Kura Oncology, Inc. Q3 FY2020 Earnings Call

Thank you for joining us for the Q3 2020 Kura Oncology Conference Call. All lines are currently muted for listening. After the presentation, we will have a question-and-answer session. I will now turn the call over to your speaker today, Pete De Spain. Please proceed.

Thank you, operator. Good morning and welcome to Kura Oncology's third 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; Dr. Stephen Dale, our Chief Medical Officer; Kirsten Flowers, our Chief Commercial Officer; and Kathy Ford, our Chief Operating 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'll 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 bright and early this morning. Kura was founded six years ago with a fundamental mission to realize the promise of precision medicines to help patients with cancer lead better, longer lives. We've made tremendous progress over that time with much of our effort centered around our lead drug candidate tipifarnib. Harnessing the power of precision medicine, we've demonstrated a compelling level of clinical activity in HRAS mutant head and neck squamous cell carcinoma, a particularly difficult-to-treat patient population, culminating in our ongoing AIM-HN registration-directed trial. We're also pioneering new approaches to expand the use of tipifarnib into larger patient populations with preclinical data that supports the potential to expand the therapeutic utility of tipifarnib to HRAS and PI3-kinase dependent tumors that may represent up to half of HNSCC. All the while, we've been optimizing, testing, and advancing our menin inhibitor, KO-539, an exciting new class of drugs for patients with acute leukemias, and we look forward to presenting preliminary clinical data for this program at the American Society of Hematology Annual Meeting next month. And we do all of this from a position of strength in terms of our proprietary assets, financial resources, and talent, the latter of which I'm pleased to say has been further enhanced with the recent addition of Dr. Stephen Dale as our Chief Medical Officer. Stephen joined us in August, most recently from Kyowa Kirin, where he served as Senior Vice President, Global Head of Medical Science, with responsibility for oncology, neuroscience, immunology, and rare diseases. Previously, he was Global Clinical Vice President and Clinical Head of Oncology at AstraZeneca, where he oversaw the development of Tagrisso for metastatic EGFR-T790M mutation-positive non-small cell lung cancer. Stephen also worked with the Iressa team on the IPASS study in patients with EGFR activating mutations, which evoked a paradigm shift in the way non-small cell lung cancer is treated. His experience with leading late-stage drug development teams, including the successful development and approval of multiple targeted therapies, is already having a profound impact on our organization as we continue to focus on our two major clinical development programs: tipifarnib in HRAS dependent HNSCC and KO-539 in AML. Now, let's dig into both programs a little deeper, beginning with our menin inhibitor, KO-539. KO-539 is a potent selective oral small-molecule inhibitor of the menin-KMT2A or MLL interaction, with downstream effects on HOXA9 and MEIS1 gene expression. We've generated preclinical data that supports the potential anti-tumor activity of KO-539 in genetically defined subsets of acute leukemia, including, but not limited to, those with rearrangements in the KMT2A gene, as well as those with oncogenic driver mutations in genes such as NPM1. We believe KO-539 represents a differentiated approach to target genetic subsets representing potentially 35% or more of the total adult population. We dosed our first patient in our Phase 1/2a clinical trial of KO-539 in relapsed/refractory AML late last year. The trial, which we've named KOMET-001, is using an accelerated adaptive design, with dose selection based on a modified toxicity probability interval, a trial design that enables treatment of a single patient per dose level early on, exposing fewer patients to dose levels that are believed to be sub-therapeutic. Although the first several escalations were conducted with single patient cohorts, we advanced to a more traditional three plus three design for dose escalation concurrent with the submission of our ASH abstract in early August to gather more data in a larger number of patients. Last month, we were pleased to learn our abstract reporting preliminary data from KOMET-001 was accepted for oral presentation at ASH. The abstract, which was posted on the ASH website yesterday morning, highlighted encouraging safety and tolerability, as well as evidence of anti-leukemic activity as of the data cutoff of August 10. We look forward to sharing a more mature data set, including preliminary data from approximately 10 patients with relapsed/refractory AML in the oral presentation at ASH on December 5. It's also worth noting we will be hosting a virtual investor event featuring two of the trial's investigators immediately following the oral session on December 5th. Please stay tuned for more details. In the meantime, we're very encouraged with the progress we have made with the study as KOMET-001 continues in dose escalation. Given the favorable safety and tolerability we've seen thus far, we now expect to determine a recommended Phase 2 dose for KO-539 in the first quarter of 2021. We continue to add clinical sites in anticipation of moving into the expansion cohorts pending additional clinical data. The planned expansion cohorts include NPM1 mutant AML and KMT2A or MLL rearranged AML, selected patient populations where we believe KO-539 has the potential to demonstrate increased clinical benefit. In addition, we're exploring options to potentially broaden the opportunity in the treatment of acute leukemias in adults, as well as the combination of KO-539 with chemotherapy and targeted therapies in the frontline. Now, let's move to our most advanced program tipifarnib for the treatment of patients with head and neck squamous cell carcinoma, a population in dire need of effective new treatments. In addition to conducting our ongoing registration-directed trial of tipifarnib in recurrent or metastatic HRAS mutant HNSCC, a trial that we call AIM-HN, we're also leveraging new advances to expand the use of tipifarnib into larger patient populations. Over the past several years, our internal translational research team led by Dr. Francis Burrows has identified what we believe to be a compelling opportunity to combine tipifarnib with inhibitors of the enzyme PI3-kinase alpha to treat HNSCC patients whose tumors are dependent on HRAS and/or PI3-kinase alpha. This work, which has been multiple years in the making, was the subject of our poster presentation at the EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics symposium, also called the Triple Meeting, a couple of weeks ago. Our preclinical data support the observation that HRAS and PI3-kinase are co-dependent oncogenes in HNSCC and suggested that a combination approach has the potential to provide meaningfully better anti-tumor activity than inhibiting either target alone. The compelling preclinical data presented at the Triple Meeting underscore the potential to combine tipifarnib with the PI3-kinase alpha inhibitor to treat patients with head and neck squamous cell carcinoma. As such, we're prioritizing the conduct of a Phase 1/2 proof of concept study of tipifarnib in combination with the PI3-kinase alpha inhibitor in advanced or unresectable relapsed/refractory HNSCC harboring PIK3CA mutations or amplifications and/or HRAS overexpression. We look forward to sharing more details with you about the trial in the months ahead. With that, I'll now turn the call over to Dr. Marc Grasso for a discussion of our financial results for the third quarter 2020.

Thank you, Troy, and good morning, 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 third quarter of 2020 were $16.6 million compared to $12.5 million for the third quarter of 2019. The increase in R&D expenses was primarily due to an increase in clinical development activities related to our ongoing trials and personnel costs and other expenses. General and administrative expenses for the third quarter of 2020 were $7.6 million compared to $5.1 million for the third quarter of 2019. The increase in G&A expenses was primarily due to increases in pre-commercial planning expenses, personnel costs, and non-cash share-based compensation. Net loss for the third quarter of 2020 was $23.8 million or $0.42 per share compared to a net loss of $16.4 million or $0.36 per share for the third quarter of 2019. As of September 30, 2020, we had cash, cash equivalents, and short-term investments of $325.4 million compared with $236.9 million as of December 31, 2019. Based on our current plans, we continue to believe 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 ongoing challenges of the global pandemic, we continue to execute on our two major clinical development programs. I'm proud of the team and pleased by the terrific progress we're making. We remain in a strong cash position, as we approach important catalysts, beginning with the first presentation of clinical data from our KOMET-001 study at ASH. With that, operator, we're now ready to take questions.

And your first question comes from the line of Jonathan Chang.

Good morning and thanks for taking my questions. First question, can you talk about the potential opportunities for KO-539 beyond NPM1 mutant and MLL rearranged AML?

Sure, Jonathan. Thanks for the question and good morning. So, it's a timely question. As you saw in the abstract, we were quite excited to be able to enroll a patient who had a SETD2, RUNX1 mutant AML. And I think that's an example that speaks to, a potentially broader application of menin inhibitors. And the way to think about it is MLL controls the expression of two critical transcription factors, MEIS1 and HOXA9. Those two transcription factors, in turn, control a set of genes that determine whether leukemic blasts remain in an undifferentiated state — sort of an angry adolescence, if you will — or if the cell differentiates and matures into a granulocyte or a monocyte, a more mature cell. What a menin inhibitor does is it blocks the action of MLL and it downregulates the expression of HOXA9 MEIS1 and switches the cell from one state to the other. Increasingly, what we're learning is that a number of mutations in AML can contribute to the tumor's dependence on the MLL pathway and SETD2 is a good example. It actually appears to modulate a particular methyl mark on histones. And the challenge, of course, is given the genetic complexity of AML, it's difficult to have preclinical models to represent all the various combinations. But we're optimistic that there is a set of acute leukemias that may be as large as an additional 15% of AML above and beyond NPM1 and MLLr, where the tumor is dependent on the MLL pathway and has two or more mutations that are driving that MLL dependence. So the SETD2, RUNX1 mutant is such an example. We're very actively investigating whether there are other instances both preclinically and clinically.

And one other question for me. Can you provide any color around how we should be thinking about the dose level you're currently treating patients at for KO-539 versus the dose level where you achieved the complete response close to the abstract?

So before we dosed a patient based on allometric scaling calculations and a lot of sort of preclinical work that we had done, we estimated that the recommended Phase 2 dose per KO-539 would be approximately 600 milligrams per kilogram QD. We were very surprised when we saw evidence of biological activity in the first three dosing cohorts, which were 50, 100, and 200, and in particular, we observed the patient with the complete response at the 100 milligram dosing cohort. What that suggested to us was that the compound was active at lower doses than we expected. We think we now have an explanation for that and that's some intrinsic properties of KO-539. But it motivated us to expand the cohort and then continue escalation. We are currently evaluating patients in a 400 milligram cohort. So we've now dosed multiple patients with 200, multiple patients with 400. If we're successful in clearing the 400 milligram cohort, we likely will then go to 600 milligrams. As you, I think your question correctly points out, we may not — that may not be the recommended Phase 2 dose, given that we're multiple times higher than where we observed the complete response. But we think it gives us the flexibility to be able to determine a recommended Phase 2 dose and potentially a large therapeutic window, which is really the ideal combination for a compound such as KO-539. So, the ASH data that you'll see will likely be from the 200 milligram and 400 milligram cohorts, in addition to what's been disclosed in the abstract. We're continuing in dose escalation and from our perspective, although we pushed the timeline out by one additional quarter, we view that as a good thing because it gives us the potential to push the dose and really explore — do we have a wide therapeutic window and flexibility in the dosing range. Hopefully, that helps address your question.

And your next question comes from the line of Peter Lawson from Barclays.

Hey, thanks, Troy. Thanks for taking the questions. And congratulations on the initial data. KO-539, are you seeing QT prolongation, and then for the metabolism of the drug, is that exclusively going through CYP3A4? Could you look through that please?

Yeah, Peter, happy to answer both of those. So, with respect to ERK inhibition and QT prolongation, let me be clear because I know there were some questions after the abstract dropped rather unexpectedly yesterday. We have not seen any evidence of QT prolongation. As I've said in previous calls, we did extensive testing preclinically. The compound shows a low propensity for any kind of QT interval prolongation or cardiac signal. We are, of course, monitoring every patient on the study closely. We've not seen any evidence of QT prolongation and we've looked very carefully. So, to the point that I was making, Jonathan, in the preceding question, I think we feel like we have very — we're very encouraged by the safety and tolerability, not just with respect to QT but overall, and we think potentially we have a broad therapeutic window. In terms of your second question, Peter, on the pharmacokinetics. So, as I mentioned, we were surprised — pleasantly surprised to see evidence of biological activity in the early cohorts. It was clear that the drug was active at doses below what we were expecting. And the abstract really, remember, is a snapshot in time. We evaluated whether it was the contribution of concomitant medications, such as Azoles and their effects on CYP3A4 inhibition that might be driving the activity of KO-539. We've ruled that out at least for now. There doesn't seem to be any dependence of KO-539 on whether patients are on moderate or strong Azoles, for example. What we do observe both preclinically and clinically is that KO-539, and at least one of its metabolites, appear to inhibit the action of CYP3A4. And by doing that, essentially they are inhibiting their own metabolism. They do it in a time-dependent manner. And so you can imagine the compound accumulates over time. We're still characterizing the pharmacokinetics and exposure. I want to stress that we've continued dosing on a once-daily schedule throughout each cohort. And as I've commented, we see very encouraging safety and tolerability. The significance of that — that auto-inhibitory activity on CYP3A4 is important because CYP3A4 is an enzyme that is present not only in the liver but in the bone marrow. It's one of the ways, believe, that bone marrow actually protects itself from xenobiotics and there are reports in the literature that you can see a number of compounds, such as FLT3 inhibitors, are deactivated in bone marrow because they're metabolized by CYP3A4. This compound appears to be resistant to that because it inhibits its own metabolism. To your final question, Peter, there are likely other metabolic enzymes also at work. And that's part of the overall package that we're characterizing as we are conducting the Phase 1 dose escalation study, really trying to understand PK exposure, key metabolites, and all of the questions. And that's the basic bread and butter of early-stage drug development; nothing really unusual to report there.

Great, thank you. And then the initial side effect profile you've seen a couple of Grade 3s. Do you think that in any way can preclude you from going higher in dosing?

No, it doesn't, not at all. And actually, Peter, let me use that as an opportunity to invite Stephen Dale to comment on those two Grade 3 AEs, what we saw, and what they might mean in terms of our ability to both dose higher and potentially expand into other indications such as pediatric. Stephen, are you able to take Peter's question?

Yeah, of course. Thank you, Troy. Hi, Peter. No, it's a great question. So as you see from the abstract, we saw two Grade 3s in the early single patient cohort escalation. One was a thromboembolic event Grade 3, and that was a patient on 100 milligrams. And one was tumor lysis syndrome, 50 milligrams. So if we look at the thromboembolic events first and we should say that, and the association or the known association of VTE with AML in acute leukemias is actually pretty well understood. It has a background incidence of roundabout 5%. So the event itself isn't atypical. The reason why the causality was assigned was a conservative approach and the SRC Meeting between the investigator and ourselves, we agreed that given the size of the clot rather than the event itself, then we would on this occasion look to assign it to causality. However, in terms of your question on, does it affect escalation? The answer is no. It wasn't deemed to be DLT. The event is an isolated event. And there was no dose interruption. There was no discontinuation of the compound KO-539 because of the event. And I think it's important to know as well. This is the patient at 100 milligrams who actually went on to have the complete remission, which was later and then found to be MRD negative through flow cytometry. And we've not seen any recurrence since this particular episode. Then looking at the tumor lysis syndrome, the patient in 50 milligrams; once again, TLS is a manifestation that is not uncommon, certainly in Hematology, and actually can be seen as a surrogate pharmacodynamic marker of biological effect that the reason for this is that the rapid breakdown of malignant cells. And the leakage of nuclear passage into the bloodstream causes various different issues such as hypocalcemia, uric acid crystallization, and all of these elements were well managed. But it shows that the drug is having an effect. And I think once again this didn't lead to any discontinuation that was drug-related in this particular case, and we haven't seen anything like this again. So hopefully that helps to put those two events into context. And once again, just to echo Troy, we're very encouraged by the safety and tolerability of the compound and we continue to escalate as part of our Phase 1a dose escalation study.

And your next question comes from the line of Marty Auster of Credit Suisse.

Hey guys. Thanks for taking the question. I think I wanted to follow up on something Jonathan mentioned as you're looking at the potential for KO-539 in other tumors that may utilize the MLL pathway or these forms, HOXA9 overexpression situations. I was curious if you could comment on what the gating steps and timeframe might look like for you to kind of make decisions about potentially including those sorts of patients in either future dose 2 cohort expansion or some other study.

So, as I indicated in my answer to Jonathan's question, we're quite keen to evaluate the potential clinical activity of KO-539 in tumors that are not NPM1 or mutant or MLL rearranged. What we require is a way of trying to enrich for those patients. One potential way to do it is a MEIS1 assay, MEIS1 expression assay, or HOXA9 expression assay that could be used in the clinic. That is something that we're working on. It's not quite ready for implementation in the clinic. But it is in active development. There are other approaches that one can also use potentially to enrich for that patient population and we're actively evaluating them internally and also talking with our investigators and KOLs. I am optimistic that we'll be in a position to have potentially a third cohort. It will probably lag behind the other two, as we're working through some of these technical challenges. The advantage, of course, of NPM1 and MLLr is that you can use next-generation sequencing to identify the patients that is standard of care. It's available at all of the sites. So there really aren't operational hurdles to implementing it in a clinical trial. When you're expanding the patient population, unless you want to go with an all-comers population, you have to do a bit more assay development, and that's where we are currently. And I imagine, Marty, that we'll have, we'll be able to give you more guidance in the coming months as to exactly how to think about that and specific timing.

And your next question comes from the line of Ren Benjamin from JMP Securities.

Thanks for taking the question. Troy, in the 10 patients or so that we're going to see at ASH, how many of them will be either MLL rearrangements or NPM1?

Yeah, thanks, Ren. No, we get this question a lot. And the trial is a dynamic, it's a dynamic process. So I don't want to pin down specific numbers. What we can tell you is we're pretty consistently guide that NPM1 mutant AML represents about 30% of the population in the relapsed/refractory setting. The MLLr represents 5% to 10%. When you get to small numbers, it's a bit spastic. So you have to, you shouldn't over-interpret it. But based on what we're seeing and the patient flow, those numbers are not unreasonable. We're not pushing people off of those numbers, if that helps give you some guidance. I want to reiterate to everyone. This is an all-comers trial. You should expect most of the patients not to fall into those categories, and that's both by request of the FDA and by design to ensure that we get an adequate picture of safety and tolerability and we also get to potentially uncover the clinical activity of the compound as we have with the SETD1s, one mutant patient. But we do think that the ASH update, Ren, will be a meaningful update beyond what you've seen in the abstract, both in terms of number of patients, follow up, and potentially new patients as well.

Got it. And I know that you were talking about biomarkers and biomarker signatures maybe outside of AML. I was remembering your comments correctly, especially when looking at other indications to go after. But within AML in this study, for example, you found SETD2 and RUNX1, can you talk about other signatures that might be popping up that's interesting, that you think you might pursue going further? And then also as we look toward 2021 and then the RP2D getting established, what is now the, I guess the path forward? Is it monotherapy studies focused on kind of like last line? Is it more combination studies and do you think you could go straight to a registrational study given the biomarker-defined indications have been able to do that?

Sure, Ren, that's great. There are three parts to your question. First, I want to be cautious about discussing potential other mutations or biomarkers because this is an area of active investigation and it's a competitive field. We're doing a lot of innovation here, led by Dr. Francis Burrows, who many of you have interacted with. We'll have more updates in the future, but I don't think we can share much more today. Regarding the study, Ren, we plan to continue as a monotherapy in the relapsed and refractory setting. We believe there is an opportunity to run a single-arm study in the U.S., focusing on response rate as the primary endpoint, similar to what has been done with IDH inhibitors and FLT3 inhibitors. Our hurdle rate is approximately 25% to 30% for the NPM1 mutant or MLLr populations, both of which have high unmet needs. NPM1 mutations in this setting usually come with other mutations like DNMT3A, FLT3, or IDH, resulting in a poor prognosis. Feedback from investigators and experts suggests there may be a path forward as a monotherapy. As for the third part of your question, we are actively conducting preclinical work to support studies that would evaluate KO-539 in combination with chemotherapy and targeted therapies in earlier lines of therapy, potentially in frontline settings. This includes looking at the seven plus three group and secondary AML, as well as combinations with FLT3 or IDH therapies. There is significant interest in the scientific and clinical communities to combine menin inhibitors across the spectrum. We need to perform the necessary preclinical work to establish the safety and tolerability of these combinations before moving forward, although this will likely follow the monotherapy studies. I realize I skipped part 2b of your question; we are currently conducting trials as a monotherapy and plan to evaluate expansion cohorts in MLLr and NPM1 mutant AML. These cohorts will initially assess clinical proof-of-concept to determine if there is a threshold level of activity. If we achieve success, the intent is for these cohorts to become registration enabling. This approach mirrors successful strategies seen with other targeted therapies in oncology, providing a strong precedent in targeted oncology and specifically in AML.

Got it. Thanks very much, Troy, and you get the award for remembering all my questions. Even I didn't remember.

Thanks, Ren.

And your next question comes from the line of Alexander Duncan of Piper Sandler.

Hi, good morning, and thanks for the questions. A multipart question on KO-539, of course, so please bear with me. The PK you've discussed and as was highlighted in the abstract is pretty interesting. So one broadly, are you aware of any other drugs that have a similar inhibition effect that was beneficial for exposure and efficacy? Secondly, do you believe the anti-tumor activity you're seeing is driven by Cmax or AUC? And based on that unique PK profile, do you still think daily dosing is required if it's Cmax-driven? And lastly, related to the last question, and the team has already touched on this, but are you concerned about the potential of KO-539 accumulation in patients over time and the potential precipitation? And maybe some color on the timing of the thromboembolic event with respect to the initiation of dosing would be helpful there? Thanks.

Sure, Alex. So in terms of the first part of your question, we don't have an immediate other example to give you, at least I don't. And I'd invite Stephen, if he does, to comment. I don't have another example of a compound we can give you that phenocopies what we're seeing with KO-539, and that's just off the top of my head. Certainly something that we can look into and get back to you on. Stephen, I don't know if you have any that could give us this kind of auto-inhibitory activity and CYP3A4?

Actually, the answer is not. It's a great question, but it's not actually come up. So, in the patient population you've given another example just at the moment, sorry.

No worries. So, Alex, let us go back to the team and see if we can give you another example to take a look at. In terms of the anti-tumor activity, I don't know that we're really thinking about it at this point in terms of Cmax or AUC. This biology is a little bit unusual, and it's not as though we're inhibiting enzymatic activity. What we're doing is blocking a protein-protein interaction, which then induces an irreversible step in differentiation. So essentially, you have to inhibit that interaction sufficiently enough that you can disassociate menin from chromatin and start the tumor rolling down the hill, but it wants to go down, right? It desperately wants to differentiate and it's prohibited from doing this from differentiating. So I think there are multiple ways you can get there. In fact, we see, the biology is pretty permissive in terms of schedule. We're able to drive differentiation with schedules ranging from continuous to three weeks on, one week off, two weeks on, two weeks off, and so forth. We are continuing to do daily dosing. That's, of course, optimal from the standpoint of compliance and patient convenience. Is it necessary? It's, again, that's something that I think we'll continue to give attention to. At this point, as Stephen mentioned in his comments to an earlier question, you typically do intermittent dosing because you're trying to dose around the toxicity. And we don't see any toxicity here. It is important that you characterize the PK and the exposure of your compound. But the advantage that one has with a menin inhibitor is because this is such a unique event, and you have only eight or nine genes that are under the control of MLL, you have the potential for a broad therapeutic window. And that seems to be consistent with what we're seeing. So at the moment, we're not seeing a reason to deviate from daily dosing. But it is certainly something that we will continue to evaluate. And then, on your final question, which is, what was the timing of the embolic event relative to dosing? Let me turn that over to Stephen. Stephen, I don't know if you have anything more to share with Alex on the specific timing of that, of the AE versus the start of dosing? If there is anything to learn there?

Yeah. And it's another, it's a great follow-up question. So neither with the, determined to be dose-limiting toxicities. I think just going back to the thromboembolic event. That patient continued dosing and actually there was an intra-patient escalation in this particular subject from 100 milligrams to 200 milligrams. And again, the 100 milligram dose we saw this complete remission. To put a bit more context around this particular case, the patient, as all these patients are very poorly, this is relapsed/refractory disease is advanced disease, and this patient had been mobilized for quite some time. So there was an inherent risk that anyway for increased risk of DVT. We've not seen any duplication of this. In terms of the tumor lysis syndrome, very similar pattern, not seen before. It's a recognized event in terms of drugs in hematology with rapid breakdown of malignant cells. And the actual events occurred in cycle one in that particular case, but again, it wasn't deemed to be a DLT by our protocol, and once again, investigators were well primed from the protocol to monitor for TLS for tumor lysis syndrome, and again, we've not had any issues with that moving forward. So nothing has stopped the escalation to date, which we carry on escalations by the Phase 1a. So hope that gives a little more context.

And your next question comes from the line of Phil Nadeau of Cowen and Company.

Good morning, congrats on the progress and thanks for taking my question. As we look forward to ASH, I'm kind of curious to hear your thoughts on how we should set our expectations? So, you've suggested that there are going to be maybe 10 patients at the meeting. Are all 10 of those patients going to be available for response? And given the percentages you've suggested in the population of MLLr and NPM1, if there are approximately 10 patients, then we expect to see maybe three NPM1 and maybe one MLLr patient, although we've already seen one. So it doesn't seem like we're going to have enough patient numbers to evaluate really response rates? So how should we be thinking about and what is intriguing efficacy? What's good? What's bad? Is it ACR? Is it some reduction in hydroxyurea? Just curious to hear your thoughts.

Yeah, Phil, it's a great question and it's another question that we get often, so I'm glad you raised it. I absolutely, we absolutely understand everyone's impatience to get to a response rate and that's kind of a natural human condition. That being said, this is a Phase 1 dose escalation study in an all-comers population, and it is that, by again, by request of FDA and by design. So I think you're characterizing it correctly, which is you're going to get an all-comers population. I think the way you're positioning it and thinking about it is exactly right. From our standpoint, if one sees evidence of clinical activity, clinical benefit in an NPM1 mutant patient, obviously, we'll all feel much better. If you see a couple of examples, you'll feel even that much better. I will stress, I will point out to you that there is really nothing magical about NPM1, and that's really the significance of the SETD2, RUNX1 mutant. So the, again the biology here is you have mutations in AML that are driving dependence of the tumor on the MLL pathway. The reason everyone is focused on NPM1 is that it's a large population and it's very well-validated preclinically. But the significance of the SETD2, RUNX1 mutant patient is you're actually seeing an example of the drug doing exactly what we hoped it would do, namely, it's inhibiting menin, the menin-MLL interaction. It's down-regulating gene expression and driving a CR. NPM1 is one special example. SETD2, RUNX1 is another. There may be others as we go along. There are a number of mutations and combinations of mutations that may be amenable to this approach. So, from our standpoint that goals of the Phase 1 have been safety and tolerability, characterize that, characterize PK and exposure and then look for evidence of biological activity or anti-leukemic activity. I think we're well on our way to checking the box on all four of those. Our goal is to reach a recommended Phase 2 dose. Ideally one where we have a wide therapeutic index; we can give very clear instructions to the investigators in the expansion phase and beyond as to what to expect and how to use KO-539 as a therapeutic in patients, and then we'll transition to the expansion cohorts and we can start to talk about response rates. Unless and until you are in a genetically enriched population, it's really premature to think about a response rate. Either if you're seeing anecdotal evidence of clinical activity, you're seeing a responder here or there. That's great. I mean, that certainly tells you you're on the right path, but I think our view is — and this is not just for KO-539, I think this is across oncology in Phase 1 — is just premature to be thinking about response rate. The trial is not designed for that, it's not designed to test that, and we will absolutely get there as quickly as we can. We're anticipating, as I said, finishing up the dose escalation in the first quarter of next year, and we've already gotten alignment from the FDA to be able to move into the expansion cohorts as quickly as possible, and we're at a point where there is good excitement for this mechanism of action. We have more patients than we have slots. So I think we're in a very, very strong position to maintain the momentum and to be able to answer your question with actual data flow. Hope that helps. There's a lot of explanation, but I hope that gives you some color.

That does, that helps a lot. And then second on the adverse events that were noted in the abstract, tumor lysis and thromboembolic event. Have you put in place any prophylaxis as part of the protocol in light of those events, or as you mentioned, it sounds like they were one-off events where they — was that just actually one-off and you haven't changed the prophylaxis since seeing those for the first time?

There isn't, there haven't been any steps implemented, Phil, in either case to prophylax patients to protect against those. As Stephen mentioned in his comments, both of those events are not uncommon in AML and people shouldn't read too much into them. There is certainly something to be aware of. But as we've dose escalated, we're now at 400 milligrams. We haven't seen any other evidence to-date. Obviously, the study is still ongoing, but we haven't seen any other evidence of either of those two events. So there really at this point is not a need for prophylaxis.

And at this time we have no further questions. I would now like to turn the conference back to Troy Wilson for any closing remarks.

Thank you, operator, and thank you all for participating in our call today. We'll be participating in several virtual Investor conferences in the weeks ahead, and we 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, of course. Thanks again and have a great rest of the day, everyone.

Ladies and gentlemen, this does conclude today's conference call. You may now disconnect. Thank you for participating.