Kura, thank you so much for joining us.
Thank you for the invitation and for hosting the conference in Vegas again.
Absolutely. Maybe just to start broadly, for those less familiar with the story, can you provide a brief overview of your two clinical programs just at a high level? I mean, you know, what is a menin inhibitor and how does it work?
Yeah. So a menin inhibitor, Jason, is an epigenetic regulator of, you know, gene expression. It does different things in different contexts. You know, 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, 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 two different directions. In diabetes, menin regulates a number of things, including pancreatic beta cell growth and expansion.
In solid tumors, you might have seen some of the intriguing data from Scott Armstrong's lab, where menin and KAT6 combine to regulate some of the downstream targets behind the estrogen receptor. You are going to see, I think, menin inhibitors play different roles, but there is always this context that they are working in terms of regulating other genes. That is the key. I think, you know, this is the gift that keeps on giving, as we will talk about, I am sure, over the next, you know, 25 minutes or so.
Yeah, absolutely. 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 pivotal data in NPM1 relapse refractory AML. Beyond the CR/CRh rates, what else do you plan to reveal and what do you think investors should be focused on?
Yeah, so there's the, you know, investors naturally focus on that, typically that which is closest to them. That's the dynamic between us and the competition, right? I think, you know, 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 relapse 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. 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.
Their 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. There is the near-term play, Jason. There is 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. 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. 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. Let's kind of go down the list, right? These patients in general, particularly in the relapse refractory, the elderly setting, this is NPM1. These patients are typically, you know, 60 years and older. They're on a lot of con meds. As a result, put a premium on the absence of drug-drug interactions and in particular on the absence of dose-limiting toxicities. Zifto 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, you know, 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, you know, 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 relapse refractory setting because you're really trying to sustain life, to preserve life. When you're talking about frontline, you want a patient on for 12 months, 18 months, 24 months, you want to make it as easy as possible. Something even as simple, just building on that, zifto 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. One of the physicians described zifto as a cruise medicine. I said, you know, I thought to myself, what is a cruise medicine?
He said, these patients, these relapse refractory patients, keep it in perspective. 10% of them will be alive at three years, right? That is 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. A drug that is given once a day that has no toxicities, that does not interact with anything else, that does not require any kind of monitoring, that is what I call a cruise medicine. That is ideal. I thought that was, you know, this is from someone who has been doing this for a long time. I think that is kind of how you have to think about it. Let us put the patients first. Yes, we need to be able to address their leukemia, but let us not make them feel sick if we can, right? That really should be our goal.
I think ziftomenib will distinguish itself, you know, very well in that regard.
Makes sense. Kura submitted its NDA March 31st, where it had breakthrough designation. I guess the two-level question here is, how have your interactions with the agency been? Granted, it's still somewhat earlier. And then, you know, if you could speculate on timelines here, you know, when do we get updates and kind of what does the pathway look for throughout the rest of the year?
Yeah. So we submitted our NDA on March 31st. That was three and a half months from date of lock, which is remarkable. And just a shout out to my development team, my regulatory team, my clean 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. If they grant priority review, then you're typically looking at a six-month review period. When we receive notice on the, you know, whether the application has been filed and we get a PDUFA date, I would expect that we'll press release that. I 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. You get, you know, 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. 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, you know, 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, you know, yes or no via priority review? I guess specifically, you know, 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, you know, the agency's goal is let's get these therapies, let's assess the benefit risk, you know, 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, you know, different review teams, but on parallel tracks. That is speculation on my part, as you say. I'm older.
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? Maybe what would be a win in terms of MRD negativity, response rates, and maybe duration of response?
Yeah, [Cameron], good question. 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%-90%. You don't want to diminish that. You're not looking, I mean, it'd 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. The way to think about it is of the patients who respond in the frontline setting, half of them will relapse within two years. Of those, 60% will relapse in the first year, 80% will relapse by the second year. 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 three years or less. To your question, there's two parts to this. There's two 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 CRs assessed in bone marrow. The reason for that is if you, again, in the literature, this is available, that's about 40%-45% MRD negativity just with 7+3. You are looking to drive a clinically meaningful benefit. As part of the MMPACT Consortium of which Kura has been a member now for several years, that was an industry-sponsored effort to work with the FDA to evidence the connection between MRD negativity and survival. The consortium did it on the basis of, you know, multiple meta-analyses and whatnot, and we got the FDA there. That is 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. Look at the timing of these patients on therapy. Again, think about, you know, 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 zifto post-transplant. In the NPM1 setting, what is striking is the number of patients who remain on zifto as monotherapy and continuation therapy for prolonged periods of time. They don't go to transplant. That is very interesting. The reason for that, of course, is if you're an NPM1 mutant patient, you're MRD negative CR, transplant is, you know, is likely contraindicated. It's not really clear what you're trying to do.
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 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, you know, and essentially with minimal toxicity or minimal interactions. That's how I'd think about it.
Great. You will receive initial insights into the dose expansion data. Removal of the adverse risk criteria, how does that impact expectations or benchmarks for response rates? Maybe how should we be thinking about the right comp to look at here?
Yeah. 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 are adverse risk. NPM1, you could get there with one of several different criteria. At the time, Cameron, I said, you know, 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 a third of patients who are adverse risk and about two-thirds who are not. The benchmark in NPM1 is again 80+%. In KMT2A, it's probably lower, call it 65%-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. 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 mg expansion. The significance of that is look at how many patients are still on therapy from the 600 mg escalation. 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 is how I would think about it. The MRD and all of that will continue to come into focus. I can tell you, like all signs on both that one and the non-intensive where we will show data hopefully in the second half of the year, potentially at ASH, you know, at this point, all the lights are green to start those phase IIIs.
Perfect. Just thinking about safety tolerability, what would be encouraging there? I know higher dropout rates and myelosuppressive-related AEs are not uncommon, but maybe at what level would these be concerning?
Good question. Myelosuppression is potentially an issue in any combination. The risk there is, you know, 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. 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 it in the initial data. ziftomenib is clean as a whistle. It doesn't exhibit any myelosuppression. 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? Look at it in that context. I do not think you are going to see any kind of additive toxicity. That is certainly one of the key takeaways. That will be true in both contexts.
Maybe if you could speak a bit to the pace of trial enrollment and any investigator feedback you received, maybe based on, you know, qualitative feedback, what has interest been like in the trial?
Yeah. 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 trials with registrational intent. In 007, much to our surprise, you know, before we'd ever started, kind of the dogma was Ven/Aza, Ven/Aza, Ven/Aza, Ven/Aza. That's true. There's certainly a time and a place for Ven/Aza. 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 seven 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.
You're seeing, like, to say that enrollment is going like gangbusters, I think would be the right adjective. That's across the board. That's in both 7+3 and in Ven/Aza. Now going to the 017 protocol, which is two parallel phase IIIs, one in intensive, one in non-intensive. 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 frontline with the exception of FLT3 patients who should take a FLT3 inhibitor in the frontline. Anyone else is eligible to come on. 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.
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. You know, once sites in the U.S., Europe, Asia have experience with ziftomenib, like they become fans, right? They become your advocates. 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.
You know, 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, you know, to allow that surrogate endpoint?
Yeah. So again, I give credit to my development colleagues for this. This is being, you know, very, having a lot of forethought. In 2018, I think J&J, for anyone else listening who was a founding member of MMPACT, I apologize. I think it was J&J that was the founding member. MMPACT is MMPACT, the MMPACT Consortium. It included, it has included Bristol, Celgene, I think Novartis at one time, Kronos. 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. There is published data, there is 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 MMPACT Consortium. And they're like, oh, okay, you know. A lot of that work had been done. And I give credit to the heavyweights 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, you know, the recent appointment of Dr. Prasad as CBER 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?
The ability to get these therapies to patients on an accelerated basis is very attractive to the agency. You, of course, have the built-in safeguard that you have EFS for the intensive and OS for the non-intensive. If you do not hit on the survival-based endpoints, you are going to lose the accelerated approval. There is a, and that should happen relatively, you know, relatively quickly as these things go in development. That should provide the safeguard to patients.
It's a good segue for the next question, but, you know, turning to the second half of this year, you've guided to presenting data from KOMET-007, frontline, non-intensive AML. So this would 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, you know, kind of a synergistic improved CR?
There is potential for an improved CR. I would be hand-waving 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 inhibitors, 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%-60%. KMT2A maybe take it down another 5%-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. I would say, I think the non-intensive 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 and 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, this is the phase I evaluating zifto plus FLAG-IDA, LDAC, and more importantly, I think, gilteritinib. Any updates you can provide there?
Just that the enrollment continues, dose escalations continue. You know, 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.
Fair. You know, 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, you know, people have been trying to put 7+3 out of business for 40 years, 30 years maybe. The thing is it really works, you know, and it's seven days. And venetoclax is a remarkable therapy, but it is not a walk in the park. You know, 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 a 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. Imagine they're on like some WhatsApp chat or something.
Giving them data and allowing them, you know, 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. Let's let the data, you know, let those regimens compete.
Got it. In 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 [tech]. You know, especially in light of everything that's happened, you know, what made this partnership make sense to you strategically and financially?
Yeah. So particularly, you know, it was, I think, met with some questions when we initially announced it. Now that, you know, 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 to 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, you know, this year for the FTIs, potentially next year for GIST. You're going to see updates on diabetes. So you have a number of different value drivers.
I have told my team, and I told investors in our one-on-ones today, I said, don't plan on going back to the equity markets ever. You know, I hope, I want them to be prepared, but we will end the year in a very similar cash position to where we started. 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.