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

There we go. So I just wanted to thank everybody for attending fireside chat with Kura, attending a conference in Miami. So very grateful everyone came down, and I hope everyone is feeling, feeling great. And hopefully, their meetings are going well. And my name is Peter Lawson. I'm hosting this fireside chat with Kura. So I am one of biotech analysts here. I just want to thank Troy Wilson, CEO from Kura, for coming down and support as well and been in person for our conference. So it's really exciting after 2 years has been at home and back in person again, thankfully.

So first question, I guess, kind of the differentiation of Kura in the oncology space or maybe you want to cover kind of a company overview and just a few seconds on that.

Sure. Yes. So first of all, Peter, thank you for the invitation. It's Pete De Spain and I were saying to each other, how much -- we've forgotten how much we enjoy actually meeting people in person. It's been such a long time. So Kura Oncology, as you mentioned, is focused in the area of targeted oncology. Three principal pillars now to the business. The first one and probably the one that's most immediate in people's minds is our menin inhibitor, ziftomenib, formerly KO-539, which we're developing for genetic subsets of acute leukemia. The second major pillar is tipifarnib in head and neck cancer. That's now in both a registrational trial as a monotherapy and more recently, as of November, December of last year, a combination study with alpelisib, again, in genetically defined head and neck tumors. And the third pillar, which is beginning to come into focus, will be initially tipi, but very quickly our new farnesyl transferase inhibitor, K0-2806 in non-small cell lung cancer in combination with osimertinib. And there, the goal is to be able to delay the onset of adaptive resistance to osimertinib, potentially other EGFR inhibitors, potentially other targeted therapies. I think you'll see that story fleshed out over the next couple of years. With each program, the theme is the same. Building on the strengths of precision medicine, targeting genetically selected populations to be able to maximize efficacy, but using thoughtful combination approaches to be able to both drive better outcomes and potentially expand the commercial potential, by going to larger patient populations. And I would just highlight for you frontline leukemia would be the goal of ziftomenib. Frontline non-small cell lung would be the goal with 2806 and osimertinib. Company had over $500 million in cash as of our last earnings update, which was a couple of weeks ago. So we're well capitalized. We give guidance -- conservative guidance into 2024. That's through significant catalysts on all 3 pillars.

Got you. I'd love to touch upon the menin, which your Kura's central problem, the story. I know the things that percolating through as well. But just as we think about its clinical hold, how is enrollment progressing and how are sites activating, et cetera?

Yes. So the hold was lifted early in the year. Once the FDA lifts the hold, it's then a site-by-site determination of what they need to be able to resume enrollment. I'm pleased to say probably 80% to 90% of the high enrolling sites in the United States are reengaged and actively screening for patients. The European sites take a little bit longer, because they have a requirement of going through an ethics review before they can restart. I think it's important to note, we have given guidance that we have full enrollment in the Phase Ib cohorts by the end of Q1. We're now guiding to the end of Q2. And given that the hold was lifted in 57 days, we probably lost about a month or so, not counting the time that we were officially on hold. So I think that speaks to the fact that the investigators are excited. They're screening patients. There's always a fair number of -- it's a very dynamic process of identifying patients and getting them through screening and getting them on therapy, but that all seems to be coming along quite nicely. As I think enthusiasm continues to build among the investigator community for ziftomenib, as they get more and more experience with the drug. And just to ask -- to answer a question, you didn't ask, but one that we do often get, the reason for the partial clinical hold was the FDA wanted to make sure that we had the right mitigation strategy in place to manage differentiation syndrome. Even with the possibility of differentiation syndrome, there's still considerable enthusiasm, right? That's recognized as an on-mechanism effect. It actually -- if you see it, it typically means that the drug is working. It's doing what it's designed to do. You just have to make sure that you manage the patients successfully. And I think the physicians feel like they have a good handle now with a standardized approach.

Got you. And because it's on target, you kind of -- that's why it's not viewed as dose-limiting toxicity? Or at what point will it be considered...

It could become a dose-limiting tox if you were getting to severe DS, right, uncontrollable DS. But that's not where we find ourselves. So maybe just to review what the FDA asked us to do is part of getting the hold lifted. It was really the beginning and the end of the process. So at the beginning, we're now requiring physicians to do blood draws on day 4 and day 10, look for elevated counts, look for inflammatory markers like C-reactive protein or ferritin. That really gives investigators and us a window into what's going on before the symptoms of differentiation syndrome really manifest. So it's a surveillance function. On the back side, if the counts are -- cannot be controlled, above, I believe, [indiscernible] then the physicians are required to hold ziftomenib until the symptoms resolve. And we've had a case of DS even since the enrollment resumed, and it was sort of mild to moderate. They never got there. Ideally, if you're doing proper surveillance, you're getting in, treating aggressively, leaning into the differentiation syndrome, the first thing you'll do is treat with steroids. It's an inflammatory reaction. You'll treat with urea, perhaps to manage the counts. You'd only escalate to other measures like cytoreductive therapy if you needed to. But -- just to be specific, I think if you couldn't manage DS, then it might become a dose-limiting tox. We've not found that. We've, in fact, found the opposite that it appears to be readily managed. And what we did coming out of the clinical hold was just standardized the process, by which all the sites are treating DS. They're now all treating it using the same algorithm. And that -- to be fair to them, that wasn't the case before. They were -- each of them would do it slightly differently.

Got you. And what dose did that happen?

That episode was seen in a patient at the 200-milligram dose. We have not seen a dose dependence. DS seems to be either on or off. It doesn't appear to be dose related. There may be other factors that predispose patients, but it does -- at least within the Phase Ib, this 200 and 600-milligram cohorts, we're not seeing a dose dependence.

Got you. Does this act as a point of differentiation for the other menin inhibitors differentiation syndrome? Does that kind of tarnish it in any way with KOLs?

No. In fact -- it was funny, I was interviewing a potential candidate to be a senior person in clinical development to join the company, and she's at a large pharma company. And very early on in the interview -- she has a background in leukemia, in fact, around in solid tumors. And she said, congratulations. And I'm like, congratulations? And she says, "yes, you're seeing differentiation syndrome." The drug is working. And then when you talk to people, who treat AML regularly, that's what they'll tell you. These drugs are designed to differentiate cells. It may speak, Peter, to a more potent compound. It may speak to a more profound pharmacodynamic effect. I think so long as that DS remains moderate -- mild to moderate and manageable and reversible, it isn't really going to be an issue. It isn't going to be certainly a point of negative differentiation.

Got you. And then I guess what we see data in Q3 of this year and what we see safety. What level of safety data will we see?

Yes. So the -- what we've guided to on the last earnings call was a top line read of efficacy and safety in Q3, probably in the form of a press release, really with the goal of saying which of the 2 doses was selected or was identified as the -- as a potential recommended Phase II dose. I can tell you if everything remains, as it is today, the safety and tolerability will be very favorable. We probably won't go into a lot of detail. And then we'll give kind of a high-level cut of the efficacy. We haven't -- we're not there yet, so I don't know exactly to what extent we'll break it down by genetic subtype or whatnot. We'll try to give as much information as we can. And then our expectation would be at the end of the year, at a clinical meeting, provide a more fulsome update of the Phase I experience. And at that point, you'll have the -- we're expecting all of the patients will be enrolled by the end of Q2, that top line data cut Q3. That will give you between 3 and 6 months of experience, even on the latest patients by the time you get to the clinical present. Maybe backing off a month or 2 for the proper data cut, but it should be a good update.

Got you. What's going to be the mix of the 2 different genetic subtypes rearranged in the mutant?

So it's -- at the moment, the epidemiology would suggest that you'd see about a 5:1 split of NPM1 to KMT2A, we're seeing closer to probably a 1:1. That ebbs and flows depending on whether patients actually make it through screening, make it onto the study. But I would say we're seeing a higher percentage of KMT2A rearranged patients then the epidemiology would suggest for 2 reasons. The first being, if the NPM1 mutant patients have other co-mutations, they may have other options. They may be eligible for a FLT3 trial or an IDH trial, for example. The -- in contrast, the KMT2A rearranged patients, they really don't respond to anything. So they will often blow through between 1 and 4, 5, 6 lines of therapy. And they are trying to find their way to menin trial. So I think you're seeing an enrichment, because of the lack of available options on the KMT2A side and the fact that there are options on the NPM1 side, and that's tilting the -- what you would expect from the epidemiology, a little bit more equal. As you go earlier, you're going to begin, I think, to see the patient percentages tracking the epidemiology. So what I would expect in the front line and perhaps in the early relapse, you'll see a higher proportion of NPM1.

Got you. Okay. So it's not a signal here that we should be worried about the scale of the NPM1. You mentioned not refractory.

No, this is an artifact of the -- this is an artifact of the fact that you're working as a monotherapy in these 2 genetically defined populations, it's nothing more than that. And truthfully -- and this is why we and certain of our competitors, I think, are moving so aggressively to get to the front line and to the early relapse, because you really want to be treating these patients earlier and in combination. And if you can do that, you lessen the risk that they're ever going to get to the relapse refractory setting. By the time you've encountered a patient, who's failed 4 or 5 prior lines of therapy, that's a pretty sick patient. It would be great if we can intercept them much earlier and actually put them into a durable remission. That will be the goal.

Got you. Do you think you're going to see similar efficacy in the different genotypes?

I have no reason to believe we're going to see different efficacy. I think again, it's small numbers. It's hard to generalize. The KMT2A patients may be a little sicker than the NPM1. That disease seems like a more difficult disease. But in terms of do you expect a different dose? No. We have no expectation of a different dose. I think the response rates are -- it's too small an end to say whether there's a difference. We're not expecting a significant difference.

Do you think that happened -- you get a difference as you move into frontline, whether epidemiology kind of or the number of patients tracks the epidemiology?

I think -- it's hard to say. I would say this. If the tumor is MLL pathway dependent, I think you have a very high likelihood of seeing clinical benefit. If you're dealing with a patient, who has perhaps multiple -- 1 or more subclones of AML. So a patient, who -- or who's developed, for example, secondary AML, those get more complicated, because the disease is by definition more refractory. I would hope, Peter, what you'd see is -- so let's take a step back for a second. With these patients, you see a biphasic response, right? The first phase is elimination of the leukemic blasts. The second phase is restoration of the normal hematopoietic complement, the platelets, the neutrophils. So you see good reduction of leukemic blasts where you start to see a difference in later line patients is, it's more difficult for them to get neutrophils and platelets back to normal levels, because they don't have a lot of residual marrow left. They're so beaten up. They've possibly been through not only multiple lines of treatment for AML, but they may have even developed their AML due to some -- they had breast cancer and had anthracycline, for example. So I think the net result of that is, as you go earlier, you're going to see the same leukemic reduction -- leukemic count reduction, but better restoration of the normal hematopoietic cells. And so the patient should actually do better in terms of a more complete response, a more durable response as you go earlier in your lines of therapy.

Got you. What kind of CR response do you think you need or where you think you get just looking at the data across Agios Index, Astellas. Is that kind of 20-ish to 30-ish range achievable or beatable?

I think it's achievable. I think it's the right range. Ideally, look, you'd like to go as high as possible, but the guidance -- the latest guidance from the FDA is 20% to 30% CR/CRH transfusion independence as a secondary endpoint. That is their guidance for registration. That assumes a null hypothesis of probably 10% to 15%, right, that you need to separate from -- in a single arm response rate-driven trial. If you can -- the other number to look at is the composite CR, the CRC and that includes CRI, CRP, MLFS. Remember that physicians at certain centers, they'll transplant as soon as the patient is MLFS. And MLFS for those in the audience, who don't know, MLFS is morphologic leukemic-free state. So it means that the marrow doesn't have any evidence of leukemia -- but the -- it's sort of aplastic, if you will, or it's lacking in, I want to say, differentiation, but that's not the right word. You can transplant an MLFS patient and some sites will do that. The FDA wants as a registrational endpoint that you get a CR/CRH. So you're going to see a mix, I think, of CR/CRH somewhere between CRI, CRP and perhaps MLFS. And the FDA will look at it on balance, because they understand that the physicians just want to see elimination of leukemia. And then for some patients, they'll take them on to transplant.

Got you. So kind of that 20%, 30% range high end or low end?

I think what we -- high end to low end. Yes, it's with a 12 -- with 212 patient cohorts, precision is a little challenging. Look, I think we have the potential to do as good, if not better than our competition. It's still early. We're still enrolling. We're seeing a very favorable benefit risk. We just -- we have to finish the experiment.

Got you. How far behind your competition do you think you are?

Yes, it's a good question. So I mean we're certainly behind. I'll acknowledge that. The most advanced competition is currently enrolling their pivotal study. They're expecting to have it fully enrolled by the end of this year, I believe. We're probably 6 to 12 months behind, if I had to guess. And the reason I give you that range in a little bit of hesitation is, if we have significantly better efficacy, then you need to enroll fewer patients, right, to get -- to be able to exclude the null hypothesis. It's also -- we will come out of this Phase Ib experience with 2 things: a very clear understanding of the benefit risk at the recommended phase -- at what we've identified as a potential recommended Phase II dose and the ability to enroll an additional 18 patients beyond the 12. So we'll have 30 patients by the time we enter Phase II. If the Phase II cohorts are 50 to 100 patients -- sorry, yes, 50 to 100 patients, we've done -- we will have enrolled a significant number of patients along the way by the end of '22. So that's why I say -- I have to acknowledge we are behind. I don't yet have a sense of how far behind. Where I think we'll make up ground is you will see us lean in aggressively to combination studies, both in the frontline and in the early relapse. And a lot of folks are focused on the front line, but the reality is -- and we'll certainly go there. Our intent is to go there with both venetoclax and azacitidine and 7+3, but there is a significant commercial opportunity in the early relapse, because about half the patients in the front line go on. And the beauty of that setting is it's a large patient population. It's much larger than the relapsed/refractory and yet the bar is not as high, as it is in the front line. The response rates are 20% to 40% with MRDs. The MRD levels are lower and what you'd like to do is get those patients, again, to a response -- an MRD-negative response, and ideally have them avoid a transplant. So you're going to see us lean aggressively into the combinations. And not to say we've surrendered the relapsed/refractory, but you have to go where the value is. And the value is clearly weighted towards those earlier lines. And I think the properties of ziftomenib will allow us to do that. It's very, very forgiving in terms of dose, in terms of safety and tolerability, it should be a very good drug to combine with.

Got you. And the reason you have the 2 doses that try and get this kind of maximum efficacy? Again...

Yes, you're trying to get the maximum efficacy for the lowest dose. That's the short-handed goal of project optimists. And I think the Phase Ib will absolutely deliver on that.

Are you getting enrollment in both okay or...

Yes, yes. There's a randomization element, so the physicians don't even get to decide. They -- if they have a patient, they pull a ticket, and it's either the 200 or the 600-milligram cohort. They can't decide [indiscernible].

And you're not seeing any kind of CYP3A4 issues having to have a strong or a weak inhibitor?

We're not -- we're not a CYP3A4 substrate, so we don't see any variability in terms of exposure due to CYP3A4.

Got you. What's the 1 side effect that you most worry about, is it differentiation syndrome?

Yes. I think that's the one you probably have to pay the most attention to. Because -- for example, if you go into NPM1 mutant patients in combination with giltritinib as an example, I think you just -- you want to make sure you pay attention to it. And so long as you know you're looking for it and you lean into it aggressively, we believe it's manageable. But we haven't seen any other toxicity that is consistent and gives us any cause for concern. We haven't had to dose reduce or dose interrupt due to any kind of toxicities. So I think that's good.

Got you. Just noticed we've got like 1.5 minutes on the time. I'd love to talk and skip forward and go to the, I guess, the next generation tipifarnib. How we should be thinking about that data coming out at AECO?

Yes. So as you saw the title is now out, and it's a -- the beautiful preclinical story around tipifarnib plus EGFR inhibitors. And osimertinib is in the title, because it's the 800-pound gorilla in frontline non-small cell lung. But we believe this is generalizable to all FTIs and potentially all EGFR inhibitors. And what it says very simply, Peter, is, there are farnesylated proteins that appear to govern the ability of non-small cell lung cancer tumors to develop adaptive resistance to osimertinib. And they do it by virtue of entering something called tumor dormancy. That mechanism by which they go through a gateway into tumor dormancy and then exit that gateway, and develop resistance and then relapse, the entry and exit appear to be farnesylation dependent. So if you block that, you block the tumor's ability to basically hide from something like a very potent drug like osimertinib, you have the -- I don't know if you're going to get a deeper response, but what you'll see preclinically is you get a much more durable response. You don't get the relapse that's characteristic of EGFR inhibitors, generally, or I should say, you see it, but it is significantly right shifted. It's much delayed. And what this -- this is the first presentation. There will be others. This very nicely sketches out the molecular machinery, the molecular mechanisms, and it provides a very strong rationale to a combo study that will start mid-year, which is tipi plus osimertinib, as we're bringing 2806 into the clinic. If we continue to see encouraging preclinical and clinical data, we'll make a substitution and we'll plug 2806 in. 2806 is a superior farnesyl transferase inhibitor, has superior drug-like properties. It's more potent, it's more bioavailable. There's no first pass effect, and it has 20 years of composition of matter IP. So it will be a very nice combination agent as we think about improving the clinical benefit for patients and driving life cycle management.

This wasn't an overnight discussion?

This has been about 3.5 years in the making. It was far from overnight.

Okay. Clock's ticking up. So I guess we've run over some. So thank you so much.

Our pleasure. Thanks for the invitation.

Hope everything is going well with the meetings and conference.

No, it's great.