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

All right. Welcome, everyone, to Credit Suisse's 30th Annual Healthcare Conference. I'm Tiago Fauth. I'm a biotech analyst here at Credit Suisse, and we're joined today by Kura Oncology. Troy Wilson, CEO, on the line with us for a fireside chat. Feel free to e-mail me any questions, and I'll try to work those in as we go along.

But as usual, we can start with a brief overview as we head into the end of the year. So Troy, I don't know, can you just kind of give us some of the highlights for 2021 and the current status for Kura Oncology? And we'll work off of that.

Sure. Yes, Tiago. Thanks. Thank you to you and your colleagues at Credit Suisse for the invitation. It's always a pleasure to chat with you. As far as 2021, we have really 3 value drivers for Kura, starting with menin, then tipifarnib in head and neck and then what we're going to do with our next-gen FTI. And maybe I'll just touch on each of them quickly. So with menin, coming off of a data presentation from an early look at our Phase Ia at the end of 2020, we have been executing against a Phase Ib. This is a study to explicitly determine the recommended Phase II dose for our menin compound for treatment of acute leukemia. We are right in the midst of that experiment right now. We are -- just to remind everybody, we are enrolling 2 cohorts: one at 600 milligrams once daily, the other at 200 milligrams once daily. Both of those doses passed the safety and tolerability in the Phase Ia and showed sufficient evidence of activity that consistent with the FDA's guidance around Project Optimus, we're doing a bit of a bake-off. We're now enrolling either KMT2A-rearranged or NPM1 mutant patients in those cohorts. The patients -- there's no explicit requirement of a certain number of genetic subtypes. The patients are randomized as to dose. It's our intent that we will enroll up to 24 evaluable patients, 12 in each arm. And with those patients, we'll look at initially safety and tolerability, pharmacokinetics and exposure and then efficacy. And we'll make a determination as to are we -- is the 600-milligram dose or the 200-milligram dose the better going-forward dose that will then define the recommended Phase II dose. We made the comments last week on our earnings call that we're seeing preliminary encouraging signs of activity in both cohorts. The study is very much ongoing. But I think we're on track both to fully enroll those cohorts and to nominate a recommended Phase II dose in the first quarter of 2022. I would expect, Tiago, that we'll announce that. And we may provide some additional color, but we would then look to a future scientific or clinical meeting to provide an update on the full Phase I experience, the Phase Ia and the Phase Ib together. Once that RP2D is set, we'll roll into a monotherapy registrational study as well as move aggressively into combination in earlier lines of therapy, including potentially the frontline as well as early relapse. That's where menin is. As far as the next program, tipifarnib, just to remind everyone, we have an ongoing registrational study in head and neck squamous cell carcinoma. That study continues to enroll. I'll confess enrollment has been a bit challenging, primarily because the patients are pretty heavily pretreated post checkpoint inhibitors. And so our ability to convert patients on the study has been lower than we had expected. But we are continuing to enroll the AIM-HN study. In the meantime, again, as we announced last week, we have now activated the first couple of sites in what we call the KURRENT study, KURRENT with a K. And that study is intended to combine tipifarnib and alpelisib to treat genetic subtypes of head and neck squamous cell carcinoma that collectively comprise about 50% of patients with head and neck. We will start initially in dose range finding on the combination in patients who have either mutations or alterations -- excuse me, mutations or amplifications of PIK3CA. Once we've set a recommended Phase II dose and schedule, then we'll look at other subtypes, including HRAS overexpression. There's a lot of really compelling preclinical data. It's known that these 2 targets are mechanisms of resistance to each other. And it's obviously a much larger patient population relative to the HRAS mutant. So we think that will help us achieve our goal of developing the first and potentially second small molecule targeted therapies in head and neck. There is the potential, Tiago, for data next year, initially safety and tolerability and perhaps an early look at efficacy given that we'll be in PIK3CA [ mutations ]. The final one, which is just kind of very nascent, is our effort in our next-gen FTI. We do get the question is that intended to be a follower to tipifarnib. It's really not. It's intended to go into large solid tumor indications. Along with a group of academic collaborators, we've identified that there are farnesylation-specific mechanisms of drug resistance. If we can block them, we believe we can significantly delay the onset of adaptive resistance to existing targeted therapies. We're planning on doing, I think, a clever approach of derisking some of the biology with tipifarnib. But if we -- if that works, we will then accelerate 2806 around it. And that will then take on this new approach of combining 2806 with other targeted therapies to address drug resistance. So I think '21 has been a good year, the pandemic notwithstanding. As we look to close this year out and look at '22 and '23, it's a really nice setup. I think you see this theme of moving from demonstrated monotherapy activity to combination, looking to drive clinical benefit and get to larger patient populations. And you see that in each of the 3 pillars of our strategy.

Perfect. No, really helpful intro. A lot of possible directions here, but let's start with menin because that's still the main focus as expected, right? So 2 big themes here. The first one, how big is the opportunity? The second one, how differentiated is your asset? So nothing unexpected, right? So -- and again, on the market size opportunity, there is some debate relative to relapsed/refractory patients and the potential to move it earlier line for NPM1 patients and KMT patients. So yes, can you just kind of recap what's the current prognosis of each one of those patient segments in the relapsed/refractory setting? And perhaps what that actually looks like in frontline?

Yes. That's a great question, a very relevant question. We can start with that. So Tiago, I think we're going to focus this answer primarily on the KMT2-rearranged than the NPM1 mutant. I will just remind everybody, we have seen some evidence of activity outside of those genetic subsets. We're not actively evaluating that pending the determination of the recommended Phase II.

Recommended Phase II, yes.

I do see an opportunity there, but it's going to be delayed a bit in time. So we typically think of the eligible patient population as 35% to perhaps as much as 50% of AML. And the way you get there is, let's just take each of those populations in turn. So if you look at AML overall, 70% of patients are not cured, and they have poor survival rates. KMT2A is known to be a very poor prognostic for patient outcomes. In the relapsed/refractory setting, patients have a median survival of less than a year. 20% of KMT2A-rearranged patients survive 5 years post diagnosis. It's similar actually for the NPM1 mutant population. So although, for example, with venetoclax and azacitidine, you see a 65% or 60%, 60-something percent response rate in the frontline, importantly, only 23% of patients achieved MRD negativity. So just to remind everybody, you can have a response and still have detectable leukemia. That does -- you're far from cured. And it's now well established that MRD negativity is correlated with survival. So I would say, Tiago, the NPM1 patient population is far from a solved problem. Yes, you see high response rates. What you're looking to do and I think what a menin inhibitor is really nearly ideally suited to do is to increase the rate of MRD negativity such that the responses are deeper and more durable. If you can do that, and you can really move patients then to nearly the complete disappearance of disease, you have the potential to turn AML into what we've seen with other hematologic malignancies, where patients can live for many years with their disease in complete remission. So we continue to see -- there's an urgent need in the relapsed/refractory setting in both subtypes. There is an equally important need in the frontline and in the early relapse. But the focus there is both on increasing response rate, but more importantly, deepening and -- the responses and making them more durable.

Got it. Perfect. And again, I'm assuming the playbook is as usual to try to get consent and approval in relapsed/refractory and then just kind of design additional trials to expand that opportunity with combination in earlier line?

Yes, I think that's right, and I think the answer is yes and, right? So yes, you want to pursue a monotherapy approval, again, assuming that the level of activity gives you confidence that, that's achievable. And we think it does. But you wouldn't wait for that to then be able to move into combination. We hear from every leukemia specialist a desire to go into combination. AML is a genetically heterogeneous disease. There are often multiple drivers. There may be multiple subclones. This is really a disease where we need polypharmacy. And that take -- you've asked a second question earlier on around differentiation. I think our current sort of working hypothesis is given the profile of KO-539 and in particular, a very favorable safety and tolerability profile, we think that will allow us to maximize the efficacy and have a good safety and tolerability profile that will both allow us to keep patients on drug and to potentially combine with either standards of care or the investigational agents. That's going to be key is you don't want a lot of dose reductions. You don't want a lot of dose interruptions. We think 539 is shaping up to have a very attractive profile in that regard. It's less important as a monotherapy. That's probably a little bit more forgiving. But as we move into combination where you have patients on multiple concomitant medications, the ability to combine them and keep them all at therapeutically efficacious levels is going to be important. And 539 is shaping up, I think, to be well positioned to do just that.

Got it. No, that's perfect. And you did a -- so again, just focusing a little bit on monotherapy, and we do get questions on what's the relative benchmark and some other targeted agents are used as potential benchmarks there. I think it's hard to go there without actually contextualizing this patient population. So I think what we've discussed in the past would be -- what would be attractive or potentially approve a 20% to 30% response rate with a 6 months median duration of response. Is that -- what exactly informs that benchmark relative to other agents out there? And I'm assuming expectations for combination therapy would be to increase upon that. But curious about any thoughts on how to contextualize any data that comes out of the class relative to other targeted agents.

Yes. I think, Tiago, you've -- not surprisingly, you've set it up exactly right. And I think what you've said is -- I'll just repeat it. I think it's consistent with the guidance that we've given. So one wants to think of -- the agency is focused on CR/CRh as an approvable end point with transfusion independence as a key secondary end point. They will also look at overall clinical activity, whether that's composite CR or whether that's -- overall response rate is really not used in AML. But it's important to look at kind of both phases of clinical benefit. So the first is disappearance of leukemia. And there, I'll just give you an example. Even with something as good as venetoclax and azacitidine, the activity -- there was a -- the -- there was an abstract recently released for ASH, where the activity of ven, aza in the KMT2A relapsed/refractory setting is the response rate is about 12%. So that's -- ven, aza is a highly effective therapy. And that's what it can do in that setting. You need to do 2 things. You need to ideally differentiate the leukemic blast such that you drive to below 5% ideally to MRD-negative disease, and then you need reconstitution of the normal blood counts. Both of those need to happen for a CR or CRh is a little bit of a step down. But -- and that's where the agency -- the agency is looking really for -- demonstrate that there is a clear benefit risk relative to a null hypothesis, right? And you can see ven, aza gives you a null of about 12%, right? Maybe it's 15%. So that's why we think about it as 20% to 30%. The other piece, and this is where the agency will look at it in totality is the agency want -- we think wants to see between 20% and 30% CR/CRh, good duration of response. 6 months is probably the right benchmark. But if you have patients where you're eliminating the leukemia and the counts haven't fully come back, that's still a big step forward.

Benefit, yes.

And as always, the agency will look at the totality of the data. So that's the way we're thinking about it, Tiago. Nothing's really sort of moved us off of those numbers. There really isn't any other effective therapy in the relapsed/refractory setting in these 2 populations.

Perfect. No, I think that's absolutely fair. So perhaps just talking about the clinical trial execution, right? And you did make a purposeful decision to perhaps delay an expected data point to some -- for some investors in order to achieve a fuller picture in next year's update. That has been confused or perhaps a lower-than-expected enrollment pace or perhaps some potential delays. Is that reasonable? Because I understand you actually can enroll a lot of patients for us into the efficacious dose for a potentially regulatory package if that -- if it comes to that. But how would you characterize the clinical trial execution and the amount of data that you're generating relative to the perceived lack of catalysts at least for 2021?

Yes. And I would say I'm sympathetic to our supporters and investors wanting catalysts. This is a business where we very much -- we have a symbiotic relationship. That being said, one has to do the right thing for the program. And what we learned in the Phase Ia was that the drug is safe and well tolerated. It shows encouraging activity in the patient populations and beyond, but it didn't do 2 things. One was it didn't give us enough information to set a dose. And it also, in our view, didn't give us enough exposure to the genetic subtypes where we thought we would see activity. I think we've corrected both of those now in the Phase Ib. And what we -- we made a very deliberate decision. I think it was the right one. What you will see in the Phase Ib, we hope and expect, is a continuation of the favorable safety and tolerability. No -- we've seen no -- really no toxicities that are adverse to continued dosing. We get a lot of questions about pancreatitis. We've never seen pancreatitis again. There was one patient in the Phase Ia that was a one-off, we think, due to perhaps vancomycin treatment. In addition, we're now in the right patient population. We're in the KMT2A and the NPM1. And what we understand from The Street is The Street wants an expectation of how is this data set going to inform what you do in the registration-directed portion as well as in combination. The Phase Ib is designed to do exactly that, to answer that question. And I think taken together, it will be a very cohesive story when investors look at the 2 pieces, the 2 portions, the Phase Ia and the Phase Ib in totality. It means we have to wait a few more months. But ultimately, I think it will address those questions. And given that the questions are what's the level of efficacy, what's the safety and tolerability and what's the differentiation relative to the competition, we know we need to address those questions. And I think our team is well on the way to doing that with the ongoing enrollment in the Ib. The other thing, Tiago, I'll say, is the Ia, given it was an escalation in all-comers, you had to kind of do enrollment in fits and starts. In the Ib, now you could -- as quickly as patients can be screened and qualified, they can come on the study and potentially receive clinical benefit. That's a very, very different setup. We have half the sites now actively screening, and so we've really seen an acceleration of enrollment. We're still guiding to first quarter. I think we have to overenroll the 24 because you are going to have patients who are not evaluable for one reason or another. But I think, again, we're on a good path to be able to do just that.

Got it. And perhaps to talk a little bit more explicitly about differentiating, you alluded to a lot of those aspects already. But you do see a lot of new companies kind of coming into the menin space, right? So beyond Kura, you have Syndax and you have also J&J, Daiichi and a couple of other agents there. So the fact that there is an increased interest in the class, do you think that, that -- how validating is that? And is it possible to prospectively declare a winner in the class? And that's always the key question, and it's an impossible question to ask, but what are going to be the factors that perhaps will determine the biggest market share takers or winner, winners in this particular space? And where do you think 539 kind of check all those boxes?

Yes. I like the way that we're positioned because, first of all, the fact that there are other entrants, I think, validates the importance of the target, both as a monotherapy and in combination, particularly in combination. These are sophisticated players. They know this space well. They know what they're doing. That's number one. Number two is what will be important is, of course, efficacy, right? Can you drive a consistent level of activity across these genetic subtypes? And what is your safety and tolerability? What's your ability to combine with other agents? Folks are very focused on the relapsed/refractory setting in monotherapy. I would just point out to you that you need to be able to do 2 things simultaneously. One is to prosecute that, but the other is also to move to earlier lines of therapy. If you can intercept patients in the early relapse setting, they won't make it to the relapsed/refractory. So whoever the companies are that get there first, get into combinations first, those patients will, by definition, begin to aggregate patients and make it more difficult for companies to come behind them. We are -- and then the final piece, Tiago, is just an operational execution. So there are questions about how you do these trials, how you conduct them. Clearly, we need to work with leading sites. We need to work with cooperative groups, but we've made a decision, it's important that we drive the protocol. It's important that we own the data. It's important that we can make changes if we need to. You have to be very, very thoughtful about how you design and architect these trials to be able to adapt in real time. And I think Stephen Dale, our Chief Medical Officer, has decades of experience and has led the development of some very successful drugs, including Tagrisso. Stephen is very much in command. As he said to me many times, "Troy, I know how to go fast," right? I know -- we did it with Tagrisso. We've done it elsewhere. It's important that everything is buttoned up and then you go very, very fast. And I think that's the way, Tiago, we're thinking about it. I don't worry too much about the competitors coming behind us. This is a challenging target. These are -- it's drugging a protein-protein interaction. We're going to see a data update from one competitor, but we haven't yet seen anything from others. I think it's way too early to call a winner. I think we need to continue to move with urgency into both the monotherapy and the combination. And then we're fortunate we have the resources, we have the expertise, and we're building the clinical networks to be able to do it.

Perfect. No, that's great. I do want to be conscious of time. So sorry, I do want to talk a little bit about the farnesyl transferase inhibitor franchise that you're building, right? So first of all, you did allude to the potential expansion of tipifarnib in combination with the PI3K inhibitor. So again, you alluded to some preclinical data. What's the rationale there? And is there any way to actually try to handicap the potential clinical profile relative to tipi monotherapy? Again, different indications, different patient subsets, so it might be difficult to do that. But how should we try to think about that opportunity in the first few data points that you may be able to generate perhaps next year? Or...

Yes. So great question. And I think one of the things thematically, Tiago, that you'll see across our portfolio and I think you're going to see it with small molecule targeted therapy generally is how do you build on the lessons of precision oncology as a monotherapy and take it into combination, where you can expand the clinical benefit, you can drive more clinical and commercial value. That's what we've been talking about with menin, with combinations. That's exactly where your question is going with this combo. What we know is from clinical experience with both agents, both tipifarnib and alpelisib, they're both active as monotherapies. They -- each represents a potential mechanism of resistance to the other. And together, they are codependent oncogenes. So for those who have experienced drugging the MAP kinase pathway or the PI3 kinase pathway, sometimes there's -- it's intolerable to be able to hit a couple of different nodes at the same time. This is one where all of the preclinical data suggests PI3 kinase alpha and HRAS in squamous cell, in -- and particularly in head and neck squamous are codependent oncogenes. And you can see that in our preclinical data. You can come in with doses that are less than what you need with either drug as a monotherapy, and it's truly an example of 1 plus 1 equals 3. So that's what the preclinical data suggests. I can tell you, we have seen patients treated with tipi in HRAS mutant head and neck who go on to develop resistance from either PIK3CA mutations or amplifications. So nature is giving you a flashing neon sign saying, "Go to the next step." But we have enough confidence with tipi as a monotherapy from the RUN data and from the AIM trial that this combination makes sense. The other reason it makes sense is you want to expand the patient population. So HRAS mutant is approximately 5% of head and neck. It varies by geography, but that's a good estimate. If you look at the 4 subtypes, HRAS mutant, HRAS overexpressed, PIK3CA mutant, PIK3CA amplified, together, those comprise 50% of head and neck. So now the value proposition from us as a sponsor to a clinician is quite different. Instead of 1 in 20 patients, you say to the physician, "Perhaps I can give you 1 in 3 or 1 in 4." That does 2 things. One is this -- for targeted therapies, it's all about genetic screening. People don't worry as much about genetic screening in things like lung and AML, but it's still not standard of care in head and neck. So you need to give physicians more reasons to do genetic screening. And the other is that the -- there are really still no good options for therapy in the second line, recurrent metastatic head and neck. So if we're able to combine that combination, Tiago, together, you have a large enough patient population if you can drive clinical activity. Now you can meaningfully either go as a novel-novel combo or potentially go against standard of care, right? And that's harder to do if you've got a -- kind of a rare mutation. In terms of next year, so we anticipate dosing the first few patients here before the end of the year. We're going as quickly as we can to find them. Sites are now screening. I would expect that we'll be able initially to have a sense of safety and tolerability of the combo. We're doing a Bayesian design to combine them. And given that we are starting in patients with either PIK3CA mutations or amplifications, we may have an early read on some efficacy data late next year. That will be the first and second of those 2 slices I described to you. Ultimately, we think there are very good reasons to combine these 2 active drugs. Both of them have shown monotherapy activity in head and neck. Our hope is 1 plus 1 equals 3. And if so, that's -- just to remind everybody, head and neck is the seventh largest solid tumor. And even as of today, there is no approved small molecule targeted therapy. It's platinum, cetuximab and checkpoints. That's really where we're at. There's some novel therapies coming, but a huge amount of unmet need for patients.

Perfect. We are running out -- so yes, perhaps just a final follow-up on your next-generation FTI. So you seem to be developing a next-generation asset. It's been a mechanism that perhaps has not been fully explored previously. What are some of the drivers, some of the challenges historically that led to you guys perhaps taking advantage of an overlooked opportunity perhaps by other developers?

Yes.

And how does that -- the new asset fits into the franchise?

Yes. So let me say right at the outset. The intent for 2806, this is like Star Trek. 2806 is intended to go places where tipifarnib has not gone before. So we're not intending to cannibalize or compete with tipifarnib in head and neck or potentially in T-cell lymphoma. We had a nice abstract published on the activity of tipifarnib as a monotherapy in T-cell lymphoma. What's clear, Tiago, is just as you said, farnesyl transferase is, I think, a validated target in oncology. There are 2 or 3 opportunities where you really can pursue monotherapy approvals, where your level of clinical activity will be high enough that it supports a monotherapy registration. By and large, because farnesyl transferase is a meta target, meaning it farnesylates a number of important proteins in the cell, you should look at combinations. The reality is the field never did that. The field was whether it was Janssen, the originator of tipifarnib or others, they looked for monotherapy activity. They did a little bit of combination work, but Janssen only combined with erlotinib, and they didn't -- they did it in all solid tumors. They didn't even do it in EGFR mutant lung. What we have found through our network of collaborators is one of the principal challenges of targeted therapy is the onset of adaptive resistance. That can be gatekeeper mutations. It can be upregulation of things like MET. It can be other pathways getting activated. And cells actually undergo adaptive resistance in predictable ways. What we have found, again, over the last several years is cells undergo a metamorphosis, if you will, where they actually work to survive a strong signal transduction inhibitor by rearranging the cytoskeleton. That is a farnesylation-specific process. If you block it and you give an FTI in combination with a targeted therapy, you can dramatically extend the onset of adaptive resistance. For physicians and patients, that's a big deal because we're getting really good at driving response rates. Now the question is how do we make it such that patients have 5 years or 10 years of progression-free survival. That's the problem we're going to try to crack. We're going into large solid tumor indications. And these will become clearer next year, but not -- head and neck is not among them. We're going to do that with tipi and alpelisib. With these other solid tumor indications, that's where -- what we're driving 2806. 2806 is an improved FTI. It's really a better drug candidate as good as tipi is. It also has 20 years of composition of matter IP. So when you take it and you combine it with leading commercial targeted therapies, that's attractive to physicians, to patients and to the commercial people. And I think the final thing I'll say to you, Tiago, that folks will like is 2806 we're targeting an IND end of next year. We'd like to use tipi as a way of derisking this biology so that we can learn. We can learn, we can adapt, we can evolve, then we will slingshot 2806 around it. And 2806 will be then the leading asset targeting this -- with the goal really of delaying the onset of adaptive resistance. And our hope is that will represent a meaningful third pillar. We're not saying a lot about it other than to answer questions about such as you've asked about why a new FTI. A lot -- our focus right now is delivering on the menin Phase Ib because that's the nearest term value inflection point. But if your goal is to get to a multibillion-dollar independent pharma with escape velocity, we think we've got 3 credible pillars and sort of multiple shots on goal to create value, and we're in a very strong cash position. So we have a fair amount of flexibility in terms of looking out in the '22 and '23 to value-creating milestones.

No, that makes sense. It does sound like you have your hands full for the next couple of years at least. So no, I appreciate the time that you spent with us on the fireside chat. Hopefully, that was helpful for everyone that tuned in. But again, Troy, always a pleasure. I appreciate the time, and good luck.

Thank you, Tiago. Thank you for the questions, and look forward to speaking again soon.

All right, awesome. Thank you.