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

Good afternoon and welcome to Barclays Global Healthcare Conference, do email me and my team if you have questions. And my name is Peter Lawson, and I'm one of the mid-cap biotech analysts at Barclays, cover and focus around oncology companies. Really delighted to have with us on stage Troy Wilson, CEO of Kura Oncology.

And I guess with that I'd love to kind of touch upon definitely the menin inhibitor and kind of how we should expect kind of data to unfold, how much more data should we expect to see and I guess that's maybe earmarked for EHA.

First of all Peter, thank you to you and Barclays for the invitation. In terms of the update, we've guided toward midyear, obviously, you have ASCO and EHA, it will be 1 of the 2 -- EHA would be a logical venue just so you get exposure to European hem/onc physicians, right, who may not have made it over for ASH. In terms of the data that you'll see, the focus is going to be on the Phase Ib cohort in NPM1-mutant AML, primarily with a focus on durability. If you remember at ASH, we had 20 patients, 30% CR rate with full count recovery. But the duration of response at that time was still immature. It was about 4, 4.5 months. That was as of in October 24 data cut -- October 24, 2022. If we fast forward to midyear, you're probably looking at an additional 6 months. So that will give both a perspective on the potential durability, which I think was a question mark. We'll give an update of all the NPM1-mutant patients on study, but it will also be more of an apples-to-apples comparison with the competition.

And I guess beyond that, I mean, so where do you think that bar is for durability to be kind of best-in-class and build a sufficient barrier of entry?

Yes. So I don't know that there's an absolute number. The -- our competitor at ASH showed a median duration -- sorry, a duration of response of 9.1 months, but that was a composite number. I don't think they broke it down. I can't remember by genotype. That's certainly -- at that time at ASH, when our duration of response was still immature, we said we thought that was a number that we could probably meet or exceed. I think anything you can do -- if you think about the overall survival for NPM1-mutant patients in the relapsed/refractory setting is about 6 months. So if you have a DOR that's approximately 6 months, 9 months beyond, that's clinically meaningful. The longer, the better. I don't think it's necessarily a winner take all, but we'll see when we present the data in midyear, what it looks like.

I guess the question is that you've been getting recently inbound, just like the idea of resistance mutations developing. And kind of how much does that hinder the use of the drug? Can you repeat dosing with a different drug, et cetera?

So we've not seen a lot of resistance mutations. We're still analyzing the data. It's -- I'm aware of kind of a handful of cases. And of that handful, a couple were patients who presented with a resistance mutation after having been on another drug, another menin inhibitor. I do think if AML is like every other cancer indication, I think the resistance arises from basically an inability to clear extramedullary disease. It makes sense, right? If you're keeping constant drug pressure and you still have tumor cells around, those cells are going to -- they're going to find a way to become resistant. Our thesis for zifto is you get -- because of the tissue penetrants, because of the very good tolerability we've said consistently, we see clearance of extramedullary disease in both the KMT2A and the NPM1. Now the penalty in KMT2A is differentiation syndrome, which I think we'll come to, but if you clear that disease, then there's no tumor to develop resistance mutations. Maybe it's early days, but it's not something -- it is possible we do see it. I wouldn't yet describe it as a major problem for ziftomenib. I think that might be a point of some differentiation from the competition, but it's early days. We're talking about Phase I data sets.

Got you. Do you think [ covalent ] menin inhibitors can kind of help alleviate that if does that become a problem?

I don't because one of the things that zifto does effectively, and this is in contrast to one of the noncovalent competitors is it degrades menin. So it inhibits menin and it degrades it. I don't think we know enough yet, Peter, as to what the covalent menin inhibitor does in patients. It's less potent in vitro, but who knows? We're -- I think we're expecting to see some data a little bit later this year. I'm interested to say. As you know, we investigated both noncovalent and covalent. That wasn't a point of differentiation.

Got you. Okay. And do you get responses on patients that have a mutation that's been acquired from a different menin inhibitor?

We didn't see responses. You see blast count reduction, you see symptomatic improvement. It hasn't been a large number. It's been -- I can think of 2 specifically. We didn't -- we weren't able to drive them to a full response, no. Ziftomenib is -- if a patient has a resistance mutation that does impair the binding of ziftomenib. It actually impairs the binding of all -- we've tested what we believe are all the menin inhibitors across all the various sponsors, and they all seem to be blunted by the mutations that are arising at the interface that have been described.

Got you. Thank you. And then as we think about these MLL rearrangements, kind of how many are there? Does that change the dynamic of if you can inhibit all those rearrangements or if it's a subset of those rearrangements?

I -- so I don't think we know enough yet. I don't think we have enough clinical data to know. And it's always -- you're always reluctant to talk about all or none, right, in oncology. It's all, as always, a CR. I think the best course of action for the MLL rearrangements will be combination, right? So bringing a couple of different drug pressures, maybe it's chemotherapy plus a menin inhibitor. Maybe it's a -- maybe it's something like venetoclax plus a menin inhibitor. That's how you're going to drive your deepest and best response. It's what we know enough -- what we know now is menin-inhibitors are showing promising clinical activity. There's a path forward for one of our competitors in registration. Ultimately, you need to be in combination. That's -- everybody sort of acknowledges that, if you want to provide the best benefit for patients.

Got you. And as we think about differentiation syndrome, do you think that in any way correlates with durability response? Or is there a good secondary read....

I think it correlates with clinical activity. What we've shown, what we showed at ASH is you can see that you're engaging the tumor. You can see blast count reductions. The reason you're not taking patients on is because they're not staying on therapy due to differentiation syndrome. Our -- as we've said on our last earnings call, our plan is to take those patients in combination with standard of care. I think -- and hopefully, by the end of this year, we'll show we can combine safely and tolerably, and we can mitigate differentiation syndrome in the KMT2A population. In the NPM1 population, it's not an issue. Our goal is, by the end of this year, to have data out that says combination effectively solves that problem.

Got you. And then having a covalent version, do you think that kind of amplifies DS? Or do you think it's -- there's a different mechanism or action going on there that helps reduce DS? Just curious on your read -- on the read.

I don't know. Without human data, you can't -- it's very difficult to model DS preclinically. It's really something that -- mice don't complain of DS, it's something you really have to see in the clinic, and we've not seen any clinical data from any reversible inhibitors. So I would be guessing at this point, what they see. Other covalent inhibitors, you do see -- I mean, you see diarrhea, right? You see GI toxicity. We've not seen any clinical data at all. Let's wait for that particular sponsor to release clinical data, and then we can all take a look at it.

And I remember you said in the past, you kind of passed on a covalent inhibitor. Why was that?

We passed on it because at the end of the day, a menin turnover is about every 6 to 8 hours. And in our experience, you needed to dose repeatedly in order to drive activity. There was no advantage relative to a reversible inhibitor. And as we've seen in the case of some of the KRAS inhibitors, having a potent electrophile on it can not only create GI toxicities such as diarrhea, but it can also hit off targets. And for chronic therapy, it wasn't obvious to us that the irreversible or the covalent inhibitors had much more to offer. Certainly something you could pursue. The chemistry is very clear, but the reversible inhibitors are driving -- I mean we have a 30% full CR rate, right? And Syndax has a 27% CR/CRh rate in the KMT2A. I'll be interested to see if the covalent inhibitor can even match that. Let's see what we see.

Got you. Phase II, how's that enrolling? And kind of how should we think about data folding out from that?

It's enrolling well, not surprisingly. People will recall the Phase Ib enrollment was very strong in NPM1. We enrolled -- I believe it was 14 patients in 3 months in the Ib with about 20 clinical sites. We're going to pretty much double that site footprint. The sites are still in the process of coming online. But we've seen very, very strong interest, strong enrollment. When we announced that the study had started, we took pains to say we had dosed multiple patients, plural, and that has continued. Given that one of our competitors, probably our nearest competitor has pushed its timelines out on NPM1 enrollments, I think -- and given the strong pace of enrollment we've seen, maybe we're 3 months behind, 3 to 6 months. I think we plan on taking advantage of every development and regulatory strategy to accelerate development. And I think we have a strong chance of catching and potentially getting ahead of them in the NPM1 cohort. We'll see.

And then I guess that difference is coming up with [ a couple of concerns ] about the 85 patients versus [ sits the odds ]. Kind of what's the right number? Why was yours larger? Is...

Ours was larger -- yes. I mean, the right number is whatever the -- how much risk the sponsor wants to take. Our 85 was driven by safety, not driven by activity. In our opinion, and this is not something the FDA imposed upon us, it was something, we volunteered, you want to have a sufficient safety database that you can support registration. The right -- typically in the FDA's mind it's about 100 patients overall at the recommended dose. So we thought 85 was kind of the right number, and it was a number that we thought was eminently achievable given the enrollment we'd seen in the Ib. We haven't been specific about the parameters around -- the efficacy parameters or the statistical plan, but it's -- we are going to take advantage of everything we can to go quickly.

And the kind of the driven by safety, is that because there's something fundamentally in the data that we should be thinking about?

No. It's not that we've seen something. It's more that you want to have enough patients that you can say conclusively you've ruled out the incidents of any kind of safety event. And in our experience, 85 is the right number. You can always -- if you set it higher, you can always go faster, right? But the risk that you run is if you set it too low, and you have to expand it then that sends a very strong signal. So we've tried to be a bit more conservative as a company, not take unnecessary risk. There's -- at that point in enrollment, Peter, there's not a huge difference between 64 and 85 patients. If you're enrolling, again, go back to the Ib experience, 14 patients in 3 months you're talking about a month or 2 in enrollment, once all the sites are up and running. It's -- there's no real material difference in time, but it's just a more substantive package, and it's one that we think is the right one to submit to the agency.

Got you. And then the potential -- I know you previously spoke about the potential enrollment including those Phase I patients into the Phase II. Kind of what was the disconnect or what was the -- how did that conversation evolve?

Yes. So we didn't take that to the agency. We basically left it as a review issue. We didn't ask the agency to opine on that, in part because it was in the context of Project Optimus, and we had enough going on with Project Optimus. Clearly, if you take a 30% CR rate with a 20-patient denominator, you can do just the statistical analysis and figure out our trial has a 95% probability of success, assuming those parameters keep up. We didn't feel, at that time in the Type C meeting with the FDA, that we needed to introduce the variable of asking them to include Phase Ib patients because in all likelihood, it would have slowed everything down. We wanted to get that answer so we could get on to enrolling the Phase II. So dealing with the FDA is as much art as it is science. We just made a judgment call. We didn't, however, foreclose the opportunity of including them. I just don't think we're going to need them because enrollment is so robust that it just adds more to the body of data. The other thing to keep in mind is our activity continue -- through the Phase Ib, continued to get better and better. And I think we're getting better in both the NPM1 and KMT2A of knowing how to manage DS. If you have a pristine Phase II data set, that's going to be reflected in your label. So folks won't be able to come back and say, "well, what about differentiation syndrome, what about this, what about that?" So it's art -- a little bit of art, a little bit of science.

Okay. There's no -- you wouldn't -- towards the end think, okay, we can now include these patients, the Phase I...

You will include them as part of the filing. The question is, can you include them in the primary efficacy analysis? You don't have to make that decision today. There are statistical tools you can use if it allows you to go faster. If, for example, you're able to take advantage of something like breakthrough therapy designation, there are ways you can go more quickly with the agency. We've been pretty guarded about what we're -- exactly we're doing. Our goal is to go as fast as possible. We think we've got the best-in-class agent in NPM1. And we are pulling out all the stops to get there as quickly as we can.

And just thinking about that, how are sites going for enrollment and up and running, et cetera? And where are you for Europe as well?

Sorry?

Enrollment of new clinical sites.

Oh. So we're -- so the U.S. sites come up more quickly. The European sites typically take an additional 3 to 6 months because they have to go through a central country review and then ethics review. The U.S. sites, we'll have them all, I think, up and running certainly in the first quarter. That's gone extremely well. As I said, the intent is to kind of double the footprint from what we had in the Phase Ib, think 40 -- approximately 40 sites globally. Interestingly, we are also in study start-up for the first combination study. And we have between the 007 protocol, which is 7+3 and venetoclax and the 008, which is primarily gilteritinib, we have a waiting list of sites. I mean we have more sites that want to participate than we probably can take on at this point. So very, very strong interest. That's where you're going to see us solve the -- I think, solve the problem with KMT2A is in combination. And we have sites lined up, ready to go.

Got you. And is the thinking evolved around the rearrangement and the differentiation syndrome has physician feedback helped? Or kind of how you think that happens where you get a delta in responses?

Well, we -- yes, I mean we know why it happens. It happens because the patients aren't able to stay on therapy because they are seeing symptoms of differentiation syndrome. Everything we've seen from experience with prior drugs, for example, IDH inhibitors. When you combine an IDH inhibitor with azacitidine, you cut the rate of differentiation syndrome in half. That's fairly simplistic. We think we'll see the same, if not better here. All the docs tell us as well, it's a logical thing to do. It's what they want to do to be able to drive deeper and more durable responses. We've just sort of decoupled the KMT2A piece for now. And we'll come back, I think, in the second half of the year and give people an update on can we combine safely? We expect we can. And does it mitigate DS? And if it does, I think it will support the thesis that we have the most potent menin inhibitor out there.

Got you. Has that idea resonated well with physicians? Has there been any worry that it's working well in the NPM1, but we've got differentiation syndrome. So does that cause any holdback in any way?

No. I think they want to know how to -- you need to make management of differentiation syndrome routine. And while we could spend more time on monotherapy, we've said, you know what, this is a world of combinations. Just -- combinations will mitigate the problem, both by tumor debulking and by clearing white cells and blast. This is the way to go. The KOLs, the physicians have been unanimously supportive. I'll just remind you, I mean people forget this. KMT2A is 5%, NPM1 is 30%. So our focus is on the 30% of the population that's in the near term, going to drive the greatest value, we'll come back and by the end of this year, I suspect. And have more to say on the KMT2A opportunity. As soon as anybody is in combination, everybody is going to be in combination because AML is a disease of polypharmacy, right? It wasn't venetoclax. It was venetoclax plus azacitidine. It wasn't 7, was 7+3. Combinations are the name of the game. You have to do them to drive durable, deep responses, whether you're considering transplant or not.

Okay. Before we transition over to tipifarnib. I have to ask just about Silicon Valley Bank kind of exposure. No need -- to Silicon Valley, but also, I guess, regional banks and nonbank lenders kind of how you kind of think about that?

So we put out an 8-K. We don't have any material exposure to SVB. And now with the Fed's action, all depositors are going to get money back. So even our immaterial money we know is not at risk. Our -- I think all companies will consider their -- can they either, through diversification or insurance, protect against something like this happening. I think that's just going to be part of what we do. We don't have any exposure that I can think of to regional banks, nonbank lenders or anything like that. We're -- other than all the noise, it isn't affecting us in any way.

Got you. You -- and then just tipifarnib, kind of what we should expect to see, I guess, the combination strategy? We hopefully see something midyear? Anything we should look at?

Well, yes, so what you're referring to is the combination of tipifarnib plus alpelisib in PIK3CA mutant head and neck. We are working toward an optimal biologically active dose. To my knowledge, we haven't yet seen any DLTs. So we continue to dose escalate, which is interesting. The -- we have to reach that OBAD, optimal biologically active dose. And then probably, Peter, we have to do a sufficiently-sized expansion cohort to be able to say, "okay, what's the effect size and the path forward." I will just use this as an opportunity to introduce. We now have the IND open for 2806. We expect to dose the first patients in Q3, you'll see a press release, a curtain raiser on next 2 opportunities for -- that will actually be with 2806. And I think I can tell you, they are KRAS mutants, and tyrosine kinase inhibitors in renal cell carcinoma. Both of those, we are going after a uniquely farnesylated protein that's driving resistance either to KRAS inhibitors or to TKIs. And you'll see more about that science at AACR here in, I think, April.

Got you. And that's kind of post the G12C kind of development, it's...

It's not post. You would -- so when you treat -- so taking just a quick step back. When we first started with farnesyl transferase, we thought we need to go after a farnesylated oncoprotein. Well, there's only one, HRAS. What we've learned subsequently is when you hit a cell with a highly potent drug like a KRAS inhibitor, like a TKI, like a PI3-kinase inhibitor, EGFR inhibitor, you induce certain proteins that are farnesylated. Those proteins drive resistance. In the case of KRAS, when you hit -- and this is well documented, you treat with a KRAS inhibitor, the PI3 kinase pathway, PI3 kinase mTOR AKT gets activated. mTOR is under the control of a protein called Rheb, Rheb is farnesylated. By blocking Rheb, you can blunt the resistance to KRAS inhibitors, drive deeper and more durable responses. Same thing in RCC. When you hit with a TKI, you induce VHL, VHL is under the control of surprise, Rheb, Rheb is farnesylated. So it's our understanding now of how to use farnesyl transferase inhibitor in cancer is don't use them as the primary hammer, use them to address the resistance that arises when you hit them with these well-understood commercial-stage drugs. And with both KRAS and RCC, we're optimistic because there's a quicker path to data, potentially a quicker path to market relative to some of the other opportunities we've looked at. So more to come.

So you'll be combining it with...

You'll be combining. Exactly. Exactly. That's the key.

But sorry, menin inhibitor as well, you're thinking about...

Everything's combination. Yes, everything's combination.

Perfect. With that, thank you so much, Troy.

My pleasure. Thank you, Peter.