Kura Oncology, Inc. (KURA) Earnings Call Transcript & Summary

Good morning. My name is Peter Lawson. I'm one of the biotech analysts at Barclays. And welcome to Bakers Global Healthcare Conference in Miami and really pleased to have on stage with me, management from Kura's Troy Wilson, CEO. And I guess maybe focus sing initially would be around menin inhibitors and combination data, pivotal and the expansion opportunities.

And I guess kind of first question is around the updates that we're going to see in the combination therapy and kind of what we should expect to see in that kind of mid-'24 update in combinations in the KOMET-007 trial?

Sure. Yes. So thank you, Peter, to you and Barclays for the invitation. So it's 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 milligrams in all 4 cohorts. So as a reminder to everyone, the 007 study is intended to evaluate ziftomenib, which is our menin-MLL inhibitor with 2 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 ven/aza, we're actually in the relapsed/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 relapsed refractory to frontline untreated. And in the 7+3, we will remove the restriction, 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 milligrams in 3 of the dose escalation cohorts, and we were still at 200 in the 4. Now we're at 400 in all the cohorts, those are -- those cohorts are NPM1 mutant and KMT 2 rearranged in each of the backbones. And the dose escalation study is 6 -- at least 6 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 6 patients times 4 cohorts, times 3 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 is designed. The reason for that is, initially, it's obviously -- it's a safety study. Everybody is always keenly looking at activity, and that's understandable. We are escalating to get a view on safety and then you expand in your target population. We would, of course, look to do a registration-enabling trial in the frontline with ven/aza, potentially in the frontline with 7+3. So that's the rationale for the trial. I give you that introduction to then say, what are the 2 most important updates. Well, the first one is 1 will probably disclose either via press release or a forum like this, and that is at what dose are we expanding? Is it 200, 400, 600. I can tell you it's probably not 200 so far. 400 seems to be going well across all 4 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 2 doses, there's a clear difference in clinical activity between 200 and 600 and 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 going to 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. We may provide an update along the way as we continue to dose escalate. But the main event is going to 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 in all 4 cohorts. And then it's a matter of enrolling the expansion and letting that data mature long enough so that we can show something. We haven't yet made a decision on how we would show the data? Would it be a company, 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 know what people want to see. The January update was primarily 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, people will look at clinical activity at the RP2D. So I think it could be midyear, could be sort of in the second half. We're just -- what we're trying to do is be very transparent about how the trial is going and what our goals are to share with folks. And I can tell you, enrollment continues to be very robust. I'm going to 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 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 zifto and in particular, and this is what we're going to see, I think, in 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. I think you've been reading my questions. The -- that pivot to frontline or removing the restrictions, how smooth would that be? Do you have to go back to the FDA? Or is that...

We don't. Yes, yes, sorry, I didn't mean to step on your question. No, that was 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 escalate to the next higher dose. Once there's a candidate RP2D, the safety monitoring committee would meet and say, okay, are we -- they'll evaluate safety, tolerability and then that committee can make the decision of now we're going to 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 background disease or you do see AEs due to the backbones, but zifto 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 and the team is just cranking away, trying to get there.

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 -- and I'm going to 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, 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 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. The FDA has the rule of, in God we trust and all others must come with data. So we've got to generate the data.

Do you think -- I guess you've probably answered that question with that comment. But do you think we'll have different doses, different...

No. I don't think so. I think -- 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 across trials on safety, but you can cross-trial compare on efficacy and 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 2 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 property in that it is it's very highly protein bound, it's very tissue penetrant. And as -- 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 want to 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 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 200 is a step in the right direction, 400 is better. I think if 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 that we're going to look at the clinical efficacy and say is 600 better than 400 because you can't do that without running a randomized Phase Ib, and we're not going to do that. We'll push the drug as high as -- we'll push the drug up to 600. 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 2 genotypes. And you might have picked up in 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. And to us, it seems to be the ideal dose for ziftomenib, whether it's monotherapy or combination.

Got you. Thank you. Over the, I guess, the last year or so, we've heard about resistance mutations and those questions kind of ebb and flow, are you seeing those emerge? Is your menin inhibitor resistant to resistant mutations.

Okay. The enemy of my enemy is my friend, the resistance of my resistance. We're not seeing resistance mutations. We've ever only reported one. If you go back to the in vitro data, ziftomenib is -- there's really 4 principal mutations, 4 gatekeeper mutations that have been characterized. Zifto is fully active on 3 of them, 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 many lives ago in a different company. We had a drug that -- we hit 2 targets, in vitro, they were tenfold different in patients, they were identical. And we like to think that patients are big hairy test tubes, but they're not. I think if you've got ziftomenib at a 600-milligram 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 the tumor a chance to develop resistance. I think that's what's going on. That's a bit of speculation, but pretty informed speculation. Keep in mind this as well, probably the best way to deal with mutations is in combination. I think once 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 and combo, people at the major centers are going to use them in combination because even early on, looking at our 200-milligram data with ven/aza and 7+3, it's strikingly better than the monotherapy. And the same is true of revumenib, right? It's the combination. Now, that's not to say that there's going to 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. So both the intrinsic properties of the drug, its tissue penetrants, its potency and the fact that using it in combination, mutations are probably much less of a concern.

Got you. And I guess with the NPM1 mutation, there's often another mutations there. And does that cloud the use of an NPM web menin inhibitor in that space?

Not at all. No, we've seen no -- so quite the contrary actually. And so there are a number of mutations that are related to the menin MLL mechanism, FLT3, IDH, BCL2, MCL1. Obviously, NPM1, KMT2 rearranged. But you -- if you open an issue of blood, like every other issue of blood seems to have 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, actually makes renders the tumor, perhaps more sensitive. Things like RAS, that's problematic, right? A completely off pathway mutation. That's where, again, you're going to 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 zifto is -- we reported this from the monotherapy, right? There's a -- I think, it's -- okay, I don't want to misstate the numbers. So 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 with 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 going to 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 going to see 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 3 regimens, gilteritinib, FLAG-IDA and low-dose AraC, but the gilteritinib ziftomenib combination is intended to address NPM1 FLT3 double mutants. That's a big population. That's half of all of NPM1, 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 ven/aza chemotherapy and other regimens. And in the preclinical models, that combination is curative. And it's curative for 2 reasons. The FLT3 inhibitor is blocking the catalytic activity of the enzyme, but FLT3s 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 this all over in 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 want to create internal competition at sites among your studies. So you'll see 008 is started. It's enrolling patients, but we're not yet leaning hard into it until 001 enrollment and 007 enrollment are complete because once those are no longer open to relapsed/refractory, then everybody shifts over to 008, right? So my ClinOps group is incredibly thoughtful and smart. And is pushing on these different trials at different sites to make sure that, that pace of enrollment continues.

When do you see an update or the initial data around 008?

Yes. You sound like me right in the company meeting. When do we see 008 data? I don't know yet. Let us 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 milligrams. And the reason for that is that gilteritinib is also associated with differentiation syndrome. So you want to 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 going to be a 2024 update, that's probably 2025. Also because, as I said, the teams -- the number one priority is get the registration-enabling trial enrolled. We've guided to midyear, and that's still the same. That's 001, 85 patients. The second, get the NDA in shape to support ziftomenib's submission to the agency, than 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 -- 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 '25 in terms of seeing data.

Great. And you touched upon this, the enrollment is going well. Could it over-enroll 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 going to enroll them, right? So it's -- you may see some over enrollment, but it -- the intent of the study is 85 patients.

I meant to ask actually for the -- any of the combination data because there's so much being generated. Can that be rolled over into some kind of pivotal trial?

It would -- when we say rolled over, so...

Or used?

Yes, 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 ultimately the agency's primary focus is safety and tolerability. You wouldn't -- I think what you're asking is, I don't think you could treat -- I don't think you could use patients in the expansion as part of the efficacy data set. I don't think you're going to do that. And the reason for that is a pivotal trial in the frontline is going to be I think we haven't finalized this, but I'm pretty sure this is how it's going to go. The triplet, ziftomenib, venetoclax, azacitidine versus venetoclax, azacitidine. So unless that data is part of a randomization, you're not going to include it in the efficacy data set. It is supportive of ultimately a submission in the label. But we will start a formal 007 registrational study with ven/aza, and then that data set 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 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, still start working through with the health authorities in getting the trial booted up to go. It may be in shape by the end of the year. I think it'd be incredibly ambitious to dose the patient before the end of the year, but we'll see.

The expansion opportunities outside blood cancers. When do we get kind of more details?

Yes, we keep teasing that. Yes, that's probably a 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 is going to go live on clinical trials, and then we're going to get a bunch of questions. So until then, we're going to kind of keep it in our back pocket. But I would look to second half '24.

Okay. So watch clin trials...

Well, watch. Correct. We're not going to hide the ball.

Perfect. Thank you so much. It was pleasure speaking to you, Troy.

Thank you.

Thank you.