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spk09: Good day and thank you for standing by. Welcome to the Q4 2021 Cura Oncology Inc. Earnings Conference Call. At this time, all participants are in listen-only mode. Later, we will conduct a question and answer session and instructions will follow at that time. If anyone should require assistance during the conference, please press star then zero on your touch-tone telephone. I would now like to turn the conference over to your host, Mr. Pete Despain, Senior Vice President of Investor Relations.
spk06: Thank you, Christian. Good afternoon and welcome to Cura Oncology's fourth quarter and full year 2021 conference call. Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer, and Tom Doyle, our Senior Vice President of Finance and Accounting. 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 Cura's filings with the SEC, which are available from the SEC or on the Cura Oncology website for information concerning risk factors that could affect the company. With that, I'll now turn the call over to Troy.
spk03: Thank you, Pete, and thank you all for joining us this afternoon. Although 2021 was a challenging year in many ways, We at Cura took the opportunity to invest in and optimize our discovery and development programs. We believe we've made significant advances in understanding the diseases we seek to target, as well as in learning how best to use our drug candidates to drive clinical benefit for patients. This past year was also one of deliberate focus on operational execution throughout the organization. Now, building on the tremendous efforts of our team, we approach a number of catalysts in the year ahead with significant momentum, resources, and enthusiasm. Our enthusiasm is supported by resumed enrollment in the COMET-001 Phase 1B expansion cohorts for our newly named MENIN inhibitor, Zifdomenib. The first several patients dosed in our Phase 1-2 combination trial of tipifarnib plus alpelisib in head and neck squamous cell carcinoma. an abstract supporting the therapeutic rationale for our next-generation farnesyl transferase inhibitor program accepted for presentation at AACR, and an expanded leadership team to support and advance our growth and execution. By mid-2022, we anticipate having three independent drug development programs to drive value in both solid and liquid tumors with meaningful data catalysts in the next 6 to 24 months. and as we approach these catalysts from a position of financial strength with an experienced team and organization and more than a half a billion in cash. Now let's take a closer look at the progress within each of our programs, beginning with our menin inhibitor, formerly known as KO539, Ziftimenib. Last month, we were pleased to receive FDA authorization to proceed with our COMET001 trial of Ziftimenib in patients with relapsed or refractory AML. the partial clinical hold was lifted following agreement with FDA on an enhanced mitigation strategy for differentiation syndrome. As we've discussed, differentiation syndrome is known to be an on-target effect associated with a number of therapeutic agents, including menin inhibitors, which may induce differentiation of leukemic blasts. Highlights of our enhanced mitigation strategy include heightened awareness, increased monitoring, and recommendations for aggressive, intervention, all to ensure physicians are fully informed and prepared to address future events should they occur. I'm very proud of our team for working so diligently with FDA and our site investigators over the holidays to resolve this issue, which speaks to our focus on operational execution. Screening for new patients began in earnest, and we're pleased to report that patient enrollment in the Phase 1B expansion cohorts has resumed. While we're excited to recruit new patients to our Phase 1B study, it's important to remember that patients already enrolled were eligible to remain on study during the partial clinical hold. And we continue to be encouraged by the safety and tolerability profile, as well as the clinical activity we're seeing with ZIFTA-MENET. Looking forward, we expect to complete enrollment of 24 patients in the Phase 1B study by the second quarter, after which we will assess the patients in each cohort for safety and tolerability, pharmacokinetics and exposure, as well as efficacy. Our goal is to identify the recommended Phase 2 dose and report top-line data from the Phase 1b by the third quarter with updated data from COMET-001 reserved for a medical meeting in the fourth quarter. Once we've identified the recommended Phase 2 dose, we plan to continue enrolling up to an additional 18 patients in the selected cohort of the Phase 1b study, enabling us to maintain momentum while we transition into the Phase 2 portion of Comet 001. We believe data from all patients treated at the recommended Phase 2 dose will have potential to contribute to the registrational patient population. Meanwhile, we continue to add sites in the United States and Europe in anticipation of the subsequent Phase 2 portion of Comet 001. We're also designing a comprehensive development strategy that builds on the potential to register Ziftimenib as a monotherapy while giving us flexibility to access larger opportunities, including earlier lines of therapy in combination more quickly. We expect to have much more to say regarding our global development strategy for Ziftimenib later this year. Now let's turn our attention to our farnesyl transferase inhibitor programs. We continue to view farnesyl transferase inhibition as a potentially valuable therapeutic and commercial franchise, one with potential to deliver multiple opportunities in oncology. Our most advanced effort is focused on patients with HRS mutant head and neck squamous cell carcinomas, or HNSCC, through our ongoing AMHN registration-directed trial of tibifarnabizum monotherapy. In addition, a growing body of preclinical and clinical data support the development of tipifarnib in combination regimens directed at larger genetic subsets. Among these potential combinations, we've prioritized the combination of tipifarnib and an inhibitor of PI3 kinase alpha. Our preclinical data suggests that HRAS and PI3 kinase alpha are codependent oncogenes in HNSCC, and that combining tipifarnib with a PI3 kinase alpha inhibitor has potential to provide meaningfully better anti-tumor activity relative to inhibiting either target alone. Furthermore, we believe this combination has potential to increase the total addressable population for tipifarnib to as much as 50% of patients with HNSCC. Last year, we announced a clinical collaboration with Novartis to evaluate the combination of tipifarnib and the PI3 kinase alpha inhibitor alpelicib in patients with HNSCC. Alpelicib is approved to treat patients with PIK3CA mutant breast cancer, and it has demonstrated encouraging evidence of clinical activity in patients with PIK3CA-disregulated HNSCC. In December, we dosed the first patient in a phase 1-2 study of tipifarnib in combination with alpelosib in HNSCC, a study which we call the current trial, and we're pleased with the continued pace of enrollment. The initial cohort includes patients who have PIK3CA-dependent HNSCC, and we expect to initiate an HRAS overexpression cohort by the third quarter of this year. Our goal with the current trial is to identify a recommended phase 2 dose and schedule for the combination. Depending on our progress in the dose escalation, we may be in a position to provide preliminary data on safety, tolerability, and clinical activity of the combination in genetically enriched head and neck patients by year end. Meanwhile, through our own internal efforts and our network of academic collaborations, we've identified some exciting opportunities for farnesyl transferase inhibitors. opportunities we believe represent significant potential value creation. Last year, we nominated KO2806 as our lead development candidate in our next-generation farnesyl transferase inhibitor program. Based upon extensive preclinical work, KO2806 demonstrates improved potency, pharmacokinetic, and physiochemical properties relative to tipifarnib. KO2806 is designed to to target novel farnesylated proteins and address large solid tumor indications of high unmet need through combination regimens with a focus on delaying the onset of drug resistance. We were recently informed that an abstract from one of our academic collaborators supporting the first such opportunity in non-small cell lung cancer has been accepted for presentation at the upcoming American Association for Cancer Research annual meeting. We're excited about this emerging opportunity and look forward to sharing more detailed information in April. In the meantime, we are planning to perform initial clinical evaluation with tipifarnib in non-small cell lung cancer while continuing our IND enabling studies of KO2806. I believe each of our programs has potential to create significant value for patients, healthcare providers, and shareholders. And I believe we have the leadership, experience, and operational and financial resources to realize that value. Toward that end, we recently expanded our senior leadership team to help support and advance our mission. This expansion was driven by three key promotions. Dr. Molly Leone to Senior Vice President of Clinical Development, Pete to Spain to Senior Vice President of Investor Relations, Corporate Communications, Tom Doyle to Senior Vice President of Finance and Accounting. In addition, Nick Scolferato, our Senior Vice President of Regulatory Affairs, has also been added to our senior leadership team. We are intentional about cultivating talent within our organization. These additions to our senior leadership team reflect the significant contributions of Molly, Pete, Tom, and Nick, as well as our confidence in their ability to help lead us into the next exciting phase of growth. In connection with his promotion, Tom's also assumed the role of principal accounting officer from Mark Grasso, who recently stepped down as chief financial and chief business officer to pursue an opportunity closer to his family. I'd like to take this opportunity to thank Mark for his more than three years of service to Cura, during which he played an important role in ensuring our strong financial position. I respect his decision to be closer to his family and wish him well in his future endeavors. With that, I'll now turn the call over to Tom for a discussion of our financial results.
spk04: Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the fourth quarter and full year 2021. I invite you to review the 10-K filed today for a more detailed discussion. Research and development expenses for the fourth quarter of 2021 were $21 million, compared to $17.5 million for the fourth quarter of 2020. R&D expenses for the full year 2021 were $84.7 million, compared to $60.4 million for the prior year. The increase in R&D expenses was primarily due to increases in clinical trial cost, development, and manufacturing activities related to our ZIFTO-MENIB program, costs related to our registration-directed trial for tififarnib, research activities for discovery stage programs, non-cash share-based compensation, and other personnel costs. General and administrative expense for the fourth quarter of 2021 was $12.1 million compared to $8.8 million for the fourth quarter of 2020. G&A expenses for the full year 2021 were $46.5 million compared to $31.5 million for the prior year. The increase in G&A expenses were primarily due to increases in non-cash share-based compensation, personnel cost, and professional fees. Net loss for the fourth quarter of 2021 was $32.7 million, compared to a net loss of $26.2 million for the fourth quarter of 2020. Net loss for the full year of 2021 was $130.5 million, compared to a net loss of $89.6 million for the prior year. The net loss for the fourth quarter and full year of 2021 included non-cash share-based compensation expense of $6.4 million and $23.6 million, respectively. This compares to $3.7 million and $12.8 million for the same periods in 2020. Our cash, cash equivalents, and short-term investments were $518 million as of December 31st, 2021, compared to $633.3 million as of December 31st, 2020. Based on our current plans, we believe that our current cash, cash equivalent, and short-term investments will be sufficient to fund operations into 2024. With that, I now turn the call back over to Troy.
spk03: Thank you, Tom. Before we jump into the question and answer session, let me lay out our anticipated milestones for 2022. Complete enrollment of 24 patients in the COMET001 Phase 1B study by the second quarter. Identify the recommended Phase 2 dose of Ziftimenib and report top-line data from the Phase 1B by the third quarter. Present updated data from the COMET001 at a medical meeting in the fourth quarter. Initiate the HRAS overexpression cohort in current by the third quarter, report preclinical data supporting the use of a farnesyl transferase inhibitor to delay the onset of drug resistance in non-small cell lung cancer in the second quarter, and submit an IND application for KO2806 by the end of 2022. With that, operator, we're now ready for questions.
spk09: Ladies and gentlemen, if you have a question at this time, please press star and then the number one key on your touchtone telephone. Again, that is star one to ask a question. Your first question is from Jonathan Chang from SVV, The Ring.
spk01: Hi, guys. Thanks for taking my questions. Congrats on the progress, and congrats to the promoted individuals. First question on ZyftoMeneb. What information could be provided in the top-line disclosure by 3Q versus the data presentation in 4Q?
spk03: Sure. Jonathan, on behalf of everyone, including the folks who we recently promoted, thank you. In terms of the data update, the top line will be just that. So, you know, we've said consistently that 539 now has demonstrated a very encouraging safety and tolerability profile. So I think the focus will really be on what's the clinical activity at each of the two doses and how did we decide to advance one dose versus the other. It'll really be top line in terms of, you know, response rate, clinical activity at those given doses. As for the presentation at a medical meeting later in the year, that's going to be the fuller picture on the full Comet 001 study. including, you know, the typical, right, safety and tolerability, PK exposure, efficacy, of course, you know, durability, essentially, you know, a more fulsome presentation on all the patients that have been enrolled thus far.
spk01: Got it. Thank you. And then second question, on the next-gen for nasal transphrase inhibitor, KO2806, and the goal of delaying onset of drug resistance, what could the opportunity and development strategy for this program look like?
spk03: That's a really good question, and we're eager to share it with you. As we indicated, the disease area will be non-small cell lung cancer. There's certainly – that's one of the largest – areas of unmet need and one of the largest market opportunities. As for the specific development strategy, Jonathan, I think that's going to have to wait until after the presentation at AACR. At that point, A lot of the data will become clear. You'll understand what we mean when we're talking about rational combinations, and you'll be able to see how we intend to initially use tipifarnib to do some de-risking while we're bringing 2806 along. it'll really be kind of a one-two punch in that area. And it's our hope and expectation that that vignette, if you will, in non-small cell lung cancer is the first of several chapters in this new story. These are entirely new foreign-isolated proteins that we've never really talked publicly about before. This data has been cooking for two to three years at this point. So really looking forward to April and AACR to roll that out with actual data for people to be able to study.
spk01: Got it. Thank you for taking my questions. Thank you.
spk09: Your next question is from Peter Lawson from Barclays.
spk02: Great. Thank you, Troy. And congratulations on all the promotions. For Zip2Menu, just Any comments around how enrollment is going with the recent lifting of the clinical hold and how sites are opening up?
spk03: Peter, thank you again. Prior to being put on the partial clinical hold, folks may remember, we had guided to having full enrollment of the Phase 1B cohorts by the end of Q1. That has now moved to Q2. And we're giving ourselves a little bit of time, just in case we need it, to be able to then look at the patients in the two cohorts and make a data-driven decision on which of the two doses, you know, we would recommend moving forward with. From that, you can tell, you know, we've slipped by approximately a quarter of Of the high-enrolling sites, the ones that have put patients on Comet thus far, 80% of those sites are reengaged, actively screening patients. As we indicated, enrollment has resumed with multiple patients on the study. So the sites are definitely stepping up, and we feel at this point comfortable that we can give the guidance to full enrollment Q2, you know, top-line data Q3, and then the medical presentation in Q4. Gotcha.
spk02: Thank you. And then just how quickly do you think you could start combination trials?
spk03: Yeah, that's a good question. So we are actively planning and preparing for combinations as we speak, even while the Determination of the recommended Phase II dose for the monotherapy is pending. As you might expect, the expectation would be that you step down at least a dose, if not two, from the RP2D and do a safety run-in. We want to make sure that we balance two things, Peter. We move as aggressively as possible while not doing anything to put the program at risk from a regulatory perspective. And, you know, we're balancing that real time. We'll certainly start those studies this year. I just think at this point we're not prepared to give – to give any more granular guidance on exactly the start time. But we're actively in preparation. As I indicated, we're looking both in the front line and in the early relapse setting at combination opportunities with Zip2Mentib.
spk02: Great. Thank you so much. Thanks for taking the questions.
spk09: Your next question is from Tiago Fout from Credit Suisse. Your line is open.
spk05: We're taking a question. So 539 still. So you did allude to it on the prepared remarks, but I want to go back to the patients that were already enrolled in the Phase 1B expansion and were eligible to remain on study. I don't know if you can share anything additionally qualitative on those patients that could have been in study for quite some time right now, or perhaps a different way to think about it. We've discussed in the past a benchmark of about 20 to 30 percent CRCRH as a reasonable range for the class. I don't know how good you still feel about that range or the potential to actually differentiate on efficacy relative to other benchmarks. Curious if you can share any thoughts on that. Thank you.
spk03: Sure, Tiago. Thank you for the question. You're correct in when you formulated the question. We had a number of patients who have remained on study throughout the partial clinical hold, and we're still in the midst of enrollment of the Phase 1B studies. Based on what we've seen thus far from the Phase 1B, our sort of qualitative commentary has been that We believe there's an opportunity with KO539 to be as good as, if not better, than the numbers that have been posted for competing programs. I want to be careful, but we are seeing encouraging safety, tolerability, and clinical activity. But, you know, it's still early days, and I don't want expectations to get out of control, but we definitely think we've got a very, very strong compound here, and everybody is, you know, super fired up to get these Phase 1B cohorts completed. Fair enough.
spk05: Great. Thank you so much.
spk09: Your next question is from Ren Benjamin from JMP Securities. Your line is open.
spk00: Hey, good afternoon, guys. Thanks for taking the questions, and congrats on all the progress. Troy, maybe just starting off, can you talk a little bit about or provide some colors to how the integration of the mitigation efforts, you know, has been going? I know that, you know, you guys got the trial started, kind of restarted in record time. You know, is that, if you can give us some color on that progress and how the initial, you know, how it's looking.
spk03: Sure, Ren. Yeah, thank you for the question. So, maybe just to set expectations and set understanding, we had already had a fairly fulsome section, you know, in the investigator brochure around differentiation syndrome. Now, that was bolstered through the discussions and the feedback that we received from the agency. in the course of getting the clinical hold lifted, but it wasn't as though we were starting with tabula rasa. We had a pretty extensive disclosure there. Really, the focus has been around increased monitoring initially, and then sort of aggressive intervention if standard of care approaches are not effective in terms of withdrawing KO539 from the patient to stop an ongoing episode of differentiation syndrome. So the beginning and sort of then along the way. Both of those were generated in consultation with the study physicians. We've got a number of investigators who are among the world's experts at managing DS, so they were great. And thus far, Ren, we have seen at least another episode of DS that was mild to moderate, managed very effectively using the now sort of heightened awareness and and revised algorithm. It doesn't appear to have dissuaded the investigators at all. They're super excited by what they're seeing, safety, tolerability, efficacy, and I think they know what they need to do. They know how to manage it. We've given them a couple of extra tools to be able to keep the patient's and thus far all indications are that was exactly what was needed. So I don't think we're seeing any real impact at all from the revised mitigation strategy on either site engagement, investigator interest, or the pace of enrollment. Got it.
spk00: And when we think about the enrollment completing and you guys giving yourself a little bit more time, You know, kind of implicit in that, to me, is, you know, also a greater understanding as to the durability of the effect, right? So not just overall response rate, but then the durability. How important is durability for you guys in deciding the RP2D? And, you know, is the timeline, if you will, like kind of still too short before you could make the appropriate decision?
spk03: Yeah, it's a really good question, Ren. We think that the timeline we've articulated is sufficient to be able to discriminate one dose from another and to be able to come and say, we believe we've identified, you know, a recommended phase two dose. That's obviously still subject to the FDA reviewing all of the data, you know, in consultation with us around an end of phase one meeting. but we think the activities we're conducting and the timelines we've laid out are going to be sufficient. Part of what we're giving ourselves, Wren, is, and we've seen others who are working with menin inhibitors comment on this, you do see, if you will, a biphasic sort of response to drugs like this. The first phase is elimination of the leukemia. The second phase is reconstitution of the normal hematopoietic system. In order to get a CR or CRH, you need to have platelets and neutrophils at the level sufficient to call a CR or CRH. In our experience, that can take two or three cycles, you know, really, particularly for patients who are, you know, who've been through multiple rounds of therapy. So, you know, we've built that in as well, but it's more, our thinking is more around let's get the patients enrolled, let's give them an opportunity to get to, you know, the best quality of response, and then the durability is going to be what it's going to be. I would tell you we feel very comfortable with the guidance we've given. We've said consistently four to six months duration of response. No reason at all to deviate from that. And ideally, again, you'd come in on the high end of that. But, you know, it's early days. We waited to be in a position where we could give what we believe to be pretty concrete guidance around the timing of this program and reaching the RP2D, and we feel good about that guidance.
spk00: Got it. And then just one final one for me. You mentioned in your prepared remarks the flexibility regarding a global development strategy, and I might be reading too much into the tea leaves here, but When I think global development strategy, I think probably most ideally with a partner. Is that something that might be in the works, or is this something that you want to do kind of by yourselves and then evaluate a partnership at a later stage?
spk03: Yeah, Red, that's a good question. So let's tease those two things apart. When we speak of a global development strategy, what we mean is, conducting trials that are not only in the United States, but ex-U.S., most notably Western Europe, but also places like certain countries in Asia. That's what we mean when we're talking about a global development program. We are, of course, always evaluating, you know, would we consider a partnership that would either allow us to do more, allow us to go faster, or allow us to lower the risk. There's certainly strong interest across the portfolio. These are things that we have to weigh as, you know, what's best for shareholders, what's best for the programs and the patients involved. But most immediately to your question, when I talk about us moving into a global development program, think of that as, at least in the most immediate case, a trial that's going to be conducted in the U.S. and then identified ex-U.S. countries, really to help drive enrollment, which is what you need in these rarer populations. The BD question or the strategic question, if you will, that's a second question, and that's one that's always out there. But that's not what I was referring to in my comments specifically.
spk00: Terrific. Thanks for the clarifications, and good luck moving forward.
spk03: Thank you.
spk09: Your next question is Ramnang Rajasong from Jefferies. Your line is open.
spk08: Great. Congrats for all the progress. A few quick ones from me. So the first one is, I think, Troy, when would you need FDA to discuss the potential pivotal plan for the 539? Do you need to weigh the full results, maybe a little bit kind of durability, or you actually can meet them after the top one beta in 3Q?
spk03: Yeah, Roger, it's a good question. So it's our understanding, you know, Once we're in a position where we believe we've identified a recommended Phase II dose, obviously there's a lot of supporting information that goes into that determination. There's the safety and tolerability, there's the PK and exposure, and there's the clinical activity. And each of those is, you know, has to be handled completely and correctly. it's not our view, Roger, that we'd be waiting on durability. It's more how quickly can we hustle to get all that data together, to get it clean, to get it into a format where we can deliver it to the agency in a way that addresses any questions that the reviewers might have. So our view is you can imagine we're doing everything we can at risk, to save time. Ultimately, we do have to say, is it this dose or that dose? Plug that in and then have the narrative descriptions and the data supporting it. But I don't think we need to, I don't think we're going to be waiting on durability, you know, to be able to provide those materials and if necessary, answer any questions that the agency might have.
spk08: Got it. That's very helpful. Thank you. Maybe just another one. understanding you are doing the tippy-up elicit combo data potentially initiated by the end of this year. So if the data looks very impressive, how would you kind of incorporate this into your monotherapy pivotal, which is ongoing?
spk03: Yeah, that's a good question. So ultimately, what one does in combination is quite different from what one would do as a monotherapy. The monotherapy is a trial where confirmed response rate in the high VAF population is the primary endpoint, and it's a single-arm trial. In the combination setting, you'd need to do some sort of randomization. You'd also want to make sure that you addressed the contributions of the individual drugs. to, you know, to the activity that you're seeing. What we can tell you is, you know, you don't see high rates of response with either tippy. You certainly don't see them with tippy in the PIK3CA population. You don't see them at all. And with Alpelastib, they're relatively rare. So if you're seeing objective responses, that's a good sign. You know, you probably would need to do some sort of randomization. At this point, we're really looking to see can we recapitulate clinically what we've seen preclinically, namely can we drive, you know, responses and can we maintain durable responses in this much broader set of patients. It's early days. We're encouraged by what we're seeing. You know, we're really trying to get our arms right now around safety and tolerability of the payer. The overall development strategy in head and neck squamous, Roger, I think that's a longer discussion and one that we're preparing for and we'll be in a position to speak to sort of later in the year, I hope.
spk08: Great. Look forward to it. Thank you. That's all from me. Congrats again.
spk03: Thank you.
spk09: Again, that is star at the number one on your telephone keypad to ask a question. Your next question is from Phil Nadeau from Coen & Company. Your line is open.
spk07: Good afternoon. Thanks for taking our questions and let us out our congratulations for the promotions. First, a question on Zyftamineb. In terms of MLLR versus NPM1 patients, do you have expected numbers of each of those genotypes in the trial, and do you hope to get an assessment of response rate for both of those at both doses, or are you fairly confident that the response rate for MLLR and MPM1 will be similar so you won't differentiate between the two?
spk03: Yeah, Phil, that's a really good question. So, The phase 1B portion of COMET is not designed to enrich. It's not designed to, sorry, it's enriched in KMT2A and NPM1, but there's no requirement of, you know, some minimum number of patients from each genotype. So we're getting what we're going to get. I think we've commented in the past, we are seeing more KMT2A rearranged patients than the relative epidemiology might suggest. probably because those patients do not have a lot of options. and they tend to just blow through lines of therapy, as opposed to the NPM1 mutant patients sometimes have commutations and are eligible to go, for example, into a FLT3 trial. So we are seeing more KMT2A than one would predict if that's 5% to 10% of the population and NPM1 is 30%. We think overall that's right, but in this relapsed refractory setting, it's perhaps a little tilted. It's our view, you know, does that matter? We don't think so. We haven't seen any indication that tells us either that we need a different dose between the two genotypes or that we should expect a different result. In fact, it seems to have more to do, you know, the quality of clinical benefit has more to do with the patient's overall fitness and perhaps other commutations such as P53 than, you know, is it NPM1 or KMT2A. It's early days. It's small numbers. But I don't think we're going – it's not our view right now that we would need a lot more. And I'll just remind you and the audience of one final thing. Remember that once we enroll these 24 patients, 12 in each cohort, we then can transition and enroll an additional 18 patients in at whichever dose we've identified. That gives us the opportunity, prior to going into the formal portion of the Phase II, of getting even a little bit better clarity and better precision, if you will, around exactly what it is we're seeing. So in totality, at the recommended Phase II dose, we expect to have 30 patients' worth of data by the time we formally transition into Phase II. Now, all of those patients, we hope and expect, will be treated as though they're eligible to be in the registrational population, but that will allow us to do any tweaking that we need to do. At this point, we don't think we need to do any, Phil, but, you know, you don't know what you don't know, so this will give us a lot of ability to make sure we're on the right path.
spk07: Perfect. And then second question, in terms of determining the recommended Phase II dose, You mentioned that exposure is one of the criteria in addition, obviously, to safety and efficacy. Do you have specific criteria for exposure, so IC90s that you want to maintain for some amount of time or PD biomarkers that you're assessing as well? Can you give us some sense of how you are going to look at exposure?
spk03: Yes, so that's a great question. So we are looking at them. We don't believe they're gating on making a determination of identifying the recommended phase 2 dose for the following reason. You know, KO539 exhibits time-dependent accumulation. We see exposures at steady state that are multiples of the exposure on cycle 1, day 1, and we don't have the sort of periodicity that that you see from once daily or twice daily dosing. You're basically bathing the target in 539. Now, you do see a difference. If you take the mean or the median exposure of patients at the 200-milligram dose versus the 600-milligram dose, you see greater exposure at the 600-milligram dose. but both of those doses appear to be covering the target sufficiently to drive clinical activity. So it's going to be part of the package, Bill, to make sure that we're giving as consistent, you know, dose and exposure as possible, but probably not going to be gating on making the ultimate determination of one dose versus the other to move forward.
spk07: Perfect. And then last question from us is on tibiflarnib in the AIM-HN study. Clinicaltrials.gov still lists that trial as completing in May 2022, but we did notice that you didn't call out a data event for that trial this year. Any sense when that could complete and when data could be released?
spk03: Yeah, so we haven't reinstated guidance, Phil, on that. We have been, I hope, pretty transparent with folks that You know, the trial's ongoing. We are seeing clinical activity that's consistent with RUN. The biggest challenge, frankly, for us has been, and this is in contrast to what we saw with RUN, the ability to convert patients that we identify, HRS mutant patients, and actually get them on the study is much lower than we had predicted. It's It's probably one in four, meaning we have to find four HRAS mutant, you know, high VAF patients for every one that we successfully convert onto the study. That has, much to our frustration, kind of delayed and enlarged the timelines around recruitment. And we, you know... That's also part of why it's been interesting to bring the current study online because there you're dealing with 20% to 50% of head and neck. we've been very pleasantly surprised with the rate of enrollment in the current study. You know, the fact that you're looking at one in two or one in three patients, it's just a completely different ballgame. So, you know, the team's doing their best to soldier on. You know, recurrent and metastatic head and neck is a tough indication. There's no approved small molecule targeted therapies. They're slogging through it to get those patients on study. Ultimately, combination and going to a broader population may help to address the challenges that we're seeing.
spk07: Perfect. That's very helpful. Thanks again for taking our questions.
spk03: Our pleasure.
spk09: I am showing no further questions at this time. I would now like to turn the call back to CEO, Mr. Troy Wilson, for closing comments.
spk03: Thank you, Operator, and thank you all once again for joining our call today. We'll be participating in the Cowan and Barclays healthcare conferences over the next several weeks, and we look forward to seeing many of you there. In the meantime, if you have any additional questions, please feel free to contact Pete, Tom, or myself. Thank you again, and have a good evening, everyone.
spk09: Ladies and gentlemen, this does conclude today's conference. Thank you for participating. You may now disconnect.
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