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spk09: Good afternoon, ladies and gentlemen, and welcome to the Q4 2023 Cora Oncology Incorporated Financial Results 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 Tuesday, February 27, 2024. I would now like to turn the conference over to Pete Despain, Head of Investor Relations. Please go ahead.
spk00: Great. Thank you, Eric. Good afternoon and welcome to Cura Oncology's fourth quarter and full year 2023 conference call. Joining me on the call are Dr. Troy Wilson, our President and CEO, 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 CURRAS filings with the SEC, which are available from the SEC or on the CURRAS Oncology website for information concerning risk factors that could affect the company. With that, I'll now turn the call over to Troy.
spk06: Thank you, Pete, and thank you all for joining us. Let's jump right in. Last month, we reported preliminary clinical data from the first 20 patients in COMET007, the phase one dose escalation trial of our MENIN inhibitor, Zifdomenib, in combination with standards of care in patients with NPM1 mutant and KMT2A rearranged acute myeloid leukemia. The first 20 patients were enrolled in fewer than four months, from July to November of last year, including five newly diagnosed patients with adverse risk AML and 15 patients with relapsed refractory AML. Ziptomenib demonstrated a highly encouraging safety and tolerability profile in combination with Cytarabine plus Donorubicin, or 7 plus 3, as well as with Venetoclax plus Azacitidine, enabling continuous administration of Ziptomenib while effectively mitigating the risk of differentiation syndrome. In fact, no differentiation syndrome events of any grade were reported among the first 20 patients. Furthermore, no dose-limiting toxicities, QTC prolongation, drug-drug interactions, or additive myelosuppression were observed. As of the data cutoff on January 11th, all five newly diagnosed patients with adverse risk NPM1 mutant or KMT2A rearranged AML treated with ziftometabin 7 plus 3 achieved a complete remission with full count recovery, for a CR rate of 100%. The overall response rate among the 15 relapsed refractory patients treated with Ziptomenib and Veneza was 53%, including a 40% ORR among the 10 patients who had received prior venetoclax, a setting with very limited effective treatment options. Notably, the CR-CRH rate among the nine relapsed refractory patients who were Mennon inhibitor naive was 56%. As of the data cutoff, 16 of the first 20 patients remained on trial, including all 11 NPM1 mutant patients. Continuous daily dosing of Ziptomenib at 200 milligrams QD was well tolerated and the safety profile was consistent with features of underlying disease and backbone therapies. As we reported on January 30th, the 200 milligram dose of Ziptomenib has been cleared in both relapsed refractory venasa cohorts and enrollment at the 400-milligram dose continues. In the meantime, I'm pleased to report we've also escalated to the 400-milligram dose of ziptomenib in the frontline adverse risk NPM1 mutant 7 plus 3 cohort, and we anticipate clearing the 200-milligram dose in the frontline KMT2A rearranged 7 plus 3 cohort shortly. At this rate, we expect to determine the recommended phase 2 dose for ziptomenib in combination with Veneza, and in combination with 7 plus 3 by the middle of this year. After determination of the recommended phase 2 dose, we plan to initiate a phase 1B dose validation expansion with Ziftomenib in Veneza in newly diagnosed patients with NPM1 mutant and KMT2A rearranged AML. In the meantime, we're now dosing patients in our COMET008 study of ziptomenib in combination with additional standards of care, including the FLIP3 inhibitor giltaritinib, flagida, or LDAC, all for the treatment of relapsed refractory NPM1 mutant or KMT2A rearranged AML. Roughly half of patients with relapsed or refractory NPM1 mutant AML have co-occurring FLIP3 mutations, and the prognosis for these patients is particularly poor. Preclinical data for ZiftoMedib in combination with FLIP3 inhibitors demonstrate strong synergistic effects compared to either single agent alone. We believe a best-in-class safety and activity profile and optimum pharmaceutical properties will enable ZiftoMedib to become a cornerstone of therapy for patients with acute leukemias. This belief is supported by growing investigator enthusiasm as evidenced by rapid enrollment across all of our ongoing Zipdomenib studies. We continue to be encouraged by the rate of enrollment in COMET-001, our Phase II registration-directed trial of Zipdomenib in patients with relapse, refractory, NPM1 mutant AML, and we remain on pace to complete enrollment of all 85 patients in the trial by the middle of this year. Our mission is to develop Zipdomenib across the continuum of care for all patients with acute leukemias whose disease is driven by the Menin pathway, including pediatrics, where poor outcomes unfortunately remain. In December, we announced Ziptomenib was selected for the Leukemia and Lymphoma Society's Pediatric Acute Leukemia Master Clinical Trial, commonly known as PEDL. As part of the study, Ziptomenib will be evaluated in combination with chemotherapy in pediatric patients with relapsed refractory KMT2A rearranged, NUP98 rearranged, or NPM1 mutant acute leukemia. In addition, we recently began dosing patients with KMT2A rearranged acute lymphoblastic leukemia, a relatively small group of patients but with a very large unmet medical need, as well as a cohort of patients who have neither NPM1 mutant nor KMT2A rearranged AML. We also have a growing body of preclinical data that supports attractive opportunities for menin inhibitors beyond acute leukemias. We're now preparing to initiate a proof-of-concept study in an undisclosed solid tumor indication later this year. Meanwhile, we continue to make progress toward a next-generation menin inhibitor, which we intend to direct to an additional, soon-to-be-disclosed indication. And with our recent financing, we remain in a strong financial position, which enables us to invest aggressively in research, development, and pre-commercial activities to maximize the value of ziftamenib and support our other pipeline assets. Now let's turn our attention to our farnesyl transferase inhibitor programs, beginning with KO2806. Despite success of targeted cancer drugs, such as tyrosine kinase inhibitors and KRAS inhibitors, a considerable need remains to drive enhanced anti-tumor activity while addressing mechanisms of innate and adaptive resistance. We are developing our next generation farnesyl transferase inhibitor, KO-2806, to address this need. 2806 was designed to improve upon the potency, pharmacokinetic, and physicochemical properties of earlier FTI drug candidates. Last year, we presented compelling preclinical data supporting the rationale for combining KO2806 with distinct classes of targeted therapies, including tyrosine kinase inhibitors and KRAS inhibitors. In October, we began dosing patients with KO2806 as a monotherapy in a phase one dose escalation trial that we call FIT001. FIT001 uses an innovative design that enables us to begin dose escalation of KO2806 in combination cohorts very early on in the study while continuing to dose escalate concurrently as a monotherapy. We're now preparing to dose the first patients with KO2806 in combination with cabozantinib in clear cell renal cell carcinoma and in combination with adagracib in KRAS G12C mutated non-small cell lung cancer by the middle of this year. Recall in November we announced a clinical collaboration and supply agreement with Mirati Therapeutics, now Bristol Myers Squibb, to support that latter study. We're encouraged that the strong operational execution seen in the Zift-O-Menib trials has carried over to the FIT-001 study and look forward to realizing the promise of the combinations. If successful, we believe KO-2806 could become an ideal combination partner for multiple targeted therapies in large solid tumor indications. Meanwhile, we continue to evaluate our first-generation FTI, Tipifarnib, in combination with the targeted therapy alpelicib, building on impressive clinical benefit we observed with tipifarnib alone in head and neck cancer. We continue to evaluate patients in the dose escalation study of tipifarnib and alpelicib, which we call current HN. Given encouraging clinical activity observed at multiple dose levels, we're adding additional patients to help inform selection of the optimal biologically active dose for the combination. Once we determine the OBAD later this year, we'll determine the next steps for the program. Importantly, we are encouraged that tipifarnib continues to demonstrate a favorable safety and tolerability profile at its full dose in combination with alpelosib. We believe this significantly de-risks development of our next generation FTI, KO2806, as we begin to evaluate it in combination with other targeted therapies. With that, I'll now turn the call over to Tom Doyle for a discussion of our financial results.
spk07: Tom? Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the fourth quarter and full year of 2023. Research and development expenses for the fourth quarter of 2023 were $32.5 million compared to $22.7 million for the fourth quarter of 2022. R&D expenses for the full year of 2023 were $115.2 million compared to $92.8 million for the prior year. The increase in R&D expenses was primarily due to increases in clinical trial costs related to our ZIFTO-MENIB and K0-2806 programs. General and administrative expenses for the fourth quarter of 2023 were $14.2 million compared to $12.5 million for the fourth quarter of 2022. G&A expenses for the full year of 2023 were $50.6 million compared to $47.1 million for the prior year. Net loss for the fourth quarter of 2023 was $42.8 million compared to a net loss of $33.1 million for the fourth quarter of 2022. Net loss for the full year of 2023 was $152.6 million compared to a net loss of $135.8 million for the prior year. Net loss for the fourth quarter and full year of 2023 included non-cash share-based compensation expense of $7.2 million and $28.1 million, respectively. This compares to $6.8 million and $26.3 million for the same periods in 2022. As of December 31, 2023, we had cash, cash equivalents, and short-term investments of $424 million compared to $438 million as of December 31, 2022. Subsequently, on January 26, 2024, we completed an oversubscribed private placement with a select group of institutional and accredited healthcare specialist investors. as adjusted for the approximately $146 million in net proceeds resulting from this private placement, Cura had, on a pro forma basis, $570 million in cash, cash equivalents, and short-term investments. We believe that our cash, cash equivalents, and short-term investments will be sufficient to fund our current operating plan into 2027. With that, I now turn the call back over to Troy.
spk06: Thank you, Tom. Before we jump into the question and answer session, let me lay out our anticipated upcoming milestones. Prezifdimenib, initiate the post-transplant maintenance program in the first quarter of 2024. Complete enrollment of 85 patients in the COMET-001 registration-directed trial in NPM1 mutant AML by mid-2024. Determine the recommended phase two dose in combination with Veneza and initiate dose validation expansion in frontline AML by mid-2024. and determine the recommended phase 2 dose in combination with 7 plus 3 by mid-2024. For KO2806, dose the first patients in combination with cabozantinib in clear cell renal cell carcinoma by mid-2024, and dose the first patients in combination with adagracib in KRAS G12C mutated non-small cell lung cancer by mid-2024. And for tipifarnib, complete enrollment of two expansion cohorts to support determination in of the optimal biologically active dose in combination with alpelicib by the end of 2024. With that, Eric, we're now ready for questions.
spk09: Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press the star followed by the one on your touchtone phone. You will hear a three-tone prompt acknowledging your request, and your questions will be pulled in the order they are received. Should you wish to decline from the polling process, please press the star followed by the two. If you are using a speakerphone, please lift the handset before pressing any keys. Your first question comes from the line of Jonathan Chang with Lurink Partners. Please go ahead.
spk05: Hi, guys. Oh, hi, guys. Thanks for taking my questions. First question on ZyftoMeneb. Can you discuss your thoughts on the combinability with Venaza and your thoughts on whether you need to adjust the dose of Ven due to drug-drug interactions and potential CYP3A4 inhibition?
spk06: Sure, Jonathan. Thanks for the question. So I'll actually direct folks. There's a revised slide in the corporate deck if you want to take a look at it. It has the exposure curve by dose on the right side, and on the left side, some of the key points, Jonathan, from the 001 study. Most importantly, you know, from the clinical data we've now generated, the human clinical data, we can say Zipdomenib is not a clinically meaningful CYP3A4 substrate. We don't have to adjust its dose at all in the presence of azoles, for example. and it is also not a clinically meaningful CYP3A4 inhibitor. In other words, to your specific question, we don't have to adjust the dose of venetoclax, which is a CYP3A4 substrate in the presence of Zipdomenib. Now, I want to be clear, the protocol does allow for the adjustment of venetoclax dosing if a patient, for example, is on a nasal. That is per the label of venetoclax. but there's no dose adjustment needed when venetoclax is combined with ziftamentib. So just to underscore, it's neither a substrate nor an inhibitor of CYP3A4.
spk05: Got it. Thanks for clarifying. And then just second question with the COMET008 study starting. Can you discuss the opportunity for ziftamentib in combination with a FLT3 inhibitor? and what are your reasons for confidence in the combinability of these drugs? Thank you.
spk11: Sure.
spk06: So, you know, the rationale is maybe just taking a half a step back. When you look at the various combinations of the 007 and the 008 protocols, what our team, you know, Molly Leone, Stephen Dale, and others on the team have endeavored to do is to provide a foundation where physicians can, in principle, combine Zip2Medib with any available standard of care, giving them maximal flexibility as they're dealing with patients in various lines of therapy. More specifically to your question about FLIP3, so FLIP3 mutants represent roughly half of the NPM1 population. And you can see that, for example, in the giltaritinib and in the quasartinib studies. The extent of overlap between NPM1 mutants and FLIP3 mutants is roughly 50%. That's number one. Number two is, if we could provide those patients with an all-oral, you know, targeted therapy regimen that was effective and well-tolerated, we think that would be broadly embraced. In our discussions with physicians, giltaritinib is very popular. And the preclinical data that we've generated, admittedly, it's preclinical, but the preclinical data combining FLT3 inhibitors with ziftomenib, the results are nearly curative. I mean, I'll say they're curative, I use that word carefully, but the potential, Jonathan, to have an all-oral regimen that could drive such a profound clinical benefit in patients we think would be very attractive. So it's a huge slice of the population, the possibility for an all-oral regimen, and something approaching a cure with excellent tolerability. In terms of managing the safety, the thing that really that we just want to make sure we pay attention to is the potential for differentiation syndrome. It was observed with the FLT3 inhibitors. However, we think that by sequencing and sort of careful monitoring and mitigation, we'll be able to deal with that. We, along with the field and the investigators, understand differentiation syndrome much better now. And so I think we're feeling optimistic that we'll be able to find a dose and schedule that gets those two agents working well together. And we'll look forward to sharing our progress later this year.
spk10: Understood. Thanks for taking the questions. My pleasure.
spk09: Your next question comes from the line of Jason Zemanski with Bank of America. Please go ahead.
spk13: Perfect. Good afternoon, and thank you for taking our questions. I'm curious about 007. As the patients continue to hopefully do well on therapy and potentially approach hematological recovery with longer duration of therapy, what are your expectations in terms of moving them off of therapy? Is the idea maybe to keep them on Zifto and maybe pull back on Veneza, as which usually happens? Or, you know, would you necessarily discontinue the menin inhibitor at some point? And then a follow-up, if I may.
spk06: Yeah, Jason, thanks for the question. So, importantly, you know, And you heard it in the prepared remarks. We don't see any additive myelosuppression. And as a result, we don't have to hold the dosing of Zifto at all to allow counts to recover. At one time, it was thought that, you know, there might be a class effect. We certainly don't see that with Zifto-Menem. To your question, which I think is well-formulated, Our experience has been that physicians use, I mean, obviously they use 7 plus 3, you know, for seven days or three days, as indicated. For Veneza, they're using it to really drive the clinical activity, and then they're pulling back. They're keeping patients on ZIFTO. I think our intent and sort of what we're seeing is that these patients are staying on ZIFTO and If they go to transplant, they might take a break while they're, you know, conditioning for transplant, but then they're coming back on to Zipto-mended monotherapy post-transplant in a, you know, in a maintenance setting, you know, sort of using the air quotes. That's how we would expect Zipto to be used. Jason is literally from day eight. And then really only with an interruption perhaps for transplant, patients would stay on Zifto-Menib until disease progression or the alternative. And we haven't had patients on long enough to say, do they no longer need to be on Zifto? Have we cured them of the disease? That's a dream, but that's for someday in the future.
spk13: Got it. And then Looking at your timelines, thinking about the bigger commercial dynamics here, you're potentially looking at a scenario where you may be a next-to-market menin inhibitor in the NPM1 space with potentially better efficacy. You know, how are you thinking about launching into this space? I guess what I'm really driving at here is, at this stage, do you get the sense that the community, the prescribing community, sees the two different menin inhibitors as more distinct versus similar? I mean, what's the feedback been like here?
spk06: Yeah. So, you know, look, we've done a small amount of sort of pre-commercial work with physicians. And what we found is when we profile the Zifto-Mentib target product profile as informed by data and we put it up against the competition, we hear sort of an overwhelming preference to use Zifto-Mentib, primarily driven by by the safety and tolerability. No, you know, no CYP3A4 liability, no dose-limiting toxicity. And I think that's only going to continue and get amplified, Jason, as we move into combinations. So, and I'm, you know, I would also say I think we're not really willing to concede yet that we're going to be second to market in the NPM-1 setting. To my knowledge, neither study has yet completed enrollment. Maybe there are some updates today from the competition, but our enrollment continues to be robust. I think we've got a well-powered study, and we intend to move very aggressively. I think we'll be well-positioned. If anything, again, I keep going back to our enrollment because all other data points, they can be shaded in various ways. Enrollment is objective. Enrollment is difficult to argue with, and we've already mentioned we continue to make progress. We're looking forward, I think, to being able to move into the 600-milligram cohort here before too long. That enrollment speaks for itself, and we expect to see that pull through into the commercial marketplace.
spk13: Got it. You had a follow-up question.
spk06: Yeah, cool.
spk13: That was the follow-up. Thank you so much for the insights and color.
spk06: Our pleasure. Thank you for the questions.
spk09: Your next question comes from the line of Lee Watek with Cantor Fitzgerald. Please go ahead.
spk04: Hi. Good afternoon. Congrats on the progress. Maybe just a couple follow-up questions from me. You know, just wondering if you can clarify the plan for data disclosure for 007 study around midyear. You know, other than RP2D dose selection, would you be sharing data at higher doses? And also, can you comment on if you have started to dose patients at 600 mc?
spk06: Yeah. So, thanks, Lee, for the questions. Let me take them in reverse order. As of today, no, we haven't started yet dosing patients at 600. I think you can hear from us, we're encouraged thus far by what we're seeing. And as you know from the monotherapy, there's nothing that we've seen that really gives us cause for concern, but one still has to run the experiment. In terms of what data one might expect, So, obviously, going back to the January update, which feels like a lifetime ago, but was just about a month ago, at that point we had 20 patients for which we shared data, and we were focused on safety, tolerability, combinability, and then some early signs of activity. The next logical update, ideally, you said it in your question, I think it's right, is around the RP2D. Are we able to dose escalate? What does that look like from, again, safety, tolerability, combinability? Is there any difference, or are we simply giving more ZIFTO? When we give an update, we'll give an update on all the patients on study. And you can tell, everyone probably remembers, Each of these four cohorts are at least six patients per dose. And I want to be careful with that. There may be additional patients simply because if we get them in screening but we're not yet ready to escalate, we might tack on a couple of more patients at a given dose. So, you know, expect six-plus patients per cohort per dose. And you can hear us moving pretty aggressively through these dose cohorts. Finally, Lee, as to timing... You know, there I think we're keeping all the options open, right? Obviously, we're going to have a presence at EHA. It's, you know, it's one of the most important heme meetings. In terms of the update on this study, you know, there might be something there. There could be something in a corporate update. I think we know what people are looking for, and we want to make sure we have that data rather than sort of being necessarily constrained by, you know, this precise timing of the medical meeting. We still have, you know, lots of time until that happens, and we're making good progress. And we'll certainly look forward to giving a more fulsome data update on 007 a bit later this year.
spk04: Okay. And then maybe a follow-up question. Sure. You mentioned about, you know, enrollment speed here. I mean, given the very strong data from 007 study last month, I guess, what is your expectation for the enrollment rate for the 008? And also in terms of clinical sites, what's the degree of overlap between these two studies?
spk06: Yeah, good question. So again, I appreciate it's a two-part question. Let me take the second part first because it's a little easier. At this point, there's sort of minimal overlap between 007 and 008. You know, we're trying not to create situations where, you know, sites are are competing, although the trial that they go on to is largely driven by the line of therapy. So the frontline patients obviously have frontline options. For 007, once we reach the RP2D, for example, for Vaneza, we'll do the expansion validation in the frontline, right? So that will be self-limiting. I think it's early. You know, Lee, we've just really, you know, gotten going. We're sort of taking the first tentative steps on 008. We'll have a better sense of how that's going as, you know, the weeks and months continue. 007 is going very robustly, as is 001. I think we have every expectation 008 will as well. We particularly expect to see interest in giltaritinib. The, you know, the investigators fondly refer to, you know, to this study as, you know, the FLT3 study. I think they're excited to see this combination, and we're excited to, you know, to get going on this study and begin to get some experience. So, you know, look forward to an enrollment update on 008, you know, again, the next time we have the microphone or a little later in the year.
spk10: Thank you very much. Sure.
spk09: Your next question comes from the line of Peter Lawson with Barclays. Please go ahead.
spk08: Great. Thank you so much. Thanks for the updates. I had a quick question on Comet 007, the combo, just why Zipto starts on day eight. If there's any worries about drug-drug interaction or just the rationale there.
spk06: Yeah. Yeah. So actually the opposite, Peter. So I don't know if you heard the answer to the question that Jonathan asked, but there's a new slide in our corporate presentation that I would direct everybody to that says as clearly as we can say it, ZIFTO is neither a CYP3A4 substrate nor a CYP3A4 inhibitor. There is no, to date, no observed drug-drug interaction. full stop, right, in anything that we've seen, either monotherapy or combo. The rationale for the day eight start is actually pretty simple. It gives you three things, three advantages. Number one, you debulk the patient. Less disease means you have a lower propensity for differentiation syndrome. You're just physically debulking the tumor. Number two, you get a baseline safety view, so you can differentiate what are effects due to the backbone versus effects due to ZIFTO plus the backbone. And number three, it gives you time to ensure that you're enrolling the right patients. particularly NPM1, sometimes the turnaround time takes several days. And so you want to make sure that, you know, you're not losing slots on patients who aren't, you know, who ultimately are not eligible. Those are the three reasons. And we've been extremely pleased by the results. I will say, as folks know, we have Bristol Myers Squibb as an equity investor back to ASH 2022. They made a $25 million equity investment. And we have a continued good relationship with them. They actually encouraged us to do that staggered dosing in all of our combos for exactly the reasons that I enunciated to you. And these are folks who do research, development, commercialization in the market. I think that was very good advice. It has served the program well.
spk08: Perfect. Thank you so much. Thanks for clarifying that. And then just on the expansion cohort, that's really interesting. So patients without NPM1 came to 2A. Are there particular mutations you're targeting, or is that kind of an all-comers approach? Just curious on how you're kind of focused.
spk06: Yeah. So thanks for the question. So to clarify for everyone, In the prepared remarks, we announced that we've dosed the first patient in an addition to 001. It's not part of the registrational study, but it's part of the 001 protocol that is looking to dose Ziftomenib at its RP2D at 600 milligrams in patients who are neither KMT2A nor NPM1 mutants. Why are we doing that? Well, if you go back to the results from the phase 1A, 1B, you'll recall we saw a number of patients, multiple patients, who had evidence of clinical benefit, blast count reduction, disease stabilization. We even went so far as a patient with a CETI to run X1 double mutant who had a CR at the 100 milligram dose. At that time, I don't think we understood, A, how to use Zifto as well as we do today, and B, really what to look for. And investigators confused, in some cases, differentiation and to progression. They're no longer making that mistake. So now it's a great time to go back into that population. It could be as much as 10% to 15% of AML, and ask the question, what do we see as a monotherapy? If we see evidence of clinical benefit, we might pursue it as a monotherapy. We might pursue it in combination. It might help broaden the scope of the combinations. Peter, to your specific question, the way those patients are selected is via an algorithm that picks among selected mutants that we have evidence confer a sensitivity to men in inhibition. So it's not an all-comers population. It is enriched, and it's enriched via an algorithm.
spk08: Got you. Perfect. Thank you so much. Really appreciate it.
spk10: Yep. Pleasure.
spk09: Your next question comes from the line of Justin Zelen with BTIG. Please go ahead.
spk12: Hi. Thanks for taking the questions and congrats on the progress. So, Troy, you mentioned interrogating menin in other indications outside of acute leukemias. You mentioned some solid tumor. and non-oncology indication. So will that be with Zifto or NextGen molecule? And do you have an idea of when we might see some early translational data from those programs?
spk06: Yeah, Justin, really good question. So let's tease those two parts apart. We really view Zifto-Menib as having an ideal properties for oncology applications. And I'll confess to you, it was partly by design and partly by good fortune. As you know, Zifto accumulates. It has very high tissue penetrance. Essentially, you are saturating the tissues with high concentrations of menin inhibitor, and there's never a time when the target isn't covered. As a consequence, that's really attractive for oncology indications where you kind of need an always-on. For non-oncology applications, you may actually want to have somewhat of a different profile. I will tell you, we've made a significant investment in next-generation compounds. We have ones for both oncology and non-oncology, and we're waiting to share the translational data until we're further along toward execution of the clinical experiment. Because let's be honest, this is a competitive field. We view ourselves as scientific innovators. We know we're going to attract competition. So we're holding those cards a little closer to the vest. but we're quite excited. We're doing the work to prepare for that study and to share with you some of those data a bit later in the year. We'll do the oncology, the solid tumor experiment, Justin, we think, with Zipto. The, you know, other applications, I think we're leaving that open, and we'll use the best menin inhibitor for the job, and I think we're going to have, you know, multiple options there.
spk12: Great. Looking forward to it.
spk10: Thanks for taking the questions. Sure, thank you.
spk09: Your next question comes from the line of Ren Benjamin with Citizens JMP. Please go ahead.
spk01: Hey, thanks for taking the questions, guys, and congratulations on the progress. Maybe just two questions for me, Troy. One, in the prior data that you guys had already reported from 07, you talked about 10 patients who had already received prior venetoclax, and you're still seeing a 40% ORR. And I don't know if this was asked before or not, but does this suggest that Venn could potentially be taken out of that regimen and a less toxic, call it ZIFTO-AZA combination, could or should be evaluated? Or does it suggest maybe something else that maybe men in inhibition is resensitizing patients to BCL-2 inhibition? That's one question. The other is more from a commercial perspective. You know, it seems, you know, you're evaluating ZIFTO throughout the continuum of AML treatment, and it might actually result, if I'm thinking about this right, in the cannibalization of ZIFTO in later lines of treatment. So how does this work in the real world, you know, as you're kind of evaluating this? Or are all these combination studies really more to... to maximize BD discussions and, and ultimately confirmatory studies will be run in the hands of a partner.
spk06: Right. Okay. So several questions, um, several questions packed in there, uh, Ren, uh, maybe taking your second question, second set of questions first. So the, yes, you will, you know, by design, uh, cannibalize those, um, cannibalize those later lines if you're successful. Our goal, I think the goal of everyone in this field is to prevent the need for use in the relapsed refractory setting by treating patients in the upfront setting. Our goal is treat patients early in lines of therapy where the benefit, the clinical benefit, is potentially much greater. Will that come at the expense of the relapse refractory? It will, but ultimately, you know, that's better for patients, offers them a better clinical benefit, and is arguably a more compelling commercial case. The combinations that we're doing We really are, you know, wanting to make, wanting to generate safety data to give physicians freedom of choice. For example, you know, there are fewer drugs approved in Europe than in the U.S. The LDAC combination might be very attractive in Europe. You know, Dr. Molly Leone, you know, who's the clinical lead and, you know, and our EVP of clinical development, for Cura has said, it doesn't really matter how you get patients to a response. If you can get them there with a quote-unquote softer response, that's better. You don't have to use a hard chemo. Your goal is to get them to a response, and LDAC might be an attractive way to do that. You heard me answer the question on FLT3. That's another option. Not so much driven by BD considerations, although I will say to you, we recognize to fully maximize the value of men and inhibition, in these various indications, as I think we've said this before, at some point we would likely need to engage a partner in some sort of strategic relationship, because that's just what it's going to take to generate, you know, multi-billion dollar sales numbers in a, you know, in a multiplayer market. With respect to your specific questions on the 007 study in Veneza, I guess a couple of clarifications. So the significance of seeing responses in patients who are venetoclax failures is You know, these are single-arm dose escalation studies. I mean, you're really kind of squinting at times to say, you know, what's clinical activity, but it's pretty well established for patients who failed then, they don't respond to then-retreatment. That, you know, I think most physicians will agree with that. That is a disease of high unmet need. How is that happening? Is it that we're, you know, we're blocking... you know, a driver mutation like an NPM1 or a KMT2A? Are we blocking MCL1? Are we interacting with BCL2 to resensitize the tumor? We're still figuring that out. What does appear to be clear is that Menin inhibitors plus Ven are better than Ven alone. That seems clear. To your question, I don't think you would go Menin-Aza. I think you might go Venetoclax-Menin inhibitor and do the doublet. You may not need the Aza. And as we've talked about in the past, you know, we will do that experiment when the time is right. We'll actually ask the question, do we need the triplet, Ven-Aza-Menin, or will the doublet suffice? And that's something you just have to figure out empirically. But going back to 007, and, you know, again, I'll acknowledge our colleagues at Syndex. We've both seen activity in venetoclax failures, and I think that's highly encouraging of the clinical benefit that these menin inhibitors can provide.
spk01: Great. Thanks for taking the questions.
spk10: Sure.
spk09: Your next question comes from the line of Brad Canino with Stiefel. Please go ahead.
spk02: Hey, good afternoon. Troy, how important does response durability become at your next combo data update?
spk11: I mean, it's important, Brad.
spk06: It's always important, but I would say, you know, I cautioned people at the time with the 200 milligram dose we're looking at an immature data cut in a dose escalation study. So I'd be careful not to over-interpret. Ideally, you should be seeing a direction of travel that is better than the monotherapy, right? Will the data be mature enough? you know, hard to say. I mean, obviously, we haven't dosed a patient yet at 600 milligrams. So, you know, if we were to disclose in the next several months, we'll be limited in terms of what we can say about durability. I do think it's important. We have every reason to believe as we go into combinations, as we go earlier, durability will improve. There isn't anything that's suggesting that There's nothing we're seeing. There's nothing we're seeing from others that would suggest that that wouldn't be the case. I wouldn't have an undue reliance on that one data point. What I would be looking for, Brad, is can we combine effectively at 600 milligrams with those standards of care? Because if you go back to the monotherapy, that's the optimal dose from a monotherapy perspective. It maximizes exposure. After that, it plateaus. It should be no different in the combos. That's the critical data point to look for. The durability will come in time, and I think we're cautiously optimistic it will inform in the right direction.
spk02: Okay. And then another question. We talk a lot about potential best-in-class drug properties on this call and in others, but as we move towards more substantial venasotriplet data from both you and and other Mennon inhibitors that are being developed, how do you expect potential differentiation might emerge in those clinical data reported in the Phase I-II studies?
spk11: Yeah. So, it's going to take the form in a couple of different ways.
spk06: So, there's a, you know, I would say, does one need to hold the Mennon inhibitor to allow counts to recover? That's question number one. When you get out into the real world in a broader population, if you have to hold the menin inhibitor, that potentially gives the disease a chance to escape. The second is... You know, one of our competitors presented data in a post-transplant maintenance study, and you can look at the rate of dose reduction or interruption or discontinuation due to AEs. And with several menin inhibitors, we're seeing a high rate of thrombocytopenia. That is not on mechanism. That's something else. We don't see that. A couple of the other compounds don't see that, but that is a characteristic of some menin inhibitors. So I think, Brad, it's going to go kind of both directions. Number one, can you keep constant pressure and constant exposure? Number two, can you really saturate all the sites in the body on a sustained basis? I would argue to you that if you can bathe a patient in a menin inhibitor, essentially indefinitely with no tox, that's probably the best thing you can do to delay recurrence. I think that's a good setup for Zifto because of its physical chemical properties, because of its tolerability. How that's going to manifest itself, that's going to take time. You're going to see it emerge in the form of resistance, and then that's going to play out in survival, but that will take some time. Something I've said pretty consistently is if you show me a race between two drugs and they're equivalent on activity, the safest, most well-tolerated, most combinable drug always wins, full stop. And I think Zipto is well positioned there. But, you know, there's not – for people who are looking for some kind of knockout blow, that's not coming, right? This is going to be a multiplayer, hopefully multibillion-dollar market that's really good for patients. We'll be competing out there. The more data we generate with Zipto, the more excited we become.
spk10: Very helpful. Thank you. Sure. Thanks.
spk09: Your next question comes from the line of Ava Privatera with TD Cowen. Please go ahead.
spk03: Hi, good afternoon. Thank you for taking our questions. So with escalation going really well in 007 and the RP2D expected midyear, when could ZIFTO potentially move into pivotal development with either chemo or van aza combos? What could be a potential design? Do you think MRD negativity could be a registrational endpoint?
spk06: Yeah, Ava, thanks. You're saving the best questions for last. So in terms of timing for development, you know, it's a little bit early. We recognize, again, it's a competitive landscape. I think realistically you probably wouldn't dose a patient in a pivotal until early next year. You can imagine we're already putting the designs together on the basis of the data we've generated thus far, right? Based on what we're seeing in the 007 study, I think we're highly encouraged. It's a matter of dropping the data in to support it. A big part of that is the lead time to actually engage with global health authorities. You know, you could potentially have the study up and running by the end of the year, but it would be very aggressive to dose a patient. I dare say it would be impossible to dose a patient just because these things take time, right? And we do need to do the expansion to make sure that we validate the dose. As for your question about MRD, probably not an endpoint at this point. I think there are a number of parties that are working as part of a consortium to try to help the field move in that direction. It's not likely to be an endpoint, but it is likely to be supportive. We do think that there's likely to be an integrated design where you'd go with an accelerated endpoint, probably based on response. and then a full endpoint based on survival. You know, and the agency's been pretty clear that's what they're looking for. Project Frontrunner, you know, they want to see that as a first approval, but the themes of Project Frontrunner carry through to designs. How can we do a seamless design? And that's very much what we'll be looking at here in the various combinations.
spk03: Thank you. That's helpful. And a quick follow-up on an earlier question about additional genetic subtypes. where you're pursuing other activity. Does this patient selection algorithm enrich for the Hox-Meese transcriptional pathway?
spk06: So there is an association, Ava. I think we remain unconvinced that if you use Hox-Meese expression as your selection algorithm, that that's going to work. What we're doing instead is mutations, which are a proxy for that, What's clear is this is a central node, right? This biology is fundamental to leukemia. It's wired into MCL1, to BCL2, to FLT3, to IDH. I don't think we fully understand all the wiring. So we're going to do our best and see if we can enrich for a signal. And I think we're particularly optimistic of what might be possible when you then go and layer that on top of, say, example, you know, venetoclax or FLT3 or something. That might give you an extra oomph. You know, back in the 1A, 1B days, people kind of shrugged. Everybody wants to see a CR, right? But actually, blast count reduction, you know, sustained disease stabilization in this setting is really clinically meaningful. And it's telling you, like, spend more time here. Look here. It's giving you a little neon sign. So that's what we're doing. And we'll see where it goes. But it's associated with hoxmease, but it's just an association. It's not going to be a direct correlation. I hope that helps.
spk03: That helps a lot. Thank you.
spk10: Sure. I would now like to turn the call back over to Troy Wilson for closing remarks.
spk09: Please go ahead.
spk06: Thank you, Eric, and thank you all once again for joining our call today. We'll be participating in several investor conferences over the next couple of weeks, and we look forward to seeing many of you there. In the meantime, if you have any additional questions, please feel free to reach out to Pete, to Tom, or to me. Thank you again, and have a good evening, everyone.
spk09: Ladies and gentlemen, this concludes the conference call for today. We thank you for participating and ask that you please disconnect your lines.
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