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

Good afternoon, everybody. Thank you for joining us today. On behalf of the entire JPMorgan Healthcare team, it is my pleasure to introduce you to Troy Wilson, President and CEO of Kura Oncology. Just as a friendly reminder, you may submit your questions through the ask a Q feature listed under the presentation. Thank you for your participation. And I'll now hand it off to Troy. Thank you again.

Thank you, [ Amy ], and thank you to our colleagues at JPMorgan for the invitation to present in today's conference. It's unfortunate that we're not able to see many of you in person, but we're going to do the best we can today and give you an update on all of the progress that we've been making at Kura Oncology over the last year and to look forward to what you'll see in 2021 and beyond. And again, I want to thank JPMorgan for this opportunity. I'm going to be calling out slide numbers for those of you who are following along. And so we'll start with just a quick forward-looking statement. Just to remind you that I'm going to be making, in today's presentation, certain forward-looking statements, and I would refer you either to the SEC's website or to our website for more information about the risks and uncertainties of an investment in Kura Oncology. If you turn now to Slide 3, this is the slide labeled investment highlights. This really provides, I think, a good overview for the company and looking forward. So we are, of course, a precision medicine company. We're focused on developing targeted therapies for the treatment of cancer. By virtue of a precision medicine strategy, we're trying to take advantage of more efficient drug development, lower cost, higher rates of success and, of course, a fast-to-market strategy. We have 2 major pillars in the company. The first is anchored by our farnesyltransferase inhibitor program. Our lead asset is a compound called tipifarnib. Which is an FTI, and it is currently being evaluated in a registration-directed study in head and neck squamous cell carcinoma. This is a study called AIM-HN that we'll talk more about in the slides to come. We anticipate starting a combination study that will look to build on the work that we've done for tipifarnib in not only head and neck squamous cell carcinomas, but other solid tumors as well. And that is an opportunity to combine tipifarnib with an inhibitor of the proto-oncogene PI3-kinase alpha. I'll talk to you about some of the scientific rationale behind that and how we see that potentially enlarging the clinical opportunity and the commercial opportunity. And then, of course, there are a number of other places that we could go with farnesyltransferase inhibitors. And I'll just, in the interest of time, just touch briefly on those. Turning to the second of the 2 major pillars: Our compound called KO-539. This is a selective inhibitor of a protein-protein interaction that is essential for the maintenance of certain genetic subtypes of acute leukemia. I'll use KMT2A, which is the gene name and MLL, which is mixed-lineage leukemia. I'll use those interchangeably throughout the presentation. They're really referring to the same thing. And the interesting aspects of this program are a large patient population, potentially 35% or more of patients with acute myeloid leukemia as well as the potential to drive profound, durable responses in these genetically selected subtypes. And we'll talk about that in the context of both the preclinical and the clinical data in the second half of the presentation. And as you'll see, we have a very aggressive and, I think, ambitious development program focused on KO-539. We're very fortunate to have the strong support of our investors. We concluded a financing recently in December. That brings our cash position on a pro forma basis, as you can see at the bottom of slide 3 to $649.4 million pro forma as of the end of September. That's important because it allows us to really drive forward on these 2 major pillars and gives -- allows us to approach everything that we do from a strong position of strength. And gives us a lot of optionality going forward. If we turn to Slide #4, just a quick word. I'm very fortunate to have a strong leadership team and Board of Directors. Just again, in the interest of time, I'm not going to go through them in detail. I do want to just highlight for those of you who perhaps haven't followed the story in a while, the recent addition of Stephen Dale as our Chief Medical Officer at Kura. Stephen was most recently at Kyowa Kirin. Prior to that, Stephen was VP of Clinical Oncology at AstraZeneca, where he oversaw the development of Tagrisso, was involved in the iPASS studies that led to the approval of Iressa and really has been at the forefront of targeted therapy in oncology for the better part of 2 decades. Turning to Slide #5. This, again, is a nice summary of the 2 pillars of the company. So on the left-hand side, you can see tipifarnib. I'll just remind you, this program has fast track designation from FDA. The initial opportunity is targeting a population of very high unmet need. These are patients who have mutations in the HRAS proto-oncogene, who also were diagnosed with head and neck squamous cell carcinoma. But we see that really as an initial landing place. And the opportunity to expand through very rational combination strategies into both a broader population in head and neck squamous and other indications. On the right-hand side, of course, menin. This is a program that's earlier in development. As you'll see, we're just concluding the Phase I dose escalation portion. The program has received orphan drug designation, and it has an opportunity to address a very large segment of the population of acute myeloid leukemia, all the way from the relapsed/refractory setting, potentially to the front-line setting and beyond in combination with various other agents, and we'll speak to a number of those opportunities again later in the presentation. So turning now to Slide #7. This is a summary of tipifarnib in HRAS mutant solid tumors. And what's key here is we are targeting a unique mechanism of action. This is the addition of a hydrophobic side chain to proteins that allows them to anchor to the cell membrane. By doing that, by disrupting that post-translational modification, if you will, we can drive meaningful antitumor activity. And that's demonstrated by the Phase II data that we profiled at ASCO in June of 2020, showing that in a relapsed and/or refractory setting of head and neck squamous cell carcinoma, we observed approximately a 50% ORR, 6 months of progression-free survival and 15 months of overall survival, really dramatic advantage relative to the 3 approved agents who represent the current standard of care. Tipifarnib has demonstrated a favorable safety and tolerability profile that gives us confidence that we'll be able to combine, as I mentioned, with a PI3-kinase alpha inhibitor as well as potentially with other drugs as well. We've received fast track designation from FDA, and we have a strong patent protection that takes us out to 2036 and potentially beyond in major markets. Turning to Slide #8. This is a summary of the mechanism of action. Notice farnesyltransferase is in blue on the left-hand side of the slide. And what we're doing is we're disrupting the covalent attachment of that lipid side chain in yellow to proteins such as HRAS. HRAS is a proto-oncogene. It's a protein that when either mutated or overexpressed, can lead to some of the hallmarks of cancer. And what tipifarnib does is it blocks the ability of HRAS, both the mutant form, now if you're looking on the right-hand side of Slide 8, the mutant form in red or the wild-type form in purple, it prevents those proteins from associating with the cell membrane. If you turn to Slide 9, the net result of that is you see displacement of HRAS from the membrane is shown in the upper left-hand corner, we see very strong antitumor activity as we would expect in the HRAS mutant patient-derived xenograft models and going across the panels along the bottom of Slide #9, a lot of the hallmarks of antitumor activity that one would want to see. These are all preclinical data. If you turn to Slide #10, you see how this now translates into the clinic. So Slide 10 is a swim lane plot of 18 evaluable patients who were enrolled on our Phase II study called RUN-HN, the goal of which was to evaluate tipifarnib as a monotherapy, again, in the recurrent or metastatic HRAS mutant head and neck squamous population. And what you can see from the swim lane plot on Slide 10 is -- let me draw your eye. The dark blue bars are partial responses. The light blue bars are patients whose best response is stable disease. And importantly, most of the patients received clinical benefit, either in the form of stable disease or partial responses. Note that there's approximately a 15% objective response rate among the 18 evaluable patients. And you can see even on this, a number of these patients have responses with durations out well beyond 1 year. So this is in striking contrast, as you'll see, to the agents that are currently approved in the second-line setting. Turning to Slide #11. Now this speaks to the data on progression-free survival. And what you can see here is there's 2 curves, red and blue. The red curve are patients who -- there are 7 patients there. Patients on the prior line of therapy of the 18. The reason they're only 7 is the other 11 had progressive disease as their best response assessment. And so they're not included here. Patients with either PR or stable disease there show a median PFS of 2.8 months. When those patients then go on to tipifarnib, you see now all 18 patients evaluable, at least on this graph and nearly a doubling of the progression-free survival even though it's the subsequent line of therapy. Typically, you'd expect to see these curves inverted. But we think this really speaks to the potential for tipifarnib to drive clinical benefit in this HRAS mutant HNSCC population. Turning now to Slide #12. We've talked about response rate. We've talked about progression-free survival. This is now overall survival. And the overall survival in this population, again, this date is censored, is 15 months, a little bit more than 15 months, which compares very favorably to the -- again, to the 3 approved agents that have OS ranges -- ranging from 6 months to 8 months in the second-line setting and beyond. So in totality, what we think is that this data really underscores the potential for tipifarnib as a targeted therapy to drive clinical benefit in HRAS mutant head and neck squamous. If you turn to Slide 13, you can see we've now -- we're now building on the results from the RUN-HN study. That study is now closed to further enrollment. And we are enrolling AIM-HN. AIM-HN is a registration-directed study of tipifarnib in this same population, patients with HNSCC, who have HRAS mutations. These are recurrent or metastatic patients who have either experienced a prior line of platinum therapy or who are platinum ineligible. The studies open in greater than 90 sites around the world. And importantly, throughout last year, we amended the study both to expand the patient population to any HRAS mutant patient and also to remove what we saw as a couple of impediments to getting patients on-study. Patients with advanced head and neck squamous cell carcinoma are very sick, they typically deteriorate very quickly. And through a process of amending the registrational protocol, we believe we've made it easier to get them on-study, get them on-study more quickly so that they potentially can receive benefit from tipifarnib. This study, as it's designed, has a 15% null hypothesis. That means we need to see approximately a 25% or greater confirmed objective response rate in order to eliminate the null hypothesis and have a positive study. Running in front of the AIM-HN study is a companion study called SEQ-HN, this is a prospective observational study that is looking really to characterize the natural history of HRAS mutant HNSCC patients who either -- or I should say, patients with HNSCC who either have HRAS mutations or who don't. We really want to understand if HRAS is a negative prognostic for treatment with other therapies. What we can speak to is there's a very high unmet need in head and neck. We believe that need is potentially even higher in patients that have HRAS mutations. And SEQ is in -- because we're screening through these patients, SEQ-HN is intend to try to help us answer that question. These studies will conclude at the same time because SEQ-HN is a matched case controlled study. And we believe it may help to support FDA labeling discussions, post-approval commitments and other commercial considerations. Finally, turning to Slide 14. This speaks to the potential unmet need and the commercial opportunity, both in the HRAS mutant and in the combination setting. So note that head and neck squamous cell carcinoma is the seventh leading cancer worldwide. And that's significant because to date, there are no approved small molecule targeted therapies in this cancer, even though globally, nearly 900,000 patients a year are diagnosed with head and neck squamous. Tipifarnib could potentially represent the first approved target -- small molecule targeted therapy in HNSCC. There remains a very high unmet need, again, in the second line. And you can see those statistics, I've mentioned them to you a couple of times before, but you can see them in the lower right-hand corner of Slide 14. We'll come back to this again as we now transition and talk about expansion opportunities for tipifarnib in both HRAS and PI3-kinase dependent HNSCC. And let me now ask you to turn the presentation to Slide 16. So importantly, we typically think about these oncoproteins as mutated. But there are other ways in which these proteins that drive these key signaling pathways can lead to either drug resistance or some of the hallmarks of tumor regenesis. And those include gene amplification as well as overexpression at the level of mRNA and protein, and that's what we're talking about here. So we did an analysis, again, from publicly available sources that showed that in the tumor types where we see activity of tipifarnib. HRAS is overexpressed at a level that is 5 to 10x higher than other tumor types. And of course, higher than normal cells. And you can see that in the orange box in Slide 16. The functional significance of that is shown on Slide 17. And here, we have 4 panels. These are patient-derived xenograft models of combinations of tipifarnib with 4 independent therapies. And you can see them going clockwise from the upper left. Cetuximab, the anti-EGFR inhibitor, platinum, TOR-kinase inhibitor and palbociclib, the CDK4/6 inhibitor. And note the color coding, tipifarnib, the growth curves are shown in red, the partner drugs are in green and the combination is in blue. The significance of this is, in all 4 examples, the combination is statistically better than either of the compounds as a monotherapy. In fact, in all 4 cases, the curves are going down and to the right, indicating at least in a preclinical setting, tumor regression. What we think is going on is that even as a wild-type protein, when it's expressed at 5 to 10x the level of other tumors or abnormal cells, HRAS is really driving a pattern of resistance to other targeted therapies. By removing the functional HRAS through defarnesylation, we can unmask the activity of the other drugs. If you turn to Slide 18 now, you can see combinations of tipifarnib plus a PI3-kinase alpha inhibitor. And again, the color coding is the same, the combinations are in blue. Notice that in each case, we're seeing either additivity or synergy that is statistically meaningful in HRAS mutants, PI3-kinase mutant as well as wild-type head and neck squamous cell carcinoma. So turning to Slide 19. This summarizes where we're going with this program. Initially, AIM-HN is targeting 4% to 5% HRAS mutant head and neck in the U.S., 4% to 8% globally. But we think there's an opportunity to build on that and target between 25% and 50% of head and neck through a combination of tipifarnib plus an inhibitor of PI3-kinase alpha. And there's very strong biology. We talk about these 2 proto oncogenes as being codependent. And you can see here the various subpopulations that we'll go after. PI3-kinase mutant or amplified, it represents 30% to 40% of HNSCC. HRAS overexpressed is 20% to 30%. And of course, the HRAS mutant, where we've done most of the work is in 4% to 8% looking on a global basis. So given this is such a large tumor type with such high unmet need, we're quite excited. We are working toward starting this study around the middle of the year, just putting all of the pieces in place. The companion PI3-kinase inhibitor, the clinical protocol, all of the study start up activities. We look forward to that starting probably around mid-year. Turning to Slide 20. Let me just say 2 important points. We have strong patent protection out to 2036 and beyond that we've been building very deliberately. And importantly, we are now working on a second-generation farnesyltransferase inhibitor, which we think will speak to potential future combinations. And what we hope to have much more to say about that in 2021 and beyond. But we've demonstrated that farnesyltransferase is a druggable target in oncology. And we think given its safety and tolerability profile, there's a lot that one can do. So again, let me invite you if you have any questions to submit them to the -- through the ask Q section of the presentation. I'm now going to turn to our other program, our menin inhibitor in acute leukemias, and I'll draw your attention to Slide 22. So KO-539 is a potent, selective and reversible inhibitor of a protein-protein interaction that, as I mentioned, is essential for the maintenance of acute leukemia. This is targeting a form of epigenetic dysregulation. As you'll see, essentially, what's happening is these leukemic blasts are stuck in a -- in an undifferentiated state. And what we're doing with this drug candidate is to remove this block on differentiation and to allow the leukemic blast to differentiate into their fully mature cells, which then ultimately die off, but leave the -- either the animals or the patients with very profound and potentially durable clinical benefit, including complete remissions. We showed data from our KOMET-001 study just last month at the American Society of Hematology Meeting, and I'm going to quickly walk through that data for you. And we see a very compelling opportunity to move not only aggressively into the relapsed/refractory setting, but also, as you'll see the frontline setting, pediatric development as well as other acute leukemias, and we'll talk through that. Similar to tipifarnib, this program has very strong IP, including composition of matter out to 2036. So Slide 23 is a schematic cartoon of what's happening. I'll draw your attention to the gene expression profile, notice HOXA9 and MEIS1, the arrows up or down. In the case of leukemia, fusions of the KMT2A or MLL gene lead to constitutive activation of HOXA9 and MEIS1. What that means is that the leukemic blasts are sort of stuck in a permanently undifferentiated state. By blocking the binding of menin, which is an essential protein cofactor to this fusion protein, and I'm talking about the cartoon on the left-hand side, you can see we downregulate HOXA9 and MEIS1, and we caused those leukemic blasts to differentiate into monocytes or whatever other mature cell types, and ultimately, they die off after several weeks. Similar sort of biology, some subtle differences with the population of NPM1. I should mention, I didn't do it on the preceding slide. These 2 populations together, approximately 5% to 10% of KMT2A, approximately a 25% to 30% of NPM1. This is a significant population of acute leukemia. Turning to Slide 24. This is the preclinical data, and it's just helpful to kind of compare and contrast to the clinical data that's to come. You can see in the upper left-hand corner of Slide 24. This is a KO-539 as a monotherapy in a model that has multiple mutations, and you can see them there in the title to the slide. And the color coding is important. 539 is in red. We're comparing it to a FLT3 inhibitor in blue and, of course, vehicle-controlled in black. What you can see with the vehicle is the animals all unfortunately pass away within a month. With treatment -- with a FLT3 inhibitor, you do see a prolongation of survival, about a doubling. But in contrast, in sharp contrast with KO-539, every animal is a long-term survivor, 10 out of 10. Even after one stops dosing with treatment with KO-539. And the significance of that, as I mentioned, if you look in the upper right-hand corner, is you're actually inducing these leukemic blasts to differentiate into mature cell types. So essentially, you're turning a malignant tumor into a nonmalignant state. And we think, again, if there's a wide safety and tolerability profile as we think there is, we think this could be a very important anchor to a combination therapy going forward. So turning to Slide #25. We have a Phase I/II study underway. We're currently in the Phase I dose escalation portion, where we're seeking to determine a recommended Phase II dose or a maximum tolerated dose. We are enrolling patients on an all-comers basis, there's no genetic selection. And we're looking, of course, for safety and tolerability for pharmacokinetics and exposure, and then for any early evidence of either biologic or antitumor activity. Once we've established and determined a recommended Phase II dose, then we'll move into the expansion cohorts and you can see 2 of them listed here, NPM1 mutant and KMT2A rearranged. And again, we're anticipating that around probably the end of the first quarter of this year. Turning to Slide 26. This is a table of the tolerability -- safety and tolerability. You can see there've been a number of grade 3 and 1 grade 4 AE. Importantly, we get a lot of questions about the pancreatitis. Importantly, the pancreatitis, the lipase and the neutrophil count were all seen in a single patient and in fact, as you'll see, they were seen in a patient who subsequently went on to have a complete remission that was MRD negative, an NPM1 mutant patient. We haven't seen any other evidence of any of these, either pancreatitis, lipase or neutrophil count reduction, there were a lot of confounding factors in that patient. And I know I've talked to a number of you about this. Importantly, we see no evidence of QT prolongation or any other clinically significant ECG changes. If we turn to Slide 27, with a very strong safety and tolerability. This is now -- the patients that have been enrolled at every dose level, we started the dose escalation portion at 50 milligrams. We had anticipated that the human efficacious dose would be about 600 milligrams. We were very pleasantly surprised when we saw a patient with SETD2 RUNX1 mutation experience a complete remission in the second of dosing cohort at 100 milligrams. That patient, as you'll see, ultimately went on through 8 cycles before the patient came off for progressive disease. Importantly, there were 2 patients in the 200-milligram cohort, the 2 NPM1 mutant patients, you can see there. One patient, in particular, the patient I just mentioned with the 3 toxicities, that patient had had 7 prior lines of therapy. And after those AEs resolved, the patient went on to experience a complete remission that was MRD negative. That patient remained on study as of the date of cutoff. Obviously, we can't speak to what's happening after the date of cutoff but exactly the sort of clinical response that we would hope to see. This is the data as of 400 milligrams. It's worth noting we're now actually evaluating KO-539 at 600 milligrams and I'll talk a little bit about that in about 2 or 3 slides. Before I do, if you turn to Slide 28, just a little bit more on the vignette of a couple of the patients that I mentioned. So the patient at 100 milligrams on Slide 28. This patient had mutations in the gene SETD2 and RUNX1. The patient experienced a complete remission at the end of cycle 3, that this patient was, again, at 100 milligrams. That patient went on for 3 cycles, ultimately began to experience a blast count increase. The patient was increased to 200 milligrams because we had cleared that safety cohort. The patient ultimately came off study after the end of cycle 8. The next vignette is the patient with NPM1, that's Slide 29. This was a 44-year-old female, as you can see multiple co-mutations, patient had experienced 7 prior lines of therapy and experienced a complete remission that was MRD-negative and a very, very strong response, remained on-study and a MRD-negative CR as of the date of cutoff, we'll obviously provide updates on all the patients on the study at the next data update. So just to summarize where we are with KOMET-001, we think it's very potent and selective. It's well tolerated with a manageable safety profile. The toxicities appear to be both reversible and manageable. There's no evidence of QT prolongation. It demonstrates encouraging signs of clinical activity, not only in KMT2A rearranged and NPM1, but we were quite pleasantly surprised to see a response in a SETD2 RUNX1 mutant patient. I didn't get into the details, but we don't seem to have any effect from concomitant administration of CYP3A4 inhibitors, typically azoles, antifungals. And as I mentioned, we're currently evaluating KO-539 and the 600-milligram cohort with a goal to reach a recommended Phase II dose -- now I'm on Slide 31, a goal to reach a recommended Phase II dose by the end of the first quarter of this year. When that happens, we want to be able to move aggressively in both the relapsed and refractory setting, you can see that with the first couple of arrows on Slide 31. So the obvious expansion cohorts in both the KMT2A rearranged and the NPM1 mutant AML. The potential to go into a third expansion cohort that would include the SETD2 RUNX1 mutant patient. Skipping over pediatric for a second, we are aggressively evaluating how best to prosecute combination of KO-539 plus current standards of care in the front line. This includes 7+3 and venetoclax plus azacitidine. We'll have more to say about that later this year. And then we also see an opportunity in, of course, pediatric development as well as other acute leukemias, where there's very high unmet need. We're fortunate now to be in such a strong cash position that we can really lean into this program, and we think we can create a significant amount of value for patients and for shareholders over the next 12 to 24 months. Turning to Slide 32, just to remind you, this is the patient population. So it's approximately 35% of AML, and you can see the breakdown there between NPM1 mutant on the left, KMT2A rearranged on the right. And of course, despite the introduction of multiple targeted therapies, there remains a very high unmet need in the relapsed/refractory setting. So our current thinking is that a registration-directed study would have a hurdle rate of approximately 25% in the -- with a duration of response of about 6 months. We think that's the right hurdle rate. Let me -- at this point, I'm going to summarize, but let me just invite, if there are any questions, if you could submit them, 1 or 2 questions are already coming in, but if there are other questions, please let us know.

The first question that's come up, and let me just address this now while we're on it. The question is, was the NPM1 mutant patient on any concomitant medications? The answer is yes. The NPM1 mutant patient was on at least 3 other medications that are thought to be associated with incidence of acute pancreatitis. That patient is extremely confounded. Just to go into it in a little bit more detail, the patient was on KO-539, experienced a C. difficile infection, went on oral vancomycin. Patient had a CT scan and was diagnosed with having acute pancreatitis. KO-539 was held for 3 days, the pancreatitis resolved, KO-539 was reintroduced and the patient went on, as I mentioned, to have a CR that was MRD-negative. Patient was on multiple concomitant medications, also had evidence of fatty liver disease. Just a very, very complicated patient history. Another question that's come up is what is the functional consequence of metabolizing or inhibiting CYP3A4 relative to our competition? Let me address that. So in our -- in the case of KO-539, what we can say from this point in the Phase I study is that the exposure of KO-539 is not -- does not appear to be affected by concomitant administration of azoles. There is some variability in the exposure. But we've looked at patients on no azoles, moderate and strong, and we don't see an effect of azoles on the exposure of KO-539. Interestingly, KO-539 is a substrate of CYP3A4, and it appears that at least one of its metabolites is an inhibitor of the enzyme. What that means is -- is an inhibitor of, I should say, KO-539 mediated metabolism -- sorry, CYP3A4 mediated metabolism of KO-539. It's hard to tell the players without a program here. So when you introduce KO-539, you see a time-dependent increase in its exposure that relates to the fact that the metabolite is inhibiting the enzyme that's breaking down the parent. We think that's probably why we saw activity at such lower doses than what we had predicted. The functional consequence of that is if that activity of the metabolite of KO-539 influences CYP3A4, then you just have -- you have to deal with that. And lots of folks ask about venetoclax. Venetoclax, if you read the package insert, there's a very clear algorithm for how to dose reduce in the presence of either a moderate or strong CYP3A4 inhibitor. You just dial the dose down. To the extent that there's a drug-drug interaction, we don't know that there will be. We don't know that the metabolite of KO-539 affects any other compound. But if there is, you just deal with that, and you'll dial down the other compounds. In the case of our competition, as we understand it, they are actually metabolized by CYP3A4 and so they are, I would say, the exposure is more dependent on whether patients are on no azoles, moderate azoles or strong azoles. In and of itself, that isn't a challenge. There are lots of drugs that are affected by CYP3A4 inhibitors. The question for both compounds will be one of safety and tolerability. I think they have their own PK and metabolic profiles in the case of KO-539, up to the 400-milligram cohort, we've been very encouraged by the safety and tolerability. We're not seeing any recurrent toxicities. We're not seeing any -- in the patients for whom there are excursions outside of the -- what you would expect the exposure to be. We're not seeing that associated with any toxicities. So KO-539 just appears to be a very well-tolerated drug that is very active. I'll let the competitors speak to their data. But I think that a lot of the game is going to be around the safety and tolerability, not only as a monotherapy but ultimately rolling forward to the combination. Do we -- another question, do we foresee any issues combining with any other therapies, such as venetoclax given the CYP3A4 interaction? I think I've addressed that question. No, we don't foresee any issues. In any combination, one has to do 2 things. You have to do a formal drug-drug interaction study. We will do that. You also have to -- you typically start at a lower dose and you have a safety run in. We will do that. But given that KO-539 is a perpetrator in the -- you need to use the FDA's language, what it means is we'll just adjust the dose of any other drug, venetoclax or whatnot to account for that. Today, we don't actually know whether 539 will affect the exposure of any other drug. But even if it does, there are well-established algorithms. And again, I would refer you to the venetoclax package insert. Another question from the audience. Where are we in dose escalation? When do we expect to hit a recommended Phase II dose and move into the expansion cohorts? So we are currently evaluating the 600-milligram cohort. That's going well. We continue to be very encouraged by the safety and tolerability. I think we have 3 paths going forward. If we clear 600 milligrams, you could, in principle, dose escalate. You could move forward at 600 or you could move forward at another dose. And the way that we'll work through that is to look at, first and foremost, the safety and tolerability, the PK and exposure. Are we seeing evidence of a plateau and then, of course, any biological clinical activity. It's not impossible. In fact, I think it's possible that we will not hit an MTD, that we will, in fact, hit an RP2D. Obviously, we're right in the midst of the study. That's not uncommon for targeted therapies in oncology. In fact, Stephen refers me to the experience that his team -- his former colleagues at AstraZeneca had with Tagrisso. It's possible we'll move forward and evaluate KO-539 in a handful of patients at a couple of different doses, just to really zero in on what's exactly the right dose. But we take great comfort out of the fact that this compound is very active, and it appears to have a very promising safety and tolerability profile. We think KO-539 has the potential to be a best-in-class menin inhibitor. So a couple more questions. I know we're coming close to the end. When will we report the next clinical update? We're guiding toward the summertime, maybe EHA or ASCO. We will not have data at the AACR meeting, there won't be enough time. And if we present the data at either EHA or ASCO, what you should expect to see is data from the Phase I dose escalation. If the expansion cohorts are underway, there won't -- probably won't be enough time between the start and the presentation, but you will get a good next update. We will, in all likelihood, provide guidance when we transition from dose escalation to dose expansion. And that will be in the form of some -- probably a press release or in connection with an earnings call. Just to give you a little bit of additional color, I know we're going to get a lot of questions. We won't be presenting clinical data in a press release. We'll save that to a future scientific or clinical meeting. The -- another question that's come in, is it your parent molecule or any metabolites that drive antitumor activity? So I'll confess to you, we're still working this through. The team is doing a tremendous amount of work to characterize the metabolism of KO-539 as well as the properties of the key metabolites. And what we can say is that it appears that at least 2 of the major metabolites appear to inhibit menin-MLL interaction in vitro. Whether they're active in human whole blood, I don't think we know that yet. But it does appear to be the biological activity of the parent and at least a key metabolite. I will highlight for you that because CYP3A4 is expressed in bone marrow, there's a difference between what you're seeing in plasma and what's going on in bone marrow, and we're in the process of sorting that out. So just to take you to the very end because we've got about a minute to wrap up. To take you to the final slide, Slide 33. We've made a lot of progress. 2020 was a great year. I think 2021 and beyond will be as good, if not better. We're driving forward both on the farnesyltransferase inhibitor program, moving into the combinations. The menin inhibitor, we're going to move aggressively into the relapsed/refractory and tee up the frontline studies. Thank you to all of you who are investors for your very strong support, and we look forward to providing continued future updates to you throughout this year. And with that, I'll conclude. Again, I want to thank JPMorgan for the opportunity to give you an update, and thank all of you.