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

Thanks so much. Good afternoon, everybody. Welcome to Barclays Global Healthcare Conference. My name is Peter Lawson. I'm one of the Biotech Equity Research Analysts at Barclays. And thank you, everyone, for taking time out of their day, of course. And if you have questions, you can always ping me, institutional investors can e-mail me at [email protected] or ping me on Bloomberg. Because we got great pleasure to introduce the management team from Kura, or at least the CEO, Troy Wilson. Thank you so much for spending time with us this afternoon.

And just as an opening question, I just ask all my companies this -- about your -- the core competency of the company and the kind of -- I guess, the differentiation at the core of Kura.

Sure, Peter. So first of all, thank you and all of your colleagues at Barclays for the chance to participate in the conference and to chat with you today. We'd love to be doing this in person, and hopefully, that will come soon. With respect to the core competencies at Kura, what I think we've done very well is to take on biological risk with small molecules and to tackle targets that are more challenging or a little bit out of the mainstream and, hopefully, bring them into the mainstream. And I'd give you 3 examples. Obviously, with tipifarnib, we've essentially, single-handedly resurrected this class of farnesyl transferase inhibitors. We just received Breakthrough Therapy Designation for our lead indication in relapsed/refractory head and neck cancer. We're looking forward to starting a combination study in the same line, second line head and neck, with a combination of 2 targeted agents, tipifarnib, the farnesyl transferase inhibitor and PI3 kinase self-inhibitor, going after a disease where, Peter, there is as yet no approved small-molecule targeted therapy. I think we've been very effective at taking this biological risk, small molecules and translating it into clinical benefit for patients. The second big application, of course, is menin. We were among the first companies to recognize the opportunity of targeting the menin MLL interaction for the treatment of patients with acute leukemia. This has the potential to really, we think, move the field of acute leukemia forward. It's a very exciting new target, and I know we'll talk about it in the follow-up questions. But there, again, I think we've taken on a first-in-class target and shown that we can convert that into clinical benefit for patients. And I'll just put a plug-in and a placeholder for us to come back to in the second half of the year, and that is we said on our earnings call recently that we are developing a next-generation farnesyl transferase inhibitor and we're specifically going into biology -- innovative biology and disease indications that people haven't seen before. This is not HRAS, this is not CXCL12. We actually have some very interesting emerging data combining FTIs with other targeted therapies to do things that haven't, frankly, been able to be done before. And there, again, I think taking our expertise at discovery, development, ultimately, we think, commercialization of small molecules and tackling these innovative and difficult areas of biology. That's really our core competency.

Okay. No, that's a good teaser. But you didn't distract us from menin.

No I didn't. I knew we'd come back to that.

So just the -- I guess a lot came up on the update that we have for the end of the quarter. Just the rationale behind this kind of what was the -- your track process of expansion plus also dose escalation, just kind of walk us through that. What's going on?

Yes, happy to do that. So the KOMET-001 study is intended to run the gamut from first-in-man through to registration in the genetically defined subtypes. And we've had regular interactions with the FDA along the way. Recently, in the context of an FDA interaction, we discussed the progress that we're making in the Phase I portion of the study. And we actually realized, Peter, that because we were escalating in an all-comers population, and we have such a wide safety window, it wasn't clear to us that we were going to reach an MTD. FDA actually -- people -- there's a certain mythology to the FDA. FDA, in our experience, are very science driven, very constructive. They want to help companies move products to patients as quickly as possible. Through this discussion, FDA agreed. And, in fact, their specific language, Peter, was given this is a targeted therapy, MTD may not be the right endpoint. And in fact, if you pursue an MTD, you run the risk of overshooting the optimum Phase II dose. And there was some confusion, candidly, after the earnings call. And what FDA is really looking for is what is the optimum Phase II dose? And the way that they define optimum Phase II dose is the minimum dose that drives maximum pharmacologic effect. So if you don't have maximum pharmacologic effect, obviously, you need to go to a higher dose. But the rationale there is don't give the patients more drug than you need to, drive the maximum pharmacologic effect and then stop. And the reason for that, ultimately, we think, is particularly in AML, patients are on polypharmacy. Imagine venetoclax, azacitidine. Patients will be on venetoclax, azacitidine, KO-539, Azoles, and then whatever else they're being treated for, antidepressants, H plus antagonists, blood pressure medications, you name it. So the FDA is really trying to encourage sponsors to come in with the lowest dose that drives full pharmacologic effect. And that's best done, Peter, not in a Phase I escalation in all-comers because, just frankly, there's not enough data points to say one cohort is better than another. You need to do it in the context of a Phase Ib expansion, which is what we're doing. So we are planning to enroll 2 cohorts, minimum 12 patients, up to 20 each. The intent is to enrich them in the genetically selected populations of KMT2-rearranged AML and NPM1-mutant AML and then ask the question, safety and tolerability, PK, PD, efficacy, do you see a distinction between those 2 consider it a lower dose and a higher dose? If the higher dose is clearly better, great, you go with the higher dose. If they're equivalent, FDA would advise go with the lower dose because, again, let's put less pill burden on the patients, less drug on the patients. Is this precedented? Absolutely. Gilteritinib, the FLT3 inhibitor from Astellas went through exactly the same process. They began dosing at approximately 20-milligrams, dosed up to 450. Ultimately picked an optimum Phase II dose of 140 milligrams, which they took into their registrational studies, but they evaluated several doses in that sort of mid- range looking to, again, what's the minimum dose in that case of gilteritinib that's driving maximum pharmacologic effect? This, I think, Peter, you'll see is an increasing trend of these targeted therapies that are extremely effective. But really, we've seen no toxicity really of note to date that we're even concerned about. So you want to make sure you get the optimum Phase II dose, and that's the plan going forward.

Yes. Do you think sometimes it's just a case of it's just captured in recommended Phase II dose, and we don't hear the -- about the moving parts within the development?

I think -- so I think there's a couple of aspects. Yes, that's true. So oftentimes, and we've seen this with other companies in this space, they might hit a toxicity in the Phase I that helps define the recommended Phase II dose. That is not this case, right? We're evaluating 800 milligrams. If we clear that cohort, I think there's a rationale to go to 1,000 milligrams. The other challenge we have, Peter, is we are working on exploratory biomarkers, MEIS1, most notably. But we don't have confidence to call a dose on the basis of MEIS1. We really we want to call the dose on the basis of efficacy because that's ultimately going to be the endpoint for the registrational trial. And in that way, Peter, it's a little different than, for example, the KRAS inhibitors, the FLT3 inhibitor where you had pharmacodynamic markers that were good predictors of efficacy. I think that story is still being written for menin inhibitors. MEIS1 is a candidate. But given, again, you don't have enough efficacy data to say is there a clear correlation between MEIS1 and efficacy, you can't really use MEIS1 as a biomarker to make a dose -- to make a recommended Phase II dose solution. So that I think -- those are the 2 biggest differences.

Okay. Do you think this kind of ultimately generates a more robust data set because you an kind of...

Yes, for sure. So we previously, if you dial the clock back, we are dosing to MTD or to an RP2D in an all-comers population. It's not a secret. We're getting some enrichment, but limited enrichment. We're perhaps getting one patient who is the ideal patient per cohort. Makes it very difficult to distinguish one cohort from another, particularly when the last update that you saw and the investors saw, it was at 200 milligrams, we had 2 responses in the NPM1-mutant cohort, one of which is an MRD-negative CR. That's the gold standard for response. So even if you see a CR at a higher dose, you have to ask the question, is that incrementally better? The way you answer that question is you say, okay, if I look across a number of patients, do I see a higher number of responses? Do I see a deeper pattern of responses. It's hard to do it on n=1 or n=2 patient numbers with these various dose cohorts. To your specific question, yes, when we're done with this, so this Phase Ib expansion cohort, again, 2 cohorts. We've aligned the endpoints of those cohorts with the endpoints of the registrational portion of the study. That is CR/CRh and transfusion independence. We'll come out of that with at least 12, if not 20, patients' worth of data that will say which of these doses is better. The good news is we think either dose is effective, right? That's not the question. The question will be which of those doses is better as the standard by which all the other trials, all the combination studies, pediatric, other indications, they'll all key-off of that RP2D determination. So you want to have the most robust data set you can. We're going to do that, and we're not going to lose much time. We think perhaps 2 to 3 months in the time required to amend the protocol. But the overall scope of development, that's -- we don't think much of an impact at all.

The wide therapeutic index, so it's kind of helped you but then kind of maybe delayed you. Do you think that could also lead to some kind of troublesome data where you don't see a dose response curve?

No, we don't think so. I think -- so let's tease those apart. As far as we know preclinically, the -- there are 2 principal competitors, right? There's us and there's Syndax. If you look preclinically, those compounds look very similar on an efficacy basis. They both drive potent activity in preclinical models. They've seen responses, we've seen responses. It's hard to say whether the compounds are differentiated on an efficacy basis. When you look at the safety and tolerability of 539, you have predictable PK, right? It's not affected by Azoles, and you don't have any really toxicity of note. That's going to be important in the relapsed/refractory setting as a monotherapy. It becomes even more important when you start to combine with other pharmacologically active agents, such as venetoclax or chemotherapy. It does make it challenging to set the RP2D. But I don't think -- it's not unexpected. It's -- I would actually rather have of a very active compound with a very wide therapeutic window and take a little bit more time to set the dose correctly than to have to have a toxicity that you have to sort of work around. So I think we're in a strong position. What it means is that investors have to wait until the second half of the year to get the data update on the Phase I experience and the rationale behind the recommended Phase II dose. A bit of a delay on the front end, negligible impact to the program overall.

Would that update be at a medical conference or be company sponsored? Or...

Yes. As we've said previously, I mean, our strong preference is to release clinical data in the context of a scientific or clinical meeting. That is both to help inform Wall Street as to the progress of the program, it's also helpful to bring along the clinical community. As hot as the menin inhibitor field is, there is a fair amount of education that one needs to do to help the -- bring the clinical community along with the potential for these compounds. And in our experience, and I think this is in line with most of the industry, that's best done, if you can, at a scientific or clinical meeting. I do think, Peter, in the second half of this year, we will have determined the optimum Phase-II dose and be able to provide more color on what were the factors that went in there. And again, I think it's going to come down to the lower dose or the higher dose. We have a high degree of confidence we're going to come out of this with -- it's not a question of are we going to get an RP2D, it's going to be, is it one or the other? That's, I think, going to be the open question.

Got you. And do you think it's kind of end of year when maybe we can all travel? Or do you think it's kind of too good?

So it's a little early to say. We are guiding to initiation of these Phase-Ib expansion cohorts in June. We're working around the clock to lay all of the bricks that have to be laid to continue walking down that path. One needs the FDA to sign off. The FDA did require us to formally amend the study, so one has to do that. And then one has to implement that amendment at the clinical sites, which requires, of course, IRB review and all of the operational aspects that have to happen. We have a small number of sites at the moment. We have additional sites waiting in the wings that we will bring on board with this amendment to help drive enrollment. I think we'll start in June, Peter. And we're -- we don't -- we're not yet giving guidance as to how long it's going to take to enroll these expansion cohorts. But you can imagine that's the question on everybody's mind. What can we do to drive enrollment to get that data set that will define the optimum Phase II dose as quickly as we can. And I think we're well prepared to do it.

Got you. The -- would we see kind of PK/PD -- or more of the PK/PD kind of profiles? Or any detail -- more details around CYP3A4 in kind of a preclinical setting or subclinical setting?

Yes. I don't think you're going to see it in a preclinical setting. So typically, you -- one talks about PK and metabolism in the context of clinical data, right, to help inform why did you choose one dose versus another, why did you choose a dosing schedule, as examples. What I can tell you is the PK and the metabolism really were not discussed in this most recent FDA interaction. The FDA is keying off of safety and tolerability and efficacy. And this discussion in this Phase Ib expansion is 100% dedicated toward which of these 2 doses is better able to drive efficacy. We will bring along -- we're still working on understanding the metabolic fate of KO-539, the effects on the pharmacokinetics and exposure. But the reason we and the agency are focused on safety and tolerability and efficacy is those integrate all available information, right? They integrate PK, they integrate metabolism. We're not seeing any signals yet, and I knock on wood. We're still evaluating the 800-milligram cohort, but we haven't seen any toxicity that we would even note as recurring, something that might potentially build in and become an MTD. That tells you that with the metabolism and the PK, with everything going on, yes, we have to characterize it so that we're doing good science. But I don't think it's ultimately going to make a determination of one dose versus the other. It's going to be in the genetically selected populations, are you seeing -- are you at the lower dose already at the plateau of efficacy? Or are you actually able to drive an incrementally better efficacy at the higher dose? That's the question we're seeking to answer. As you can imagine, Peter, that determination then sets the starting dose for the first-line combinations and everything else we do, so it's critical that we get that answer right. The good news is, it appears we have a wide window, both as far as safety and tolerability and efficacy, to be able to select one of these doses. We just have to do our best to pick the best one.

Got you. And so the -- if there's any more kind of PK/PD profile situated for data, that would probably -- that wouldn't be presented earlier than the clinical data?

We don't think so because it's -- then it's just hanging out there in isolation. And I think the question that -- the natural follow-up question would be, okay, what does that mean in terms of what you're seeing in the clinic and how you're setting the dosing schedule? And so you need to couple those 2 together. We will, I think, likely provide an update on -- what I can tell you, Peter, is we're seeing increases in exposure with increasing dose. I don't want to go so far as to call them dose linear or dose proportional, we're still doing the work, right, at multiple successive time points. Cycle 1, day 1, and then on as the patients stay on study. But we are seeing increased exposure. If we weren't, that would help define the RP2D. But we continue to be able to add more drug as we increase dose. The metabolism is an interesting question. The hypothesis is one potential mechanism is -- were somehow inhibiting CYP3A4, I don't know if that's where we're going to end up because, again, we don't see any influence of Azoles on the exposure of 539. You would think if that was the major metabolic enzyme, you would see what others have seen with other drugs. That's not what we're seeing. There's clearly some metabolic process that the metabolites of 539 are inhibiting, and that's leading to time-dependent accumulation, but we're still sorting it out in vitro and in vivo, and I think we'll have more to say about it. It doesn't appear to really affect the dosing, the schedule, the tolerability. It's even too early to say whether it would affect other drugs. We've not seen anything in the clinic that has suggested we can't combine with pretty much everything else out there that's being used in acute leukemia.

How is enrollment going for, say, NPM1 versus the rearranged patients? How should we be thinking about that trend at the end?

Yes, so our experience has been that -- again, it's a small data set. And I wish I could tell you that every patient that was identified in prescreening and screening ultimately makes it on the study. They don't. They'll come off for unrelated -- they'll come out of screening for a variety of reasons. It does appear that the frequency of NPM1 is consistent with the fact that it's a larger population. And in that regard, Peter, we have no basis to push people off of the assumption that 30% of the population is NPM1, 5% to 10% is KMT2A rearranged. Now the clinician do their best to try to direct patients to those therapies they believe will have the greatest benefit, but it's -- you can have the patient that looks ideal genetically and that patient develops an opportunistic fungal infection the week before they're due to be dosed, and you say, okay, well, that's the realities of this population, right? Most of these patients succumb to opportunistic infection. So I think we're going to see more NPM1 than we see KMT2A. It's early to say kind of what's the split that, but I would suspect we'll see more NPM1.

Got you. So you're see your next-generation kind of tipifarnib, what's -- so the combination strategy, do you think it could be a monotherapy? And where do you think it could potentially go?

So I teased you and now you're asking that as a question. No, no, it's fair. So it's a next-generation farnesyl transferase inhibitor. As good a drug as tipi is, we actually think it could be better, right? You'd like ideally give it once a day, you'd make it more potent, you'd make it more consistent, less intra-patient variability. There's a number of ways that we've learned that we can improve on this class. We do -- we -- Peter, we are interested in combinations with other targeted therapies going after large indications. And what I can tell you is through a network of collaborations, we've identified some very interesting completely unexpected biology that is, of course, uniquely farnesyl-related proteins that are very relevant when you're looking at combinations with other targeted therapies. What's interesting is -- and this happened because we've basically brought this class back over the last 5 years. And now you have a number of academic labs working very hard on the biology and the combos. I don't want to pull the curtain back fully, but it's not going to be going into HRAS-mutant indications. It's not going to be going into CXCL12. This is an entirely new area and is really -- is building on, again, as we talked about with our capabilities at the beginning, it's building on some innovative biology that has grown up. And I think we're uniquely positioned to take advantage of it. It'll much -- we want to keep the focus on menin, we want to keep the focus on tipi. But in terms of building value for patients and shareholders, that will become an increasingly important third leg of the stool.

Okay. So -- and it's -- you wouldn't be thinking about combining it with, say, KRAS inhibitor or it touches upon that build it seems?

So this is where I'm going to have to be -- let us roll it out in the right way. You are -- I'll tell you this, you're getting warmer. I'll tell you that much. So you're thinking about it in the right way. The question is are there small molecule targeted therapies where you could make a meaningful difference by combining with tipi -- or with an FTI, excuse me, I misspoke. Stay tuned. That is probably as much as I can say. We're still tying down the various pieces, still figuring out the translation from the preclinical to the clinical environment. But it'll be exciting, and it'll be differentiated from everything else you've seen out there, consistent with, I think, what -- we've done it twice before, I'm optimistic we can do it again.

Got you. You've gained the award. You've made me overrun. I've been pretty strict with time. So thank you so much, Troy. Always a pleasure talking to you, and thanks for joining us on the Barclays Global Health Care Conference.

Thank you, Peter. Great to talk to you.

Thank you so much. I'll hand it back over to the operator.