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spk04: Good afternoon, ladies and gentlemen, and welcome to the third quarter 2023 Cura Oncology, Inc. Earnings Conference Call. At this time, all lines are in listen-only mode. 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, November 2, 2023. I would now like to turn over the call to Pete Despain, Head of Investor Relations. Please go ahead.
spk05: Thank you, Lester. Good afternoon and welcome to Cura Oncology's third 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.
spk08: Thank you, Pete, and thank you all for joining us. Let's jump right in. We believe our lead drug candidate, Ziftomenib, is well positioned for market leadership with multi-billion dollar global revenue potential in acute leukemias and beyond. Our conviction is supported by a growing body of clinical data as a monotherapy and more recently in combination with standards of care, a rapid pace of enrollment in our ongoing studies driven by strong clinical data and robust enthusiasm among investigators and patients, and a best-in-class safety and tolerability profile that we believe will enable Ziptomenib to become a backbone of therapy across the continuum of care for AML patients. Ziptomenib is a once-daily oral drug candidate that targets the MENIN-KMT2A protein-protein interaction and has potential to address all patients for whom the MENIN-KMT2A pathway is a disease driver, representing up to 50% of patients with AML. In our Phase 1 trial, Ziptomenib demonstrated an impressive 35% CR rate and 45% overall response rate in 20 patients with NPM1 mutant AML treated at the recommended Phase 2 dose of 600 milligrams. Importantly, Ziptomenib demonstrated a favorable safety profile and was well-tolerated, with no evidence of drug-induced QTC prolongation or myelosuppression, no patterns of toxicity, and adverse events consistent with underlying disease. Building upon the strength of the data from our phase one trial, we initiated a phase two trial of Zipdomenib in patients with NPM1 mutant, relapsed, or refractory AML earlier this year. The registration-directed trial is expected to enroll a total of 85 patients in the United States and Europe. We continue to be encouraged by the pace of enrollment in the trial, which in our view speaks to the size of the NPM1 mutant patient population in the relapsed and refractory setting, as well as ZyptoMENIP's potentially meaningful advantages in safety profile and clinical activity relative to available therapies. We expect to complete enrollment of all 85 patients in the Phase II registration-directed trial no later than mid-2024. Increasingly, our clinical investigators refer to ZyptoMENIP as a potentially transformational therapy. We believe their enthusiasm reflects not only their experience with it as a monotherapy, but the tremendous potential benefit to patients that could be realized by advancing Ziptomenib to earlier lines of therapy and combining it with standards of care. Indeed, our vision for Ziptomenib is that it can provide benefit to leukemia patients throughout the continuum of care, enabling deeper and more durable remissions in the frontline and relapsed refractory populations in combination, and as a potent monotherapy in the maintenance settings. Clearly, if Zipdomenib can do that, it has potential to transform the treatment of AML and ultimately to transform the commercial market for antileukemic therapy. It is these transformations in the standards of care that have enabled meaningful advances for patients in areas such as CML, lymphoma, and multiple myeloma with corresponding increases in market opportunity. Although AML is lagged behind these other areas due to the complexity, heterogeneity, and aggressive nature of the disease, we believe Zipdomenib may represent an inflection point for treatment of leukemia and potentially other diseases. As first steps toward realizing this vision, we're evaluating Zipdomenib in combination studies, both in newly diagnosed and relapsed refractory acute leukemia, including NPM1 mutant 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 to prioritize those combinations that represent the largest unmet medical need and the greatest potential commercial value. 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. We began dosing patients in the first of our combination studies, which we call COMET-007, in the middle of this year. COMET-007 is a phase one dose escalation study designed to assess safety, tolerability, and preliminary activity of ziptomenib in combination with either venetoclax and azacitidine in patients with relapsed refractory NPM1 mutant and KMT2A rearranged AML. or standard induction cytarabine-donorubicin chemotherapy, commonly known as 7 plus 3, in NPM1 mutant and KMT2A rearranged patients in the frontline setting. We're very pleased with the pace of enrollment in the COMET007 study, which currently includes patients with newly diagnosed and relapsed refractory NPM1 mutant and KMT2A rearranged AML across the United States. At this rate, we anticipate being in position to share preliminary data with sufficient follow-up from 20 patients in Comet 007 in early Q1 2024. We expect the data set to include safety and tolerability from NPM1 mutant and KMT2A rearranged patients treated with Zipdomenib in both settings. We're also working to initiate our COMET-008 study of ziptomenib in combination with additional standards of care, including the FLT3 inhibitor giltaritinib, as well as our post-transplant maintenance program for ziptomenib, both of which are expected to begin in the first quarter of 2024. Meanwhile, we continue to make progress toward a next-generation menin inhibitor, which we intend to direct to additional, as yet undisclosed, indications of high clinical, commercial, and strategic interest. As we continue to build the clinical data sets that we believe will support FDA registration and commercialization of Zipdomenib, we recently enhanced our own commercial expertise with the addition of Brian Powell to our senior leadership team as our chief commercial officer. Brian joined us over the summer with more than 20 years of experience in building commercial brands in hematology and oncology with expertise in patient-focused strategies across sales, marketing, and market access for global biotech and pharmaceutical products. He's already making an impact in the organization as we continue to realize the significant potential of Ziptomenib as well as our rapidly emerging farnesyl transferase inhibitor programs. We continue to unlock the substantial therapeutic and commercial value of farnesyl transferase inhibition and believe this novel mechanism is uniquely positioned to augment clinical benefit in multiple large solid tumor indications. Last month, we presented positive results from our AIM-HN registration-directed trial of tipifardib in patients with atras mutant head and neck squamous cell carcinoma. The results were featured during a late-breaking mini-oral session at the European Society for Medical Oncology Congress in Madrid. Our AIM-HN data demonstrate that if one understands the proper biological context in which to use an FDI, it has the potential to drive meaningful clinical benefit for patients. We believe these data validate therapeutic value of farnesyl transferase inhibition as we look to advance beyond our initial strategy to target HRAS mutant tumors. With our AIM-HN data in hand, we continue to evaluate whether the combination of tipifarnib and alpelisib has potential to extend the clinical benefit observed in the AIM-HN trial to a broader set of HNSCC patients in our ongoing current HN study. We continue to evaluate patients in the dose escalation study to inform selection of the optimal biologically active dose for the combination. Once we determine the OBAD, we'll continue to evaluate whether the activity supports development and commercialization of the combination in HNSCC. One of the most important takeaways thus far from current HN is that tipifarnib demonstrates a favorable safety and tolerability profile at its full dose in combination with alpalasif. We believe this significantly de-risks development of our next generation farnesol transferase inhibitor, KO2806, as we look forward to evaluating it in combination with other targeted therapies. With the success of targeted therapies such as KRAS inhibitors, tyrosine kinase inhibitors, and EGFR inhibitors, there's now considerable focus on the development of companion therapeutics that have potential to drive enhanced antitumor activity and address mechanisms of innate and adaptive resistance. Last month, we presented exciting preclinical data at the triple meeting, supporting our rationale to combine KO2806 with Adagrasiv in KRAS G12C mutated non-small cell lung cancer and with Cavozantinib in clear cell renal cell carcinoma. A week later, we announced the first patient was dosed in the FIT001 phase one dose escalation trial of KO2806. Concurrent with the dose escalation as a monotherapy in the FIT001 trial, We also plan to evaluate KO2806 in dose escalation combination cohorts with Atagracib and Cabozantinib. Earlier today, we announced a clinical collaboration and supply agreement with Merati Therapeutics to evaluate the combination of KO2806 and Atagracib in patients with KRAS G12C mutated non-small cell lung cancer. Under the terms of the agreement, Kuro will sponsor the phase one study and Merati will supply us with Atagracib for the study. This collaboration highlights the potential to address the urgent need for more durable and effective treatment options for patients with cancers driven by the KRAS G12C mutant oncogene. We look forward to collaborating with Mirati, an established leader in targeted oncology. We expect to begin dosing KO2806 in combination with Atagracib in KRAS G12C mutated non-small cell lung cancer. and in combination with cabozantinib in clear cell renal cell carcinoma by the middle of 2024. If successful, we believe KO2806 could become an ideal combination partner for multiple targeted therapies in large solid tumor indications. We look forward to sharing our continued progress in the months ahead. With that, I'll now turn the call over to Tom for a discussion of our financial results.
spk09: Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the third quarter of 2023. Research and development expenses for the third quarter of 2023 were $29.3 million compared to $25 million for the third quarter of 2022. The increase in R&D expenses was primarily due to the increase in clinical trial cost related to our Zipdominib and KO2806 programs. General and administrative expenses for the third quarter of 2023 were $13.1 million compared to $11.6 million for the third quarter of 2022. Net loss for the third quarter of 2023 was $38.6 million compared to a net loss of $35.5 million for the third quarter of 2022. This includes non-cash share-based compensation expense of $7.1 million compared to $6.4 million for the same period of 2022. As of September 30, 2023, we had cash, cash equivalents, and short-term investments of $452.6 million compared to $438 million as of December 31, 2020. We believe that our cash, cash equivalents, and short-term investments will be sufficient to fund our current operating plan to mid-2026. Today we are filing a shelf registration statement and corresponding prospective supplement for an at-the-market facility for our common stock. We are refreshing our shelf, which was set to expire next month, along with an ATM, in order to maintain good corporate housekeeping. With that, I now turn the call back over to Troy.
spk08: 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. Presifdomenid, report preliminary clinical data from 20 patients in the COMET-007 trial in combination with veneza or 7 plus 3 early in the first quarter of 2024. Dose the first patients in the COMET-008 trial in combination with additional standards of care, including the FLT3 inhibitor giltaridinib in the first quarter of 2024. Initiate the post-transplant maintenance program in the first quarter of 2024 and complete enrollment of 85 patients in COMET-001 registration-directed trial in NPM1 mutant AML by mid-2024. For tipifarnib, determine the optimum biologically active dose in combination with alpelisib and determine next steps for the program by mid-2024. And for KO2806, dose the first patients in the FIT-001 dose escalation trial in combination with Atagracif. in KRAS-B12C mutated non-small cell lung cancer and with cabozantinib in clear cell renal cell carcinoma by mid-2024. With that, Lester, we're now ready for questions.
spk04: Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have any questions, please press star followed by the number one on your touchtone phone. You will hear a three-tone prompt acknowledging your request. Should you wish to cancel please press star followed by the number two. If you're using a speakerphone, please lift the handset before pressing any keys. One moment for your first question. Your first question comes from Jason Szymanski from Bank of America. Your line is now open.
spk10: Good afternoon, everyone. Thank you so much for taking our question and congrats on the quarter. Regarding the upcoming comment 007 update what do you think investors should be looking for from the data what's necessary before the community can start to feel confident about potential for combinations and we know what are we looking for in safety and efficacy and then a follow-up if I may sure yeah do you want to ask the follow-up now Jason or you want to wait and let me answer this one why don't we go ahead okay
spk08: So in terms of what investors should expect, so 007 is a phase one dose escalation study, as I indicated. We are evaluating Zipdomenib in combination with Veneza in the relapsed setting and with 7 plus 3 in the frontline setting. Importantly, we're evaluating KMT2A and NPM1 mutant patients separately in separate cohorts. So there are six patients per cohort. So think of it as four cohorts times six patients each. That's 24 patients at a 200 milligram dose. And then as we dose escalate, 24 patients at 400, 24 patients at 600. In terms of what to look for, whether it's our data or anyone else's data, I think you start with safety and tolerability, ability to combine drug-drug interactions. You know, do you have to discontinue doses? Do you have to dose reduce? And then ultimately, of course, there's, you know, there will be activity, although it's, of course, in combination. I think, Jason, we feel confident based on the monotherapy data that we've shared thus far from the 001 study. If you recall, we had a, you know, among 20 patients with NPM1 mutant AML, we had a 35% CR rate with full count recovery. Thus, we have no QTC prolongation. We have no drug-induced myelosuppression. We have no predicted adverse drug-drug interactions. We're once daily. We're not a sensitive CYP3A4 substrate. All of those considerations will become important as you look to combine with these standards of care. This will be a preliminary look. We wanted to get it out there so that investors could assess safety, tolerability, ability to combine, and importantly, ability to mitigate DS. That was a question that we were getting a lot as to why do you see a difference between KMT2A and NPM1. And we feel confident, Jason, that in early Q1, when we share the data with you, among those 20 patients, we'll be able to answer investors' questions. We will, of course, hopefully continue dose escalation and look to reach a recommended phase 2 dose in each of those two settings to then help inform the design of ultimate registration enabling Phase 2-3 studies, but one step at a time.
spk10: Got it. And then in terms of the opportunities here, how do you prioritize, you know, 7 plus 3 versus Veneza, the frontline versus maintenance? And I guess... Among those two, is one better able to kind of give you a glimpse into how a combination with a FLT3 would look?
spk08: Yeah, so two good questions there. Let me take them kind of in order. You know, if you look simply at the commercial opportunity, Venetoclax combinations and maintenance probably stand the tallest, again, given some baseline assumptions that are probably more detailed than we have time for right here. But ultimately, what we'd like to do, you know, And I think it'll be important, you know, we look toward doing this eventually with someone, right, through some sort of partnership with a strategic partner. You really want to be able to position Zipdomenib in every combination setting. Why do I say that? You referenced specifically FLT3. FLT3 is half the NPM1 mutant combination. You now have quazartanib approved in the frontline. You have giltaritinib approved in the relapsed refractory setting. That's half of NPM1. It's 15% of AML. In the preclinical models that we and Syndex have both enabled through publications, That combination is curative in a preclinical setting. So if you had an oral regimen that could drive that kind of clinical activity, that would be pretty impressive. I think, Jason, what we'd like to do, and you see us doing it, we are laying the foundation for what I think is the broadest and potentially most value-creating menin inhibitor franchise in AML. And that's going to be frontline. That's going to be relapsed. That's going to be maintenance. Then you also heard us reference additional, you know, undisclosed indications that we're thinking about directing our next-gen menin inhibitor to. We'll speak more to that. You know, we pick our spots carefully, but there again, our goal is to have not just a best-in-class menin inhibitor, but truly a best-in-class franchise throughout the continuum of care.
spk02: Perfect. Thank you for the color. Our pleasure. Thank you. Your next question comes from Peter Lawsons from Barclays.
spk04: Your line is now open.
spk06: Great. Thank you so much. Thanks for taking the questions. Troy, just follow up on the comment seven. Beyond safety and differentiation or lack of differentiation benefit, what are the response rate bars or durability bars you want to hit there as well?
spk08: Yeah, Peter, it's a good question. Let me give you a caveat, and then I'll kind of give you the numbers to think of. So the caveat is the numbers I'm about to cite you come from either retrospective analysis or phase three studies, right? And there's always kind of an emotional desire to compare those numbers to a phase one dose escalation study. We all do that at our peril. I just want to give that important caveat. I think one of the things we do is very, very credible drug development, and let's just put that out there. That being said, the bar for those standards of care, the kind of what you would expect in the front line in 7 plus 3, you're looking at, depending on the literature reference, a 70% to 90% CRCRA trait. In Veneza, in the relapse setting, you're looking at roughly a 40 to 60% CRCRH rate. So that's kind of the way to think about it. Our goals, of course, are safety, tolerability, you know, are there drug-drug interactions that require changes in dose or interruptions? You know, of course, combinability, ability to mitigate DS, and then, of course, efficacy. We'll be looking at that as well. I'll just highlight for you, and this is why I took pains to explain to Jason's question, it's 24 patients at 200 milligrams. So we're going to share 20 patients' worth of data, but the goal, of course, should be let's get a robust data set of up to 72 patients, across the cohorts to help inform our recommended phase two dose for each of those two regimens. But I hope that, A, gives you the numbers, and B, gives you the appropriate context in which to think about them.
spk06: Great. Thank you. And then just on 2806, and that covers antonib combination, just the kind of way you're thinking about driving that, would that be a partnership as well, like you did for the KRAS, or would that potentially be an IST?
spk08: Yeah, so just to be clear, because you have a couple of things in your question. So let's start with the clinical collaboration between Mirati and Cura. Mirati is supplying Adagracib to us. They've, of course, had input on the protocol. You know, they have all of the appropriate, you know, safety reviews and whatnot. We're not yet formally co-developing that combination together. This is early days. It's an exploratory study. They're supplying it under a supply agreement. With cabozantinib, our expectation is that given that we'll be in the labeled indication and cabozantinib is fairly widely used, we'll be going into a second-line setting. That will largely be covered by insurance, thus not an immediate need for a clinical collaboration and supply agreement or even any other agreement. Cabozantinib is well understood. And if you, again, look at the preclinical data that was published at the TRIPLE meeting, very, very impressive activity in a second-line setting. And in particular, even after patients have progressed on one TKI, the combination of a second TKI plus 2806 really drives meaningful benefit. And that's, again, a lot of the things that we've learned about FTIs over the years. They have anti-angiogenic properties. They have other reasons that make that combination really pretty slick. And so we'll look forward to getting into that combination again, you know, approximately middle of next year.
spk06: Perfect. Thank you so much.
spk02: Our pleasure. Thank you, Peter. Your next question comes from Roger Song from Jefferies.
spk04: Your line is now open.
spk07: Great. Congrats for the progress, and thanks for taking the question. A couple from us, maybe still focusing on the combo, given that will be the most important upcoming data readouts you will have. Maybe just to drill down some of the details, Troy, if you can, for those 20 patients, how balanced we should see for the first line versus the relapsed reflectory and the MPM1 versus the KMT2A, understanding you have two cohorts by the dosing, but how balanced within the dose we will be able to look at it, and then also just confirm That 20 patient all will be from the 200 milligram, but not the 600 milligram. That's my first question. Thank you.
spk08: Sure. Yeah, Roger. So, let me take your second question first. So, we're starting the dosing at 200 milligrams. Obviously, I don't want to, you know, there's an intention to escalate all four cohorts. I don't want to speak to exactly sort of what you'll see yet, but what I can tell you with respect to your first question is we have KMT2A and NPM1 as six patient each separate cohorts for each of the two regimens. I can tell you this. They're all enrolling well. There's strong activity for each of the four of those cohorts. We anticipate that the data set, when you see it in early Q1 next year, will be well balanced in terms of NPM1 and KMT2A, both frontline and relapsed. So, again, an early data set, but we think an important data set in terms of addressing this question of can we mitigate differentiation syndrome. And it's just a credit to our team. And we talk a lot about being highly encouraged. We started dosing this study in July. We're already at a point where if we can guide to giving you data in early Q1 24, you know, our team is just crushing it on the operational execution. And we'll, of course, continue to dose escalate as appropriate. That's why I want to be careful how we answer the question on exactly what dose level. Let's just, you know, when we share the data, we think it'll address these questions around safety, tolerability, combinability, ability to mitigate DS, et cetera. We'll, of course, look then to providing a subsequent update that'll continue to flesh out that picture.
spk07: Sure. Yeah, I agree. It's pretty rapid enrollment. And then so don't want to lose sight of your pivotal monotherapy data, the study for MPM-1. So I think that's the first time you will close the enrollment by mid-year. Just curious, any statistical plan you have disclosed to us in terms of maybe any interim analysis or the null hypothesis? What is the minimum follow-up to have the final readout? And since you are guiding the enrollment completion, any guidance around the timing of the readout? Thank you.
spk08: Sure, Roger. So, there's, again, a few questions in there. So, this is the first time we've really put it on our milestone slide, you know, drawing a line. as far as completion of enrollment of an 85-patient study no later than the middle of next year. I'll note that one of our principal competitors is expecting to enroll its NPM1 cohort now sometime between Q1 and Q2 of next year, a 64-patient study. So we're clearly, I think, neck and neck and closing ground. The reason we picked 85 patients was driven by safety and tolerability. That always has to be paramount. That's why we're doing 007 the way we're doing it. That's really what the FDA wants to see. even in these devastating diseases. So, 85 patients plus the experience we have in NPM1 from the Phase 1 study, we think gives us approximately 100 patients. That should meet the agency's expectation as far as safety and tolerability. We have not disclosed a statistical plan or the you know, the null hypothesis, I can tell you we are being very conservative. We are, I think, quite encouraged by the 35% CR rate with full count recovery in the Phase 1B that we saw, but we're giving the trial every opportunity to be successful, and we're taking advantage of every opportunity we can to pull the timelines forward. So, I think it's important to put that out there as far as disclosure of data. That was the last of your questions. Let's, let's get to that. Maybe a little, a little farther along. We want to make sure we've got really clear visibility into the end of enrollment. And as you, as you know, You need enrollment, you need follow-up, you need data cleaning, and ideally your data release coincides with a scientific or medical meeting. We want all those stars to align. We're working on it. We'll give you an update when it's appropriate. I think I've answered all your questions, Roger, but tell me if I missed anything.
spk07: No, that's great. Thanks. Thanks, Troy, as always, and congrats again. That's all from us.
spk02: I appreciate the questions. Your next question comes from Lee Watzek from Cantor Fitzgerald.
spk04: Your line is now open.
spk01: Hey, great. Thanks for taking our questions. Just wondering, Troy, if you can, you know, just comment on the combo data from your competitor released from Azure App Store this morning. And then since you had some initial experience with your own combo, I understand it's not, you know, really apples to apples, but just from the safety perspective, how do you see a trend relative to your competition?
spk08: Yeah, Lee, really good question. Two good questions. So I think, you know, let's just, a lot of drug development is sort of pattern recognition and learning from the past. And if we go to, you know, other areas where people are developing targeted therapies, safety, tolerability, drug-drug interactions, ability to combine are what stymie everybody, right? We've seen this in the KRAS field, ability or not to combine with checkpoint inhibitors. We've seen it in combining with, you know, inhibitors of the RAS pathway and the PI3 kinase pathway. It's why we're so excited about 2806 and Adagracib. Here's no different. I think, Lee, some of the critical questions are going to be, you know, what are the drug-related AEs that you see both as a monotherapy and in combination? Are you seeing high rates of neutropenia, thrombocytopenia, febrile neutropenia? That's what we're seeing. You would, of course, expect activity. The standard of care gives you activity, right? But what you're really looking for is are there going to be challenges that are going to be posed in AEs being able to either administer the standard of care or really optimize it. I'll just go back to what do you already know about Zipto? We've given you a very robust data set at the 600 milligram dose that I believe, despite the data from the handful of competitors here at ASH, really shows that we have a best-in-class you know, menin inhibitor from the perspective of safety and tolerability. That's going to have two important considerations, Lee. One is the challenges that limit the duration of exposure in combo. That's one of the things you want to focus on. And the other, of course, is the maintenance setting, right? You want to have the most benign compound there. So that's what we as, you know, sort of players in the field are looking at as we look forward to the ASH presentations. And I would say, you know, we're looking forward to sharing our early clinical data with you. It's early, but we're encouraged by enrollment and looking forward to sharing it in Q1.
spk01: Okay, that makes sense. And then maybe just a follow-up on your own combo data in Q1. I'm just curious, is there any reason to expect different responses in NPM1 versus KMT2A?
spk08: So, again, let's go back to the standards of care. You would expect, in general, the KMT2A patients to not respond as well, but depending on what regimen you look at, what line of therapy, it's pretty close. You know, it's Venaza, I believe, for NPM1 is in the mid-40s. KMT2A is kind of in the low 40s. You know, there's not, you can't drive a truck between them. But in general, the KMT2A patients, you know, probably do a little worse as you look across different regimens. We'll, you know, I do want to be careful, Lee, again, that, you know, it is, though, as tempting as it is We want to just be careful whether we're looking at our data or at our competitors' data. You want to make sure you have enough patient experience before you try to draw any kind of conclusions on activity because you're looking also at duration, at MRD. There's a whole lot of factors here. Our goal is to keep patients on therapy months or even years. And that's going to be driven by safety and tolerability. That's, you know, it is going to be maintaining clinical activity, but safety and tolerability is really going to be paramount. And it'll be an interesting next, you know, next two or three months here.
spk01: Great. Thank you.
spk02: Sure. Thank you. Your next question comes from Justin Sullen from BTIG.
spk04: Your line is now open.
spk03: Yes, hi. Thanks for taking our questions. This is Mukherjee on for Justin. So on the topic of the combination study with ZIFTO, you know, you've elaborated on the efficacy bar that, you know, one would want to look for, but could you just give a bit more color on the safety bar that one would be looking for, at least in the context of the various cytopenias, knowing that myelosuppression is very much characteristic of agents in the front line and the latifactory setting? Thanks, and I have a follow-up question.
spk08: Georgie, so, yeah, I mean, you know, what you worry about, of course, and I think you've correctly called it out, cytopenias are not uncommon in, you know, in the frontline setting. You know, you do see not insignificant myelosuppression with venasa. So, to the extent that you have an AE profile, a drug-related AE profile that runs the risk of compounding that, what you run the risk of is You know, are you going to need to dose reduce? Are you going to need to discontinue? Are you going to require continuous monitoring, whether it's QT or, you know, various cytopenias? That's what you're looking for. The biggest risk and the thing that gets the combinations of any flavor in trouble is when the toxicity profiles are overlapping. In a phase one study, just to put it simply, you're looking to show a combo safety profile that's at least no worse than than the standard of care, right? It's rare that you do better because you're not mitigating the toxicities, but you're not looking for a lot of additive toxicity. That's where you can create issues. So the other thing is you're potentially looking to improve upon the backbone as you have additional experience with your agent and other agents in terms of how to combine. Right? Can you take certain things away? Can you do dose optimization? But that's, you know, that's later on down the line. For these early combo studies, you know, it's really about what's the safety of the backbone and then what's the safety of your agent plus the backbone. I do want to, Jito, since you asked the question, I want to just call something out. And it's a credit, I think, to our team. The way our study is designed, we begin patients on the standard of care on day one. We dose them for seven days, and then we start Zipto on day eight. There's really three reasons for doing that. Number one, you get a safety baseline on the standard of care. So that helps you deconvolute any tox that you see in the combination. Secondly, of course, it allows you time to genotype. And then third, it helps to debulk the patient further mitigating the risk of differentiation syndrome. I don't want to speak to what others are doing, but we found that approach to be very successful, and it's something that we're implementing kind of across the board, starting with these two combinations. And as you hear, in 008, we're going to roll out to some additional combinations, most notably giltaritinib.
spk03: Got it. That makes perfect sense. And just the second question I had, turning to the FTI programs, Could you just share your thinking and strategy a bit more broadly around this program? What would you be looking for from a safety and efficacy perspective to justify moving TIPI forward as a monotherapy or the Alpelisib combo? Thanks.
spk08: Yeah. So, sorry. You're asking specifically about TIPI or about 2806? I just want to make sure I understood the question. You asked about TIPI and head and neck?
spk03: Yeah, perspective on both programs would be helpful.
spk08: Okay, so with head and neck, I mean, and this was one of the takeaways from the AIM data that was presented by Dr. Ho in the mini oral session at ESMO. You know, you have, at best, in the second line, you know, with standard of care, a 20% response rate. The third line, it's 5%. TIPI as a monotherapy is driving, you know, sort of meaningful activity with very, and it has a favorable safety and tolerability profile. What we know is, you know, TIPI is not active as a monotherapy in the PIK3CA setting. Alpelacib is reported to drive only stable disease. Clearly, if you can drive responses with reasonable durability and you have an acceptable safety and tolerability profile, then you start to look at it. The bigger question, and let me come to 2806, is As you're hearing, you know, this is a busy quarter. I think subsequent quarters may be equally busy. We have a number of investments in ZIFTO. You've heard, you know, relapse setting, frontline settings. We're going to start into maintenance. You're hearing us now push forward with 2806 in both non-small cell lung and renal cell carcinoma. I'm interested if there's an opportunity with 2806 in pancreatic cancer, RAS-driven pancreatic. I think that's a huge unmet need and a huge opportunity in a rapidly evolving space. The other thing, gee, we've got to do is be good fiduciaries and say, you know, how can we be as disciplined on the investment side as we are on the scientific and clinical side? And that's the calculus we go through on a pretty regular basis. So we're going to get everything we can out of head and neck, and then we're going to fold that into, you know, where do we make these investments? Where are we going to drive the greatest amount of value for patients, for employees, and for our shareholders? And that's how we'll do it.
spk02: Thank you. Sure. Your next question comes from Phil Nadeau from Tiggity Cowan.
spk04: Your line is now open.
spk02: Hello? Hey, Phil?
spk12: Eva? Is that you? Hey, guys. Sorry about that. Of course. Thanks for taking our question. Quick question from us on the updated enrollment timelines. When do you think you'll have clarity to really say when the enrollment in the pivotal trial is going to complete? Do you think that's likely early next year or... or will we know it completes once it's completed?
spk08: I think, Phil, so today, you know, we put down in our milestone slide for the first time, it's no later than mid-2024. Based on what we're hearing from the competition guiding that they'll complete enrollment, you know, Q1, Q2, I think even that, let's hit that, we're super competitive, right? We're maybe a few weeks apart or, you know, maybe a couple of months at the most. We're going to do everything we can to drive enrollment. We've resisted the urge, even though we continue to say we're highly encouraged, we've resisted the urge to pull those milestones in until, you know, it's really a fait accompli. So I would say to you, don't anticipate us to move any milestones on enrollment of our NPM-1 pivotal. I think we're very much to do as well as that, if not better. And I would say just stay tuned.
spk12: Fair enough. Thanks for taking our question.
spk02: Our pleasure. Thank you, Phil. Your next question comes from Brad Canino from Stifel. Your line is now open.
spk11: Thank you. Troy, I just want to pull back and ask a question about the Mennon class in general. I think the street view is that KMT2AR is the more sensitive population to Mennon inhibition, It might just be because the name of the alteration is more similar, but nevertheless, some struggle with investing in this class because the best efficacy is then expected in this smaller patient population. But as I was reflecting on all the men and data sets this afternoon from J&J, from Syndax, and of course your own, the common trend is to actually see more responses in NPM1. And I want to know, where do you stand with your synthesis of the data across the class? Should we on the street actually recalibrate and expect the best efficacy to be confirmed in the larger NPM1 population? Thanks.
spk08: Yeah, Brad, it's a good question, and thank you. It's actually not a question I've heard before, and I think it is worthwhile to set expectations. So we have to be careful what we're talking about here, right? The registrational endpoints for the relapsed refractory setting are CR-CRH. For the frontline setting, they will be CR. For the maintenance setting, they will be survival. Other companies, and we got a raft of abstracts out, are reporting ORRs, you know, in one case even including stable disease, MLFS, CRIs. Those are all measures of clinical activity, and those are important. But I think the registrational endpoints are, at least at this stage, are what's important. Can you drive a CR-CRH? And in the frontline, can you drive a CR? The reason I frame it that way is that can be a little confounded by are you getting full count recovery? Are patients going on to transplant? So that's why CRC is also worth looking at. We probably wouldn't go beyond CRC. And at this point, I think although, again, emotionally, intuitively, it makes sense that KMC2A should be more sensitive. In reality, we're seeing activity, pretty robust activity in both populations across the class, and I think that's only going to improve in combination. What we're really hoping in combination to do is can we drive deeper responses? Can we eliminate extramedullary disease and minimal residual disease? Can we drive, you know, lengthen the time to recurrence and drive better survival? That's, and I'll go back to something I said a couple of, you know, as an answer to a couple of calls ago. That's going to come down to who has the ability to keep menin pressure on in the presence of combo, and then ultimately in the maintenance setting as a monotherapy without having to jump through a lot of hoops. That's what we've seen with every targeted therapy. There's no reason to believe Menon's any different. I think Zipto has to stand pretty tall when you look at it that way.
spk02: Appreciate it. Thanks, Troy. Our pleasure. Thank you.
spk04: Ladies and gentlemen, as a reminder, should you have any questions, please press star followed by the number one on your keypad.
spk02: There are no further questions at this time. Dr. Troy, please proceed with your closing remarks.
spk08: Thank you, Lester, and thank you all once again for joining our call today. We'll be participating in the Stiefel Healthcare Conference and the Jefferies London Healthcare Conference in a couple of weeks. We look forward to seeing many of you there. In the meantime, if you have any additional questions, please feel free to contact Pete, Tom, or me. Thank you, and have a good evening, everyone.
spk04: Ladies and gentlemen, this concludes today's conference. Thank you for participating. You may now disconnect.
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