Kura Oncology Inc (KURA) 2020 Q2 法說會逐字稿

Good day, everyone. Welcome to the Kura Oncology 2Q 2020 Financial Results and Corporate Update Conference. Today's call is being recorded.

At this time, I'd like to turn things over to Mr. Pete De Spain, Kura's Vice President of Investor Relations. Please go ahead, sir.

Thank you, Kellyanne. Good afternoon, and welcome to Kura Oncology's Second Quarter 2020 Conference Call.

Joining me on the call from Kura are Dr. Troy Wilson, our President and Chief Executive Officer; and Dr. Marc Grasso, our Chief Financial Officer and Chief Business Officer. Jim Basta, our Chief Legal Officer; Kirsten Flowers, our Chief Commercial Officer; Kathy Ford, our Chief Operating Officer; and Dr. Bridget Martell, our acting Chief Medical Officer, are also with us and available to answer questions.

Before I turn the call over to Dr. Wilson, I would like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company.

With that, I will now turn the call over to Dr. Troy Wilson, President and CEO of Kura Oncology.

Thank you, Pete, and thank you all for joining us this afternoon. At Kura, we're committed to advancing 2 exciting programs: our farnesyl transferase inhibitor, tipifarnib; and our menin-KMT2A inhibitor, KO-539, each with potential to make a significant impact on the lives of patients with cancer.

We're advancing these programs during an exciting time in oncology drug development with an increased understanding of biology, better uptake of precision medicine and a sense of urgency to bring new and better therapies to patients. At the same time, we continue to operate against the challenges of the global pandemic as we adapt to an ever-evolving remote working environment. We expect this disruption and uncertainty to continue for the foreseeable future as the threat of COVID-19 remain.

In response to these challenges, we've implemented a number of mitigation steps, as outlined on our call last quarter, including streamlining our clinical development program. These efforts have enabled us to focus our efforts on those programs with the highest potential to create value for patients, to create greater operational leverage and help to ensure a strong cash position as we approach important catalysts. The results of this exercise is a focus on our 2 major pillars: tipifarnib in HRAS-dependent head and neck squamous cell carcinoma, or HNSCC, including HRAS-mutant and HRAS-overexpressed HNSCC; and KO-539 in acute leukemias, including KMT2-rearranged AML and NPM1-mutant AML. These programs share key attributes, namely, small molecule drug candidates, targeting oncogenic driver mutation in disease indications of high unmet need that have characterized a number of successful precision medicines in oncology.

Let's start with an update on KO-539, a program that continues to generate significant interest. KO-539 is a potent and selective small molecule inhibitor of the menin-KMT2A protein-protein interaction. Preclinical data supports the potential for potent antitumor activity in genetically defined subsets such as KMT2A fusion and rearrangements as well as NPM1 mutations. As a reminder, KO-539 has received orphan drug designation from FDA for the treatment of acute myeloid leukemia. We believe KO-539 represents a differentiated approach with the potential to target at least 35% of patients with AML.

We were pleased to see the presentation of a competitor program at the American Association for Cancer Research Annual Meeting in April, which represented the first public report that a menin-KMT2A inhibitor can drive meaningful antileukemic activity in KMT2A-rearranged AML patient. The encouraging data underscores our excitement around KO-539, which is a chemically distinct molecule with different physical, chemical and drug-like property. Our Phase I/IIa clinical trial of KO-539 in relapsed/refractory AML, which we've named KOMET-001, continues in dose escalation.

We remain focused on our goal of reaching a recommended Phase II dose and schedule, after which we intend to open expansion cohorts in NPM1-mutant and KMT2-rearranged AML - selected patient populations where we believe KO-539 has potential to demonstrate increased clinical benefit.

In addition, we're exploring options to expand the label, potentially broadening the opportunity in the treatment of acute leukemias in both children and adults as well as the combination of KO-539 with chemotherapy and targeted therapies. We intend to submit an abstract for presentation of the KO-539 program at the American Society of Hematology Annual Meeting, and pending acceptance of the abstract, look forward to sharing the initial clinical data in December. In the meantime, we continue to add clinical sites to the study in anticipation of moving into the expansion cohorts.

Now let's turn our attention to tipifarnib in HRAS-mutant HNSCC. We reported updated clinical outcome data from our Phase II RUN-HN study of tipifarnib at the American Society of Clinical Oncology Virtual Scientific Program in May. The data showed a median overall survival of 15.4 months, median progression-free survival of 5.9 months and an overall response rate of 50% among the 18 evaluable patients with recurrent metastatic HRAS mutant HNSCC. Patients in the study had a median of 2 prior lines of therapy, and robust activity was seen despite prior resistance to chemotherapy, immunotherapy and/or cetuximab.

Outcomes for 3 FDA-approved therapies for relapsed metastatic HNSCC are poor with reported median OS of 5 to 8 months, PFS of 2 to 3 months and ORR of 13% to 16% in the second line. We believe a median OS of 15 months is unprecedented in this patient population and represents a substantial improvement compared to historical benchmarks with current standards of care. These data support our efforts in HRAS-mutant HNSCC, a population in dire need of effective new treatment, and they reinforce our confidence in the ongoing AIM-HN registration-directed trial.

As discussed on our last quarterly call, we've amended the AIM-HN trial to enroll all HRAS-mutant HNSCC patients regardless of variant allele frequency. The amendment expands the proportion of HRAS-mutant HNSCC patients who are being treated in the registration-directed trial. It's worth noting that the trial's primary outcome measure, ORR in patients with high HRAS-mutant variant allele frequency, remains unchanged. However, the amendment enables us to assess the potential clinical benefit in the overall HRAS-mutant HNSCC population as well. We believe tipifarnib has the potential to provide a meaningful benefit to these patients.

In addition to pursuing the first registrational opportunity in recurrent or metastatic HRAS-mutant HNSCC, we're also planning for how we can expand the use of tipifarnib into larger patient population. In particular, we're increasingly interested in HNSCC patients whose tumors are dependent on HRAS and/or PI3 kinase alpha as evidenced by overexpression of the HRAS protein or PIK3CA mutation or amplification. HRAS and PI3 kinase alpha are believed to be codependent pathways in HNSCC.

Our preclinical data support this notion and suggests that a combination approach has the potential to provide meaningfully better antitumor activity than inhibiting either target alone. Specifically, additive or synergistic activity was consistently observed with administration of the combination of tipifarnib and a PI3 kinase alpha inhibitor in a panel of 16 patient-derived xenograft models, representative of these HNSCC genotype. These patients may represent significant subsets of HNSCC patients with distinct biology that may be targetable by tipifarnib. It's estimated that up to 20% of HNSCC patients have tumors that overexpressed HRAS, and an additional 35% have PIK3CA-dependent tumors.

Although the precise overlap between the HRAS-overexpressed and the PI3K-dysregulated HNSCC population is still being evaluated, we believe the total addressable population for tipifarnib may be as high as 50% of HNSCC. Based upon the unmet need and our encouraging preclinical data, we're prioritizing clinical development of tipifarnib in combination with a PI3K inhibitor as a strategy to treat both HRAS and PI3K-dependent HNSCC patients. We continue to do more work on this front and anticipate presenting our preclinical data at an upcoming medical meeting.

With that, I'll now turn the call over to Marc Grasso for a discussion of our financial results for the second quarter of 2020.

Thank you, Troy, and good afternoon, everyone. I'll provide a brief overview of our financial results here on the call and invite you to review our 10-Q filed today for a more detailed discussion. Research and development expenses for the second quarter of 2020 were $13.7 million compared to $11.4 million for the second quarter of 2019. The increase in R&D expenses was primarily due to an increase in clinical development activities relating to our ongoing clinical trials and personnel costs and other expenses.

General and administrative expenses for the second quarter of 2020 were $7.5 million compared to $4.5 million for the second quarter of 2019. The increase in G&A expenses was primarily due to increases in professional and legal fees, pre-commercial planning expenses, personnel costs and noncash share-based compensation.

Net loss for the second quarter of 2020 was $20.5 million or $0.40 per share compared to a net loss of $14.9 million or $0.38 per share for the second quarter of 2019. As of June 30, 2020, we had cash, cash equivalents and short-term investments of $338.9 million compared with $236.9 million as of December 31, 2019. This includes net proceeds of approximately $134.9 million from a public offering completed in May 2020. We anticipate the additional proceeds will extend our cash runway by at least 12 months. We are, therefore, updating our guidance that our current cash, cash equivalents and short-term investments will be sufficient to fund current operations into 2023.

With that, I will now turn the call back over to Troy.

Thank you, Marc. Despite the continuing challenges posed by the pandemic, we remain steadfast in our commitment to advancing our tipifarnib and KO-539 drug development program and improving the lives of patients with cancer. I'm pleased by the progress we're making and look forward to sharing further updates with you in the months ahead.

With that, operator, we're now ready for questions.

(Operator Instructions) We'll hear first today from Martin Auster with Crédit Suisse.

This is Tiago on for Marty. So was curious if you could provide us any updates on the impact of COVID and enrollment for tipi in the AIM study. I'm curious if you have seen a pickup in enrollment at clinical trial sites or any other metric that may help inform or estimate potential timing for that data. I know there's a lot of uncertainty, but any color will be helpful.

And the follow-up will be just on what's the actual mechanistic rationale for the synergy that you're actually seeing for clinical models of tipi with the PI3K inhibitor?

Thanks. A great question. So on the enrollments in the AIM-HN study, we are seeing some improvements in the number of patients who are presenting to our clinical sites. Just to remind everyone, this study is operating in 90 sites around the globe. And we saw a pretty significant drawdown in the number of patients presenting as COVID was rolling through various geographies. That's coming back. I don't think it's all the way back, but we've definitely seen some improvement. We -- I don't think we're at a point yet where we can give clear guidance on the timing for full enrollment. I'll also just remind you that with the implementation of the amendment of the protocol, that typically takes 3 to 6 months to work its way through the sites around the globe. So between the amendment and COVID, at this point, I think we're still a little bit too uncertain to give guidance. But we are seeing improvement and continuing to execute on that study.

The second question that you asked on the mechanistic rationale. The RAS proteins, HRAS, MRAS, KRAS, they all interact with PI3-kinase. HRAS appears to have a special and codependent relationship with PI3-kinase. And we'll have more to say about this, as I said in the prepared remarks in the scientific meeting. But suffice it to say, is a couple of interesting pieces of data. If you delete the binding domain between HRAS or PI3-kinase, you can't transform cells with mutations in either oncogene. Another way of saying that is you need the presence of both of those oncoproteins in order to be able to drive tumor agenesis with either HRAS mutations or PIK3CA mutations. And as you'll see, so we've updated our corporate presentation, for those of you who have a chance to look at it, with a couple of new slides from preclinical data on the combination. And what's interesting is that you'll see the combination is active, as we indicated, in the HRAS overexpressed in the PI3-kinase, either mutant or amplified population, as well as even interestingly in the wild-type population. And I think that speaks to probably the importance of those 2 oncogenes in head and neck squamous cell carcinoma. And note that all of that data was generated at doses that are less than either drug used as a single agent, again, speaking to the additivity or the potential for synergy.

It would be interesting to see, I think we're looking forward to seeing whether we can replicate that data in the clinic. Obviously, if we can, it opens up a very expansive opportunity in head and neck cancer. I think there's very strong scientific and clinical rationale. And we are working very diligently to prepare for starting that study probably sometime early next year.

We'll hear next from Peter Lawson with Barclays.

This is Mitch on for Peter. The first question is, what kind of data for KO-539 do you expect at ASH? And can you comment on how many patients? And if you expect there to be any NPM1 patients?

Yes. Thank you for the question. We anticipated -- I'm going to leave you deeply unsatisfied. At this point, given that we're now under the embargo, we're not going to comment on the numbers of patients or the composition of sort of genetic background. I'll tell you that the investigators made a determination that the data we have to date, they thought was worthy of presentation at ASH, and we agree with that wholeheartedly. We are still working our way toward a recommended Phase II dosing schedule. So we're not there yet. But we're looking forward, hopefully, if the abstract is accepted to providing a fuller update at ASH.

Great. And then could you just comment on the go-forward plans for the development of tipifarnib with PI3K inhibitors? And just kind of like what trial designs might look like? Or any color on what we can expect going forward?

Yes. Happy to try to give you some more color on that. So it will look, I think, like a traditional sort of Phase I/IIa escalation. We need to, of course, determine that the combination can be given with a tolerable regimen that allows you to drive antitumor activity. The toxicities that have been observed for both the PI3-kinase alpha inhibitors and tipifarnib appear to be -- they appear largely to be nonoverlapping, maybe with the exception of some mylosuppression that one can deal with in the clinic. So what we'll do, of course, is start and see whether we can combine the 2 agents together. And then at that point, we're considering a couple of different approaches. One is to enrich for the various population, either in HRAS-overexpressed population or PI3-kinase-dysregulated population.

We are developing assays for the HRAS overexpression. The PI3-kinase mutations can be detected using traditional next-generation sequencing. Still working through exactly the details of what that trial design looks like as well as the partner compounds. There are multiple PI3-kinase inhibitors out there that could be good potential partners for tipifarnib in this indication. And we're in the midst right now of determining which of those they want to move forward with. So hopefully, we'll have more information to share with you either later this year or early next year.

From SVB Leerink, we'll hear next from Jonathan Chang.

Just first, a clarification question. The intent to submit language, is that a reflection of the extension of the ASH submission deadline to Monday?

It is, Jonathan. That's exactly what it is. So for everyone's benefit, ASH extended the submission deadline from this week to Monday of next week. I think it's Monday at midnight. So we'll, of course, take advantage of every last day we can to update data and so forth. But we intend to submit an abstract by the deadline.

Got it. And just one last question. Has the COVID-19 pandemic impacted enrollment in operations in the KO-539 study?

Yes, it did actually early in the study, and it affected it in that it was difficult to initiate clinical sites and to access a couple of sites that were participating in the study. There were certain sites that just shut down completely and weren't even in a position where they could do remote site initiation visits. We seem to largely be through that now, Jonathan, thankfully. And so although we saw some disruption in the initial setup for the study as the pandemic was breaking, I think we're through that and kind of on a steady pace now. And as I mentioned in the prepared remarks, actually continuing to add sites to the study in anticipation of moving into the expansion cohorts, if and when we reach the recommended Phase II dosing schedule.

We'll move on to Chris Shibutani with Cowen.

This is Pam Barendt on for Chris. A couple of questions on the upcoming ASH presentation, hopefully, if it's accepted. Congratulations on the almost submission. How long will you continue to enroll all comers? And are you seeing any drug-drug interaction to date?

So let's take those questions separately, Pam, and thank you for the congratulations on the almost submission. So we will enroll all comers until we formally move into the expansion cohorts. The protocol is designed specifically not to enrich for particular genetic subtypes in the dose escalation and then the phase where we determine and validate the recommended Phase II dosing schedule. And that's the whole point of them moving into the expansion cohorts.

In terms of have we observed any drug-drug interactions, are you -- is that another way of asking, for example, about CYP3A4 metabolism? Because as you know, I mean, this is a monotherapy study, right, in the relapsed refractory population. So we're not -- we're deliberately not doing any combinations or looking formally at any drug-drug interactions. But is your question kind of getting to that?

Yes. Specifically, have you seen CYP3A4 inhibition?

Yes. So I would say let's hold that question until we get to the presentation of the data. As we've said, the hope and expectation when the data is presented is that we'll speak to, of course, the safety and tolerability, the pharmacokinetics and exposure, any pharmacodynamics and then antileukemic activity. And as we've also said, most of these patients are on strong CYP3A4 inhibitors. So it is something, of course, that we have been paying attention to since the protocol was initially prepared and run through the site. I think we'll save the answer to that question until we're able to talk about it in the context of the full ASH data set, again, presuming that the abstract is accepted.

Got it. And one more question, if I can, on the menin inhibitor. Do you have any plans at this time to go into ALL?

Yes. It's definitely a population of very high unmet medical need. That population is treated quite differently than AML. It's something that I think we are looking at very actively. We haven't made any public announcements of an intent to enroll a cohort. But certainly, if one sees activity in the KMT2-rearranged myeloid phenotype, you would expect to see it also in the lymphoblastic phenotype. And I think it's a matter of whether rather than when -- sorry, it's a matter of when rather than whether if we reach a point where we've got activity that justifies moving forward. So something we're looking at, haven't yet made a commitment to move into ALL in parallel.

We'll move next to Joe Pantginis with H.C. Wainwright.

I wanted to focus on 539, and if you could provide a little bit of a reminder and maybe some color with regard to sort of the early discussions with the FDA in determining the starting dose. And what I'm getting at is, obviously, with the new drug, you want to potentially start as low as you can, but then you're also balancing having to potentially start as close as you can to potentially efficacious dose in such an advanced population in AML.

Yes. Yes, Joe, thank you for the well wishes and for the question. So this Phase I study was pretty plain vanilla. In discussions with the agency, we proposed starting at a fraction of the -- of what we believe the human efficacious dose to be, and that's driven completely by the preclinical model. People have asked how many cohorts do you expect. And my answer has been more than 1 and fewer than 20. And I think we're making good progress in that regard. There wasn't -- sometimes you see compounds going in, and you have a pretty good expectation that you're going to be at a human efficacious dose right out of the gate. That wasn't where we started based on the predictions from the preclinical model. And of course, I want to be respectful of ASH and not speak to any of the clinical data. But it was a traditional design where we start a number of cohorts down. And then as it was drafted, it's single-patient escalation until we either experience the DLT or reach what we predicted the human efficacious dose to be.

(Operator Instructions) We'll hear now from Reni Benjamin with the JMP Securities.

Congrats on the progress. Troy, maybe just starting off with 539. You have 2 genetically defined patient populations. Can you just talk a little bit about the need for differentiating those 2? Do we expect different roughly sort of efficacy or safety between those 2 patient populations or the biology is such that they should relatively be in line? And maybe related to that, you're looking at relapsed/refractory -- the relapsed/refractory patient population, what are your thoughts in regards to the potential combination and moving it frontline?

Yes. Ren, thank you for the questions. So we can speak to what we see in the preclinical data and the rationale. And to remind everyone, at a dose of 50 milligram per kilogram dosed once a day orally by via oral gavage, in the patient-derived xenograft models, we saw curative effects in both the MLL or KMT2-rearranged models as well as the NPM1-mutant models. So there wasn't a differentiation as far as efficacy is concerned preclinically. And we didn't -- it's hard to draw conclusions in terms of tolerability in those models since they're not really designed for that. We would have an expectation, I think, on the basis of that, that there's a good reason to believe you would see a similar phenomenon in patient. You never know until you run the experiment which is what we're doing now.

I will remind you that in the case of the KMT2-rearranged population, that is a very negative prognosis. Those patients typically do not respond well to anything, which I think is why we may have seen an enrichment in the Syndax study that they presented at AACR. In the case of NPM1, NPM1 on its own is actually a favorable prognostic as far as AML is concerned. But once you get -- develop comutations, FLT3, DNMT3A, for example, then it switches and becomes a moderately negative prognostic. So you would expect that if you were seeing patients in the relapsed/refractory setting, those patients are likely going to be NPM1 with various comutations. I can't say that -- I shouldn't speak generally, but that would be your expectation in terms of the basis of the standard of care. And so as far as that's concerned, both of those populations are at pretty high unmet need in the relapsed/refractory setting.

The second or third part of your question was how do you think about moving forward. So there are really 3 big buckets: there's chemo intensive, there's chemo ineligible and then there's secondary AML. And each of those segments has its own established standard of care.

We would expect that initially, we'd likely combine with those standards of care, again, in genetically selected populations. I think the goal in oncology generally is to move away from a chemotherapy -- to move to a chemotherapy-free regimen. You might imagine 2 or 3 targeted therapies together. But I think you're going to do that step-wise. We're doing all of that work now in addition to opening sites in anticipation of expansion cohorts. We are talking with key opinion leaders, with our investigators and with others about the standards of care, the unmet need in the frontline and how one might think about developing 539 in the various populations. And I'm hopeful that we'll have more to say about that in the months and the years ahead. Does that answer your question?

It does. It does. And just switching gears as a follow-up with tipi. The combination approach, I think you mentioned it would be a PI3K alpha inhibitor. I'm kind of curious from a biological perspective why an isoform specific versus the pan-PI3K inhibitor? Have you have you chosen which PI3K inhibitor that's out there you want to combine with as you move forward? And how that study could look just given that -- correct me if I'm wrong, that there currently aren't any PI3K inhibitors that are approved for head and neck squamous cell?

Yes. So again, 2 good questions, and maybe we can tease them apart. As far as the isoform selectivity of the PI3-kinase inhibitor, remember that those isoforms are restricted in their expression in various tissues. So delta and gamma, for example, you typically see in the immune compartment, which is why they are used for B-cell malignancies, potentially for T-cell malignancies as well as the hope of inflammatory disease.

Alpha and beta are much more what you would think of as solid tumor isoforms. And alpha, in particular -- PI3-kinase alpha is -- I think it's the second most frequently mutated oncogene after p53. The results as a monotherapy have been modest, but that's maybe not surprising now that we kind of understand how signaling -- how these different signaling cascades can compensate for one another, and there's feedback and so forth. It's -- I think you'll end up with the same answer, Ren, from an efficacy perspective, combining a pan-PI3- kinase inhibitor as an alpha selective inhibitor with tipifarnib in HNSCC where they may differentiate it in terms of tolerability. If you don't -- if you're not hitting, particularly given that tipifarnib does have some myelosuppressive effect. If you can spare the immune compartment, you'd rather do that. So that -- it's a combination of you get all the efficacy and better tolerability by going with the isoform-selective inhibitors. You're correct that there is currently no PI3-kinase inhibitor, either alpha or any other flavor that is approved in head and neck. There are a number of PI3-kinase inhibitors that are in various stages of development. A quick search on PubMed will show you. And I don't want to give -- I don't want to say too much about our evaluation and selection process, but there are a number of options out there that we're actively evaluating. And I think we'll be in a position to say more, hopefully, later this year or early next year.

Congrats on the progress.

Thank you, Ren.

And with no other questions, I'd like to turn things back to Dr. Wilson for any closing remarks.

Thank you, operator. And thank you all once again for participating in the call today. We'll be participating in the Wedbush PacGrow Healthcare Virtual Conference next week and look forward to speaking with many of you then. In the meantime, if you have any additional questions, please feel free to contact Pete, Marc or me. Thank you, and have a good evening, everyone.

And again, that will conclude today's conference. Thank you all for joining us.