candidate RP2D, the safety monitoring committee would meet and say, "Okay. Are we" you know, they'll evaluate safety, tolerability, and then that committee can make the decision of, "Now we're gonna expand," and then pivot into another population. And you don't know what you don't know. I mean, this is why we run these studies.
But everything we've seen in the monotherapy experience, everything we've seen thus far in combo is encouraging, right? There's no safety signal. There's no really AE of any consequence. It's all, you know, background disease. Or you do see AEs due to the backbones, but ziftomenib continues to be incredibly clean, and very safe and well tolerated. So personally, I'm optimistic we'll get to 600 milligrams. I think that gives the best whole-body exposure. It gives the best potential to drive meaningful clinical benefit in these leukemic patients. You know, and the team is, the team's just cranking away trying to get there.
Gotcha. So that 600 is clearly a goal to get to. There's nothing kind of flag in that you can't get to 600?
There's nothing we've seen. I mean, I'm gonna knock on wood for those who are listening. Knock on my head. There's nothing we've seen that gives us pause yet. You never know until you know. But typically, right, what would limit you from dose escalating? It would be a dose-limiting toxicity. Dose-limiting toxicities typically don't materialize out of nowhere, right? They grow in over time. The fact that we didn't see it in the monotherapy, and we escalated, remember, you know, even above 600 up to 800, we haven't seen any DLTs or any real safety signals of consequence in the combos at 200 or 400, it gives you confidence that 600 will be achievable. But we'll see. You know, the FDA has the rule of, you know, "In God we trust, and all others must come with data.
Exactly. I'm not sure.
We've gotta generate the data.
So, do you think and I guess you've probably answered that question with that comment. But do you think we'll have different doses?
No.
Different?
I don't. I don't think so. I, I think the, you know, there was a lot of eagerness to do cross-trial comparisons when we showed the data in January, right? The cardinal sin of drug development is to do cross-trial comparisons. You can actually compare cross-trials on safety, but you can, you can't cross-trial compare on efficacy, as in particularly single-arm trials. People try to do it all the time. It's fraught with challenges. But from a safety perspective, you're seeing it's identical between the two populations. I will tell you this. It's our view that particularly in the KMT2A population, 200 is clearly active, but we think a higher dose is probably preferred. And it goes back to something I said, which is, ziftomenib has an unusual, an unusual property in that it is, it's very highly protein-bound. It's very tissue-penetrant.
And that's, in fact, why we saw the differentiation syndrome that we saw in the monotherapy. That's all mitigated now in combination. But it, you really wanna get to those higher doses in our experience to be able to give patients the best possible outcome because the KMT2A rearranged leukemia is highly disseminated. And so if you know, you think about it, you need to get to a certain concentration in order to push the drug out into all the tissues and resolve that leukemia. So, you know, 200 is a step in the right direction. 400 is better. I think the way that the decision will be made. Maybe I'll reframe your question slightly. The way that we will make the decision on what is the right dose is 100% safety and tolerability.
It's not as though we're gonna look at the clinical efficacy and say, "Is 600 better than 400?" because you can't do that without running a randomized, you know, phase Ib, and we're not gonna do that. We'll push the drug as high as we'll push the drug up to 600. That's that dose is actually determined by the PK and exposure. And, if we can get to 600, then that's the going forward dose in both of those two genotypes. And you might have picked up and the audience as well, we announced on our earnings call a couple of weeks ago, "We're now evaluating ziftomenib in non-KMT2A, non-NPM1 patients in our 001 study." There again, we're going at 600 milligrams because 600 milligrams is safe. It's well tolerated.
To us, it seems to be the ideal dose for ziftomenib, whether it's monotherapy or combination.
Gotcha. Thank you. Over the, I guess, last year or so, we've heard about resistance mutations, and those questions kind of ebb and flow.
Yep.
Are you seeing those emerge? Is your menin inhibitor resistant to resistant mutations?
Exactly. The enemy of my enemy is my friend. The resistance of my resistance. We're not seeing resistance mutations. We, we've ever only reported one. If you go back to the in vitro data, ziftomenib, there's really four principal mutations, four gatekeeper mutations that have been characterized. Ziftomenib's fully active on three of them. There's no loss of potency. In vitro, there's a 17-fold loss of potency on the fourth one, which actually is a major mutation. But, that's why I think the dose is important because, and I saw this, you know, many lives ago in a different company. We had a drug that had hit two targets. In vitro, they were tenfold different. In patients, they were identical.
We like to think that, you know, patients are, are big hairy test tubes, but they're not. I think if you've got, you know, ziftomenib at a 600-mg dose, that's part of why we're not seeing mutations. You're actually getting into all the nooks and crannies. You're differentiating the tumor. You're not giving you're not giving the tumor a chance to develop resistance. I think that's what's going on. That's a you know, that's, that's a bit of speculation, but pretty informed speculation. Keep in mind this as well. Probably, probably the best way to deal with, with mutations is in combination. I think once, you know, ziftomenib and revumenib are approved, I would be surprised if people use them as monotherapy.
I think once you have a well-established safety database in combo, you know, people at the major centers are gonna use them in combination because even early on, looking at our 200-milligram data with venetoclax and 7+3, it's strikingly better than the monotherapy. And the same is true of revumenib, right? It's the combinations. Now, that's not to say that there's gonna be approval or we would promote it, but the docs use these drugs however they think they should be used. And I think it speaks to why the enrollment in the combo is so rapid is that that's always been the right way to go, right, is to use ziftomenib as part of every possible standard of care. That will also help address mutations.
Both the intrinsic properties of the drug, its tissue penetrance, its potency, and the fact that using it in combination, mutations are probably much less of a concern.
Gotcha. I guess with the NPM1 mutation, there's often another mutation there.
Mm-hmm.
Does that cloud the use of an NPM or a menin inhibitor in that space?
Not at all. No. We've seen no, so quite the contrary, actually. Any, so there are a number of mutations that are related to the menin-MLL mechanism, FLT3, IDH, BCL2, MCL1. Obviously, NPM1, KMT2A rearranged. But if you open an issue of Blood, like, every other issue of Blood seems to have some new menin, some new rare menin mutation. There was one just a couple of weeks ago. What those seem to do is actually reinforce the tumor's dependency on menin-MLL. It actually renders the tumor perhaps more sensitive. Things like RAS, that's problematic, right, a completely off-pathway mutation. That's where, again, you're gonna address that with some sort of combination regimen. But in our experience, it doesn't complicate the situation.
And in fact, we've been encouraged to see that ziftomenib is. We reported this from the monotherapy, right? There's, I think it's okay. I don't wanna misstate the numbers. It's a high rate of complete response in either NPM1 FLT3 mutants or NPM1 IDH mutants who have previously failed those targeted therapies. You're still able to drive them to a response. That suggests, and that's actually encouraged physicians to begin to think about moving menin inhibitors earlier in lines of treatment. So what we're seeing is physicians may treat patients with a FLT3 inhibitor if they're a FLT3 mutant patient, but they're not gonna do multiple FLT3s. They'll then shift to menin. They have a willingness to use menin inhibitors ahead of IDH inhibitors because they appear to be more active than IDH.
I think the more experience they get, the more you're gonna see that. That you've given me just an opportunity to mention the other trial, the other combination trial, which is 008. That's explicitly looking at, there's three regimens: gilteritinib, FLAG-Ida, and low-dose Ara-C. But the gilteritinib-ziftomenib combination is intended to address NPM1 FLT3 double mutants. That's a that's a big population. That's half of all of NPM1. It's NPM1 FLT3 is 50% of the NPM1 population. The promise of that combination is twofold. It's an all-oral regimen, reasonably good tolerability, particularly relative to the myelosuppressive potential of venetoclax chemotherapy and other regimens. And in the preclinical models, that combination is curative. And it's curative for two reasons. The FLT3 inhibitor is blocking the catalytic activity of the enzyme, but FLT3's expression is MLL-dependent.
So you're both shutting down expression of FLT3 and you're blocking its catalytic activity. And that seems to be enough to actually tip the cell over into apoptosis, which is not necessarily what you see with FLT3 as a monotherapy. So there's a lot of promise of that. We're being very strategic in how we roll these trials out. You have 001. You have 007. You have 008. You don't wanna create internal competition at sites among your studies. So you'll see 008 has started. It's enrolling patients, but we're not yet leaning hard into it until 001 enrollment and 007 enrollment are complete because once, once those are no longer open to relapse refractory, then everybody shifts over to 008, right?
My clin-ops group is incredibly thoughtful and smart and is you know pushing on these different trials at different sites to make sure that pace of enrollment continues.
Gotcha. When have we seen an update or the initial data around 008?
Oh, yeah. You sound like me right in the company meetings. When will you see 008 data? I don't know yet. Let's get enough patients on so it's a dose escalation. I believe, Peter, it's actually starting at a dose lower. It's actually starting at 100 mg. And the reason for that is that gilteritinib is also associated with differentiation syndrome. So you wanna make sure that you sort of step through it carefully. Do you give them simultaneously? Do you sequence them? That's the cohort that I think is generating the most interest. It's still early days on that study. I wouldn't, at this point, expect that that's gonna be a 2024 update. That's probably 2025, also because, as I said, the team's number one priority is get the registration-enabling trial enrolled.
We've guided to mid-year, and that's still the same. That's 001, 80-85 patients. The second, get the NDA, you know, in shape, to support ziftomenib's submission to the agency. Then 007, getting to that recommended phase II dose. We're already working on the designs for the pivotal, in the frontline combo setting. 008 is, you know, my team tells me everything can be a priority. It just can't all be a priority at the same time. So 008, I think, is probably more, you know, 25, in terms of seeing data.
Great. Thank you so much.
Sure.
you touched upon this. The enrollment's going well. Could it over-enroll for 001, so your pivotal trial?
It could over-enroll, by virtue of the fact that once you screen it once you bring a patient on the study and you screen, you're gonna enroll them, right? So, that you may see some over-enrollment, but, you know, the intent of the study is 85 patients.
Gotcha. Oh, I meant to ask, actually, for any of the combination data 'cause there's so much being generated.
Uh-huh.
Can that be rolled over into some kind of pivotal trial?
It would when we say rolled over, so.
Or used?
Yeah. It is used, right? It is supportive of an eventual submission. I mean, ultimately, with the FDA, every patient you treat goes into the safety database. And that's, you know, that's ultimately the agency's primary focus: safety and tolerability. You wouldn't. I think what you're asking is, I don't think you could use patients in the expansion as part of the efficacy dataset. I don't think you'd be gonna do that. And the reason for that is, a pivotal trial in the frontline is gonna be, I think, we haven't finalized this, but I'm pretty sure this is how it's gonna go, the triplet: ziftomenib, venetoclax, azacitidine versus venetoclax, azacitidine. So unless that data's part of a randomization, you're not gonna include it in the efficacy dataset.
It is supportive of ultimately a submission and the label, but you know, we will start a formal 007 registrational study with venetoclax. And then, you know, that dataset will be sort of sanctified, if you will, to help support an ultimate frontline registration. I don't think you can shortcut it. It's not like when you're doing monotherapy registrations early on in development. Those combo randomization studies have to be done differently. But you know, I'm optimistic that we will have that trial kind of in shape, probably be dosing patients early next year. But we're looking to second half of the year to start working through with the health authorities, getting the trial booted up to go. It may be you know, it may be in shape by the end of the year.
I think it'd be incredibly ambitious to dose a patient before the end of the year, but we'll see.
Gotcha. The expansion opportunities outside blood cancers.
Mm-hmm.
When do we get kind of more details?
Yeah. We keep teasing people with that.
Yeah.
Yeah. That's probably second half 2024. What we're doing is actually planning the trial. So we'll plan to say something when what we're anticipating is the trial design's gonna go live on clinical trials, and then we're gonna get a bunch of questions. So until then, we're gonna kinda keep it in our back pocket. But I would look to second half 2024.
Okay. So watch clinical trials or your.
Well, or watch Kura yeah. We're not gonna hide the ball. I mean.
Okay.
So yeah.
Perfect. Thank you so much.
My pleasure.
For speaking to you, Troy.
Thank you.
Thank you.