Earnings Call Transcript - KURA Q3 2023

Operator, Operator

Good afternoon, ladies and gentlemen, and welcome to the Third Quarter 2023 Kura 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. This call is being recorded on Thursday, November 2, 2023. I would now like to turn over the call to Pete De Spain, Head of Investor Relations. Please go ahead.

Pete De Spain, Head of Investor Relations

Thank you, Lester. Good afternoon, and welcome to Kura 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 Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company. With that, I'll now turn the call over to Troy.

Troy Wilson, CEO

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 multibillion-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 ziftomenib to become a backbone of therapy across the continuum of care for AML patients. Ziftomenib 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, ziftomenib demonstrated an impressive 35% CR rate and a 45% overall response rate in 20 patients with NPM1-mutant AML treated at the recommended Phase 2 dose of 600 milligrams. Importantly, ziftomenib 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 1 trial, we initiated a Phase 2 trial of ziftomenib 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 ziftomenib'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 2 registration-directed trial, no later than mid-2024. Increasingly, our clinical investigators refer to ziftomenib 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 ziftomenib to earlier lines of therapy and combining it with standards of care. Indeed, our vision for ziftomenib 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, as ziftomenib can do that, it has potential to transform the treatment of AML and ultimately to transform the commercial market for anti-leukemic therapy. These transformations in standards of care have enabled meaningful advances for patients in scenarios such as CML, lymphoma, and multiple myeloma with corresponding increases in market opportunity. Although AML has lagged behind these other areas due to the complexity, heterogeneity, and aggressive nature of the disease, we believe ziftomenib may represent an inflection point for treatment of leukemia and potentially other diseases. As first steps towards realizing this vision, we're evaluating ziftomenib 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 ziftomenib 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 KOMET-007 in the middle of this year. KOMET-007 is a Phase 1 dose escalation study designed to assess safety, tolerability, and preliminary activity of ziftomenib in combination with either venetoclax and azacitidine in patients with relapsed/refractory NPM1 mutant and KMT2A rearranged AML or standard induction cytarabine daunorubicin chemotherapy commonly known as 7+3 in NPM1 mutant and KMT2A rearranged patients in the frontline setting. We're very pleased with the pace of enrollment in the KOMET-007 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 KOMET-007 in early Q1 2024. We expect the data set to include safety and tolerability from NPM1 mutant and KMT2A rearranged patients treated with ziftomenib in both settings. We're also working to initiate our KOMET-008 study of ziftomenib in combination with additional standards of care including the FLT3 inhibitor gilteritinib as well as our post-transplant maintenance program for ziftomenib, 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 ziftomenib, we recently enhanced our own commercial expertise with the addition of Brian Powl 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 ziftomenib 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 tipifarnib in patients with HRAS 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 FTI, it has the potential to drive meaningful clinical benefit for patients. We believe these data validate the 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 the 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 to the combination. Once we determine the optimal biologically active dose, 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 alpelisib. We believe this significantly derisks the development of our next-generation farnesyl transferase inhibitor KO-2806, 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 the 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 KO-2806 with adagrasib in KRASG12C-mutated non-small cell lung cancer and with cabozantinib in clear cell renal cell carcinoma. A week later, we announced the first patient was dosed in the FIT-001 Phase 1 dose escalation trial of KO-2806. Concurrent with the dose escalation as a monotherapy in the FIT-001 trial, we also plan to evaluate KO-2806 in dose escalation combination cohorts, with adagrasib and cabozantinib. Earlier today, we announced a clinical collaboration and supply agreement with Mirati Therapeutics to evaluate the combination of KO-2806 and adagrasib in patients with KRASG12C-mutated non-small cell lung cancer. Under the terms of the agreement, Kura will sponsor the Phase 1 study and Mirati will supply us with adagrasib 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 KRASG12C-mutant oncogene. We look forward to collaborating with Mirati, an established leader in targeted oncology. We expect to begin dosing KO-2806 in combination with adagrasib in KRASG12C-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 KO-2806 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.

Tom Doyle, SVP of Finance and Accounting

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 costs related to our ziftomenib and KO-2806 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, 2022. 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 prospectus 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'll now turn the call back over to Troy.

Troy Wilson, CEO

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 ziftomenib, we report preliminary clinical data from 20 patients in the KOMET-007 trial in combination with ven/aza or 7+3 early in the first quarter of 2024. We dosed the first patients in the KOMET-008 trial in combination with additional standards of care including the FLT3 inhibitor gilteritinib 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 KOMET-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 KO-2806, dose the first patients in the FIT-001 dose escalation trial in combination with adagrasib in KRASG12C 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.

Operator, Operator

Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. Your first question comes from Jason Zemansky from Bank of America. Your line is now open.

Jason Zemansky, Analyst

Good afternoon, everyone. Thank you so much for the question and congrats on the quarter. Regarding the upcoming KOMET-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 the potential for combinations and what are we looking for in safety and efficacy? And then a follow-up if I may.

Troy Wilson, CEO

Yes. Do you want to ask the follow-up now, Jason, or do you want to wait? Let me answer this one.

Jason Zemansky, Analyst

Why don't we go ahead?

Troy Wilson, CEO

So in terms of what investors should expect so 007 is a Phase 1 dose escalation study as I indicated. We are evaluating ziftomenib in combination with ven/aza in the relapsed setting and with 7+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 and 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, do you have to discontinue doses, do you have to dose reduce. And then ultimately, of course, there will be activity although 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 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 differentiation syndrome. 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 shared 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 help inform the design of ultimate registration-enabling Phase 2/3 studies but one step at a time.

Jason Zemansky, Analyst

Got it. And then in terms of the opportunities here, how do you prioritize 7+3 versus ven/aza, 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 FLT3 would look?

Troy Wilson, CEO

Yeah. So, two good questions there. Let me take them kind of in order. If you look simply at the commercial opportunity, venetoclax combinations and maintenance probably stand the tallest. Again, given some baseline assumptions probably more detail than we have time for right here. But ultimately, what we'd like to do and I think it will be important, 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 ziftomenib in every combination setting. Why do I say that? You referenced specifically FLT3. FLT3 is half the NPM1 mutant combination. You now have quizartinib approved in the front line, you have gilteritinib approved in the relapsed refractory setting, that's half of NPM1 is 15% of AML in the preclinical models that we and Syndax have both enabled through publications, that combination is curative in a preclinical setting. So if you add an all-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 undisclosed indications that we're thinking about directing our next-gen menin inhibitor to, we'll speak more to that. 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.

Jason Zemansky, Analyst

Perfect. Thank you for the color.

Operator, Operator

Thank you. Your next question comes from Peter Lawson from Barclays. Your line is now open.

Peter Lawson, Analyst

Great. Thank you so much. Thanks for taking the questions. Troy, just to follow up on the KOMET-007. Beyond safety and differentiation or lack of differentiation benefit, what are the kind of the response rate bars or durability bars you kind of want to hit there as well?

Troy Wilson, CEO

Yes, 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 that excite you come from either retrospective analysis or Phase III studies, right? And there's always kind of an emotional desire to compare those numbers to a Phase I dose escalation study. We all do that at our peril, right? I just want to give that important caveat. That being said, the bar for those standards of care, that kind of what you would expect in the front line in 7+3, you're looking at, depending on the literature reference, a 70% to 90% CR/CRH rate. In ven/aza, in the relapse setting, you're looking at roughly a 40% to 60% CR/CRH rate. So, that's kind of the way to think about it. Our goals of course are safety, tolerability, are there drug-drug interactions that require changes in dose or interruptions. Of course, combinability, ability to mitigate differentiation syndrome, 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 II 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.

Peter Lawson, Analyst

Great. Thank you. And then just on 2806 and that cabozantinib combination, just like kind of where 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?

Troy Wilson, CEO

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 Kura. Mirati is supplying adagrasib to us. They've of course had input on the protocol. They have all of the appropriate safety reviews and whatnot. We're not yet formally co-developing that combination together, right? 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 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 approximately the middle of next year.

Peter Lawson, Analyst

Perfect. Thanks so much.

Troy Wilson, CEO

My pleasure. Thank you, Peter.

Operator, Operator

Your next question comes from Roger Song from Jefferies. Your line is now open.

Roger Song, Analyst

Great. Congrats for the progress. Thanks for taking the question. A couple from us. Maybe still focusing on the combo given that will be the most 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 time versus the relapsed/refractory and NPM1 versus 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 or will be from the 200-milligram, but not a 600-milligram. That's my first question.

Troy Wilson, CEO

Sure. Let me address your second question first. We're starting the dosing at 200 milligrams. There is an intention to escalate across all four cohorts, but I can't provide specific details on what you can expect just yet. Regarding your first question, we have KMT2A and NPM1 with six patients each in separate cohorts for the two regimens. I can confirm that enrollment is going well, and there is strong activity in all four cohorts. We expect that when the data is released in early Q1 next year, it will be well-balanced between NPM1 and KMT2A in both frontline and relapsed settings. While this will be an early data set, we believe it holds significance in addressing the question of whether we can mitigate differentiation syndrome. This reflects positively on our team, and we’re excited about the progress. We began dosing this study in July, and we're already in a position to provide data in early Q1 2024, which speaks to our team's excellent operational execution. We will continue to dose escalate as needed, which is why I'm cautious about the specifics regarding the dose level. When we present the data, we believe it will clarify questions related to safety, tolerability, combinability, and the ability to mitigate differentiation syndrome. We'll also plan to provide a follow-up update to further develop that narrative.

Roger Song, Analyst

Sure. Yeah, I agree. It's pretty rapid enrollment. And then so I don't want to lose sight of your pivotal monotherapy data study for NPM1. So I think that's the first time you guide 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 non-hypothesis? What is the minimum follow-up to have the final readout? And since you are guiding the completion of enrollment, any guidance around the timing of the readout? Thank you.

Troy Wilson, CEO

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 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 are 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 non-hypothesis. I can tell you that 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 get to that maybe a little further along. We want to make sure we've got really clear visibility into the end of enrollment. And 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.

Roger Song, Analyst

No that's great. Thanks. Enjoyed as always, and congrats again. That’s all from us.

Troy Wilson, CEO

I appreciate the question.

Operator, Operator

Your next question comes from Li Watsek from Cantor Fitzgerald. Your line is now open.

Li Watsek, Analyst

Hey, great. Thanks for taking my questions. Just wondering, Troy, if you can just comment on the combo data from your competitor released this morning. And then since you had some initial experience with your own combo, I understand it's not really apples-to-apples. But just from the safety perspective, how do you see a trend relative to your competition?

Troy Wilson, CEO

Yeah. Li, really good question, two good questions. I think a lot of drug development is pattern recognition and learning from the past. And if we go to other areas where people are developing targeted therapies, safety, tolerability, drug-drug interactions ability to combine are what everyone is focused on, right? We've seen this in the KRAS field, the ability or not to combine with checkpoint inhibitors. We've seen it in combining with inhibitors of the RAS pathway in the PI3 kinase pathway. That's why we're so excited about 2806 and adagrasib. Here is no different. I think, Li, some of the critical questions are going to be what are the drug-related adverse events 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. But what you're really looking for is are there going to be challenges that are going to be posed in being able to either administer the standard of care or really optimize it. I'll just go back to what you already know about Ziftomenib. 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 menin inhibitor from the perspective of safety and tolerability. That's going to have two important considerations, Li. One is the challenges that limit the duration of exposure in combination is one of the things you want to focus on. And the other, of course, is the maintenance setting. You want to have the most benign compound there. So that's what we as players in the field are looking at as we look forward to the ASH presentations. And I would say 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.

Li Watsek, Analyst

Okay. That makes sense. And then maybe just a follow-up on your own combo data in Q1. I'm just curious if there is any reason to expect different responses in NPM1 versus KMT2A?

Troy Wilson, CEO

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. It's ven/aza, I believe for NPM1 is in the mid-40s. KMT2A is kind of in the low 40s. You can't drive a truck between them. But in general, KMT2A patients probably do a little worse as you look across different regimens. I do want to be careful again that 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 minimal residual disease, I mean there are a whole lot of factors here. Our goal is to keep patients on therapy for months or even years. And that's going to be driven by safety and tolerability. It is going to be maintaining clinical activity but safety and tolerability is really going to be paramount. And it will be an interesting next two or three months here.

Li Watsek, Analyst

Great. Thank you.

Troy Wilson, CEO

Sure. Thank you.

Operator, Operator

Your next question comes from Justin Zelin from BTIG. Your line is now open.

Jeet Mukherjee, Analyst

Yes, hi. Thanks for taking our questions. This is Jeet Mukherjee on for Justin. On the topic of the combination study with ziftomenib, you've elaborated on the efficacy bar that 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 frontline in the relapsed refractory setting? And I have a follow-up question.

Troy Wilson, CEO

Sure, Jeet. So yeah, I mean what you worry about, of course, and I think you've correctly called it out. Cytopenias are not uncommon in the frontline setting. You do see not insignificant myelosuppression with ven/aza. 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 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 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 I study, just to put it simply, you're looking to show a combo safety profile that's at least no worse 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 later on down the line. For these early combo studies, it's really about what's the safety of the backbone and then what's the safety of your agent plus the backbone. Jeet, 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 ziftomenib 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 toxicities 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 gilteritinib.

Jeet Mukherjee, Analyst

Got it. That makes perfect sense. And just a second question I had. Turning to the FTI program. 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 tipifarnib forward as a monotherapy or the alpelisib combo? Thanks.

Troy Wilson, CEO

Yes. So – sorry, you're asking specifically about tipifarnib or about 2806. I just want to make sure I answer the question. You asked tipifarnib and head and neck.

Jeet Mukherjee, Analyst

Yeah. Perspective on both programs would be helpful.

Troy Wilson, CEO

Okay. Regarding head and neck, one key takeaway from the AIM-HN data presented by Dr. Ho at ESMO is that in the second line with standard care, the best response rate is 20%, and it's only 5% in the third line. Tipifarnib as a standalone treatment shows significant activity and has a favorable safety and tolerability profile. However, we know that tipifarnib is not effective as a single agent in the PIK3CA setting, while alpelisib has only been noted to result in stable disease. If there's potential for meaningful responses with good durability and an acceptable safety profile, we need to consider it. Moving on to 2806, this is a busy quarter, and I anticipate the following quarters will be equally active. We are making several investments in ziftomenib, with developments in relapsed and frontline settings, as well as maintenance. We are also advancing 2806 for non-small cell lung cancer and renal cell carcinoma, and I see a potential opportunity for 2806 in RAS-driven pancreatic cancer, which represents a significant unmet need. Additionally, we must be prudent in our investments, ensuring we maintain discipline on the financial side as much as on the scientific and clinical sides. Our approach will be to maximize the benefits from our head and neck initiatives and integrate that into our investment decisions, focusing on delivering the greatest value for patients, employees, and shareholders.

Jeet Mukherjee, Analyst

Thank you.

Troy Wilson, CEO

You’re welcome.

Operator, Operator

Your next question comes from Phil Nadeau from TD Cowen. Your line is now open.

Phil Nadeau, Analyst

Hello? Hey Troy.

Troy Wilson, CEO

Of course.

Phil Nadeau, Analyst

Thanks for taking our questions. A quick question from us on the updated enrollment timelines. When do you think you have clarity to really say when the moment in the pivotal trial is going to complete? Do you think that's likely early next year or will we know it as complete once it's completed?

Troy Wilson, CEO

I think, Phil, so today 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 Q1, Q2. I think even that let's hit that. We're super competitive right? We're maybe a few weeks apart or maybe a couple of months at the most. We're going to do everything we can to drive enrollment. We've resisted the urge given that we continue to say we're highly encouraged. We've resisted the urge to pull those milestones in until it's really a data complete. So I would say to you don't anticipate us to move any milestones on enrollment of our NPM1 pivotal. I think we're very much to do as well as that, if not better. And I would say just stay tuned.

Phil Nadeau, Analyst

Fair enough. Thanks for taking our question.

Troy Wilson, CEO

Our pleasure. Thank you, Phil.

Operator, Operator

Your next question comes from Brad Canino from Stifel. Your line is open.

Brad Canino, Analyst

Thank you. Troy, I just want to pull back and ask a question about the menin class in general. I think the street view is that KMT2Ar is the more sensitive population to men inhibition, which might just 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 the smaller patient population. But as I was reflecting on all of the menin 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.

Troy Wilson, CEO

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 to wrap abstracts out are reporting overall response rates, in one case even including stable disease, minimal residual disease, CRIs, those are all measures of clinical activity and those are important. But I think the registrational endpoints are at least at this stage, what's important. Can you drive the CR/CRH, and in the frontline can you drive the 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 transplantation? So that's why CR is also worth looking at. We probably wouldn't go beyond CR. And at this point, I think although again emotionally intuitively it makes sense that KMT2A 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 length in the time to recurrence and drive better survival. And I'll go back to something I said 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 menin is any different. I think ziftomenib has to stand pretty tall when you look at it that way.

Brad Canino, Analyst

Appreciate it. Thanks, Troy.

Troy Wilson, CEO

Our pleasure. Thank you.

Operator, Operator

There are no further questions at this time. Dr. Troy, please proceed with your closing remarks.

Troy Wilson, CEO

Thank you, Lester, and thank you all once again for joining our call today. We'll be participating in the Stifel 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.

Operator, Operator

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