Well, good morning, everyone. My name is Jason Zemansky. I'm one of the SMID Cap analysts here at B of A. Thank you so much for joining us on this our second day of our 2024 health care conference here in Las Vegas. I'm so pleased to introduce for this KURRENT talk Troy Wilson, President and CEO of Kura Oncology. Troy, thank you so much for joining us.
My pleasure, Jason. Thank you to you and B of A Securities for the invitation.
Absolutely. Well, maybe to start broadly, to provide some context, especially for those a little bit newer to the story, can you talk about the emergence of the menin inhibitors? I mean, how did we get here, especially when some of the mutant classes you're pursuing have been known or recognized for decades?
Sure. So, spoiler alert, KMT2A or MLL has also been known for decades. It just took us that long to really get chemical matter. Way back 20, 30 years ago, people recognized there were a class of leukemias called mixed lineage leukemias. They had done a lot of the genetics. It was the great work of a number of academic groups that figured out that there was actually druggable matter here and that by developing menin inhibitors and they're called menin inhibitors because they block the interaction of menin with the MLL protein. It's also called the KMT2A protein. That basically by disrupting that protein-protein interaction, you disrupt a lot of downstream gene expression. And when I got involved, I was actually introduced to a group at Michigan that did a lot of the pioneering work by the Leukemia and Lymphoma Society.
And they had some pretty amazing nonclinical data in leukemia models in vitro and in vivo. A long time later came the story around NPM1. There's another story around diabetes. There's potentially, as we'll talk about, I'm sure, later this year, a story in solid tumors. I think menin is going to end up being a really interesting target for a lot of reasons. And the work that we and other companies are doing in leukemia, I think, is just the beginning.
Well, great. I think that's a perfect segue. The next 12-18 months are likely to be pivotal in Kura's evolution. So let's walk through a number of upcoming catalysts. But given the background that's inherent in this question, you announced yesterday enrollment has been completed for the registrational KOMET-001. This is a study of ziftomenib, monotherapy for R/R NPM1-mutant AML. By any measure, this was extraordinarily rapid. Why do you think interest is so robust?
Interest is so robust because the drug works. That's the bottom line, right? These are patients who until relatively recently, this was a death sentence. These are very sick patients. Relapsed refractory patients with leukemia have a very poor prognosis. The power of menin inhibitors is, and ziftomenib in particular, very encouraging safety and tolerability. You're not dragging along a lot of toxicities with you. Something I didn't touch on in your previous question, you're doing something pretty fundamental. Most of the targeted therapies, they block enzymes. That means you've got to block that enzyme 100% of the time. What a menin inhibitor does is it breaks up two proteins, and it actually tricks the cell from going from an immature cell to a mature cell. That's a one-way trip.
So you only have to block that protein-protein interaction long enough to trick a leukemic blast to become a mature cell. It lives a few weeks, and it dies off. The power of that, Jason, is we're seeing activity in patients who've failed IDH inhibitors, who've failed FLT3 inhibitors, who've failed venetoclax, for example. We internally set a goal of 18 months for enrollment in KOMET-001. We actually came in at fewer than 16 months. Had we not had the KOMET-007 and the KOMET-008 trials also enrolling in relapsed refractory, we would have come in even faster than that. And I think it's, again, it speaks to when you have a great drug and you have a high unmet need, the patients come out of the woodwork.
Yeah, absolutely. Well, help us put this into context here. At the recommended phase 2 dose, ziftomenib led to 35% CR rates. Can you put this into context here for this patient group in leukemia? What does it mean? And then what should we expect moving forward, at least for this new 85-patient cohort?
Yeah. So what it means so there's 2 aspects to the response rate of interest in this trial. So the FDA has sort of given everybody informal guidance that it wants to see a 20%-30% CR/CRh rate and a median duration of response of 4-6 months. We've never deviated from that. I think our competitors have never deviated from that. And the reason for that is the survival of a fourth-line patient, for example, with these tumors is like 2 months, 2.5 months. So if you've got a median duration of response of 4-6 months, that's clinically meaningful in the eyes of the FDA. I would expect I'd love to say you're going to see a 35% response rate. The trial's ongoing. I don't think you're going to see that. I think you're going to see between 20% and 30%.
That's what we designed the trial for. That's what we powered it for. If it ends up being greater than 30%, that's great. It doesn't need to be to satisfy approval. Just last week, ziftomenib was awarded Breakthrough Therapy designation in this indication. And that's actually a higher bar than approval now in oncology. I'll remind everyone, if KOMET-001 is successful, that enables Kura to submit a marketing application for full approval. The other thing it means I mentioned there were two elements of this. So one is you clear the leukemia. The other is you allow the patient's immune system to reboot, and you get counts back. That's important because, unfortunately, many of these patients with leukemia, they die of opportunistic infection. So there's a very strong push-pull among physicians to find regimens that are not immunosuppressive because patients can get into trouble.
The fact that we saw a 35% CR rate with full-count recovery in that phase 1b, those patients all had essentially a full immune system after having this devastating leukemia. That's important because, as we and we'll talk about, I'm sure, in the questions to come, as you now think about moving ziftomenib to earlier lines of therapy, you think about moving it into combination with other standards of care, the fact that it's so effective at clearing leukemia, and yet it allows the immune system, it's absolutely non-myelosuppressive, non-immunosuppressive. That's a really powerful combination.
Well, great. I think that's a perfect segue. I know Cameron from the team was anxious to ask some questions. Cameron?
Yeah, thanks. So earlier this year, you provided your KOMET-007 update. First insights into ziftomenib combos with 7+3 and Ven/Aza. Given the context of smaller populations, cycles, and dosing, what were your biggest takeaways from the data?
Yes. I think there were two takeaways, Cameron. And I think we were surprised as well as many, many investors and analysts. The first big surprise was there was zero incidence of differentiation syndrome. So just briefly, as a monotherapy, these menin inhibitors are inducing differentiation. That's what I talked about. That is a class effect. They all do that. Ziftomenib is so potent, it's so tissue penetrant, that when it's on its own in the KMT2A subset, which is about 5% of AML, it differentiates the tumor so effectively, it can put the patient into a crisis. A lot of people may be familiar with tumor lysis syndrome. Same idea. It's called a differentiation crisis. We had said when you do it in combo, that problem should be mitigated. And in fact, it was. We saw zero instances of differentiation syndrome.
I said at the time, I'll say it again, Cameron, don't get emotionally attached to 0%. It's not going to be 0%. What you want it to be is low, manageable. Ideally, you give the patient a couple of days of steroids. They stay on drug, and the differentiation, it never really becomes medically significant. That's where you want to go. That was the first big takeaway. The second big takeaway, I think, was even at a 200 milligram dose, the combos were more effective than I think people expected. We saw a 100% CR rate among 5 patients in the 7+3 cohort. The benchmark there was 30%-35%. That's the – if you think about the control arm for the Jazz product, the chemo product, that's about what you saw. In the venetoclax azacitidine, it was more active than ziftomenib alone.
Importantly, it was active in patients who'd already failed venHMA. So those patients' physicians will tell you, if a patient's failed venHMA, they don't have a lot of options left. And you're seeing both for Kura and for Syndax, you're seeing a significant number of patients who are responding. That's the 200-milligram dose. The cohorts are now enrolling so quickly, we're at 600 milligrams with three of the four cohorts. We're at 400 milligrams in the fourth cohort, the KMT2A 7+3. But that, again, we are more than 70 patients on study at this point. And that's almost as large as the monotherapy registrational study. That's why I say to you, we have to be careful not to create internal competition among our studies. But people are just clamoring to get on ziftomenib. The enrollment has exceeded our expectation, but we had pretty high expectations.
Great. And then maybe to provide some additional context here, there's optimism from the team that ziftomenib is going to be an ideal combo partner, especially when you think about safety profile. While these data were admittedly early, I guess, did it meet your expectations here? Can you kind of talk on that?
It did. It did. I mean, I think we were always optimistic. And I actually, on the question of differentiation syndrome, I actually want to acknowledge we have Bristol Myers Squibb as an equity investor in Kura. They made an equity investment attached to a right of first information. They actually strongly encouraged us to do the regimen that we're doing, which is seven days of the backbone and then ziftomenib on day eight. They actually encouraged us to do that across the combos. That was very good advice, right? They do research, development, commercialization in the space. They were spot on. I would say, Cameron, something you said. So what do we know from that combo? No DLTs, no DDIs, no QT, no additive myelosuppression. Everything's looking good from a safety and tolerability perspective.
You have to have a best-in-class agent is going to rest on a foundation of best-in-class safety and tolerability. That allows you to push the dose. That's why we were able to escalate so quickly to 600, is that once we tweaked it and we figured out how to mitigate DS, we were off to the races. And everything else at that 200 milligram dose looked good, looked, I think, as good or better than we expected. That's continued to look good as we've climbed through the cohorts.
Perfect. And then what duration and/or patient numbers would you need to see to maybe extend the confidence from this initial update? Or maybe what constitutes a full data set here?
Yes. That's a great question. So there's really at least 2 full data sets. So I mentioned there are 4 cohorts. Each cohort is 3 doses. Each dose is 6 patients. That's 72 patients all in. We're over-enrolling in some of those doses. And I'll remind you, in Ven/Aza, we're recruiting in relapsed/refractory. In 7+3, we're recruiting in patients who have adverse risk. Once the team identifies an RP2D, the safety monitoring committee can then waive the trial onto the expansion cohorts. We said on our earnings call, there are 7 potential expansion cohorts. Imagine NPM1 and KMT2A. Now you're frontline Ven/Aza, you're frontline 7+3, now adverse risk. You're Ven/Ziftomenib, probably forgetting one of them. Oh, and you're still going forward in relapsed/refractory. That's the expansion phase. There's a couple of major data updates.
You should expect safety, tolerability, clinical activity to get even better as you go into the frontline setting, into healthier patients. The fact that it's already so good in the relapsed refractory, I think, bodes well. But let's see. We haven't been a lot more specific, but that's the way we think about it, is the expansion piece sorry, the escalation piece and then the expansion piece. And yeah, I think we're moving toward that as fast as we can.
Perfect.
You're looking at two separate mutational subclasses. And so I'm curious, with the data trickling in, does it appear that ziftomenib is more potent in, say, NPM1 versus KMT2A or vice versa at this point?
I think it's fair to say that KMT2A is a slightly higher bar in that if I had a criticism of the data at 200, it's perhaps that you wanted to see more activity in the KMT2A population. That may come with higher dose. The KMT2A, I mean, that's a very, very difficult prognosis. In terms of their sensitivity to ziftomenib, there really isn't a difference. In terms of the biology, the presence of co-mutations, when you're getting patients in the relapsed refractory setting who failed Ven, who have failed targeted therapy, who may be on multiple transplants, it's so confounded. It's hard to make sweeping statements. We've been very encouraged. I will tell you, and I think, again, our competitors will agree, physicians will use these drugs in combination. And in fact, if you give them the choice we had to encourage them as the monotherapy study was enrolling.
You can see how fast the combo's enrolling alongside. Help us get the monotherapy enrolled so we can get the drug approved. They will use these drugs in combination. We have to be careful with commercial promotion about what we do. But ultimately, that's where you're going to end up. In combination, ideally as early in the treatment course as possible, and then keep them on menin inhibitors in maintenance.
Got it. Well, just out of curiosity, what is the benchmark for both 7+3 and Ven/Aza in these settings? I just kind of want to put a line in the sand in terms of beating that line to kind of justify that interest in using menin inhibitors.
Yeah. So I think, again, let's just focus on the escalation for now before we'll do the expansions in time. 7+3, adverse risk, the number we use is 30%-35%. People may push back and say, well, I can find some small reference of seven patients that's 50%. OK, fine. It's 50%. That's the benchmark. Frontline, both populations, adverse risk. Adverse risk is older than 65, I believe, or 70, ELN or co-mutations. Those are what tip people over into adverse risk. KMT2A, by definition, adverse risk. The Ven/Aza relapsed refractory, there, Jason, you got to this is why we broke the data out the way we did. Are they menin experienced? Are they menin naive? That raises the bar. Are they ven/HMA experienced or not? As I said, ven/HMA, if you've failed that, your expected response rate with Ven is about zero.
So that's why we're very encouraged by what we're seeing. I think even at the 200 milligram data, you were better than ziftomenib as a monotherapy. Let's see what we can do as we go to higher doses.
Great. Before we move on, pace of enrollment or of updates moving forward, has that been changed at all? I mean, what are your expectations for later this year and maybe next?
With the monotherapy, you started off by saying full enrollment. We guided expect to see topline data early in 2025. What's driving that is you need six months from the last patient dosed plus enough time to clean the data. I'm not sure anybody wants us to deliver data on Christmas morning. People want to be with their families. Early 2025 is kind of the right way to think about that. You will see an update on the combos at some point this year. We've kept it open. Obviously, we're coming up quickly on EHA. You have ASH at the end of the year. That's a logical place. We did a corporate update in January. What we're going to try to do is get enough data that we can say something substantive, right?
If we show data at 200 and 400, everybody's going to hopefully be pleased, but then say, OK, and how's 600 going, right? So we have the flexibility. We have the strong capital position that we can kind of pick our spots. As we're able to be more specific, we will. I think you should expect you will see a data update. At this point, we're kind of keeping all the options open. A couple of other things. You will see us show you preclinical data and start a trial in solid tumors. That's going to come later this year. And then we've teased everybody that there is an opportunity in non-oncology indications, and we're doing work there. I would expect to see an update there as well. I do think there's a real opportunity for menin inhibitors to go beyond the initial leukemia indications.
We will continue to be very data-driven in how we do that.
Perfect. Maybe taking a step back, can you touch on your overall combination strategy beyond 7+3 and Ven/Aza, which are obviously well-established in earlier line settings? But which combination approaches are most interesting to you and why?
So the one that probably stands the tallest is FLT3, FLT3 inhibitors. And you have sort of three approved agents. You have quizartinib, gilteritinib, and midostaurin, other drugs in early development coming behind them. FLT3 is 25%-30% of AML. It's half of NPM1. And FLT3, NPM1 co-mutants are a very negative prognosis for patients. There's interest. We've heard from investigators, say publicly, they'd like to have an all-oral regimen with no myelosuppression to drive responses and potentially get patients to transplant or get them to cure. We are running in KOMET-008, the combination of ziftomenib plus gilteritinib. Gilteritinib is a very effective FLT3 inhibitor. Quizartinib also looks very interesting. They have kind of mutually exclusive approvals.
That one has to be high on your list because in non-clinical models, which is today all we have, that is some of the most potent synergy we've seen, is those two together. Does that make sense? It does because menin inhibitors are upstream from FLT3. So FLT3 inhibitors are blocking the catalytic activity of the enzyme. Menin inhibitors are downregulating FLT3's expression. It's like the perfect combination. I would say we'd probably put that one at the top. What we'll do, Jason, is pick our spots as far as commercial, company-sponsored trials and then let the investigators and the cooperative groups go crazy. There are many other combinations you could do, but FLT3 has to be part of your strategy if you want to have a dominant sort of franchise in leukemia.
Perfect. Well, I appreciate this question, maybe somewhat theoretical, and I'm hoping you indulge me here. But mechanistically, what do you think the menin inhibitor is providing in a combination regimen? Is it specifically preventing, say, a common escape pathway? Is it more broadly addressing the proliferation issues? What I'm trying to tease out here is when we think about the menin inhibitors beyond AML, what sort of application do you think that they could have? And you kind of alluded to this earlier.
Yeah, I did. And I appreciate the question. I'll give you what we know. It seems pretty clear we understand the interaction between FLT3 inhibitors. I didn't mention IDH1 and IDH2 inhibitors, but you have the same drill. IDH sits downstream from menin. Those combinations are also very potent. In fact, in the monotherapy phase 1b, you saw ziftomenib driving high response rates in patients who had failed either FLT3 or IDH1 and IDH2. The big question, Jason, that I don't have an answer to, and maybe Scott Armstrong or others do, is what's driving the activity with venetoclax? Is it that you are affecting MCL1? Is it that you're affecting BCL2? You clearly are. Is that what's driving the additive activity? I don't think we know yet. We're trying to figure it out. A lot of the academic community is trying to figure it out.
It's pretty clear that there's something going on there. It's above my understanding, above my pay grade to tell you yet exactly what it is. But it looks like a solvable problem. We'll figure it out.
Interesting. And then as you think about the role of menin inhibitors in the treatment paradigm, is there a world in which they become foundational overall? Or do you think they're more relegated to certain subclasses, however big they end up being?
Yeah, I think it's the former. So I think it's foundational. Menin is the AML equivalent the way I think about it is in chronic myelogenous leukemia, we have BCR-ABL. BCR-ABL is the fundamental disruption that sets you down that course. Menin MLL is as close as you can get. If, in fact, you just upregulate MEIS1 and HOXA9, you don't have to do anything. Just upregulate those two genes, you can induce cells with full-blown leukemia. That's why, in fact, 80% of infants with leukemia have menin disruptions. It's that foundational. I think you'll see it become what I hope you'll see is what we've seen with IMiDs, with CD38 in myeloma. It wasn't that long ago. Myeloma was a death sentence, right? And everybody was transplanted. Now, it's not uncommon for patients to go 10 years. They're pentarefractory, right?
It's because I give credit to the IMiDs we've had multiple versions of them they're in the frontline. They're in every combination. They're in maintenance. That's what you're going to see with menin. And that's where I'm very optimistic about ziftomenib, that it has no DDIs. It has no toxicities. It's extremely well-tolerated. It should be you use it up front. You can use it in the relapsed/refractory setting. You can use it. It's the ideal maintenance agent. Hopefully, AML if we're still sitting here 10 or 15 years from now, hopefully, AML looks a lot more like myeloma than it does today.
Great. Well, maybe one more on menin, if I may. Can you talk about the post-transplant maintenance program recently initiated? What's going to be key here for regulators? And then maybe on the back end of that, can you touch on what motivated you or the decision to make this investigator-sponsored?
Yeah. Well, I'll take the second question first. My team is fond of telling me, Troy, everything can be a priority. It just all can't be a priority at the same time. So you need a safety run-in in post-transplant maintenance in order to be able to go and have a conversation with health authorities about the design of a post-transplant maintenance study. Ideally, you're doing a placebo-controlled trial. If you want an analog, look at the Morpho study that was done with gilteritinib. There's a lot of lessons to be learned. And we're actually working with one of the key investigators there. The other thing is it helps to have investigators really invested in running ISTs and cooperative groups. This isn't a logical one.
You asked you're looking for enough of a safety predicate that you can go and say to the health authorities, this is the safety in the post-transplant maintenance setting. This is the design of a proper post-transplant maintenance study. We'll have more to say about that. The team is busy chopping a lot of wood right now in hustling ziftomenib to the NDA submission, delivering on the combos. It's literally the solid tumors. It's literally you can't do everything at the same time. But that's a very important part of it. Probably more to say in 2025.
Fair enough. Well, in the time we have left, I definitely did want to touch upon the FTI program. Looking at the KURRENT- HN trial, data is expected for a half of next year. What is a positive outcome in your mind?
Yeah. So we already have one positive outcome. You haven't seen the data, but we've alluded to it. The fact that we were able to dose escalate tipifarnib and alpelisib, this is a targeted combination in an extremely hard-to-treat population. So recurrent and metastatic head and neck is as hard as it gets. Third-line recurrent and metastatic head and neck looks like pancreatic. If you have a 5% response rate, you're in good shape. We are enrolling second, third, and later-line patients. Start with safety. The way to think about an FTI and we have two of them. We have tipifarnib and KO-2806 is it is the ideal combination agent for certain big classes of targeted therapies. Why do I frame it that way? We've gotten really good at shrinking tumors. We have KRAS inhibitors and EGFR inhibitors and this and that.
90% of patients with metastatic disease die of their metastatic disease. We do not do a good enough job of dealing with adaptive resistance, with innate resistance. That's where the FTI comes in. So to your question about tipifarnib, the fact that you can combine alpelisib, a lot of people will tell you alpelisib has a very checkered safety profile. That hasn't been our experience. It's actually been very, very effective to combine those two. We're seeing enough activity that we've done dose optimization at different doses. Is there a commercial play there? Let's see. We're doing 2806, which is everything you like about tipifarnib. And we fixed the two or three things that needed to be fixed. It's a brand new NCE. It's gone incredibly quickly. We dosed the first patient in November. We dosed the first patient in combination with cabozantinib in February.
We're on target to dose the first patient in combination with adagrasib. We were able to do a very innovative strategy with the FDA, basically saying, we know so much about farnesyl transferase because of the 5,000 patients dosed with tipifarnib allow us to go faster. And the FDA was very good to work with and allowed us to do that. That's the goal. Can you block the innate and adaptive resistance that invariably arises around these targeted therapies? You should look for safety, tolerability, activity in current that's better than standard of care. It's 20% second-line. It's less than 5%. Show me anything. And recurrent metastatic PIK3CA mutant head and neck, which is where we're doing the dose optimization.
Makes complete sense. All right. So cabozantinib and RCC, adagrasib, and NSCLC. What else makes sense with an FTI down the line?
So if the FTI works, I have a bit of a personal history with the RAS inhibitors, as some people know. The beauty of the FTI is that it doesn't care. The innate and adaptive resistance arises independent of the mechanism of RAS mutation. So we see additivity or synergy with G12C, G12D, G12V, pan-RAS inhibitors, right? So you have, I mean, there is, you're seeing in KRAS kind of what we saw in PD1, PDL1. It looks like the 405 freeway in Los Angeles at rush hour. The FTI potentially combines with more than one of them and could allow you to deal with the innate and adaptive resistance that arises. We're going to get started with adagrasib and G12C because there's such a good understanding of the safety data. And then if we see additivity or synergy, let's see where we go.
But it's a really clever way of coming at KRAS kind of orthogonally to what everyone else is doing.
Great. Well, exciting times. Really looking forward to those data readouts. Thank you so much for joining us, Troy.
Thanks for all the questions from both of you. Really appreciate the time.