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

Okay. Well. Welcome, everybody. I'm Marty Auster. I'm the lead SMID Cap Biotech Analyst at Crédit Suisse. Thanks for joining us again at the 29th Annual Credit Suisse Healthcare Conference. Up next, we've got Kura oncology. I've got Troy Wilson, President and CEO of the company, to make a presentation on Kura Oncology. We'll be conducting maybe a brief Q&A at the end, time allowing. If anybody in the audience has any questions, please shoot me an e-mail, and I'll work those into the -- to that brief Q&A session at the end of the presentation. Troy, let me hand it over to you. Thanks for joining us today.

Thank you, Marty, and thanks to you and Crédit Suisse for the invitation to participate in your conference. Good morning, everyone. Today, I'll be giving an overview of Kura Oncology and the progress that we're making in advancing our 2 wholly owned assets for the treatment of cancer. And just to be clear, here on the next slide, I will be making forward-looking statements. I would refer you to either the SEC's website or to our website for more information about Kura Oncology and the risks and uncertainties of an investment in the company. As I mentioned in the intro, Kura is a targeted oncology or precision medicine company. We are advancing 2 wholly owned assets. The first is tipifarnib, which is our farnesyl transferase inhibitor, with a focus in head and neck cancer. The second program is KO-539, our menin-MLL inhibitor for the treatment of patients with certain genetic subtypes of acute leukemia. Both of the 2 programs are using biomarkers and a precision medicine guided approach, they have the potential for an accelerated development path and a fast-to-market strategy. And we'll be going through each of these 2 programs in the various sub bullets in the slides to come. We've been very fortunate to have the strong support of our investors in addition to 2 potentially first-in-class programs. We also are in a very strong position operationally and from a cash perspective, we had $325.4 million in cash as of the end of September, and we're projecting that, that will take us with runway into 2023. We're also fortunate at Kura to have a very strong team. Just recently, we celebrated the addition of Dr. Stephen Dale, who joined us a couple of months ago as our Chief Medical Officer. Stephen was in senior leadership roles at both Kyowa Kirin as well as AstraZeneca, while at AstraZeneca, Stephen oversaw the development of Tagrisso, the Astrazeneca's EGFR-T790M mutant inhibitor program. He was also intimately involved in the iPASS studies, which really ushered in a paradigm shift in the way in which targeted therapies were viewed for the treatment of cancer. And Stephen joins others on the leadership team, who all have very significant expertise. We're also fortunate to have a very strong board. Faheem Hasnain is our lead independent director. And you can see the other Board members who bring a very diverse set of perspectives and experience to the company. As I mentioned, the 2 programs that we're going to focus on today really represent the two central development pillars for Kura Oncology. On the left-hand side here of Slide 3, we have tipifarnib. Tipifarnib is targeting at present tumors, head and neck tumors, that have mutations in the proto-oncogene HRAS. The program has been awarded Fast Track Designation by FDA. We think there's an opportunity to address a very significant unmet need in head and neck squamous cell carcinoma patients with HRAS mutations. And as we'll talk about in the middle of the presentation, we're also quite excited to explore the potential to take tipifarnib in combination with another targeted therapy into a much broader subset of head and neck patients. On the right-hand side of Slide 5 here, you can see KO-539. This is a very different program. It targets an epigenetic regulation of leukemic blast. It's targeting the menin-MLL protein-protein interaction. This program has received Orphan Drug Designation from the agency. It has the potential to treat 35% or more of patients with acute myeloid leukemia who fall into certain genetic subtypes. And I'm sure we'll talk about that in the Q&A. We are very pleased to be presenting the first preliminary clinical data for KO-539 at the upcoming American Society of Hematology Meeting in the first week of December, and we'll talk about that a little later in the presentation. Before we get there though, let me review the progress that we continue to make with tipifarnib in HRAS mutant solid tumors. So this is a molecule that is a farnesyl transferase inhibitor. This is a -- as far as we can tell a unique mechanism of action in oncology drug discovery and development. And we'll talk a lipid about the biology in the next slide. At this year's ASCO, ASCO 2020, we showed a Phase II data from our ongoing study in relapsed and refractory patients with HRAS mutant HNSCC. We were very pleased to report a 50% confirmed objective response rate. The patients demonstrated approximately 6 months of progression-free survival, and as you'll see, 15 months overall survival. And this is pretty remarkable in a setting where the overall survival with the existing agents is in the range of 6 to 8 months. Tipifarnib demonstrates a favorable safety and tolerability profile both as a monotherapy, and we think that will help support its use with other targeted therapies. And we'll talk about what we're going to do with PI3 kinase, a PI3 kinase self-inhibitor. As I mentioned, we have Fast Track Designation. If the current registration-directed trial is successful, we believe there's the potential to submit for accelerated approval for tipifarnib, and there is a potential to go far beyond what we're doing with head and neck squamous cell carcinoma. But as you'll see, the unmet need and the size of the patient population are significant, so that is our current focus. As far as intellectual property, we have both issued and pending patent applications that we think provide a good coverage to 2036 and potentially beyond in major markets. So here on Slide 8, we have the -- some of the biology of tipifarnib. Tipifarnib is unusual, as I mentioned. It's a unique mechanism of action in oncology as far as we can tell. And what we're doing is, we're not blocking the enzymatic activity of RAS. Rather, we are blocking the ability of, in this case, HRAS to be where it needs to be within the cell. Typically, the RAS oncogenes -- or the RAS oncoproteins, excuse me, are tethered to the inside of the cell membrane by various lipid groups. For installation is one such lipid modification. And you can see here that lipid is added to HRAS. It's covalently attached via the farnesyl transferase. What tipifarnib does as a farnesyl transferase inhibitor is it blocks the activity of that enzyme. And it prevents HRAS, both wild-type HRAS and the mutant form, from associating with the cell membrane. What that does is shown on the next slide. So the activity of a farnesyl transferase inhibitor, this is all preclinical data now on Slide 9, drives not only antitumor activity in HRAS mutant models, as you can see in the upper right-hand corner of Slide 9. But it also drives a number of the hallmarks of antitumor activity. And you can see them there, reductions in MAP kinase pathway signaling inductions of apoptosis, cell cycle arrest angiogenesis; and interestingly, differentiation of malignant squamous cells into differentiated cells. This is preclinical data, as I mentioned. This biology manifests itself in the clinic as shown on Slide 10. So Slide 10 is a swim lane plot from the ongoing Run-HN Phase II study in relapsed/refractory in HRAS mutant head and neck patients. This study is now close to enrollment. We're continuing to monitor the progress of the patients. And this is a slide from a presentation that was given at this year's ASCO. And just to guide your eye, the patients with partial responses are shown in dark blue. Patients with stable disease are shown in light blue. Those patients who are not efficacy evaluable are in light gray. And what you can see is there's roughly a 50-50 mix of patients with partial responses and patients with stable disease, and that's significant for 2 reasons. The confirmed objective response rate is approximately 50%. That's significantly higher than what we observed with the currently approved agents in second-line therapy, which have objective response rates ranging from 13% to 16%. Importantly, if you look at the patients in totality, you see a very high rate of clinical benefit, which includes both patients with partial responses and those with stable disease. So in this subset of HRAS mutant patients, we think there's really the potential to drive a meaningful clinical benefit. So on Slide #11, now moving from objective response rate to progression-free survival. This slide, Slide 11, shows the PFS curves for patients on study with tipifarnib in the blue line and patients -- each of the patients on his or her last prior therapy. And the interesting thing about this is -- this -- each of these patients is his or her own control. So typically, what you see as you move to subsequent lines of therapy in oncology is a reduction in the progression-free survival roughly by half with each line of therapy. In contrast, what you're seeing here is almost a doubling of the progression-free survival of the patients on tipifarnib relative to their last prior therapy. And again, we think that speaks to the potential to drive meaningful clinical benefit. These patients are clearly doing better on tipifarnib than they did on their last prior therapy. That we can now extend that to the next slide, and this is -- this was really the punchline of the ASCO presentation in June. And this is now the translation of objective response rate to overall survival. And we were really pleased to see that it's a small number of patients. It's only 18 patients. But we're seeing a median overall survival in this population of 15.4 months. And I'll just again remind you that the 3 approved agents in the second line have objective survival ranging from 5 to 8 months. So 4 patients with HRAS mutations and high variant allele frequency, this data collectively really suggests that there's the potential to drive clinical benefit. We're now extending beyond that Phase II study that was RUN-HN. That study is closed to further enrollment. We are enrolling in AIM-HN, which is summarized here on Slide 13. So in the top half of the slide, you can see that we're enrolling patients with recurrent or metastatic disease. We're open in approximately 90 sites. Earlier this year, we made an amendment to the study to enroll all HRAS mutant patients. And we did that really out of a request on behalf of physicians who do not have effective options for therapy in the second line. This trial has a no hypothesis of 15% in the high variant allele frequency population. What that means is that if we're able to see a response rate of 25% or higher, the trial should be positive. And we're hopeful it should support an application for accelerated approval. In parallel to AIM-HN, we're running SEQ-HN. SEQ-HN is a prospective observational cohort. What this is intended to do is really characterize the effect of HRAS mutations on patients in the front line. We do have solid numbers for the overall population. We're continuing to gather data on how patients do who have HRAS mutations. And this is an important element of this. It's our hope, this is really the front end of AIM-HN, patients come in for screening. And those who are -- who have HRAS mutations are eligible to enroll in AIM-HN. Those who do not are eligible to be monitored in SEQ-HN. And if this study is successful, it's our hope that it will support labeling discussions as well as post-approval commitments and other commercial considerations. In terms of the market opportunity, head and neck is the seventh largest -- head and neck squamous cell carcinoma, I should say, is the seventh largest cancer worldwide. There are approximately 885,000 cases per year. And roughly half of those patients die each year from head and neck squamous. The outcome for patients is pretty dismal. You can see the numbers. I've referred to them several times. You can see them in the lower right-hand corner here of Slide 15. With an overall survival in the second line of 5 to 8 months, a progression-free survival of 2 to 3 months, and as I've mentioned, an overall response rate of 13% to 16%. When you compare that to the data that I showed you on Slides 10, 11 and 12 of this presentation, I think you'll agree that tipifarnib compares very favorably to these approved second line agents. So that's the effort underway with the HRAS mutant population. Over the past several years, our translational research group, led by Francis Burrows has been working to understand the potential to expand the utility of tipifarnib to other populations. And that's shown here on Slide 16. So when one is thinking about oncoproteins, you can really think about them in several different states. We can think about them as mutant. We can think about them as overexpressed, namely, there's more wild-type protein. Or -- which is at the message level or the protein level. Or we can think about them as amplified, where you have multiple copies of the gene. In each of those cases, you have proteins, in this case, HRAS, that are driving the MAP kinase pathway and driving all of the associated hallmarks of cancer. And that can lead to both, as you'll see, resistance to other therapies and to a promotion of disease. What we've discovered is that there are several tumor types. And you can see them here in the graph on Slide 16, including head and neck squamous, lung squamous and urothelial carcinoma where we see the expression of HRAS. And this is wild-type HRAS that is a multiple, 5x to 10x what you would observe in other tumor types. And for here, we've shown controls in colorectal, pancreatic and lung adenocarcinoma. The significance of that overexpression is shown on Slide 17. So these are patient-derived xenograft models, preclinical models, where we've combined tipifarnib with 4 other therapeutic agents. And you can see the color coding. So the red curves are tipifarnib as a monotherapy. The green curves are each of the 4 drugs as a monotherapy. And then the blue curves are combinations of those agents together. And what we observed is that it really doesn't matter what the therapeutic mechanism is. HRAS overexpression appears to drive resistance to both tipifarnib and these other targeted therapies. But when you remove the HRAS by blocking for an installation, you're able to drive a consistent and improved pattern of clinical activity -- or sorry, a preclinical activity, a antitumor activity, as shown here on Slide 17. If you now sort of telescope in and you focus on PI3 kinase alpha, in particular you can see that the same phenomenon continues. So in this Slide 18, we have 3 panels here that include HRAS mutant on the left-hand side, PIK3CA, this is the PI3 kinase alpha mutant in the center, and then the wild type. And what we see is a consistent level of either additivity or in many cases, synergy, when we combine tipifarnib with an inhibitor of PI3 kinase alpha. This is significant because PI3 kinase alpha mutant mutations and amplifications are of common in head and neck squamous cell carcinoma. So you have 2 codependent oncoproteins, HRAS and PI3 kinase. And by blocking both of them, we're able to drive much better activity in these preclinical models than we can drive with either drug alone. Let me just also highlight if you read the fine print at the bottom, you'll see that these studies were conducted at dose levels lower than each compound used as a monotherapy. And the significance of that is we're assuming that we will not be able to combine at a full dose. And so the hope is that as we are dose escalating in the clinic, we'll see the potential to unveil the clinical activity. I've covered a number of these points on 19 before. Let me just go to the center of the slide and highlight for you part of why we're so excited about this. So if we think about the HRAS mutation and overexpression population as well as the PI3 kinase, PIK3Ca is the gene. Those 2 populations together, they comprise approximately half of all of head and neck cancer. And that's significant, given there are 885,000 cases of head and neck squamous every year globally. So if we're able to drive meaningful antitumor activity with the combination in one or more of these subsets, we think we have the potential to build on the very strong data that we've generated for tipifarnib in the relapsed/refractory setting and really expand the patient population to be able to bring clinical benefit to many, many more patients. This study is scheduled to start around the middle of next year. We're just putting all of the various pieces together to support the clinical trial. One final slide on the intellectual property before we transition to the menin program. I just want to highlight that I think we're in a very strong position as far as IP is concerned. We have, as I mentioned, a number of issued patents around the world and many, many more patent applications that provide exclusivity up to 2036. We continue to file applications as we continue to do more work. We are also working on a novel farnesyl transferase inhibitor, really with the hope -- we think there's a meaningful opportunity with tipifarnib and other things that we could do with farnesyl transferase inhibitors. So we have a novel FTI program in early discovery that we may say more about in the years ahead. With that, now let me transition from the work that we did on tipifarnib in head and neck squamous cell carcinoma to the work that we're doing in -- with KO-539 in acute leukemias. This is very different biology than what we were talking about. Here, we're targeting a protein-protein interaction, and you can see it there. It is an inhibitor of menin KMT2A or MLL. KMT2A is the K for lysine, methyl transferase is 2A. That's where the name comes from, and that's the new nomenclature for the gene. This is a novel mechanism of action. What it does is it removes a block on differentiation in leukemic blast. It allows those leukemic blasts that are immature. I think of them as angry adolescents. It allows them to mature to fully differentiated cells. And you see clearance of the leukemic burden in preclinical models. And very excitingly, one of our competitors has shown, at least in the MLL patients, we also see that effect in patients. As I mentioned, we're quite excited to share with all of you the Phase I/IIA data from -- a preliminary clinical data from our Phase I/II dose escalation study. That data will be presented in an oral presentation at ASH, and I have the details here coming up in one of the later slides. Our development strategy is at present, once we reach a recommended Phase II dose, we intend to expand into 2 genetically defined populations. One of them is the KMT2A or MLL-rearranged population. This comprises about 5% to 10% of AML. The other is the NPM1 mutant population. This comprises approximately 30% of AML. As we'll talk about, we have seen evidence of clinical activity in at least one patient who is neither KMT2A rearranged nor NPM1 mutant. We think there may be an opportunity to drive clinical activity in that population as well. There's more work to be done, and I'll speak to that in a couple of slides. And similar to tipifarnib, we're in a very strong patent position, IP position. We have composition of matter coverage out to 2036 and potentially beyond. The mechanism of action is shown here on Slide 23. We have the KMT2A population on the left, the NPM1 mutant population on the right. In both cases, what one is doing is with these inhibitors, is dissociating menin from MLL from chromatin. When that happens, you inactivate MLL, which is a histone methyl transferase. And you down regulate the expression of 2 target genes, [COXA9 and MIS1 ] that are critical to the maintenance of leukemic blast. [ COXA9 and MIS1 ] are central actors. They control a gene expression program that determines whether these leukemic blasts maintain a stem-like phenotype or a differentiated phenotype. And so by shutting down expression of those 2 genes, you're really able to switch the leukemic blast from one state to the other. They differentiate, and ultimately, they undergo apoptosis or they're cleared by the immune system or some other mechanism. And the consequence of that is you can drive very robust and persistent responses in preclinical models. And that's what shown here on Slide 24. So in the upper left-hand corner of the slide, you can see 3 curves, black, blue and red. And this is in a very aggressive model. Francis Borough is our Head of preclinical translational research, calls this the cockroach model because nothing can kill it. And you could see it has 4 mutations in the genes NPM1, DNMT3A, IDH2 and FLT3. With vehicle, you see a very rapid deterioration. All of the animals are -- have died within a month. With quizartinib, the FLT3 inhibitor, you see really a doubling of survival, which is significant and very exciting. But then look at the red curve. Upon treatment with KO-539, every animal is a long-term survivor even after you stop dosing. And that's significant. In our hands in these preclinical models, you can keep these animals as live -- alive as long as you care to pay the husbandry fees at the vivarium. So you do see these very robust persistent clearance of disease that then leads to long-term survival. You can see another graph on the upper right-hand corner where we're looking at the CD45 positive marker. This is a marker of leukemic blast. You can see the disappearance with the red curve and really the blowout after relapse with the FLT3 inhibitor. And the other encouraging thing is that 539 is very well tolerated in both the preclinical models, and as we'll talk about in the clinical in patients. And has a very favorable tolerability profile, which we think will allow us to drive significant antitumor activity. KO-539 is being evaluated in an ongoing Phase I/IIA study called the KOMET trial 001. This is an accelerated dose titration. It's using a what's called an [ MPTI2 design. ] And it basically allows us to move up through the early dose escalation cohorts using single patient escalations. We've now moved into, as you can see, as you may have seen from the publication of our abstract, to a more traditional 3 plus 3 design. And that's really to characterize the safety and tolerability, the pharmacokinetics and exposure as well as the pharmacodynamics and antileukemic activity. Once we reach a recommended Phase II dose, we already have alignment from FDA to move into at least 2 expansion cohorts. And you can see them here, one in the NPM1 mutant population, the other in the KMT2A-rearranged population. And there we'll look to continue to assess safety and tolerability. And of course, we're looking for antitumor activity. If we see good antitumor activity, as we expect, our intent is that those expansion cohorts have the potential to become registration-enabling. Some of the updates, we had a ASH abstract that was published last week, somewhat unexpectedly as many of you know. And these are just the headlines from the ASH abstract. So as of the data cutoff of August 10, 2020, there were 6 patients enrolled with relapsed/refractory AML. Three of those patients were evaluable as of the data cutoff. As I mentioned, we initially started dosing at 50 milligrams PO that's orally once daily. At the 200-milligram dose, we then enlarged the cohorts from single patients to a 3 plus 3 design. Because at that point, we had good safety and tolerability, evidence of activity and we wanted to understand the compound in more patients. We've seen evidence of biologic activity thus far at every dosing cohort to date, including the very first one. We were very excited to see a complete response in a patient with, I should say, with negative minimal residual disease in a patient with SETD2 and RUNX1 co-mutation and this was at the 100-milligram dose. That really indicated to us that not only was the compound well tolerated, but it was showing biologic and antitumor activity, antileukemic activity at a level lower than what we were expected. We continue to dose escalate. We're currently at the 400-milligram dose, so we're 4x higher than where we were with the SETD2/RUNX1 ]patient. Thus far, we've been very pleased the compound is very well tolerated. It has a manageable safety profile. We have not seen any dose-limiting toxicities, any dose interruptions or any discontinuations related to drug-related adverse events. We haven't had any deaths relating to the drug. We have had 2 patients as of this data cutoff who discontinued treatment due to disease progression, but that's not unexpected. The peak drug concentration is between 2 and 3 hours. And the oral elimination half-life is greater than 24 hours. This compound has a profile that's consistent with once-daily dosing. And as I've mentioned now a couple of times, we are intending to present updated safety and tolerability data, pharmacokinetics and efficacy data in an oral presentation at ASH on December 5. And that's shown here, here are the details. We will be hosting a virtual investor event immediately following the oral session with a couple of the investigators from the study, who will help to provide more insights into the activity and the safety and tolerability in the program for KO-539 that we won't' have time to cover in the oral presentation. And then finally, the opportunity. As I mentioned, we think this has the potential to drive clinical benefit in 35% or more of AML patients. And you can see the way we get there, it's 30% of the NTM1 mutant population, 5% to 10% is the KMT2A-rearranged population. And then if one considers there may be activity in other mutants such as what's demonstrated with the SETD2/RUNX1 co-mutant patient at 100 milligrams, we think that could be up to another 15%, which would all told give us about 50% of the AML population. Obviously, there's a lot more work to be done, but I think it's a very exciting program. We're well positioned with good safety and tolerability, good pharmacokinetics and exposure. It's very strong biologic and antileukemic activity. We're well positioned to move into those expansion cohorts and to pursue this program very aggressively. So just to wrap up, Kura Oncology is a targeted oncology company. We are continuing to advance our 2 wholly owned assets, tipifarnib and KO-539. They each have opportunities. We've coupled them with very strong evidence of biological activity and patients' populations who have very high unmet need. And this has been a successful formula for research, development and commercialization of targeted therapies. It's our intent to continue to resource these programs aggressively. We're very grateful for the strong support of our investors, and I'm grateful to you for the chance to tell you more about the company. And happy to take, Marty, any questions from you or from the audience.

Yes. And I know I think we're running up at the end of the clock here and people need to get to their next meetings. But maybe just a quick one on KO-539. At the upcoming ASH date, could you frame again for us how many patients you expect to kind of have a report on? And can you break down the dose level of those patients would be at?

Yes, Marty, happy to. So as I mentioned, we're currently at the 400-milligram dose. And we're coming up on the deadline for having the presentation ramped and into the [AV system. ] We have had one patient at each of 50, 100 and 200. We had to replace the 200-milligram patient. So think of it as we have 3 or 4 patients at each of the 200- and 400-milligram dose. Not all of the patients are going to be valuable for efficacy because the trial is ongoing, but we should be able to give you a very good insight into where we stand at the 200- and 400-milligram dose. And it's our intent if we clear the 400-milligram cohort, to dose escalate to 600 milligrams, which I may not have mentioned that was the predicted human efficacious dose before we ever started the clinical trial. So I think we're in a very strong position. It won't be the full picture, Marty, but I think it will get you most of the way there in terms of what to expect from the Phase I portion.