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

Good morning, everyone. My name is Federica Lussana. I'm part of the healthcare investment banking team at JPMorgan. It is my pleasure to introduce you to our next presenting company, Kura Oncology. The speaker is Troy Wilson, President and Chief Executive Officer. As a kind reminder, after this session, we have a breakout session in room Sussex. Thank you, everybody.

Good morning, and thank you for the introduction. I am Troy Wilson. I'm the President and Chief Executive Officer of Kura Oncology. And I'd like to start by thanking JPMorgan for the gracious invitation to let us attend the conference and give you an update on the progress that we've been making at the company. Just to start off, I'll just refer you to our forward-looking statement and our filings, both on our website and on the SEC's website, for additional information about Kura. So Kura is really capitalizing on the advances in the discovery and development of precision medicines for the treatment of cancer. We are advancing a pipeline of targeted drug candidates, and we have 3 candidates in the -- in our pipeline, treating both solid tumors and hematologic malignancies. We really, as you'll see, as we go through the programs, we go where the science takes us. And we're utilizing a precision medicine approach that allows us to move more rapidly through development with a fast-to-market strategy but then build on initial success to go both to earlier lines of therapy as well as additional indications. We have 3 molecules in our pipeline. Tipifarnib is our most advanced asset. It is an inhibitor of the enzyme farnesyl transferase. We have a number of studies underway. Most notably, we have a registrational study ongoing in HRAS mutant head and neck cancer. And we have a second registrational study in -- that is planned in angioimmunoblastic T-cell lymphoma and as well as you'll see a number of other studies underway to broaden the potential market opportunity and patients that we can treat. For our 2 pipeline assets, KO-947 and KO-539, those are inhibitors of the enzyme ERK and the menin-MLL interaction, respectively. Each of them is in Phase I. 947 is very near to the end of its Phase I dose-escalation trial. And as you'll see, we anticipate moving forward into a recommended Phase II dose evaluation, and menin is a bit earlier and is currently in dose escalation. With those 3 wholly owned assets, we have a number of development milestones that I'll point you to in 2020, and we're fortunate to have strong support from our investors. We have approximately $250 million in cash as of the end of September. We've built a very strong leadership team and Board. I just want to highlight the most recent addition to our leadership team. We were thrilled to recruit Kirsten Flowers as our Chief Commercial Officer, Kirsten was most recently Senior Vice President of Commercial Operations at Array BioPharma. Prior to that, she had a very successful career at Pfizer Oncology. She's driven the launch of a number of targeted therapies in oncology, and we couldn't be happier that she's joining a very strong team. I also want to acknowledge the addition of Diane Parks to our Board. Diane was previously in senior commercial roles at Kite Therapeutics, Pharmacyclics, Genentech as well as other companies, and she joins a very, very distinguished group on our Board. Both the leadership and the team give us great direction and guidance. In terms of pipeline, here shown on Slide #5. At the top, we have the programs for tipifarnib. We're going to walk through independently the programs that are targeting solid tumors with HRAS mutant -- HRAS mutations as well as those -- both hematologic malignancies and solid tumors that are driven by the CXCL12 pathway. Just to clarify on this slide, the green denotes trials where we've now had a successful Phase II proof of concept using prespecified endpoints. The blue arrows are trials that are still in progress. For 947 and 539, as I mentioned, those are still relatively early in development in Phase I. So tipifarnib, as I mentioned, is a unique asset. In fact, it's the only farnesyl transferase inhibitor currently in development for the treatment of cancer. And we -- this really was one of the reasons we started the company, and we've brought the program a tremendously long way, I think, in the past number of years. For those of you who are less familiar with farnesyl transferase. This was a very err active area of research and development about 15 to 20 years ago. At that time, there were programs in a number of major pharma companies. People thought that it could be used to target KRAS. But without exception, all of those programs, although there was some anecdotal evidence of clinical activity, they were all shuttered for lack of enough activity to drive to registration. When we started Kura in 2014, we in-licensed a compound out of J&J, actually, the entire program, and that's tipifarnib. And we've now built, we think, the preeminent leadership position on farnesyl transferase inhibitors in oncology. So we're at a point where, as you'll see, we have paths to accelerated approval with single-arm response-driven trials in relapsed/refractory setting. We're going to talk about head and neck and then angioimmunoblastic T-cell lymphoma. Leveraging off of both of those registrational studies, there are opportunities for life cycle expansion using either dysregulation in the MAP kinase pathway with HRAS or CXCL12 pathway biomarkers to move to larger opportunities and additional patient communities through a very rational label expansion strategy. And then we're quite proud of the intellectual property estate that we've built around tipifarnib. We have a number of issued and pending patents, although these -- although tipifarnib was developed a number of years ago, we've been very successful at building, we think, quite a formidable IP estate. So that takes us to the point where we think we've really well positioned from a leadership perspective to maximize the value for cancer patients of farnesyl transferase inhibition. So Slide #8 is a few key points on tipifarnib. I mentioned a number of companies had programs 10 or 15 years ago. Janssen's was the most advanced. There were more than 5,000 patients treated when Janssen was the sponsor. And interestingly, there were durable -- there were anecdotal reports of durable activities. So patients with acute leukemia, with lymphoma, with pancreatic cancer, breast cancer, bladder cancer, objective responses in the relapsed/refractory setting, but never a high enough level of activity to support a registration. And the secret was, the story was, it's a targeted therapy that at that time was not being developed in a precision way, right? This predated EGFR inhibitors. It predated ALK. So we really took what we thought was an active and very well-tolerated agent and brought it to the modern era with a modern precision medicine approach, and of course, the tools and technologies, such as next-generation sequencing. We've discovered proprietary biomarkers, HRAS, CXCL12 as well as others. And as I mentioned, those have been validated in a number of Phase II proof-of-concept studies. The compound is extremely well tolerated with 5,000 patients treated. We like to say that if there were a safety signal, we likely -- it would have been seen by now. And so we're well positioned to be able to build on that initial foundation of clinical safety and activity. I want you to keep 2 things in your mind at the same time. And that is farnesyl transferase is an unusual target. And as such, it's able to have activity in 2 very different patient populations. So one, patients who have mutations in the proto-oncogene HRAS, the second patients who have dysregulation of the CXCL12 pathway. That's unusual. And it's unusual because tipifarnib blocks the activity of the enzyme shown here in blue on the left-hand side of Slide 9. Farnesyl transferase is itself not an oncoprotein. It is a protein that other proteins require -- an enzyme, I should say, that other proteins require to be able to be attached to the interleaf of the cell membrane. HRAS is a good example. So HRAS needs to be anchored to the cell membrane in order to be part of a competent signaling complex, driving tumor agenesis. If you can disrupt that attachment, then you can drive durable responses in patients. And you block both the wild type and the mutant. The key is you want to enrich for the mutant population. We'll talk about CXCL12 in a few minutes. Here on Slide #10. This is the latest installment in an ongoing story. We have been evaluating tipifarnib in various HRAS mutant populations. The most advanced of those efforts is in head and neck squamous cell carcinoma. And what I'm showing here is data that we most recently presented at the triple meeting in October. This is a study in second and third-line patients with HRAS mutant head and neck squamous. It's worth noting that there are really very few standards of care in this setting. There are 3 approved agents, immune therapy and anti EGFR. But in totality, they provide limited clinical benefit. And those agents have response rates ranging from 13% to 16% and a median progression-free survival of 2 months in the second line. In contrast, you can see in the bold in the figure, tipifarnib is driving a 56% response rate. That's a confirmed response rate with a median progression-free survival of 6.1 months and a duration of response at this data cut of 19 months. So really pretty remarkable increase in activity over the current standard of care. On the basis of this Phase II data, we've now -- we are now conducting a registrational study, AMHN. That study started in November 2018, and it's 59 evaluable patients with recurrent or metastatic HRAS mutant head and neck cancer who are post platinum, and we anticipate full enrollment by Q1 2021, that's next year. And if that trial is successful, we believe it will form the basis of an application for accelerated approval. We are also evaluating how we can move to earlier lines of therapy and to broader opportunities, and that's transition to this next slide, #11. One of the additional studies that has been conducted as an investigator-sponsored study here in HRAS mutant urothelial carcinoma. This study is conducted by Dr. Park at Samsung Medical Center. And as you can see here in the relapsed/refractory population, Dr. Park reported a response rate of 33% and a median progression-free survival of 5.1 months. We think there's an interesting opportunity. Urothelial carcinoma is increasingly being characterized molecularly. And similar to head and neck, there are opportunities to combine with checkpoints and other agents to be able to maximize therapeutic activity. We do see clinical activity in other tumor types, and I've listed them on the right-hand side of Slide 11, so for example, lung squamous cell carcinoma as well as other squamous cell carcinomas. This population is approximately 7,500 patients in the U.S. across all lines of therapy. And as I mentioned at the outset, there is no other farnesyl transferase inhibitor in development in oncology, and there's really no other targeted therapy that is targeting the HRAS mutant population. So it's an opportunity to really take full advantage of the activity of tipifarnib that we've seen. So that concludes the update on HRAS mutant solid tumors. I'm now going to shift to the CXCL12-dependent tumors. And as I said at the outset, you need to keep these 2 in your mind. Our work here came out of an observation that when you looked at the data that Janssen and others have generated, they had responses in tumor types that you couldn't explain on the basis of HRAS mutations. For example, acute leukemia, lymphoma, HRAS mutations are really not found in those diseases. So we thought there was probably some other molecular mechanism that would explain the activity that we were seeing. And we did a -- over the past several years, we've been working in peripheral T-cell lymphoma as a proving ground, and we've identified proprietary biomarkers that characterize the CXCL12 pathway. CXCL12 is a homing signal for B and T cells. It's a chemokine. It's a chemoattractant. It binds to 2 receptors, CXCR4 and CXCR7, and you can do a Google search, right? Google is the greatest engine ever discovered for drug discovery. If you just search CXCL12 -- I'm not kidding, actually. Search CXCL12, and you will see that it is a negative prognostic for a number of solid tumors. So we ran a prospective study once we had identified the relationship between CXCL12 and tipifarnib. And what I'm showing you on Slide 13 is an update from one of the arms of that study. So we studied tipifarnib in a subtype of T-cell lymphoma called angioimmunoblastic T-cell lymphoma. And the reason we did that is AITL. AITL is about -- AITL and AITL-like lymphoma represents about 1/3 of PTCL. It's also been characterized as very rich in CXCL12. So one can enrich for clinical benefit without the need for a companion diagnostic. Essentially, the pathologist makes a determination that the patient has AITL. That patient is then eligible to go on, for example, our tipifarnib trial. And what you can see here, this -- the waterfall plot on the left-hand side, these patients have experienced a median of 3 prior lines of therapy. So this is a fourth line setting. You would typically be expecting a response rate maybe in the single digits. What we see here is an objective response rate of 50% and a median duration of response of 6.6 months, and these patients are ongoing on study. We have identified the chemokine signaling is highly redundant, highly complicated. We have identified additional biomarkers that allow us to actually drive even higher rates of response, and we've taken all of that now and gotten end of Phase II feedback from the agency and agreement on a second registration-directed study in AITL and AITL-like histologies, and you can see that on the bottom of here at Slide 13. So we intend to conduct 128 patient study in relapsed/refractory patients who experienced at least one prior systemic cytotoxic therapy. The study has 2 independent primary objectives, a response rate in AITL and a second response rate in a molecularly defined subset that will be determined retrospectively. Again, the advantage of this is there's no requirement for a companion diagnostic up-front. You can think of this analogously to what Seattle Genetics did very effectively with ALCL. ALCL is a disease that's characterized by CD30, so you don't need to have a molecular diagnostic for CD30 as your first registrational study. We intend that this study will start in the second half of this year, and if successful, would support an application for accelerated approval. One of our secret weapons, in addition to the team, is the fact that we're sitting on a 5,000 patients clinical database. Now with the observations and the insights into CXCL12, we go back through the Janssen data and a lot of things begin to make sense. For example, Janssen observed clinical activity in lymphoma in patients who have disease in their bone marrow. And what we realized is now is the reason those are the patients who respond as those patients are high in CXCL12. The CXCL12 is attracting leukemic blasts into the bone marrow. When we go back through the Phase II and Phase III data that Janssen conducted, you can see it's a couple of vignettes here on Slide 14, we're able to determine that this same paradigm of high CXCL12 allows us to enrich for responses in DLBCL and in AML as well as in CTCL and other diseases. And those represent -- and you can see the third bullet, those represent potential label expansion opportunities, very analogous to what, again, other companies have done with targeted therapies in both the hem and solid tumor space. One interesting note is that CXCL12 plays a role both in liquid tumors and in solid tumors. In solid tumors, it's a negative prognostic in pancreatic and gastric and lung. Janssen conducted a 660-patient randomized Phase III trial of gemcitabine plus tipi versus gemcitabine plus placebo. That overall trial was negative. But when we analyze that study retrospectively with through -- using the insight of CXCL12, what we see is, in the fourth bullet there from the top, an overall survival benefit of nearly 4 months in the second line -- I'm sorry, in the frontline setting, in patients who would be characterized as having high CXCL12. Now this is a retrospective analysis with all the appropriate caveats. But the preclinical data that we've conducted suggest that there's a strong additivity, a potential synergy between tipifarnib and the current standards of care. And we can also enrich for CXCL12 by counter-screening for KRAS, and that's shown in the upper panel. So we intend to conduct a Phase II proof-of-concept study. The promise would be that we could treat up to 1/3 of pancreatic patients in the second-line setting whose disease is being driven by CXCL12. And again, it's the opportunity to take this overall population and to extract the most active subset. So now with the science behind us that we can now translate that to a -- what we believe is a pretty compelling opportunity to grow the market opportunity from the initial relapsed/refractory indications of HRAS mutated head and neck and AITL to additional lines as well as going earlier in a treatment setting, 7,500 patients on the left-hand side, approximately no greater than 30,000 on the right-hand side. So really a very large opportunity and one where there is no other targeted therapy targeting either of these 2 biomarkers. So an interesting contrast to the other oncology targets out there. You may be wondering about IP given the age of the molecule. Indeed, the composition of matter patent has expired. But given that we've unlocked the clinical activity, we've been very pleased with the progress that we've made at the -- not only the U.S. patent office but patent offices around the world. We now have, I believe, more than 10 patents issued globally that cover biomarkers, methods of use, doses schedules, and they are as broad as any farnesyl transferase inhibitor. So that makes it very difficult for anyone to come in behind us and potentially compete with us. There are also opportunities. We are exploring rational combinations, both with immune therapy and targeted agents preclinically. We intend to do that clinically, and we've initiated a novel farnesyl transferase inhibitor program. And I would draw your mind to what, I think, Celgene did very effectively with the IMiDs. They started with thalidomide then Revlimid then pomalidomide. You may want to use tipifarnib for one indication and a new FTI for a second indication. Let me just give you a really quick update on our ERK and menin programs. Our ERK inhibitor, KO-947, is currently in Phase I dose escalation. We're anticipating reaching a Phase II -- recommended Phase II dose, and we plan to go forward in head and neck and esophageal squamous cell carcinomas. Preclinically, we can drive very high activity, and I've already touched on the very high unmet need in head and neck squamous. We have a number of posters and presentations on our website, if you're interested in digging into this data in more detail. But this is consistent with the theme of precision medicine. We want to identify those patient populations that are most likely to receive clinical benefit. So here on Slide 21, we are -- we hope, nearing the end of the dose-escalation portion of the trial, we expect to characterize the pharmacokinetics, the pharmacodynamics and any evidence of antitumor activity in an enriched population. And it's our goal to have that data this year and then be able to make a determination as to the next steps. KO-539 is our other program, our menin-MLL inhibitor. This is a completely different approach. Here, we are blocking a protein-protein interaction that is critical to a gene expression program that drives the proliferation of acute leukemias. Our molecule, KO-539, blocks the interaction between the protein and orange menin and the MLL protein. And we believe the eligible patient population is approximately 40% of AML patients. This program was granted Orphan Drug Designation in July, and we started dosing in September. And I have just one slide on the data, but it makes an important point. Most of the agents to treat acute myeloid leukemia are cytotoxic. And they have -- if you look in the upper right-hand side of this slide, they have the classical, they knock down the blasts, they keep the blasts down in blue as a FLT3 inhibitor, keep it down for a period of time and then you get an explosive blowout as the tumor relapses. In contrast, what 539 does is it removes a break on differentiation. So the blasts, you're not killing the blasts. You're actually allowing them to do what they are, sort of, the pent-up demand. They fully differentiate and then those cells die off. And as a consequence, we get these very robust persistent responses. There's potential for activity as a monotherapy and in combination. So we started this trial in September 2019. We are early in Phase I dose escalation. It's our intent, again, to characterize the pharmacokinetics, the pharmacodynamics, of course, the safety and tolerability. And we're hopeful that as we continue to climb up through the dose-escalation cohorts, we see evidence of antitumor activity. At present, we are screening in all comers. We do intend to enrich in both the NPM1 mutant and the MLL rearranged populations. The last slide of the presentation is just what you can look forward to in the financial highlights. So as I've mentioned, working from top to bottom, we'll have further updates on the progress that we're making in the HRAS mutant solid tumors with additional data in -- potentially in urothelial and possibly other tumors in 2020. We are looking forward to full enrollment in AMHN early next year. In the CXCL12 pathway indications, we have work undergoing in acute leukemia with a trial in CMML, initiating a registrational study in AITL and that proof-of-concept study I described in pancreatic cancer. It's an important year for the pipeline, both 947 and 539. We are working toward concluding the Phase I and reaching a recommended Phase II dose and having data to report we hope later this year. $250 million in cash. And with that, I'll conclude, and thank you for your attention. If any questions, happy to take them in the breakout. Thanks so much.

This is Troy Wilson, President, Chief Executive of Kura Oncology. I'm here with Marc Grasso, our Chief Financial Officer and Chief Business Officer in the breakout session, happy to take any questions.

Can you characterize what the potential size of the menin inhibitor market could be over time?

Sure. So the question was can we characterize the potential commercial opportunity for the menin-MLL inhibitor. The best estimates are that we could potentially address 40% of the AML population and that really is 2 distinct populations. One of them are tumors that -- although they don't have MLL fusions, they have mutations in the protein NPM1. That comprises about 25% to 30% of AML. And then the second population are tumors that have either fusions or partial tandem duplications in the MLL gene. And in that case, you don't need other mutations that the tumor, sort of, always on, and that's probably anywhere from 5% to 10% of AML with a larger fraction in the other acute leukemias. So overall, that -- the best estimate is as a monotherapy, 40%. There is some potential to treat other mutations such as DNMT3A, FLT3. But I would say the preclinical work there is a little less evolved and probably need more insights, both clinically and preclinically before we'd go there.

And then so, given the mechanism in the relatively clumpiness of the animals. Can you talk about the potential of combining it with a lot of other AML drugs?

Sure. So the question is what is the potential to combine a menin-MLL inhibitor, and in our case, KO-539 with other agents for the treatment of acute leukemia. So based on the preclinical data, the compound really is quite clean. There isn't any overlapping talks that we've seen with the, sort of, standard induction chemotherapy or the other targeted therapies. So again, we're early in the safety evaluation in Phase I, but the preclinical data suggests the compound should be pretty clean. We might anticipate -- we do anticipate differentiation syndrome in Phase I. That a -- that is part and parcel of the mechanism of action. But that's been seen before with the IDH inhibitors, and physicians are now well equipped to -- both to diagnose it and to treat it. The potential to combine the -- again, the mechanism of action of a menin-MLL inhibitor is to remove a break on differentiation and allow these tumor cells to fully differentiate. And in that regard, it should combine very nicely with FLT3 inhibitors, with IDH inhibitors as well as with chemotherapy in a frontline setting. We -- once we reach a recommended Phase II dose, if things are looking good, and we're seeing antitumor activity, we would intend to initiate a pediatric study. We'd like to get to the pediatric population as quickly as possible. That's a population of extremely high unmet need. MLL fusions are seen as early as 6 months in the population. But there -- we do anticipate there will be an opportunity, again, if -- at the recommended Phase II dose, if things look good, to combine with other targeted therapies, and ultimately, chemotherapy. And there's a lot of interest from companies that have agents in this space because none of the prior agents demonstrates these robust persistent responses that characterize a menin-MLL inhibitor. Got it. Okay. Well, if there are no further questions, I want to thank all of you and for those of you listening on the webcast. We appreciate your time. Thanks.