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

[Audio Gap] stage is my associate, Cameron Bozdog. For this session, I'm very pleased to have join us Troy Wilson, CEO of Kura. Thank you so much for joining us.

Thank you for the invitation and for hosting the conference in Vegas again.

Absolutely. Well, maybe just to start broadly for those less familiar with the story. Can you provide a brief overview of your 2 clinical programs, just at a high level, I mean, what is a menin inhibitor? And how does it work?

Yes. So menin inhibitor, Jason, is an epigenetic regulator of gene expression. It does different things in different context. And I think I was probably the first person to identify menin inhibitors in the commercial space now 10 years ago. At that time, we thought it was just this very small sliver of acute leukemia, KMT2A rearranged. As it turns out, there -- it's relevant to probably up to half of leukemia, again, working by a mechanism in that case that differentiates leukemic blasts. It's relevant to GIST. We now have a trial running of ziftomenib in combination with imatinib. There, menin is actually regulating the expression of KIT. So you're attacking KIT, which is the key genetic driver of gastrointestinal stromal tumors from 2 different directions. In diabetes, menin regulates a number of things, including pancreatic beta cell growth and expansion. And then in solid tumors, you might have seen some of the intriguing data from Scott Armstrong's lab where menin and KAT6 combined to regulate some of the downstream targets behind the estrogen receptor. And so you're going to see, I think, menin inhibitors play different roles, but there's always this context that they are working in terms of regulating other genes. That's the key. And I think this is the gift that keeps on giving as we'll talk about, I'm sure, over the next 25 minutes or so.

Yes, absolutely. Well, maybe just to dive right in, the upcoming ASCO meeting is shaping up to be critical for Kura with the presentation of the highly anticipated ziftomenib peripheral data in NPM1 relapsed/refractory AML. So beyond the CR/CRh rates, what else do you plan to reveal? And what do you think investors should be focused on?

Yes. So there's the -- investors naturally focus on that typically that which is closest to them. And that's the dynamic between us and the competition, right? And I think there is a place in the market for multiple menin inhibitors. That's actually good for patients. I think you'll see that our data in the specific relapsed/refractory NPM1 mutant space is very competitive with the data that's been published. A competitor just had a publication in blood just last week. I think you'll see we're very competitive. I think we're going to differentiate very favorably on safety and tolerability. And the reason I highlight that is that ultimately, you're going to see tomorrow, in fact, our abstract from the European Hematology Association Congress, where we're showing the expansion cohort of ziftomenib plus intensive chemotherapy. And there safety and tolerability is important because you can keep these patients on drug, same thing in the non-intensive setting, same thing as you go to other combinations. So there's the near-term play, Jason. There's the longer-term play. I think -- I hope what you'll take away from that ASCO data is this is a drug that's active. It's safe. It's generally well tolerated. There's really no surprises. And it looks to combine very well and probably be the market leader across different lines of therapy, particularly as we go into these different combinations.

Interesting. So you mentioned safety tolerability as a key potential differentiator. Let's dive a little bit deeper on this. I mean, beyond kind of the CR/CRh rates, what would be encouraging here?

From a clinical activity or safety and tolerability?

Safety and tolerability.

Safety and tolerability. So -- let's kind of go down the list, right? These patients in general, particularly in the relapsed/refractory, the elderly setting, this is NPM1, so these patients are typically 60 years and older. They're on a lot of conmeds. And as a result, put a premium on the absence of drug-drug interactions and in particular, on the absence of dose-limiting toxicities. Ziftomenib has no clinically meaningful DDIs. It has, as you'll see, I think, no clinically meaningful toxicities to speak of. That makes it very easy to combine. You don't have to worry that the patient is going to take something that is going to shift the benefit risk in the wrong direction. The other is -- and we've talked about this in the past, the absence of cardiotox. Unfortunately, AML has a number of drugs that have -- that interact with the cardiac tissue, everything from the antifungals to the FLT3 inhibitors to intensive chemo. It's less relevant, Jason, honestly, in the relapsed/refractory setting because you're really trying to sustain life, to preserve life. But when you're talking about frontline, you want a patient on for 12, 18, 24 months, you want to make it as easy as possible. Something even as simple, just building on that, ziftomenib is once a day. It's a once-a-day drug. We had an ad board meeting on Friday. We had 15 docs in. We walked through the revumenib data, through the ziftomenib data, and one of the physicians described ziftomenib as a cruise medicine. And I said -- I thought to myself, what is a cruise medicine? And he said, these patients, these relapsed/refractory patients, keep it in perspective, 10% of them will be alive at 3 years, right? That's how grave this illness is. He said a lot of times, they want to maintain their quality of life. They want to take a cruise. And a drug that is given once a day that has no toxicities that doesn't interact with anything else, that doesn't require any kind of monitoring, that's what I call a cruise medicine, and that's ideal. I thought that was -- this is from someone who's been doing this for a long time. I think that's kind of how you have to think about it. Let's put the patients first. Yes, we need to be able to address their leukemia, but let's not make them feel sick if we can, right? That really should be our goal. And I think ziftomenib will distinguish itself very well in that regard.

Makes sense. So Kura submitted its NDA in March 31, where it had breakthrough designation. I guess the question -- 2-level question here is, -- how have your interactions with the agency been granted it's still somewhat early? And then if you could speculate on timelines here, when do we get updates? And kind of what does the pathway look for throughout the rest of the year?

Yes. So we submitted our NDA on March 31. That was 3.5 months from data lock, which is remarkable. And just a shout out to my development team, my regulatory team, my clin ops team. We've really tried to close the gap on the competition. When we submitted it, because we have breakthrough therapy designation, we requested priority review. Now that is at the discretion of FDA. But if they grant priority review, then you're typically looking at a 6-month review period. And when we receive notice on the -- whether the application has been filed and we get a PDUFA date, I would expect that we'll press release that. Actually took your questions in opposite order, excuse me. I have been, I think, speaking for my team, very pleasantly surprised with how proactive, how collaborative, how engaged the agency has been. I cannot say enough good things about them. Again, this may be in part because we have breakthrough therapy designation, and so you get -- that's the real benefit. I think I said that at the time it was granted. When BTD matters is when you're in regulatory review because the agency prioritizes those applications because of the unmet need. But we've, to date, seen no interruption, no disruption. They have been just a pleasure to work with. It is early, and we continue to monitor. We are doing everything we can to make it easy for them, understanding that they have a lot going on and a lot of applications probably to review.

Got it. You've been doing this for a while. What do you think really kind of factors into the decision for yes or no via priority review? And I guess, specifically, with another menin inhibitor that's already been approved, does that change the agency's calculus?

I'll say, look, it's always at the agency's discretion. I think the fact that there is another menin inhibitor approved, but in a different indication. In that case, KMT2A rearranged AML where that drug has breakthrough therapy designation. I think the agency's goal is let's get these therapies, let's assess the benefit risk, let's do a proper review and then let's get these to patients as quickly as we can. I don't think we really expect that there is another product on the market or in review really to factor into the agency's discussion. It's likely reviewing them in parallel on different review teams, but on parallel tracks. But that's speculation on my part, as you say, I'm older.

So as you look to additional updates from the frontline 007 expansion cohort for the FIT 7+3 group, what should we be expecting in terms of updates here? And then maybe what would be a win in terms of MRD negativity, response rates and maybe duration of response?

Yes, Cameron, good question. So you're going to see the abstract that was done as of a data cut that was months ago expect new and updated data at EHA. In that context, maybe I think it's important to sort of talk about what's the problem you're trying to solve because I hear when I get questions, I hear some confusion. 7+3 in NPM1 mutant patients, you would expect the complete response rate to be 80% to 90%, you don't want to diminish that. You're not looking -- I mean, it would be great if you could drive 100% all the time. That's likely not realistic, but you're looking for high rates of response. That's not really where the problem is. The way that I think about it, there's a reference -- there's a 2018 blood reference, I think it is, where they go through the timing -- the percentage of patients who go to relapse and the timing to relapse. And the way to think about it is of the patients who respond in the frontline setting, half of them will relapse within 2 years. And of those, 60% will relapse in the first year, 80% will relapse by the second year. And so what you're trying to do with these triplet combinations is to deepen the response to delay the inevitable relapse. Once they relapse, their life expectancy is 3 years or less. So to your question, there's 2 parts to -- there's 2 dual primary endpoints. One is MRD-negative CR. The other is event-free survival. On the MRD-negative CR, importantly, what we're using is MRD-negative CR as assessed in bone marrow. And the reason for that is, if you -- again, in the literature, this is available, that's about 40% to 45% MRD negativity just with 7+3. So you're looking to drive a clinically meaningful benefit. As part of the IMPACT consortium, of which Kura has been a member now for several years, that was an industry-sponsored effort to work with FDA to evidence the connection between MRD negativity and survival. And the consortium did it on the basis of multiple meta-analysis and whatnot, and we got the FDA there. That's why the FDA was open to that accelerated endpoint. What I would look for out of this data set, Cameron, is high levels of response, good safety and tolerability, minimal to no dose interruptions, dose reductions. MRD is going to be an evolving story because it has to be assessed again in bone marrow and ideally centrally. But look at the timing of these patients on therapy. And again, think about -- compare it to the relapse -- to where they're relapsing on 7+3. What you're going to see with the KMT2A patients, they almost all go to transplant and then they go on to ziftomenib post-transplant. In the NPM1 setting, what is striking is the number of patients who remain on ziftomenib as monotherapy and continuation therapy for prolonged periods of time. They don't go to transplant. That is very interesting. And the reason for that, of course, is if you're an NPM1 mutant patient, you're MRD-negative CR, transplant is likely contraindicated. It's not really clear what you're trying to do. So the ability to offer these patients continuation therapy is really very different from anything we've seen before. That also plugs directly into the commercial case. That's what makes menin inhibitors and ziftomenib different from other agents that have come before, where -- and it's back to the question Jason was asking, why is safety and tolerability important? It's important because you want these patients to take this drug once a day and essentially with minimal toxicity or minimal interactions. That's how I'd think about it.

And then you'll receive initial insights into the dose expansion data, so removal of the adverse risk criteria. How does that impact expectations or benchmarks for response rates? And maybe how should we be thinking about the right comp to look at here?

Yes. So in the dose escalation phase at the request of the agency, we escalated in patients who had AML, NPM1 mutant or KMT2A rearranged AML with adverse risk. KMT2A by definition, or adverse risk, NPM1, you could get there with one of several different criteria. And at the time, Cameron, I said probably the best comp is the Vyxeos control arm, intensive chemotherapy in an adverse risk population. That was about a 33%, I think, 35% CR rate. Let's be generous and say it's 50%, right? We showed data at ASH where the NPM1 mutant was 100% CR, the KMT2A was 83%. I said at the time, don't get emotionally attached to 100%. You should see robust rates of CR as you now move into the expansion. The expansion is all comers. All comers means you have about 1/3 of patients who are adverse risk and about 2/3 who are not. So now the benchmark in NPM1 is, again, 80-plus percent. In KMT2A, it's probably lower, call it, 65% to 70%. You're looking to do as good as that. You don't want to antagonize. You don't want to bring the CR rate down. You're looking to do that or better and then again, deepen the response, drive a more durable response. We're going to show you data from the 600-milligram escalation and the 600-milligram expansion. And the significance of that is look at how many patients are still on therapy from the 600-milligram escalation. And that goes to that question of can you keep these patients in response without going to transplant for prolonged periods of time, save the transplant for later, give them a higher quality of life. That's how I would think about it. It will -- the MRD and all of that will continue to come into focus. But I can tell you, like all signs on both that one and the nonintensive where we'll show data hopefully in the second half of the year, potentially at ASH, at this point, all the lights are green to start those Phase IIIs.

Perfect. And then just thinking about safety tolerability, what would be encouraging there? And then I know higher dropout rates in myelosuppressive-related AEs are not uncommon, but maybe at what level would these be concerning?

So good question. Myelosuppression is potentially an issue in any combination. And the risk there is, as companies present data, like focus on the registrational endpoint. For example, in ven/aza, ORR is not the registrational endpoint. CRC is not. It's CR, right? You need to get full count recovery. That is your registrational endpoint. So if you have an agent that has myelosuppressive activity, that can be problematic. It can cause dose adjustments, interruptions. You've seen this in the monotherapy data. You've seen in the initial data. Ziftomenib is clean as a vessel. It doesn't exhibit any myelosuppression. It doesn't -- there's no need to adjust the dosing of either chemo or ven/aza. You shouldn't really see any safety and tolerability. You are going to see treatment-emergent AEs, but you will see that those very much sit right on top of what you would expect from baseline disease, right? So look at it in that context, I don't think you're going to see any kind of additive toxicity. That's certainly one of the key takeaways. And that's -- that will be true in both context.

Maybe if you could speak a bit to the pace of trial enrollment and any investigator feedback you received, maybe based on qualitative feedback, what has interest been like in the trial?

So all the cohorts, I think, are enrolling well. The more data we generate, the more excitement there is. Let's talk about 007 and then 017, which is the registration -- the trials with registrational intent. In 007, much to our surprise, before we'd ever started, kind of the dogma was ven/aza, ven/aza, ven/aza, ven/aza. And that's true. There's certainly a time and a place for ven/aza. But the frontline KMT2A patients, they all go to 7+3. They all want the prospect of a transplant. That's their best chance for a cure. They're generally younger and healthier. Interestingly, if the older patients have to do 7 days of intensive therapy, but not go through transplant, they're more willing to consider intensive chemo, particularly if they can take a menin inhibitor in a continuation setting. So you're seeing like -- to say that enrollment is going like gangbusters, I think, would be the right adjective. And that's across the board. That's in both 7+3 and in ven/aza. Now going to the 017 protocol, which is 2 parallel Phase IIIs, one in intensive, one in nonintensive. The feedback that we've gotten from sites is this is super smart. It's like one-stop shopping. You can enroll any patient who's eligible in the front line with the exception of FLT3 intensive patients who are -- who should take a FLT3 inhibitor in the front line. Anyone else is eligible to come on. And for sites that have the resources to only be able to do one global Phase III, this is attractive because they don't have to kind of mix and match protocols. This was Mollie Leoni's idea, and it's part of why we did the deal with Kyowa Kirin that we did because we're now, I think, out in front of the competition, trying to basically pick up all the best sites. And once sites in the U.S., Europe, Asia have experience with ziftomenib, like they become fans, right? They become your advocates. So that 017 protocol is allowing us, I think, to be very competitive in terms of getting the very best sites for the trial going forward.

For your chemo combination, you're pursuing a trial design that would leverage MRD negativity for accelerated approval -- first for AML. What did you have to demonstrate to FDA to make them comfortable to allow that surrogate endpoint?

So again, I give credit to my development colleagues for this. This is being very -- having a lot of forethought. So in -- I think it was 2018, I think J&J -- for anyone else listening who was a founding member of IMPACT, I apologize. I think it was J&J that was the founding member. IMPACT is MMPACT, the IMPACT consortium. And it included -- it has included Bristol, Celgene, I think Novartis at one time, Cronos. And it was an effort, Jason, between industry and the agency to do a meta-analysis to help substantiate the link between MRD negativity, not mutant specific, but generally with survival. So there's published data, there's unpublished data. When we did the briefing documents for the Phase IIIs and the question came up from the reviewers, well, how are you going to handle this? We were like, well, we're members of the IMPACT consortium. And they're like, oh, okay. A lot of that work had been done. And I give credit to the heavy weights who were there. I would not be surprised if one of those who is a menin competitor chooses to take a very similar design because they have all the data we have. The FDA is data-driven. And there was some consternation around the recent appointment of Dr. Prasad as [indiscernible] and comments that were made in the context of multiple myeloma. I think there, the issue was these patients are potentially living 10 years. Are there safety concerns with accelerated approval? In AML, we've talked about it. The unmet need is staring you in the face, right? And so the ability to get these therapies to patients on an accelerated basis is very attractive to the agency. And you, of course, have the built-in safeguard that you have EFS for the intensive and OS for the nonintensive. And if you don't hit on the survival-based endpoints, you're going to lose the accelerated approval. So there's a -- and that should happen in relatively quickly as these things go in development, that will -- that should provide the safeguard to patients.

It's a good segue for the next question. But turning to the second half of this year, you've guided to presenting data from KOMET-007 frontline non-intensive AML. So this will be a ziftomenib plus ven/aza combo. Ideally, what do you think a menin inhibitor can provide on top of ven/aza? Is the former just eliminating an escape mechanism? Or is there potential for kind of a synergistic improved CR?

There is potential for an improved CR. I would be handwaving if I told you I knew exactly what's driving that. We have -- and I think we've commented on this publicly. We've seen evidence where menin inhibitor, ziftomenib, in particular, can resensitize -- appears to resensitize patients to venetoclax. I don't know that I can tell you why that's happening. That seems to be happening. That's what we're hearing from the docs. You would look -- so in that context, Jason, in contrast to the intensive chemotherapy, there, your CR rate for NPM1 is about 50% to 60%. KMT2A maybe take it down another 5% to 10% from that. You can make a clinically meaningful improvement in CR, which is why you don't need MRD negativity in the non-intensive setting. And I would say, I think the nonintensive update will be a meaningful update. The only thing you and investors have seen to this point is really safety in the relapsed/refractory setting in a dose escalation. We now have expansion cohorts in both the frontline and the relapsed/refractory setting with ven/aza and look forward to sharing that data later this year. I think you'll see that it's meaningful.

Got it. Looking at KOMET-008, so this is the Phase I evaluating ziftomenib plus FLAG-IDA, LDAC and more importantly, I think, gilteritinib. Any updates you can provide there?

Just that the enrollment continues, dose escalations continue, there's good interest. It isn't really yet a focus this year on presenting data. We are kind of -- you called out GILT, and I think that's appropriate. It's important to remember that in the relapsed/refractory setting, half of your NPM1 mutant patients will have a FLT3 co-mutation likely. And part of the dynamic is not necessarily us versus our menin competitor, it's menin inhibitors versus other out-of-class competitors. So the option of publishing data that potentially combines gilteritinib and ziftomenib, I think, provides a really interesting option. Stay tuned. My team tells me regularly, "Troy, everything can be a priority." It just can't all be a priority at the same time.

You bring up sort of an interesting point. I think if you talk to most docs, ven/aza seems to be the combo partner that they point to in terms of opening up use in the frontline setting. Do you think that's still the case?

I think it's evolving. I think that people have been trying to put 7+3 out of business for 40 years, 30 years, maybe. The thing is it really works and it's 7 days and venetoclax is a remarkable therapy, but it is not a walk in the park. It has some challenging toxicities. I think you want to give docs options. It's interesting to see -- and this is -- let's go back to your very first question. These monotherapy studies and hopefully, the approvals, the academic or the physician community views them as significant proof of concept of the mechanism and they license to combine as they see fit, right? They treat these patients. They know all these agents. They've worked with them. They all talk amongst one another. I imagine they're on like some WhatsApp chat or something. And so giving them data and allowing them -- if you look at the practice patterns of MD Anderson versus Memorial, they look very different. You want to give physicians the options with what they feel most comfortable is the right thing for their patients. And let's let the data -- let those regimens compete.

Got it. Well, the brief time that we have left, I did want to give an opportunity to discuss the partnership that you mentioned earlier with Kyowa Kirin. Especially in light of everything that's happened, what made this partnership make sense to you strategically and financially?

Yes. So particularly it was, I think, met with some questions when we initially announced it. Now that every other day is some new headline risk in biotech. The ability to stay in a very strong financial position to go toe to toe with an organization like Janssen and to really move ziftomenib aggressively into these various lines of therapy. I think our goal is maximize the value of ziftomenib initially in AML for as many patients as possible. But Jason, it also allows us to make the investments in GIST, in diabetes, and in our FTI program. And you're going to see clinical updates again throughout this year for the FDIs, potentially next year for GIST, you're going to see updates on diabetes. So you have a number of different value drivers. And I have told my team and I told investors in our one-on-ones today, said, don't plan on going back to the equity markets ever. I hope -- I want them to be prepared. But we are -- we will end the year in a very similar cash position to where we started. And I think that puts us in good stead to be able to create value for patients and ultimately for investors.

Sounds good. Troy, been a privilege and a pleasure. Thank you so much for joining us.

Thank you both. My pleasure.