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spk10: Good afternoon, ladies and gentlemen, and welcome to the Q2 2023 Cura Oncology, Inc. Earnings Conference Call. At this time, all lines are in listen-only mode, and following the presentation, we will conduct a question and answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Thursday, August 3rd, 2023. I would now like to turn the conference call over Over to Mr. Pete Despain, the Head of Investors Relations. Please go ahead.
spk01: Thank you, Kelsey. Good afternoon and welcome to Cura Oncology's second quarter 2023 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'll now turn the call over to Troy.
spk05: Thank you, Pete, and thank you all for joining us this afternoon. Let's jump right in. In June, we reported updated data from the COMET-001 trial of our MENIN inhibitors at the MENID, including durable activity in patients with heavily pretreated and co-mutated relapsed refractory NPM1 mutant acute myeloid leukemia. These data were featured during a late-breaking oral session at the European Hematology Association Annual Congress in Frankfurt. As of the April 12th data cutoff, seven of the 20 patients with NPM1 mutant AML who were treated at the recommended phase two dose, 600 milligrams, achieved complete remission with full count recovery for a CR rate of 35% and an overall response rate of 45%. This represents one of the highest response rates reported for a targeted therapy in the setting of relapsed refractory leukemia. An eighth patient who had a CR with partial count recovery after treatment with Ziftamentib subsequently evolved to a CR with full count recovery after transplant and remained unsteady as of the date of the eHow presentation. In addition, a patient with NPM1 mutant AML treated at 200 milligrams remained on ziptomenib for 36 cycles as of the cutoff date. The median duration of response for all NPM1 mutant patients was 8.2 months, with a median follow-up of 8.8 months. Continuous once-daily dosing of ziptomenib was well-tolerated in the Phase I study, and the reported adverse event profile remained consistent with features of underlying disease. As a reminder, NPM1 mutant AML accounts for approximately 30% of new AML cases annually and represents a disease of significant unmet need for which no approved targeted therapy exists. Once the disease becomes relapsed or refractory, the prognosis for NPM1 mutant AML patients is especially poor. NPM1 mutant AML is further compounded with commutations such as IDH and FLT3. Notably, in our phase one study, 33% of patients with FLT3 co-mutations, 50% of patients with IDH co-mutations, and 50% of patients with both FLT3 and IDH co-mutations achieved a CR on Zyptomenib, all of whom had failed prior treatment with IDH and or FLT3 inhibitors. We remain impressed with the ability of Zyptomenib to drive durable remissions as a monotherapy in this difficult to treat population And we believe these data further demonstrate its potential best-in-class product profile. Building on momentum generated by our EHA data, enrollment in our Phase II Registration-Directed Trial of Zyftomenib in patients with relapsed refractory NPM1 mutant AML continues to outperform projections, which speaks to both the size of the population and its significant unmet needs. Our study is expected to enroll a total of 85 patients in the United States and Europe. In parallel with our efforts to advance Zipdomenib as monotherapy, we're conducting a series of studies in combination with current standards of care in earlier lines of therapy and across multiple patient populations, including NPM1 mutant AML and KMT2A rearranged AML. Our approach to combinations is to establish Zipdomenib as a foundational therapy that can be combined safely with various commonly used regimens and then prioritize those combinations that represent the greatest unmet medical need and the greatest potential commercial value, namely venetoclax and FLT3 inhibitor containing regimens. Combination approaches also offer the potential to mitigate differentiation syndrome, particularly in the KMT2A rearranged population, as has been previously demonstrated in the development of IDH inhibitors in combination with azacitidine. In that regard, I'm pleased to report we're now dosing patients in the first of our combination studies, which we call COMET007, in both the newly diagnosed and relapsed refractory settings. COMET007 is a Phase I study designed to assess safety, tolerability, and preliminary activity of ziftomenib in combination with either venetoclax and azacitidine or standard induction cytarabine-donorubicin chemotherapy, commonly known as 7 plus 3. The study is expected to enroll patients with NPM1 mutant or KMT2A rearranged AML across sites in the U.S. and Europe. We anticipate having preliminary data from the COMET007 study in the fourth quarter of 2023 or the first quarter of 2024. We're also working to initiate our COMET-008 study of ziftomenib in combination with additional standards of care, including the FLT3 inhibitor giltaritinib later this year. In addition, we expect to begin our post-transplant maintenance program for ziftomenib in the first quarter of 2024. We are very excited about the potential for these studies to further demonstrate the value of our menin program and establish ziftomenib as a backbone of therapy across the continuum of care for AML patients. Now let's turn our attention to our farnesyl transferase inhibitor programs, beginning with tibifarnib. We continue to work to unlock the substantial therapeutic and commercial value of farnesyl transferase inhibition, and we believe this novel mechanism is uniquely positioned to deliver clinical benefit in multiple large solid tumor indications. The first such opportunity is in head and neck squamous cell carcinoma, through the combination of tipifarnib and the PI3 kinase alpha-selective inhibitor, alpelicib. Head and neck cancer is the seventh most common cancer worldwide, and it remains a significant unmet medical need with no approved small molecule targeted therapies. The objective response rate for the three FDA-approved therapies for treatment of HNSCC in the second line ranged from 13% to 16%, with median progression-free survival of two to three months and a median overall survival of just five to eight months. Recall we previously reported the first demonstration of a durable clinical response with the combination of tipifarnib and alpelicib in a patient with PIK3CA-mutated squamous cell carcinoma of the tonsil. Since that time, our dose escalation study has continued with no dose-limiting toxicities to date observed for the combinations. We are encouraged both by the safety profile as well as the clinical activity we're seeing in the trial, which we call current HN, with continued evidence of activity at multiple doses and enhanced activity relative to our expectations for either drug alone in this population. We are now evaluating patients in the study's highest planned dose cohort to help inform selection of the optimal biologically active dose for the combination. Once we determine the OBAD, we intend to initiate a small dose expansion of patients with PIK3CA mutant HNSCC to validate the safety profile and activity of the combination at the recommended phase two dose. Meanwhile, we've generated a growing body of preclinical data that supports the combination of farnesyl transferase inhibitors with multiple classes of targeted therapies to either prevent or delay emergence of drug resistance in large solid tumor indications. In April, we presented encouraging preclinical data at the American Association for Cancer Research annual meeting, supporting the potential use of FTIs in combination with two additional distinct classes of targeted therapies. The first of two posters revealed robust synergy between tipifarnib and the standard of care anti-angiogenic tyrosine kinase inhibitor, or TKI, exitinib, in cell and patient-derived xenograft models of clear-cell renal cell carcinoma. The second poster reported regression of multiple models of KRAS inhibitor-resistant non-small-cell lung cancer by the addition of tipifarnib to either adagrasib or satorasib therapy. These promising preclinical data illustrate the potential for FTIs to drive enhanced antitumor activity and address mechanisms of innate and adaptive resistance to targeted therapies. In addition, we believe these data strongly support our rationale to combine our next-generation farnesyl transferase inhibitor, which we call KO2806, with TKIs in clear-cell renal cell carcinoma and with KRAS G12C-specific mutant-specific inhibitors in non-small-cell lung cancer. Earlier this year, we received FDA clearance of the investigational new drug application for KO2806 for treatment of advanced solid tumors. We intend to evaluate the safety, tolerability, and preliminary antitumor activity of KO2806 in a phase one dose escalation study, which we're calling FIT001. We've begun site activation in FIT001 and look forward to dosing the first patients in the study later this year. Concurrent with the dose escalation as a monotherapy, we plan to evaluate KO2806 in dose escalation combination cohorts in advanced solid tumors, beginning with clear cell renal cell carcinoma. 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 second quarter of 2023. Research and development expenses for the second quarter of 2023 were $28.2 million compared to $24.3 million for the second quarter of 2022. The increase in R&D expenses was primarily due to the increases in clinical trial costs related to our Zipdomenib and KO2806 programs. General and administrative expenses for the second quarter of 2023 were $11.8 million compared to $11.1 million for the second quarter of 2022. Net loss for the second quarter of 2023 was $37.2 million compared to a net loss of $34.8 million for the second quarter of 2022. This includes non-cash share-based compensation expense of $7 million compared to $6.5 million for the same period in 2022. As of June 30th, we had cash, cash equivalents, and short-term investments of $477 million compared to $438 million as of December 31st, 2022. This includes net proceeds of approximately $94 million from our public offering completed in June of 2023. We believe that our cash, cash equivalents, and short-term investments will be sufficient to fund our current operating plan to mid-2026. With that, I now turn the call back over to Troy.
spk05: Thank you, Tom. Before we jump into the question-and-answer session, let me lay out our anticipated milestones for the remainder of this year and next year. For Zifto-Mediv, dose the first patients in the COMET-008 combination trial in the second half of 2023. Preliminary data from the COMET007 combination trial in the fourth quarter of 2023 or the first quarter of 2024, and dose the first patients in the post-transplant maintenance program in the first quarter of 2024. For tibifarnib, initiate dose expansion in the current HN trial in mid-2024. And for KO2806, dose the first patients in the FIT001 dose escalation trial as a monotherapy in the second half of 2023, and dose the first patients in the FIT001 dose escalation trial in combination with a targeted therapy in clear cell renal cell carcinoma in the second half of 2024. With that, Kelsey, we're now ready for questions.
spk10: Thank you. Ladies and gentlemen, we'll now begin the question and answer session. Should you have a question, please press the star followed by the one on your touchtone phones. You will then hear a three-tone prompt acknowledging your request, and your questions will be polled in the order that they are received. Should you wish to decline from the polling process, please press the star followed by the two. And if you are using a speakerphone, please lift the handset before pressing any keys. One moment, please, for your first question. And your first question comes from Jonathan Chang from Lear Inc. Partners. Please go ahead.
spk08: Hi, guys. Thanks for taking my questions. First question, can you give us any more color around enrollment progress and the registration-directed study of zyptomenib and NPM1 mutant AML? And what do you mean by outperforming projections?
spk05: Sure. Thanks, Jonathan, for the question. So, we have guided or I should say we anticipate full enrollment of the 85 patients in the study approximately the middle of next year. just to take a half a step back, just to remind everyone, we sized the trial at 85 patients because it was our view that for a potentially best-in-class therapy, the agency would likely want to see approximately 100 patients' worth of safety data at the recommended Phase II dose. It's still early days, Jonathan, but in terms of both site activation and now enrollment of patients on the study, we are, you know, ahead, quite a bit ahead of where we expect it to be. And we obviously have enrollment curves under different scenarios. We haven't yet made any adjustments to our guidance in terms of timing of overall enrollment. We want to see how the rest of the summer goes and a little bit into the fall. Sometimes you see a slowdown in the late summer. So we want to just be mindful of that. But what we want to communicate is there's very strong interest in among both physicians and patients, and that seems to be translating directly into enrollment. There also, Jonathan, appear to be more patients than I think we had anticipated, both from potential, you know, competitors and other folks who've tried to enroll trials in the NPM1 space. You know, there was some sort of anecdotal comments out there that it might be challenging to enroll. That hasn't been our experience at all. In fact, quite the opposite. And since, you know, through EHA and now on the other side of EHA, we're seeing very, very, very strong interest, which is translating into enrollment. And I think that's driven, Jonathan, in part because of the data that I just very summarily walked through. The fact that we're seeing activity in patients who failed FLT3, patients who failed IDH, patients with various co-mutations. I don't think we're seeing a siphoning off of patients to those other trials. Instead, we're seeing very strong interest in putting them on the ZIFTO monotherapy study. And we have every expectation that's going to translate into the combos. You know, which is, it's even earlier days there, but I think we're quite encouraged.
spk08: Got it. Thank you. And second question, can you discuss the post-transplant maintenance opportunity for Zifto-MedEv?
spk05: Sure. Yeah, and let me just clarify there. We're actually going to do both a post-transplant maintenance as well as just a maintenance. without requiring transplant. And let's talk about how those are different. So, first of all, without needing to get the transplant, our protocols have made allowances for patients to be able to stay on study. So, for example, patients who are enrolled in 7 plus 3 plus ZIFTO can stay on ZIFTO in a maintenance type of setting. And we've built that in everywhere we can. So that's obviously important and I think has the potential to drive value. Our team, I think, is thinking very cleverly of the post-transplant setting, Jonathan. And what we're shooting for is to be able to capture patients no matter how they get to transplant, whether they've had a prior menin inhibitor or not, no matter where they've gotten, if they meet the entry criteria and they're on the other side of transplant, they'll be eligible to go into that study. It's our view, Jonathan, that given we have such a favorable safety profile, we have no QT prolongation, we have no evidence of drug-induced myelosuppression, you know, we just have a very, very attractive safety profile. You know, we really have the opportunity to be a preferred agent in the maintenance setting. And we've heard, you know, from sophisticated parties, that's a very attractive commercial opportunity. If you can keep patients on there for a year or two, you know, that has the potential to drive really significant value, both for the patients as well as for the value of the overall enterprise. So, and then the final thing, Jonathan, I'll comment on is, you know, we're trying, if people have been paying attention to the way we've laid these studies out, Thus far, all the studies we've undertaken are Cura-specific studies, Cura-sponsored studies, so that we can drive the timing. And, you know, they're all sort of very much value-creating. With the maintenance study, we'll do an initial Phase I study as an investigator-sponsored study to gather enough data, and then we'll flip it over into a Cura-sponsored study if it makes the transition into a Phase II-III study. So we're trying as much as we can to retain control of the studies to be able to drive timelines and execution, and thus far that's working quite well.
spk08: Understood. Thanks for taking the questions.
spk05: Our pleasure. Thank you.
spk10: Thank you. And your next question comes from Roger Song from Jefferies. Please go ahead.
spk07: All right. Congrats for all the progress and thanks for taking the question. I think you mentioned you already started the first combo trial, which is very encouraging. Maybe, Troy, you can give us some color around the enrollment progress so far and how should we think about the expectation for the initial data later this year, early next year, in terms of the number, maybe the activity you are looking for, and also when you will potentially decide the IP2D. Thank you. multiple parts, sorry.
spk05: Yeah, that's okay. I'll take each of them, Roger. And if I miss one, please remind me or correct me. So first of all, just a comment on the design of the trials. So these are dose escalation trials. Each of the genotypes is being treated separately with standard of care. So in the context of 7 plus 3, we have a KMT2A cohort. We have an NPM1 cohort. These are typically six-patient escalation cohorts, and we're starting at an N-2 dose, a 200-milligram dose. Similarly for the venetoclax-containing regimen. I'll remind you that in the phase one, there really was no dose dependence within between 200 and 600 milligrams as it pertained to differentiation syndrome. And that's important because you talked about kind of how do we think about data and RP2D. So as with any study, you know, first and foremost, what we're going to focus on, I think, you know, and we're guiding to fourth quarter this year or or at the latest first quarter next year, is safety and tolerability, specifically with respect to differentiation syndrome. So, can we safely combine with the current standards of care? We believe we can. And importantly, do those standards of care help mitigate the differentiation syndrome that was seen in the KMT2A population? And so, The question of activity, Roger, is a good one. However, as you appreciate, the backbone therapy has a meaningful level of clinical activity. So that really isn't going to be anything I think we can speak to. That's really when you get further on and you take... Once you're at a dose that is the optimum biologically active dose or the RP2D, you'll take it potentially into an expansion cohort, and then we can get a better sense of clinical activity relative to the backbone alone. The update as it pertains to the end of this year or early next, Although we fully expect there will be clinical activity, I think we want to make sure we step through it. Safety and tolerability, can we mitigate differentiation syndrome, and then how are we making progress in the dose escalation? And we expect, Roger, ultimately to have 40 U.S. sites in the Phase 1a. We have a handful of them that are open now and enrolling patients. That number will increase in the weeks and months ahead. But thus far, again, interest has been very robust. And we have a philosophy, Roger, with this trial and the accompanying 008 trial, of what we sort of call no patient left behind, right? A patient who presents at a physician's office, if he or she needs a venetoclax-containing regimen, they can go on ven plus zifto. If they're better suited for 7 plus 3, they can go on 7 plus 3 plus zifto. When we get to 008, there's a lot of interest in combining with giltaritinib. Those of you who saw the data from Quisertinib that supported the recent FDA approval, you saw that half of those FLT3 patients in the quiz trial were NPM1 commutants, fully 50%. So there's a lot of interest in combining MENID inhibitors with FLT3 inhibitors, and our team is is moving as aggressively as possible to get 008 open as soon as we can. So I hope that gives you some color, Roger. And I think I addressed all the components of your question, but let me know if I need to follow up on anything.
spk07: No, that's great. That's great. Okay, so that's very clear now. Maybe just shift gears to the TIPI. So understanding you're figuring out the RP2D for them, but in the past you seem to – kind of guide towards the data release around the mid-year for the RP2D. And now you're kind of guiding towards the expansion cohort second half next year. So maybe just let us know what's the current thinking around the TP. Thank you.
spk05: Yeah, it's a good question. And I think it's the reasonable question and the right question. So in short, Roger, the combination is both better tolerated and more active than we expected. That's the short answer. So if we take a step back, before we ever dosed a patient, when investors and analysts asked me, what's the greatest risk? I said from my perspective, the greatest risk is the challenges with combining tipifarnib and alpelicib. Particularly, we as an industry have not had good success in combining inhibitors of the MAP kinase pathway and inhibitors of the PI3 kinase pathway. We have been, I think, very pleasantly surprised at the safety and tolerability that we've seen with this combination. We have seen evidence of hyperglycemia, but it hasn't been dose-limiting. It hasn't inhibited in any way our ability to escalate both tippy and alpelicib. And just to put a point on that, now this final escalation cohort is a full dose of tippy, 600 milligrams twice a day, and a full dose of alpelicib, 300 milligrams daily. Honestly, I was surprised. I wouldn't say shocked, but pleasantly surprised. The other thing, Roger, is we're seeing evidence of clinical activity. Now, in this population, that's why I cited to you second-line head and neck, you're typically seeing response rates in the teens, 13% to 16%, and really challenging PFS and OS, PFS of two to three months. you can assume we are seeing responses. I don't want to get into the granularity of the data, but we're seeing activity at, we're seeing, first of all, good safety and tolerability. We're seeing activity at different dose levels. We do need to make sure that we select the optimum biologically active dose, and that's the lowest dose at which we have full activity and acceptable safety. So, you know, we're sorting that out. I think the critical questions and the reason we're guiding to next year is what dose is that? And then importantly, what level of activity are you seeing at that dose to help inform what a phase two, three trial might look like? Just to remind everyone, HRAS mutant is 4% to 6% of the population. PIK3CA mutant is 15% to 20% of the population. We've seen that reflected in the enrollment curves and the enrollment on this study. We could potentially be treating up to a quarter of head and neck cancer, Roger, but we want to make sure we get it right. And we've already shown, we showed the example of the patient with the tonsil, the metastatic head and neck cancer from the tonsil. you know, an 85% tumor reduction after one cycle and a durable response. So the next critical question is, what's the dose? And then how do you think about the safety, tolerability, and activity to frame the opportunity for a registrational trial in a disease where there's been no approved small molecule targeted therapy? That's the work we have to do. And the team's cranking as fast as they can. We think reasonable guidance on that expansion cohort is sort of middle of next year.
spk07: Excellent. Thanks, Troy, for all the comments. That's it from us. Thank you.
spk10: Thank you. Your next question comes from Peter Lawson from Barclays. Please go ahead.
spk03: Thanks so much for taking the questions. Just kind of a, firstly, a follow-up around the maintenance setting and whether resistance mutations could preclude ZIFTO from being used in that maintenance setting, and then a Another question just around moving ZIFTO beyond AML and ALL into other heme indications, solid tumors, or other diseases. Thank you.
spk06: Sure.
spk05: Yeah. Thanks, Peter, for the question. So, we don't think resistance mutations are going to be a big threat to using ZIFTO in the maintenance setting. We've only ever seen one patient of the ones we've tested, the 29 or so we've tested, who developed a resistance mutation while on ZIFTO. And people might ask the question, well, you know, was your assay sensitive enough? And my answer would be, you know, we don't see any evidence of resistance mutations driving progression or resistance to ZIFTO. Patients do develop resistance. They do progress, but it doesn't appear to be due to these resistance mutations. That's part number one. You know, we've got about a 3% to 4% rate of resistance mutations in the data that we've sampled thus far, Peter. But the other important point is ziftamenib is fully active on two of the three mutants, and it retains, you know, meaningful activity on the third, the 327 mutant. And that's in contrast, you know, to a number of the other inhibitors in the class. And we've actually seen that as we spoke to around EHA. We've seen that when we treated patients who have come to our study having failed another menin inhibitor, we do have a measure of clinical activity. Long story short, Peter, we don't think it's going to make a difference. We think ZIFTO is very well positioned for the maintenance setting. And importantly, Peter, even probably more importantly, it's very easy to use. It doesn't have any other toxicities thus far that have revealed themselves that would require sort of extra detection or extra vigilance in that setting. So I think we're looking forward to using ZIFTO in the maintenance setting. And forgive me, Peter, the second part of your question is,
spk03: Yeah. Oh, additional indication. The question was expanding outside heme indications or other heme indications into solid tumors and other diseases. Just your thoughts there and where you are.
spk06: Sure.
spk05: So I think there, Peter, you want to be data-driven. There are other opportunities that we see beyond acute leukemia for menin inhibitors. I think one needs to be very mindful of the potential impact of the inflation reduction act. And, you know, long story short, the best analysis we have, and we've talked to all the experts, including CMS, is that we can do anything within AML, and we stay out of the Inflation Reduction Act by virtue of having an orphan designation that covers AML. Once you go to another indication, be it ALL, be it, you know, any of the others, you potentially put your program at risk of being included in the IRA. And I think, we think, Peter, the appropriate way to mitigate that risk is we have a next-generation menin inhibitor program. We've taken everything about ZIFTO that we think can be improved, and the team is, you know, has a very attractive compound. That would be the one we would probably take into additional indications. be those other solid or liquid tumors, be that potentially diabetes. We've got multiple opportunities for additional menin inhibitors. And just given the evolving sort of legal and regulatory and pricing landscape, I think one wants to be thoughtful there. We think we can drive significant value just in AML alone. And you hear us, right? We're talking about frontline relapse refractory maintenance, We really think you can transform the standard of care and transform the market, and we're going to do everything we can with ZIFTO in that setting. If there's additional opportunities, I think we might do some early exploration, but we'd likely pick those up with a second-generation compound, and that way you can really drive the full commercial value for the franchise.
spk09: Great. Thank you so much. Really appreciate it. Pleasure.
spk10: Thank you. And your next question comes from Lee Wasik from Cantor. Please go ahead.
spk11: Hey, congrats on the quarter and thank you for taking our questions. I guess first one is on Phase 2 Pivotal Study of Zip2. Choi, can you maybe just clarify if you have seen greater traction in terms of patient enrollment after your IHA update in June, I mean, especially for some of the EU sites that you have. And also for the potential, you know, combo data later this year or early next year, can you give us a sense of the, you know, the variables here? Is it, you know, just a matter of enrollment speed or you want to, you know, reach a certain number of patients or a certain period of follow-up? before you disclose the data?
spk05: Yeah, Leith, thanks for the question. So on the first question, it's, you know, when you do this with any trial, you do, you know, you do feasibility studies and you, you know, you have a, you know, an enrollment curve. And that enrollment curve is driven by the feedback that you get from the sites. How many patients do they see? How many do they think they can put on, et cetera? And our clinical operations group, you know, has done that very well with the 001 study. We are ahead of our projections, Lee. And I think, you know, There are a lot of reasons for that. I think it's physician excitement. I think it's the data itself. I think there's more patients than perhaps we expected, and we're not losing them to other studies. It's hard to say kind of – it's hard to isolate one variable. What we're communicating is for people who think there's going to be a big gap in terms of time to market, I think we have a different view that's perhaps informed by data. particularly in that NPM1 setting. And you fully expect, you know, if the combination trials go well and we have good safety and tolerability, that you would expect that traction to continue. Because everyone acknowledges that you know, as these molecules, you know, eventually go in front of the FDA and potentially come to market, we're still, you know, AML is a disease of combination therapy. So the party that can get to the combinations with the highest, best safety, best tolerability, combinability, and activity is ultimately going to be the market leader. And we think that sets up very nicely for Zifto. So I expect that that excitement and enthusiasm will pull through as you know, into the combo studies. With respect to the second part of your question, Lee, in terms of how we think about data release, so we understand that one of the questions in the minds of all of the analysts and the investors is, can we mitigate differentiation syndrome through co-administration of the standard of care regimens, and does that unlock the activity of ZyftoMedib more fully, particularly in the KMT2A rearranged population? It's a, every indication, you know, everyone we talk to tells us that that's likely the appropriate path forward, but you have to do the work. You have to actually, you know, do it. That's why I'm focusing initially safety, tolerability, mitigation of DS. DS is typically something you see in between cycle one and cycle three. Once the leukemia is eliminated, there's no risk of DS. And if you're not eliminating the leukemia, the patient's likely going to progress and leave the study anyway. So you know relatively early on if you've mitigated DS. I don't think we're going to share data. We're not going to, you know, dribble the data out with an eyedropper on a patient-by-patient basis. We want to get a sufficient number of patients on study that we can come to you and say, here's the data, and we can draw some meaningful conclusions. And I've indicated to you, you know, these are six patient dose escalation cohorts. So the numbers get to be meaningful pretty quickly, even when we're, you know, in the first dose escalation or two. We don't know yet will each of the, you know, are the genotypes and the various combinations going to enroll at different rates? We don't have enough clarity into that yet. What we've been encouraged by is that just as with L01, you know, physicians are finding patients, screening, patients are coming on study. You know, the machine is working. And I think as we look toward our next earnings call, Lee, in November, as we look toward ASH and the end of the year, I think we'll be in a position, you know, to possibly give a meaningful update on why we think ZIFTO has a best-in-class profile. Hope that helps.
spk11: Yeah, okay, thank you. I have a second question. So in terms of the patients that you're enrolling into the Pivotal Study with co-mutations, do you have a sense of the, in terms of, you know, the breakdown for FLIP3 versus IDH co-mutations?
spk05: No, at least I don't think so. You're talking, Lee, about the breakdown of co-mutations in patients enrolled on the study? Is that what you're asking? Yes. We are seeing – so I think it's early days. We're seeing very high levels of co-mutation. That's why I highlighted for you, you know, if you go pull the quizartinib label, 50% of the FLT3 are NPM1 co-mutated, right? So you need to be able at some point to combine with the FLT3 inhibitor or you've given up 15% of the population. We're seeing that as well, Lee, both FLT3, IDH. DNM T3A, you know, all the central actors. It's very similar to what we've seen in the 1B. I don't think we have specific breakdowns yet in terms of the co-mutational content in the population.
spk11: Okay, thank you.
spk09: Sure.
spk10: Thank you. And your next question comes from Bradley Canino from CIFL. Please go ahead.
spk00: Hi, this is for Brad Canino. Congrats on the progress. So, first question is on tibifarnib. Glad you're seeing responses and some limited safety issues. How should we be thinking about the contribution of parts for TIPI and PIC-RAE in the next data? And then will we be getting data in both the HRAS overexpressed population and PIC-3CA?
spk05: Yeah, Bijan, so thank you. So let's, if I may, let's take those in opposite order. So earlier this year, we announced that we were not going to continue enrolling in the HRAS overexpressing cohort. We were going to focus our effort in the PIC3CA mutant. And that was really for a you know, we, as with every company, we have finite resources and we have more things we can invest in than we, than we have, um, you know, funds with which to invest. So particularly as you hear us articulate, you know, everything we're doing with ZiptoMedib, um, If one wants to identify the OBAD, the best place in our experience to go is in those patients who have driver mutations in the target oncogene, whether they be HRAS mutant in the case of the RUN and the AIM studies or PIK3CA mutants in the case of the current studies. If you're going to define the OBAD, you know, go there because that's where you're going to have the potential of the greatest level of activity because the closer you get to a driver mutation or I should say a gain-of-function mutation in a driver oncogene, typically that's where you see the highest activity. That doesn't, Bijan, preclude that once we get the OBAD, we would come back and investigate either HRAS overexpressed or PIC3CA amplified. We just want to do it in stages. And we want to be good stewards of capital, good fiduciaries, and be smart about doing drug development. So we are, you know, the picture's coming into focus in the PIC3CA mutant. Your question around contribution of parts. So, Tipifarnib, you would expect, it has no ability to drive responses in a PIK3CA mutant population as a monotherapy. That I can say with great confidence. Alpelisib, in the experience of Novartis, has had a very limited ability to drive responses, and those responses typically, I'm aware of only one, are typically not durable. What you're seeing here, you know, we have some very nice preclinical work that our translational research team published showing that the mechanistic rationale for why this combination is so effective in this disease and how TOR, and particularly REB, you know, allows you potentially to drive more activity on PIK3CA. it's clear to us that the combo has better clinical activity than either drug as a monotherapy. At this point now, you know, we're just continuing to gather data and gather confidence. I will say something. I didn't get a chance to address it with Roger's question, but the other thing that gives us great confidence in is as we look to 2806, And we've already given you a heads up. Look at TKIs in renal cell. Look at mutant selective inhibitors in KRAS. The fact that we can safely combine TIPI and alpelicib and get activity that is at a minimum additive, possibly better than additive, maybe synergistic, I think, bodes very well for as we are now preparing to advance 2806 into the clinic. Because if you look at second-line RCC, you know, again, you're talking about a response rate with TKIs that's in the teens. And the activity in KRAS inhibitors is impressive, but the resistance happens pretty rapidly. And I think that entire field is looking for the preferred combination partner. Is it SHIP2? Is it SAUCE? You know, what do you do? I'm going to tell you, we think FTI stands a very strong chance of being a preferred partner in both of those settings. And the tibial pellucid data potentially gives us an opportunity into head and neck. And it also then, I think, again, votes well for 2806. But let's start dosing patients on that study and see if that's correct.
spk09: Yeah, great. Thanks for the comments there. Sure. Appreciate the question.
spk10: Thank you. And your next question comes from Justin Zelen from BTIG. You may go ahead.
spk02: Yeah, hi. Yeah, hi. This is for Justin. Thanks for taking our questions. Was just looking to get your take on your view on menins for diabetes based on recent competitor data at ADA, and I had a follow-up question.
spk05: Sure. we're following, as many are, we're following that data with interest. There's certainly a relationship between men and inhibition and beta cell regeneration. I think in our minds, there's so still a lot of gaps and questions as to, you know, what exactly is going on there. What we've decided to do is to, you know, we'll continue to watchfully wait that data set. We're actually evaluating ziftomenib as well as a number of other menin inhibitors in the appropriate models of diabetes, both as monotherapy and in combination. And I'm hopeful that we'll have some data later this year to make an assessment as to, do we see an opportunity? And if so, how do we make sure we take advantage of it? If there's an opportunity for menin inhibitors in diabetes, I'll tell you today, we'll find a way to maximize that value for shareholders, either through a partnership or an out-licensing. I doubt we'll become Cura Diabetes, but we will find a way to get the value in it. But importantly, and this is an answer I gave previously, our view is you probably want to do that with another menin inhibitor. both because you don't necessarily want your diabetes compound and your oncology compounds to have the same safety database. And number two, from the standpoint of the Inflation Reduction Act, you've kind of shot yourself in the foot. So we have, you know, we have, as I said, a next generation menin inhibitor that we've been bringing along. That may, if the data supports it, and we're going to look for, you know, the recommendation from our translational research and clinical colleagues to that's how you'll see us generate value with men and inhibitors in diabetes, is through a next-generation compound. And I'll tell you this, if it's there, I have no doubt we can generate a best-in-class compound. It's just a matter of let's be disciplined, let's do the right experiments, and let's generate the data and see.
spk02: Makes sense. And just as a follow-up, I was hoping you could maybe just clarify the number of patients being treated for the head and neck expansion cohort for tipifarnib? And secondly, what other indications outside of head and neck and RCC are most promising for FTIs in your view?
spk05: Yeah, great question. So within head and neck, you know, you probably want an expansion cohort of sort of, and I'm just, I'm spitballing here, sort of 6 to 12 patients, you know, similar to what we did with ziftomanib in the phase 1b. You want to have enough enough clinical data there that you've got a strong steer on how to think about future development. So that's that. In terms of other indications, we've got, I think, very good and evolving clinical data, both with tipifarnib as a monotherapy and increasingly tipifarnib and alpelisib. You know, although we terminated enrollment in our AIM study, we terminated it for operational feasibility. We didn't, you know, the compound's active. It's actually quite active. But again, in a world of limited resources, you have to make some difficult choices. And we would do our best to try to capture both the HRAS mutant and the PIK3CA mutant population, which is about a quarter of head and neck. For that, I would think about tipifarnib and alpelacib. You would then want to come with a second and possibly a third FTI and think about RCC and how you crack the KRAS riddle. At this point, you know, you want to generate data. You want to make sure you have optionality. But, you know, there have been questions about, you know, TIPI, the composition of matter patent has expired. But once you bundle it up with Alpelisib, our IP colleagues have done a great job of building a strong patent estate around, you know, FTIs and head and neck cancer that we can leverage And if we could beat it, you know, if we could get Tippi and Alpelisib to market for patients, like that would be an amazing accomplishment. There's no targeted, no small molecule targeted therapy approved. If you then wanted to come along with another FTI and try to beat it, great. But I always joke, walk, then run, then run the four-minute mile. So let's keep TIPI and Alpelisib moving along. You'll see us put increasing resources on 2806. And at this point, we don't have to make a decision. We want to generate data in both RCC and KRAS. and continue to mine the chemical space for more FTIs and see where we go. Those are three very significant solid tumor indications. And, you know, I think the data set's coming together nicely. It's turning out to be, you know, who knew that the killer application of FTIs was going to be back to KRAS where it all started, but just as a combination therapy. that would be sort of coming home, if you will. I hope that's where we end up.
spk02: Makes sense. Thank you so much.
spk10: Sure. Thank you. And our last question comes from Ren Benjamin from JMP Securities. Please go ahead.
spk12: Hey, guys. Thanks for taking the questions. Troy, can you talk to us a little bit about maybe the strategic rationale for starting off with RCC and and what's the unmet need there versus, you know, starting off with KRAS or KRAS Mutant and NS-CLC. And then, you know, a question for kind of all your combination programs. Are you, you know, in any sort of discussions with the companies that are marketing the approved drugs that you're combining, you know, either Zifto or Tippy with in order to set up, you know, an MTA or, you know, try to get some free drug? I mean, how important is that for... kind of cost mitigation and maybe enrolling patients quickly and getting the clinical trials off the ground?
spk05: Sure. It's a great question, Ren, and let me take it in parts. So with respect to RCC going first, we are improving as an organization, fundamentally different than where we were just a few years ago. really have a great cross-functional effort as we think about, you know, going from sort of preclinical R&D all the way through to lifecycle management. And so we've done the work on renal cell carcinoma. We've talked to the KOLs. We've done the market research. We understand the landscape. And we'll speak more to our specific partner in RCC probably a little later this year. But that's ran a relatively more mature space. We know what, you know, it's still evolving, but it's relatively more mature. So, for example, the docs were very clear. If we could enable them to use TKIs in the second line, that would be phenomenal. And if you look at the preclinical data that Francis' group has generated, there's really potent synergy between tipifarnib and TKIs, most notably exitinib, in that setting. So it's a great setup. The docs love it. In my view, we can't get there fast enough. Now take KRAS. KRAS is an emerging area. I know it's got a lot of heat, a lot of light. It is a rapidly evolving area. It's clear that resistance is going to be something that everybody's going to have to contend with. and TOR, target of rapamycin, which is one of the targets that we deal with with TIPI and 2806, that seems to be a central actor in driving resistance to KRAS inhibitors across the board, whether they're mutant selective, whether they're RAS on, whether they're G12C or G12D. If you hit KRAS, TOR gets engaged and tries to develop resistance. The tumor tries to find a workaround. So we're just being very deliberate and making sure that we're making the right decisions. With respect to your last question, are we trying to build clinical collaboration or supply agreements? The answer is yes. Ideally, you either want the drug to be reimbursed or you want to work with the sponsor to try to get, you know, a drug-sharing agreement or a clinical collaboration. We did that, of course, with Novartis initially with the Tipi Farnab-Alpelisib trial, and you can assume, you know, we are taking a similar strategy as we think about the opportunities for 2806. Terrific.
spk12: Thanks for taking the questions.
spk09: Sure. Thank you.
spk10: There are no further questions at this time. Mr. Troy Wilson, you may proceed with closing remarks.
spk05: Thank you. And thank you all for joining our call today. We'll be participating in the Cantor Healthcare Conference next month and hope to see a number of you there. In the meantime, if you have any additional questions, please contact Pete, Tom, or me. Thank you again for attending our call and have a good evening, everyone.
spk10: Ladies and gentlemen, this concludes your conference call for today. We thank you very much for participating and ask that you please disconnect your lines. Have a great day.
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