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spk02: Please stand by. Good day and welcome to the Cura Oncology second quarter 2022 conference call. Today's conference is being recorded. At this time, I would like to turn the conference over to Pete DeSpain, Senior Vice President of Investor Relations. Please go ahead, sir.
spk05: Thank you, Sarah. Good afternoon and welcome to Cura Oncology's second quarter 2022 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'd 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 will now turn the call over to Troy.
spk00: Thank you, Pete, and thank you all for joining us this afternoon. Last year, as we continued in dose escalation with our menin inhibitor, Ziftamenib, in an all-comer population of patients with relapsed or refractory acute myeloid leukemia, we sought FDA feedback regarding the design of our registration-directed trial. In the context of those discussions, FDA advised we spend more time in our Phase I study to identify an optimal dose. Guidance we now know was part of a broader FDA initiative in oncology drug development aptly named Project Optimus. In agreement with FDA, we enrolled a Phase Ib study with two dose expansion cohorts, 200 milligrams and 600 milligrams, each comprised of 12 patients with NPN1 mutant or KMT2A rearranged relapsed refractory AML. I'm pleased to report we've nearly completed our assessment of these patients in the expansion cohorts for efficacy, safety, and tolerability, as well as pharmacokinetics and exposure, and we believe we've identified a recommended phase two dose for Zyft-Amendib. We're working diligently to gather the data package for submission to FDA and look forward to sharing the recommended phase two dose for Zyft-Amendib later this year pending the agency's review, along with top line data from the Phase 1B study, with a more complete data set reserved for presentation at a medical meeting in the fourth quarter. In the meantime, enrollment in COMET-001 has continued, and we're pleased to announce that we've enrolled an additional 18 patients in the Phase 1B study in less than three months at what we believe to be the recommended Phase 2 dose, an indication of the continued enthusiasm surrounding zift amenib among investigators and patients. We continue to believe data from all patients treated at the recommended phase two dose will have potential to contribute to the registrational patient population. In parallel with our efforts to advance zift amenib as a monotherapy, we've been working to operationalize a series of combination studies in the relapsed and frontline settings. We've designed these studies to assess the safety, tolerability, and therapeutic activity of Ziftimenib in combination with current standards of care in AML, including venetoclax and azacitidine, FLT3 inhibitors, and standard induction, cytarabine, donorubicin chemotherapy, commonly referred to as 7 plus 3. We remain enthusiastic about the potential for Ziftimenib in the treatment of acute leukemias as we prepare to transition into the Phase II registration-directed portion of COMET001 and initiate our combination studies pending determination of our recommended Phase II dose. Although our MENIN program continues to capture much of the attention, we remain just as motivated by opportunities for farnesyl transferase inhibition in oncology. One of the first therapeutic applications of an FTI as a targeted therapy was via direct inhibition of an oncogenic protein, namely HRAS. We've demonstrated the potential for tififarnib to drive durable responses in recurrent and metastatic HRS mutant head and neck squamous cell carcinoma, or HNSCC, and our ongoing AMHN registration-directed trial continues in that indication. More recently, we've begun efforts to build upon the initial monotherapy activity of tififarnib with a focus on overcoming drug resistance. Late last year, we initiated the current HN study designed to evaluate the combination of tipifarnib and dalpelicib, an inhibitor of PI3 kinase alpha, in selected HNSCC patient cohorts. We believe that HRAS and PI3 kinase alpha are codependent oncogenes in HNSCC, and the combination of the two inhibitors has potential to provide improved antitumor activity relative to the inhibition of either target alone. The combination also has potential to increase the total addressable population for tippy-farnib to as much as 50% of patients with recurrent and metastatic HNSCC. The initial cohort of the current HN study includes patients with PIK3CA-dependent HNSCC, and I'm pleased to report that we recently dosed the first patient in a second cohort comprised of patients with HRAS overexpression. Our goal with the current HN trial is to identify a recommended Phase II dose and schedule for the combination in each patient cohort. We're encouraged by the preliminary safety and tolerability of the combination, as well as early evidence of clinical activity, and we believe we may be in a position to share preliminary proof-of-mechanism data from patients in the PIC3CA-dependent HNSCC cohort later this year. Beyond HNSCC, we continue to elucidate the role of FDIs in preventing or delaying the emergence of resistance for certain classes of targeted therapy with potential to drive deeper and more durable responses in large solid tumor indications. One of these emerging combination opportunities was unveiled earlier this year at the American Association for Cancer Research annual meeting. The preclinical data generated through a collaboration within CIRM support potential for tipifarnib to prevent emergence of resistance to osimertinib and other potent EGFR inhibitors in EGFR mutant non-small cell lung cancer. We're preparing to initiate a phase one study of tipifarnib in combination with osimertinib in EGFR mutated non-small cell lung cancer, which we call current lung, later this quarter. We intend to perform initial clinical evaluation of tipifarnib and osimertinib to gather valuable experience and data, while in parallel advancing KO2806, the lead development candidate in our next generation FTI program through IND-enabling studies. KO2806 represents a next-generation farnesyl transferase inhibitor with improved PK, exposure, and bioavailability relative to tibifarnib. In addition to combining FTIs with EGFR inhibitors, we continue to investigate combinations with other potent targeted therapies in preclinical studies that may represent additional opportunities. We intend to evaluate KO2806 in combination with these targeted therapies, and we remain on track to submit an IND application for KO2806 in the fourth quarter. With that, I'll now turn the call over to Tom for a discussion of our financial results.
spk01: Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the second quarter, 2022. I invite you to review our 10-Q filed today for a more detailed discussion. Research and development expenses for the second quarter of 2022 were $24.3 million compared to $21.1 million for the second quarter of 2021. The increase in R&D expenses was primarily due to increases in our clinical trial cost related to our ZiptoMed program and personnel cost. General and administrative expenses for the second quarter of 2022 were $11.1 million compared to $12.6 million for the second quarter of 2021. The decrease in G&A expenses was primarily due to the decreases in personnel cost and professional fees. Net loss for the second quarter of 2022 was $34.8 million compared to a net loss of $33.7 million for the second quarter of 2021. As of June 30, 2022, we had cash, cash equivalents, and short-term investments of $450.3 million compared to $518 million as of December 31, 2021. Based on our operating plan, we continue to believe that our cash, cash equivalents, and short-term investments will fund current operations through 2024. With that, I now turn the call back over to Troy.
spk00: Thank you, Tom. Before we jump into the question and answer session, let me lay out our anticipated milestones for 2022. For our Mennon inhibitor program, determine the recommended phase two dose for Zifdimenib in consultation with FDA and report top line data from the phase one B study later this year. Present updated data from Comet 001 at a medical meeting in the fourth quarter. And for our FTI programs, initiate the phase one current lung study of tipifarnib plus osimertinib this quarter and submit an investigational new drug application for KO2806 in the fourth quarter. With that, Sarah, we're now ready for questions.
spk02: Thank you. If you would like to ask a question today, please signal by pressing star 1 on your telephone keypad. If you're using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, please press star 1 to ask a question, and we'll pause for just a moment to allow everyone an opportunity to signal for questions.
spk03: And we'll take our first caller from Jonathan Chang, SVB Securities.
spk10: Hi, guys. Thanks for taking my questions. First question, on timing of the top line system data, Can you provide any additional color on how you're thinking about when to disclose the top-line data?
spk04: Sure, Jonathan.
spk00: Thanks for the question. As we indicated, Jonathan, you know, our goal here is to determine the recommended Phase 2 dose in consultation with FDA. We're at a point where we are completing our assessment and preparing to submit the package to FDA. That should happen shortly. What we don't have as much visibility into is the process and the timeline by which FDA reviews that. Unlike, for example, in the case of an IND submission, there isn't a 30-day clock. We certainly believe that we're going to submit a package that should address all of their questions. We'll stand ready if they have additional questions or need us to look at the data in any different way. At this point, I think that the best we can say is we're probably looking at late in Q3. It could potentially slip into Q4, just depending on the timing with FDA.
spk10: Got it. Thank you. And I guess, are you able to provide any color on the identification of the RP2D and the regulatory interactions? I guess, what boxes remain to be checked before officially declaring the RP2D?
spk00: Yeah. So, maybe just to take a quick step back, you know, we undertook this Phase 1b study really as an exercise in dose optimization. And this is part of the FDA's initiative around Project Optimus. It's becoming standard for targeted therapies. I can tell you it's our view, now having conducted the Phase 1A and the Phase 1B, that the Phase 1B was absolutely the right thing to do. We've gathered a tremendous amount of information about the clinical activity, the safety and tolerability, the PK, in addition to how to manage the on-target AEs, such as leukocytosis and DS. So it was absolutely the right thing to do. I think we're going to emerge from this, in our view, with a very strong data package supporting the recommended Phase 2 dose. We just don't want to jump the gun at this point. And it isn't so much, Jonathan, a check-the-box exercise as it is, you know, the FDA is looking for information relating to clinical activity, safety and tolerability, PK and exposure, really across all the patients enrolled in the study to this point, but with a particular emphasis on the Phase 1B patients, and integrating that and analyzing that to really make a strong recommendation that supports advancement as a monotherapy and that sets the dose for any and all future combination studies. That's why this is so critically important. And, you know, I can't stress enough. I think we did, although it took a bit longer, given the profile we had with Zipdomenib and given what we were seeing, absolutely the right experiment to do.
spk10: Got it. Thank you. And just last question for me. On the additional 18 patients enrolled in Comet 001 since May, how many of these patients could we see data on? on for the top-line disclosure and for the fourth quarter medical meeting presentation? Thank you.
spk00: Yeah, that's a good question, Jonathan. So, it's been our intent from the beginning, and this was actually guidance that we received from FDA, to conduct the Phase 1B using the same endpoints as will ultimately be used in the registrational portion of the Phase 2. As such, the data that we're gathering is, you know, to use a, for lack of a better word, it's sanctified, right? These are patients that we hope and expect will be part of the registrational totals. And we're certainly treating them as such. That's partly perhaps what, you know, it's helpful to have people understand is You really need to make sure the data coming from the sites is robust, it's clean, you've checked it. You know, this ultimately, we hope, will become part of the submission. That's true also, Jonathan, for the additional 18 patients and, of course, all subsequent patients we would enroll. So, we're balancing here, you know, is there incremental value in sharing additional data versus the time lost of then having to potentially replace those patients. You put at risk. when you're sharing data from sanctified patients in a registration-enabling study. You put those patients at risk if you keep doing data cuts. So, at this point, I'm not expecting, Jonathan, that you're going to see more than the initial 12 patients in each cohort in the top line result. At ASH, you'll see, of course, the data from the phase 1A and the phase 1B, it's not our current expectation that we'll go beyond the initial 12 patients in each cohort. At this point, you know, we might be able to speak qualitatively to it, but we don't want to, we're doing everything we can to try to maintain momentum and close the gaps, and we don't want to put those patients at risk.
spk10: Makes sense.
spk04: Thanks for taking the questions. Our pleasure, Jonathan. Thank you.
spk02: Thank you. And next we'll move on to Tiago Font with Credit Swift.
spk06: Great. Thanks for taking the question. Congrats on the progress. So I understand you might be fairly limited in what you can share at this point, but to the extent that you can provide any qualitative comments, wondering about the enrollment proportion between the two genetic subtypes, if that is consistent with prior competitor experience. I don't know if you can also talk about consistency of efficacy response between those two subpopulations. And perhaps just trying to understand a little bit better the future for the FTI franchise. So if you have 2806 expected to enter clinic in Q4, perhaps Q1, depending on how that shakes out with the IMD filing, and you have recently initiated the combo trials for TP, right, with both PI3K and EGFR, Do we expect to develop the same combo simultaneously? Would it make sense to establish proof of concept with TIPI and perhaps progress with 2806 for a registrational trial? Curious if there is any characteristics that would make TIPI a better candidate for a given combo or how that's going to evolve over time. Thanks.
spk00: Yeah, Tiago, thanks for that. It's a three-part question. Let me take each of the parts in turn. So on your first question around enrollment, it ebbs and flows. I would say we see a pretty healthy balance between NPM1 and KMT2A rearranged patients. Again, it ebbs and flows kind of at any given point in time. It seems enriched in KMT2A rearranged AML patients relative to what the overall epidemiology might suggest. You'd expect it to be roughly four or five to one. We're seeing more of kind of an equal weighting, if you will, but a lot of interest among physicians who want to enroll both populations. So I think we're going to continue to see strong enrollment as we transition into phase two in those ultimate registrational cohorts. Relating to activity, what I can tell you there is our thoughts remain consistent that we're thinking of the cohorts as being approximately the same size. namely 50 to 75 patients each, that should tell you, you know, that statistical design should tell you we're looking to meet or exceed really the same bogey, right? And that is 20 to 30% CR-CRH rate, four to six months durability, transfusion independence as a secondary endpoint, we think that number of patients is probably in the right range to allow us to deliver successful phase two cohorts in both the KMT2A and the NPM1. So that's as much as I think we could say. Of course, we'll have the flexibility to be data-driven. On the third part of your question that relates to the strategy around the FTIs, you make an important point. And we're really trying to solve several things simultaneously. So the first is data generation. I think our mindset has evolved to the highest best use of STIs may be in combination with these other targeted therapies. You've seen PI3-Kinase Alpha. You're going to see GFR. We hope a third and even a fourth that you'll see later this year or early next year. So part of that is just data generation. Does the clinical data recapitulate what you see pre-clinically? We've got some very exciting pre-clinical data. The second is, how do you think about development and commercialization regionally or globally? I think we feel pretty comfortable that we could take a tippy-farnabell-pelicib combo forward in the U.S. and Europe. Should the data support that into a registrational study in the recurrent metastatic setting? Obviously, we would need to have alignment with Novartis, with whom we're in a clinical collaboration. We have a very good relationship with them on this program, and and look forward to working with them. That's a bit of a special case, Tiago. I think as we think about Osimertinib or other opportunities, that's where you begin to think about 2806. And so what you're seeing with the current lung study is a chance to learn, are we seeing the early indicia that are consistent with the preclinical data around the opportunity to delay the onset of resistance to Osimertinib? If we do, if we see encouraging data, the intent would be to slingshot 2806 around Tippie and take that forward with Osimertinib. It's no surprise to anyone that is a massive potential opportunity, even if we assume we're targeting only 20 or 30 percent of the osomertinib population. But given this is completely novel biology, novel farnesylated targets, we thought there was value in de-risking it clinically with tippy while we put the work in. And I alluded to selected combinations in the Phase 1 study for 2806. You can imagine that an EGFR inhibitor will be in that mix. So, Tiago, we'll continue to, you know, we've got preclinical work, we've got clinical tools, we can think strategically and commercially. Ultimately, I think we're optimistic that 2806 is a better FTI, but the unmet need in recurrent metastatic head and neck is so great. that if we see compelling data that supports moving forward with TIPI and Alpelisib, I think we will, and then we'll look to beat our own data. But we'll put that in our bucket of high-class problems if that's where we end up. Did I answer that? I think I answered the three parts of your question, but tell me if I missed anything.
spk06: Thanks again for taking the question. Appreciate it.
spk04: Pleasure.
spk02: Thanks. Thank you. And next, we'll move on to Peter Lawson-Barclays.
spk08: Great. Thank you. Thanks for taking the questions. Troy, just the 200 and 600 milligram dose, which do you think sets you better for first-lining combination use? And then, is there anything you're seeing in the data that makes you, the men in data, anything that makes you incrementally more positive or incrementally more negative?
spk04: Yeah, it's a good question, Peter.
spk00: So, maybe to take a step back to the first part of your question, what we're really looking for, first and foremost, is safety and tolerability, right? This is still ultimately a phase one study. Efficacy remains, even though we are conducting it pursuant to registrational endpoints. You know, we're all in such a rush, but ultimately it is still a safety study. We feel like we have a good safety window at both doses. We have the ability to dose at either dose and potentially to move between them as needed. So that I think is first and foremost. We've been looking at clinical activity, PK and exposure, pharmacodynamic markers as well, and we're looking forward to sharing that with you. You'll get a glimpse of it in the top line. You'll get a much more fulsome picture at ASHE. I think it's a very nice setup for a monotherapy and potentially in combination. We're feeling, as I said in response to Jonathan's question, it was the right experiment to run. One of the things that we've learned as we've transitioned from 1A to 1B is we see leukocytosis. It's rare, but we see cases of differentiation syndrome to the uninitiated. Leukocytosis can look like progression. And, you know, you have a patient who's failed three or four lines of prior therapy. They go on a MENIN inhibitor. You start to see leukocytosis, which means it looks like the counts in the periphery are going up. What we've learned is that is not necessarily progression. That's actually the cells doing exactly what they are programmed to do when you block the MENIN-MLL interaction. they're moving into the periphery, and then they live there for a couple of weeks and begin to die off. So that kind of learning, Peter, is invaluable, both as a monotherapy and setting up for success, and then thinking about in combination. If you start to see things in combination, you need to really understand, okay, which element of the combo is it coming from? With respect to the second part of your question, You know, our enthusiasm continues. I'm trying, and hopefully I'm succeeding, in just maintaining a very steady course. We remain encouraged about the potential for Zip2Mentive. We're looking forward to sharing the data. We are very, very much living this experience of Project Optimus, and You know, we look forward to sharing the data with the FDA and hopefully gaining their alignment. I think we'll be in a good position come the top line data and ultimately the presentation at a medical meeting to be able to support the idea that there's a strong path forward here as a monotherapy and potentially, you know, we're very well set up in combination to be best in class. So, you know, time will tell.
spk04: Great. Thank you so much.
spk02: Our pleasure. Thank you. We'll move on next to Roger Song with Jefferies.
spk09: Great. Thank you for taking the question. Maybe just a couple of clarifications from us, Troy. So first of all, I see what you said is since May, you're starting to enroll additional 18 patients. in the RP2D arm alone. So maybe just can you clarify that's the case, maybe that imply you already decide RP2D in May based on the profile you have been seeing that time?
spk00: Yeah, Roger, and I'm going to be very different here to the FDA on this. The protocol, as was originally agreed to with the FDA, gave us the flexibility to enroll 12 patients at each of the two doses and then to continue enrollment in either cohort, depending on the way the data went. And so we've done exactly that. We've enrolled the 24 patients where we nearly completed the assessment. We've continued enrolling at what we believe to be the optimum dose. I want to choose my words carefully out of respect for the agency. We'll be able to come back and tell you that is the recommended phase two dose once we have their alignment. Obviously, we feel at this point that the data is trending in the right direction, that we want to try to both give every patient the best chance for clinical benefit or benefit risk, if you will, and as I said in response to the earlier question, to try to close any gaps
spk09: enrollment and maintain the momentum for the program excellent thank you okay and the next question is related to the regulatory interaction understanding you have not final your data analysis for those 24 patients but have you got any kind of a or having any discussion with the FDA regarding this RP2D package and kind of decide what kind of data you want to include in that package?
spk00: Yeah, that's a very good question, Roger. So, as part of the discussions when we were agreeing with FDA on the design of the Phase 1B study, you know, they were very clear on what they were looking for as far as the data coming out of the Phase 1B in terms of assessing benefit-risk. And I have characterized that in kind of the three columns of efficacy data, safety and tolerability, PK and exposure, and then any other data we want to include, you know, to help support the benefit-risk at, you know, what we would feel is the appropriate recommended Phase 2 dose. Nothing there has changed. We have regular interactions with the FDA. I don't want to get into the specifics, but nothing on that guidance has changed at all. Where we are is this data has to be, you know, this data has to be, again, sanctified, right? These are patients that we hope and expect will ultimately be able to be included in a registrational package. As we're pulling data out of the sites, as we're pulling it out of the vendors, we have to make sure it's clean. We have to make sure it all ties out. I don't think the answer is going to change, Roger, between now and when we ultimately submit the package. The FDA is looking for a level of credibility, of excellence, of professionalism that we intend to meet or exceed. They were clear with their instructions on what they're looking for. We're going to deliver them that. We're also going to then, Roger, as every company I suspect does, we'll prepare for any other questions they might have, right? So they get the data. Do they want to look at it a different way? Do they maybe have a question about cutting it this way or that way? This is the kind of scenario planning that you do, and our team is all over that. We'll be ready. to provide the FDA any additional information that they need or any further analysis to help support the recommended phase two dose. We found them to be very collaborative and to be very clear on what they need, and we're hoping we can move through this as efficiently as possible.
spk09: Yeah, that's very good. Great. Maybe just very quick last one. Maybe just to confirm, this additional 18 patients on the you know, optimal dose, additional 18 patients won't be part of this RP2D package or FDA not requiring or not asking for the data from those 18 patients.
spk00: Yeah, so just to be clear, Roger, the FDA has, you know, I'm going to rely on my legal background here. The FDA has jurisdiction over every patient on every study, right? So they can ask whatever they want to ask. And particularly as it pertains to safety, if there are safety updates, you know, you're obligated to share that with them. But let's go back to the point of the exercise. We believe that the 24 patients who comprise the Phase 1b population at the 200 and 600 milligram dose are going to be what's needed. We'll provide any additional safety updates as needed, but we're not expecting to have to keep doing data cuts. Obviously, if the FDA asks, we're of course going to work with them and comply, but that's not the expectation going in.
spk09: Very good. Okay, great. I think that's it from us. Thank you. Thank you, Troy.
spk04: Thanks, Roger.
spk02: Thank you. And next, we'll move on to Lee Watzak with Cantor Fitch-Darrow.
spk12: Hey, guys. Thanks so much for taking my questions. I guess one question on the demand. I mean, you're finishing enrollment in May and now we're in August. I guess, for, you know, differentiation syndrome, we know that it typically occurs early in treatment. So, I guess, is it safe for us to assume that, like, there's less risk now for seeing, I guess, serious cases?
spk00: Yeah, Leah, I'm glad you asked that question. So, just to remind everybody, you know, we were earlier this year on a partial clinical hold related to a case of differentiation syndrome. At that point, we implemented some revised guidance around how to manage differentiation syndrome. And, you know, it's been our experience, Lee, as the trials continue to enroll, that, you know, although we do see differentiation syndrome, it's relatively rare and infrequent. But in cases where you see it, the severity of the DS appears to be less now than it was prior to the implementation of the revised DS guidance. And our goal all along has been, you know, this is, so leukocytosis and differentiation syndrome are on mechanism AEs, right, if you will. The cells are doing exactly what you're programming them to do. Our goal is to try to provide the investigators, the clinicians, with the tools to keep any cases of DS or leukocytosis, you know, at grade one, grade two, kind of mild to moderate, keep it away from the more severe grades. I think we've been more successful in that as the trial's gone on. We've learned a lot. And, of course, the physicians who have the greatest facility are the ones who have the most experience with the drug, not unlike what we've seen, for example, with venetoclax and tumor lysis syndrome. It took a while for investigators to develop an expertise and an understanding of what to look for and how to mitigate it. So I would say... Not only are we seeing perhaps less frequent, but certainly less severe DS, and that's trending in the right direction. That should also only get better as we move into certain combinations with cytoreductive agents, because that's one of the means of mitigating DS. is to provide something like Cyterabine as a way of managing counts. So that's why I think we're optimistic that we're on track to be as good as, if not better, than our competition. The arrows are, at this point, it's an ongoing trial, but the arrows are going in the right direction.
spk12: Okay, great. Thank you for the color. I guess my second question is about, you know, TB combination. And you mentioned from the phase one, I guess, current head and neck study, you've seen some preliminary, I guess, activity. So I wonder if you can expand a little on that. I guess what have you seen so far that gives you the confidence that the activity is real? And maybe remind us what a benchmark is. And also, I guess you mentioned that you might, I guess, present some data later this year. Can you give us a sense of what we should expect?
spk04: Sure. So, good question.
spk00: Another three-part question. Let me take each of them in turn. So, typically, you know, we've worked, me and several others here, we've worked in and around the MAP kinase and PI3 kinase pathways for a long time on different agents. By and large, the industry has not been successful at combining inhibitors of the MAP kinase pathway and the PI3 kinase pathway due to overlapping toxicity. So first and foremost, you know, the fact that we're seeing an acceptable safety and tolerability profile is a big, I think, a big advance. That wasn't clear. That's where I would have assigned the greatest amount of risk. Because, you know, preclinical models are only so good at predicting toxicity. We're at a point where we are in dose escalation, and we remain encouraged by what we're seeing as far as safety and tolerability. That's usually been kind of the stopping point for most combinations on these pathways. But the equally important and perhaps more intriguing is we're seeing early evidence of clinical activity. So what do we mean by that? Well, that's, if you will, tumor regression. That's a clinical endpoint. Now, when we talk about proof of mechanism, what we're looking for is examples in a handful of patients that really recapitulate the preclinical data that we've published. You can see it in our corporate presentation. It's available on the AACR presentations on our website. You see synergistic activity combining alpelicib and tipifarnib in each of the four subsets in head and neck cancer, the two HRAFs dependent and the two PIK3CA dependent. You see synergistic activity across all four subsets. Even early in dose escalationally, we're seeing some early evidence that that is trending in the right direction. And I'll just remind you, in the PIK3CA population, tibifarnib is inactive, and alpalisib really drives stable disease. So if you're seeing tumor regression, if you're seeing response, durable response, that's trending in the right direction. That's the way to think about a potential data update later this year. I would contrast that with what we would term as proof of concept Proof of concept we usually keep as you reach a recommended phase two dose and schedule, and then you do an expansion cohort such that you can get closer to what you would think of as an ORR. That's proof of concept. I wouldn't look for that data until probably middle of next year. But your final question is kind of what's the threshold? So, you know, the threshold for success in our view, if you're in the range of 30% objective, you know, confirmed responses and above, you're in the right range to be able to think about taking this combination forward relative to the existing standards of care in the recurrent and metastatic head and neck. It's, you know, right now the three approved agents are are Opdivo, Keytruda, and cetuximab or Erbitux. They provide monotherapies kind of in the teens, maybe the low 20s. If you could do better with an all-oral regimen, we think that would be a big deal. And to remind you, potentially allow us to treat up to 50% of recurrent metastatic head and neck.
spk03: Great. Thank you so much. Thank you. And next, we'll move on to Ren Wang.
spk07: Benjamin Benjamin with JMP security a good afternoon everyone thanks for taking the questions and congrats on the progress maybe Troy just starting off with you know this FDA review again I'm trying to just get a better handle are you looking for them to confirm kind of your your you know the rp2d that you have selected and the go-forward strategy, or are you looking for something more, you know, guidance-oriented, right? So you give them both the data sets and, you know, it's more of like a collaborative effort to decide what the, you know, go-forward RP2D should be.
spk00: Yeah, Ren, I appreciate the question. We're looking for FDA's input, but we're looking for FDA to – to analyze and hopefully to agree with our recommendation. We're gonna give them a recommendation and let them respond to that rather than seeking their input, sort of making it a jump ball, if you will. We're not gonna do that. Just to remind everyone, FDA needs to agree with any registrational plan, which means they have to agree with the registrational dose. And so this is the predicate to starting the registrational portion of the COMET-001 study or starting any combination study. But to your specific question, Ren, we will put to them, here is what we believe is the minimal safe and efficacious dose pursuant to Project Optimus. Here's the data supporting that, you know, and seek their feedback and address any questions. That's the way we're intending to do it.
spk07: Got it. And then as part of this discussion, will you be, you know, talking about the registrational study and getting kind of like the FDA blessing on that? Or is that a subsequent discussion, you know, after this is completed?
spk00: No, you're absolutely right, Ren. So it's option one in your options. We will look to gain alignment from the FDA on the path forward in the registrational study as a monotherapy. Okay.
spk07: Perfect. Okay. And then just switching gears real quick to the current lung study that'll be started. Can you talk a little bit about, you know, from the preclinical work, do you have a sense how exactly or what type of specific resistant mutations seem to be impacted by TIPI? I seem to recall that like T79, T790M, C, I think it's 797S, mutations are the typical mutations that we're looking for that confer resistance to OC. Just kind of trying to get a sense about that. And then I know that you're going to be measuring ctDNA as a biomarker, you know, for efficacy, but can you also use that as a biomarker to follow resistance?
spk04: Yes.
spk00: So, both really good questions, Ren. So, what we're What this seems to be evolving to is, let's step away from EGFR and even from osimertinib for just a second. You often ask the question, if you have a potent signal transduction inhibitor like osimertinib or a KRAS, for example, why don't we see CRs, right? Why do we see PRs? This is a question I've been asking myself for the better part of 15 years, as I've been working across various targets. And one potential mechanism is there are a subset of cells that are called drug-tolerant cells. When you hit them with a potent signal transduction inhibitor like Osimertinib, there's a subpopulation that you just don't kill. And a reason you don't kill them is those cells actually fundamentally rewire. They actually de-differentiate, and they are able to cycle in the presence of Osimertinib. And the way that they get into that drug-tolerant state is through a farnesylated protein, one of the row proteins. Once they've developed some sort of resistance mutation, REN, then they re-differentiate, and then they can take off in the presence of osimertinib or another EGFR inhibitor. Osimertinib happens to be the 800-pound gorilla, which is why it's the one we started with. But that re-differentiation and that exit of drug-tolerance is also farnesylation-dependent. So now when you combine osimertinib plus tipifarnib in patients who haven't seen osimertinib, what the preclinical data says happens is you prevent those drug-tolerant cells from entering a state of drug tolerance. so they become more susceptible to Osimertinib. Now, I don't know if clinically we're gonna be able to drive CRs. We have some preclinical data that suggests in some context that's possible, but the way it appears to manifest itself, and it's not just EGFR, It appears any EGFR inhibitor, ALK inhibitors, BRAF inhibitors, you'll potentially see other potent signal transduction inhibitors later this year. You're preventing drug tolerance, and therefore you're delaying the onset of resistance because you're not giving this subpopulation a chance to sit there and cycle and develop drug resistance. So the key is you've gotta hit it before the resistance happens. If you wait until the resistance happens, the way most other therapies work, you've waited too long. The beauty of it, of course, is, you know, the hope is you could take OCIE's 18-month or 19-month median PFS and go 50% greater. That would be a huge advance for patients. And we're not the only ones trying to do this, but I think what will be significant is OCIE is just the tip of the iceberg. It's a pretty big tip, but it's the tip of the iceberg. increasingly encouraged that this is a phenomenon of farnesylation-dependent drug tolerance that's true across multiple small molecule drug targets, which really sets up the TIPI 2806 as a story that's going to pay dividends over the next two, three, four, five years.
spk07: Got it. Which leads me to focus in on what you're going to look for, particularly for a go-no-go decision, because it seems like median PFS would be way too long.
spk00: Yes and no. So I'm sorry. You reminded me that in my long-winded answer, I didn't answer your ctDNA question. So we will be looking at ctDNA. AstraZeneca and the clinical investigators understand the ctDNA profile. For everyone else on the call, this is circulating tumor DNA. And what it allows you to do is you don't have to do a solid tumor biopsy. You can do it blood-based. You can both watch disappearance of the mutant allele, so in this case T790M. You can also watch for reemergence of resistant alleles. And it's a way to kind of gauge how, you know, it's equivalent to MRD negativity, if you will, in the AML instance. We're going to be looking at that, Ren. If things start to go in the right direction, I think we'll accelerate. But ultimately, PFS is the right endpoint. And, you know, the downside of that is OC has a very long PFS. The upside is it's a huge opportunity and one where a 2806-osimertinib combo, we think, potentially provides really a significantly better clinical benefit over osimertinib alone. There will be, we're asking ourselves the question, Ren, and I want to acknowledge, you know, we recently retitled Kirsten Flowers to be both Chief Commercial Officer and Chief Corporate Strategy Officer. We are looking for other instances of this where we can go get an endpoint even faster. So can you, for example, like take KRAS, for example, could you go from six to eight months median time to relapse to extend that out maybe 10 months or 12 months. I would say stay tuned on that. A lot of preclinical work going there, but that would go alongside and help support this idea. And we've come just such a long way from targeting HRAS to now targeting the row proteins, REB, this whole family of uniquely farnes-related proteins that drive drug resistance. It's a nice story. And we look forward to sharing more of it probably early next year on the other side of the Mennon updates.
spk07: Got it. There's one final question for us. You know, farnesylation continues to, I guess, gain in more and more popularity. We're noticing more papers, you know, kind of focusing in on this mechanism of action, especially in different diseases, including neurological ones like Alzheimer's and the like. I know that you guys don't necessarily want to branch out there, but I'm kind of curious, do you have any BD discussions? Do you have any inbounds with interest kind of to partner your FTI library?
spk00: So, yeah, so I don't want to speak to specific discussions, Wren. The papers that you're describing out of the University of California at Santa Barbara are very provocative relating to the tau proteins and foreign distillation issues. One of the things that we're doing, Ren, is, and I don't know if it's 2806, but I'll just say colloquially it could be 2807, is a blood-brain barrier penetrant FTI. So, you know, let me not sort of talk yet to the partnering discussions. Once you have a hammer and you show that, in this case, you show you can block FT, farnesyl transferase, People, you know, Francis Burroughs and our translational team have a huge number of collaborations ongoing. The ozimertinib one came from Inserm in France, who came to us really with insights into foreign installation biology-specific proteins, and they needed the molecular expertise. They needed the drugs, which we provided. We have other examples of that. So I would say stay tuned.
spk07: Great. Thanks for taking the questions.
spk04: Pleasure.
spk03: Thank you.
spk02: And once again, if you would like to ask a question today, you may do so by pressing star 1. Next one, we will take Ava Privatera with Cohen.
spk11: Hi. Thanks for taking our questions. Back to the upcoming top line disclosure for ZIFTO. I know you had previously mentioned that it will include composite CR. Can you remind us if it will also include MRD status or any of the PK and exposure data?
spk00: Yeah, Eva, thanks for the question. As far as the top line data, we're expecting CR, CRH, CRC rate. We haven't yet decided to be perfectly frank on MRD status. We're very encouraged by what we're seeing, but that's one where we just haven't made a determination. If you don't see it in the top line, you'll see it at ASH. I think the PK and exposure really isn't appropriate for a top line cut. That's probably more appropriate for a more fulsome discussion of the clinical data at ASH. So I'd probably hold that off until then.
spk11: Great. Thank you. And will the efficacy be broken down by genetic subtypes?
spk00: It will. Yes, it will. And you'll see it certainly, I think, both in the top line and at ASH.
spk11: Great. Thank you. And just one more point of clarification. You had mentioned in your remarks that you expect 50 to 70 patients in each of the registrational cohorts for each genetic subtype. Would this be in addition to the 30 from the Phase 1B at the RP2D, since those patients can be counted as part of the registrational data?
spk00: Yeah, so I think the question is, we're going to need to have 50 to 75 patients who meet the criteria for inclusion. That's the focus. That literally falls out of the 20% to 30% CRH rate that we're aiming for. The patients that have been rolled up to this point are a mix of the two genetics. We know in total we're going to need approximately 50 to 75 patients per cohort. We're obviously trying to get as many as we can, but sometimes patients will get knocked out or the FDA won't allow you to count them, so oftentimes you'll over-enroll a bit just to ensure that that happens. That's our way of saying, relating to this question of are you seeing equivalent activity between the two the two genotypes, the best way we think to answer that is to say we're planning on running similarly sized cohorts. So that should tell you something, right, without getting into the specifics.
spk11: Perfect. That's very helpful. Thank you.
spk04: Our pleasure. Thank you, Eva.
spk02: Thank you. And there are no further questions, so that will conclude our question and answer session today. I would now like to turn the conference back over to Dr. Troy Wilson, President and Chief Executive Officer, for any additional or closing remarks.
spk00: Thank you, Sarah, and thank you all once again for joining our call today. We'll be participating in the Wedbush PACRO Healthcare Virtual Conference next week. Look forward to seeing a number of you there. In the meantime, if you have additional questions, please feel free to contact Pete, Tom, or me. Thank you again, and have a good evening, everyone.
spk02: Thank you, and that does conclude today's teleconference. We do appreciate your participation. You may now disconnect.
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