Kura Oncology, Inc.

Good afternoon, ladies and gentlemen. Welcome to the Cura Oncology Third Quarter 2024 financial results call. At this time, all participants are in a listen-only mode. Later, you will have the opportunity to ask questions during the question and answer session. You may register to ask a question at any time by pressing star one on your telephone keypad. Also, today's call is being recorded, and if you should need any operator assistance during the call today, please press star zero. Now, at this time, I'll turn things over to Mr. Pete DeSpan, head of investor relations. Please go ahead, sir.

Great. Thank you both. Good afternoon and welcome to Cura Oncology's Third Quarter 2024 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. Dr. Molly Leone, our executive vice president of clinical development, is also with us and available to answer questions. 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.

Thank you, Pete, and thank you all for joining We continue to generate what we believe is a robust clinical data package to support the broad development of our men in inhibitor program beginning with -O-Menim. We believe -O-Menim is well positioned to transform the treatment of men in dependent AML so that patients with cancer may lead better, longer lives. Earlier this week, two abstracts reporting preliminary data from our COMET 007 combination trial of -O-Menim were posted on the website of the American Society of Hematology. As of the June 21st data cutoff, the abstracts continue to support a potential -in-class safety and tolerability profile for -O-Menim as well as robust and durable activity in combination with standards of care, including Venetoclax plus azacytidine as well as Cytarabine plus Donorubicin, commonly known as

7 plus 3. In the Phase 1A dose escalation

portion of the COMET 007 study, -O-Menim combined with Venetoclax was well tolerated and demonstrated promising activity in relapsed refractory patients. No DLTs or -O-Menim induced QT-C prolongation were reported. On target differentiation syndrome was observed in 12% of patients, including three of 20 KMT2A rearranged patients, and all patients had resolution of DS with appropriate management. Encouraging clinical activity was observed at both 200 and 400 milligram dose levels, including activity in previously Venetoclax exposed NPM1 mutant and KMT2A rearranged patients. Updated results, including data from the 600 milligram cohorts, will be reported at ASH. In the AML frontline adverse risk population, we are very encouraged by the safety and tolerability profile, rates of complete response, and rates of MRD negativity. Notably, no events of differentiation syndrome were reported at 200 or 400 milligrams, including among KMT2A rearranged patients, suggesting -O-Menim can be safely combined with induction chemotherapy. We're particularly encouraged by the fact that in the context of the very challenging 7 plus 3 adverse risk AML patient cohorts, 100% of the 15 NPM1 mutant AML patients and 84% of the 19 KMT2A rearranged patients remained on study as of the data cutoff, one year after study start. Here again, updated results, including data from the 600 milligram cohorts, will be presented at ASH. We look forward to sharing a more mature data set, including data from more than 100 patients with NPM1 mutant or KMT2A rearranged acute myeloid leukemia next month. In the meantime, I'm pleased to report that all four cohorts in the phase 1A dose escalation portion of COMET007 have cleared the highest dose and advanced into the phase 1B expansion study at 600 milligrams. The phase 1B expansion study includes multiple combination cohorts, most notably -O-Menim plus Venasa in newly diagnosed NPM1 mutant or KMT2A rearranged AML as well as -O-Menim plus 7 plus 3 in newly diagnosed NPM1 mutant or KMT2A rearranged AML, removing the requirement for patients to have high risk disease. Each combination cohort is enrolling independently and we expect to enroll at least 20 patients per cohort. We believe the phase 1B expansion study will continue to lay the groundwork for helping us to redefine the current standards of care for newly diagnosed patients with NPM1 mutant or KMT2A rearranged AML in both the fit and unfit populations. We anticipate sharing preliminary data from the phase 1B expansion study at a medical meeting in 2025. In addition to our ongoing COMET008 study of -O-Menim in combination with additional standards of care including the FLIP3 inhibitor GILTA-RITINib as well as FLAGIDA and low dose Cytarabine. Roughly half of all patients with relapsed to refractory NPM1 mutant AML have co-occurring FLIP3 mutations and the prognosis for these patients is poor. Preclinical data for -O-Menim in combination with FLIP3 inhibitors has shown strong synergistic effects compared to either single agent alone. When we look across the fit, unfit and FLIP3 mutant AML frontline populations, we believe a best in class safety and efficacy profile and optimal pharmaceutical properties could enable -O-Menim to become a cornerstone of therapy for patients with acute leukemias. Ultimately our mission is to develop -O-Menim across the continuum of care for all eligible patients with acute leukemias whose disease is driven by the Mennon pathway. A critical first step toward that mission is establishing -O-Menim as the best in class Mennon inhibitor for patients with relapsed and refractory NPM1 mutant AML. As a reminder, -O-Menim is the first and only investigational therapy to be granted breakthrough therapy designation for treatment of relapsed and refractory NPM1 mutant AML. NPM1 mutant AML represents approximately 30% of new AML cases annually and is a disease of significant unmet need for which there is no approved targeted therapy. FDA awarded BTD based on data from our COMET001 trial recognizing -O-Menim's potential as an innovative medicine for patients with this devastating disease. Supporting data from the Phase 1 portion of COMET001 were recently featured in a leading clinical oncology journal, the Lancet Oncology. We completed enrollment in the registration directed portion of COMET001 earlier this year, enrolling more than 85 NPM1 mutant patients in fewer than 16 months. We look forward to sharing top line results from this pivotal study next year as we continue to work closely with FDA to expedite development and review of -O-Menim as a monotherapy. Meanwhile, we've generated a growing body of preclinical data that supports opportunities for Mennon inhibitors beyond leukemias, including the potential for -O-Menim in the treatment of certain solid tumors. Last month at the EORTC NCIAACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, we reported preclinical data supporting the combination of -O-Menim and Matinib for the treatment of advanced gastrointestinal stromal tumors or GIST. The combination showed unexpectedly robust and durable anti-tumor activity in both the Matinib-sensitive and the Matinib-resistant GIST patient derived xenograft models and in all cases the combination was significantly superior to a Matinib monotherapy. Mechanistically, the data reveal a kit-dependent mechanism with -O-Menim and a Matinib combining to sharply reduce kit expression and or activity, effectively silencing both the ERK and AKTM TOR signaling pathways and driving robust cell cycle arrest and apoptosis. Given that a Matinib is well established as the frontline standard of care in patients with GIST and generic versions are available, we believe a Matinib represents a promising combination partner for -O-Menim. In August, we received FDA clearance of our investigational new drug application for -O-Menim for treatment of advanced GIST. We're now prepared to initiate a proof of concept study evaluating -O-Menim and a Matinib in patients with advanced GIST after a Matinib failure in the first half of 2025. If successful, the potential opportunity in GIST appears to be agnostic to the mutational status of kit in GIST, suggesting an opportunity to explore the combination for nearly all patients, including those in the frontline setting. Earlier this year, we reported preclinical data supporting the potential therapeutic utility of Menin inhibitors in the treatment of diabetes. We are advancing multiple next generation Menin inhibitor drug candidates targeting diabetes and other metabolic diseases, and we expect to nominate the first of these next generation development candidates in the first half of 2025. Now let's quickly turn our attention to our Farnesyl transferase inhibitor programs. Despite the success of targeted therapies, a considerable need remains to drive enhanced anti-tumor activity while blunting the effects of innate and adaptive resistance. We're developing our next generation Farnesyl transferase inhibitor, KO2806, to address this need. KO2806 was designed to improve upon the potency, pharmacokinetic, and physical chemical properties of earlier FTI drug candidates. We've generated a growing body of preclinical and clinical data that demonstrate the potential for KO2806 as a companion therapeutic to augment the anti-tumor activities of targeted therapies, including tyrosine kinase inhibitors, KRAS inhibitors, and pan-RAS inhibitors. Late last year, 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 enabled us to begin dose escalation of KO2806 in combination cohorts very early in the study while continuing to dose escalate concurrently as a single agent. Earlier this year, we dosed the first patient with KO2806 in combination with cabozantinib in clear cell renal cell carcinoma, and in August, we dosed the first patient in combination with adagrassiv in KRASG12C mutated non-small cell lung cancer. As a reminder, the study of KO2806 and adagrassiv is supported by a clinical collaboration and supply agreement with Maradi, now a Bristol-Meier Squibb company. If successful, we believe KO2806 could drive enhanced anti-tumor activity and become a combination partner to multiple targeted therapies in large solid tumor indications. Meanwhile, we continue to evaluate the combination of tippifarnib with the targeted therapy alpellicib in PIC3CA-dependent head and neck squamous cell carcinoma in a study we call CurrentHN. We believe there may be a meaningful opportunity to combine an FTI with a PI3-kinase alpha inhibitor and look forward to presenting preliminary clinical data from the CurrentHN trial at a medical meeting in the first half of 2025. With that, I'll now turn the call over to Tom for a discussion of our financial results.

Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the third quarter of 2024. Research and development expenses for the third quarter of 2024 were $41.7 million compared to $29.3 million for the third quarter of 2023. The increase in R&D expenses was primarily due to the increases in clinical trial costs related to our ZipDomented and KO2806 programs. General and administrative expenses for the third quarter of 2024 were $18.2 million compared to $13.1 million for the third quarter of 2023. Net loss for the third quarter of 2024 was $54.4 million compared to a net loss of $38.6 million for the third quarter of 2023. This included non-cash fair-based compensation expense of $8.3 million compared to $7.1 million for the same period in 2023. As of September 30, 2024, we had cash, cash equivalents, and short-term investments of $455.3 million compared to $424 million as of December 31, 2023. 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.

Thanks, Tom. Before closing, I'd like to take this opportunity to welcome Dr. Michael Vasconcelos to our board of directors. Mike is an accomplished biopharmaceutical executive with more than 25 years of oncology, drug development, and experience and industry leadership. His extensive experience in R&D and regulatory affairs combined with his leadership across both large and emerging companies are invaluable as we advance our Mennon inhibitor and FTI programs to market while continuing to create value for patients and shareholders. Now, before we jump into the question and answer session, let me lay out our anticipated upcoming milestones. For our Mennon inhibitor program, present updated data from the COMET 007 trial of -MEN-IV in combination with Venasa and 7 Plus 3 at ASH in December 2024. Report top-line results from the COMET 001 registration-directed trial of -MEN-IV in NPM1 mutant relapsed refractory AML in early 2025. Present preliminary data from the Phase 1B expansion portion of COMET 007 at a medical meeting in 2025. Initiate a proof of concept study evaluating -MEN-IV and imatinib in patients with advanced GIS in the first half of 2025. And nominate a next-generation Mennon inhibitor development candidate targeting diabetes in the first half of 2025. For our Farnesyl transferase inhibitor programs, identify the maximum tolerated dose for KO-2806 as a monotherapy by the end of this year. Initiate one or more expansion cohorts for the combination of KO-2806 and capyloxanthinib in renal cell carcinoma in the first half of 2025. And present data from the current HN trial of Pellisib and PIC3CA-dependent Hedonexquimus cell carcinoma in the first half of 2025. With that, Bo, we're now ready for questions.

Thank you, Dr. Wilson. Ladies and gentlemen, at this time, if you do have any questions or comments, simply press star 1. You find your question has already been addressed. You may remove yourself from the queue by pressing star 2. Once again, that's star 1 for any questions. We go first afternoon to Lee Waspac at Cantor. Lee, please go ahead.

Hey, guys. Congrats on the progress and thank you for taking my questions. Troy, I guess how you're thinking about the potential of using MRD negativity as part of the frontline endpoints? And then for the MRD data, a negativity data that was just presented in your ASH abstracts, is there any difference in the methodology used by you versus your peers?

Yeah, great question, Lee. I'll give you my answer and then I'll ask Molly to comment if she can. So for everybody's benefit, I mean, the base case scenario for these frontline studies is that you're using survival as the endpoint. There may be an opportunity to use MRD negativity as a surrogate endpoint in an accelerated design, but I wouldn't consider that the base case. I think although there's good evidence to support it, that's not yet sort of the path that has been given the green light by the health authorities. It is something that we intend on discussing with them here in the relatively near future. So I think Lee, we'll be able to come back to you and others on this call probably early next year with an update on the regulatory strategy, the trial design and endpoints. We're certainly going to try to reach for that. I don't know if we'll be successful. I think we can make a strong case, but we're using survival as the base case and MRD negativity as the upside case. I'll let Molly add her thoughts to that. And Molly, if you could also maybe comment to Lee's question on how our methodology may differ from others.

So Troy is exactly right. While we know that we'll be able to use a survival endpoint in each of the indications we wish to pursue, MRD negativity is a clear and obvious new way to be looking at the benefit for these patients. We've seen it in other studies as they're pursuing their indications turn out to be an excellent surrogate. So we do think there's a good argument to be made with the health authorities to use it as part of the study, but how we can use it and to what extent it would be able to be allowed to be used as an endpoint is very much up for discussion and nothing we are able to confirm or deny at this point because we have yet to have those discussions. With regards to our MRD data and our abstracts, you'll notice we were more quiet about it in the relapse refractory setting due to the fact that we get less samples in that setting and there are much more varied type of methodology used to assess them as you might imagine. So what we plan to do is to actually give a uniform answer to what our MRD negativity looks like in these particular patients. Frontline setting, we did provide the local test results. They are done more consistently because they're used to make standard of care decisions with regards to transplant, etc. So we did provide those site-based tests, but we do plan also on running those centrally so that we can give a Okay.

And then for the SIXMIC data that you'll present at ASH, I just wonder if you can give us a sense of number of patients, follow-up and what types of data that we might see.

Yeah, Lee, thanks for that. So we've said we're anticipating showing data on more than 100 patients at this point. That will, I think you can see by the abstract, we're kind of halfway there. You'll see additional patients at the different dose levels. We're planning on really updating every patient on the study as of their status with respect to response as well as duration of any clinical benefit. In terms of what to expect, given that the activity is pretty robust at 200 and 400, we're expecting to see sort of pretty consistent activity. We get asked a lot, do we expect a dose response? Not clear if one expects a dose response with these high levels of activity, but something that you'll see is we actually do see interestingly a dose response with respect to safety and tolerability, i.e. as you go higher in dose, the safety and tolerability actually improves, which might seem counterintuitive, but that helps to support, as you know, we've moved forward now into the expansion cohorts at 600 milligrams across all the cohorts, and that's partly driven by activity. It's also a significant component of safety and tolerability. So you'll see that, you'll see sort of that, it'll actually be, I think, a meaningful update even relative to what you see in the abstracts.

Got

it, thank you.

Sure.

Thank you. We go next now to Jonathan Chang at Learing Partners.

Hi guys, thanks for taking the questions. As we're starting to see longer-term data for ZIFTO and other men and inhibitors in the space, how has that impacted your thinking on what the opportunity could be for the class, and what do you see as the key factors determining how long patients can stay on treatment and benefit? Thank you.

Yeah, Jonathan, thanks for that question. That's actually,

while I appreciate that there are a significant number of folks that sort of want to get into the scrum of comparing one relapsed refractory data set against another, one of the big take-home messages from our abstract is something I think you're alluding to, which is what's beginning to emerge in the frontline setting. So just for everybody's benefit, if you go and you read the abstract for the frontline 7 plus 3, you'll notice as of the data cutoff in June, 15 out of 15 NPM1 mutant patients and 16 out of 19 KMT2A rearranged patients remained on study on therapy as of the data cutoff. And for some of those patients, that study had been going at that point for a year. So what we've said consistently, Jonathan, is there is clearly a significant unmet need in the relapsed refractory population. Those patients are in dire need of options. But as one thinks about the commercial opportunity, clearly if we can intercept patients early in their treatment journey and provide clinical benefit, whether that is in the form of continuation therapy, i.e. they get a response, they stay on -O-Meneve, don't necessarily go to transplant, or in the alternative, they get a response, they go to transplant, and then they go back on Zift-O in a post-transplant maintenance. That's what we're seeing, we think, beginning to emerge in the 7 plus 3 adverse risk frontline population. The fact that you have 90 plus percent of the patients, again, as of the data cutoff, staying on study. That's not even survival, right? That's on the front line. Again, I think that the way I've always thought about it is adverse risk 7 plus 3 is about as hard as it gets in the frontline setting. We're hopeful that that trend continues now that we're in the expansion cohorts for the frontline 7 plus 3 without adverse risk, i.e. all comers, as well as the frontline Venasa. If we can take these frontline patients, keep them on a response and keep them on therapy for a year, 18 months, potentially even longer, that's where you really begin to see significantly inflecting the disease. That's what, in our thinking and our models, really helps drive the commercial case. I think we're excited to share with you the update for both the relapse refractory and the frontline. That frontline picture is beginning to come into focus. I think it looks pretty attractive relative to the competition.

Understood. Thanks for taking the questions.

Thank you. We'll go next now to Jason Zemansky at Bank of America.

Good evening. Congratulations on the progress and thanks so much for taking our questions. Regarding the combination updates at ASH, what should we be thinking in terms of benchmarking win here? Is safety still the focus or do you expect the data at that point to be mature enough to gain key insights into efficacy and then a follow-up?

Yeah, so let's start with that Jason.

Molly, maybe you want to take Jason's question in terms of how we think about benchmarking. Maybe we can start with the relapse refractory and then we can talk a little bit about the frontline

and sort of what the benchmarks would be.

Realistically, in the relapse refractory setting, these patients have for the most part failed venetoclax and as we know that's the extremely poor prognostic factor for doing well on any therapy. For KMT2A, you'd probably set the bar at less than 10% potential response rate for NPM1 slightly higher but the data tends to suggest that overall the survival would only be 2.4 months or so in these particular subsets of patients. That helps see how bleak the situation is. We think any improvement obviously over that would be very significant but as you point out, really the goal is safety and tolerability with a phase one dose escalation and the fact that we've been able to safely escalate through the 600mg dose without DLTs and as Troy referred to, see not only the ability to escalate safely but to see improved safety as we escalate is an extremely strong sign that we are getting good activity as we increase in doses. Troy, is there anything you would add?

No, not to that Molly but maybe you could help set expectations for frontline and how we think about that in the adverse risk population.

Absolutely. Our best comparison for the frontline is the Vixios control arm which put the response rate at about, for a composite response rate at about 60%. That would be your CR, your complete response, your complete response with partial hematologic recovery and your complete response with incomplete hematologic recovery. About 60% and an overall survival of about six months. Again, in these adverse risk patients, not a good setting to see but again, we're seeing excellent ability to be able to escalate the dose. These patients are staying on for very significant periods of time. As Troy alluded to, very few have come off study even in our 200mg cohort which has been going on for well over a year. So far, I think we're seeing signs that make us encourage to keep moving forward.

Got it. That's helpful and maybe to circle back on your comments on tolerability and safety, the team's been guiding away from a 0% DS rate which makes sense but I'm curious, is there a level that you think would be especially encouraging in both the 7 plus 3 and Venase settings and is there a ceiling here as well?

Go ahead, Molly. You take that. Sure.

We traditionally thought that as long as it was easily controllable, easily addressed, 20% or less DS rate is extremely tolerable. What I always like to remind people is that for the grading of differentiation syndrome, grade 3 simply means that a patient was hospitalized for the event. In these patients, they're extremely fragile and tend to have fevers of unknown significance and other symptoms that might need urgent intervention. They're hospitalized all the time. So a grade 3 DS is not necessarily associated with extremely severe symptoms. What we're seeing is grades 2 and 3 DS that are very easily controlled and what's different from the monotherapy is it doesn't appear that we need to interrupt drugs to be able to control them. Steroids and supportive care do seem to be sufficient. So just to summarize, a reasonable severity level, probably about 20% and with the ability to treat easily and quickly, get these patients continued on therapy is where we would set the bar.

Great.

And I'll just add to that,

yeah, Jason, I'll just

add to that. You'll expect to see when we give the full data, the DS rate drop to single digit percentages. So I think we're encouraged. We've seen it primarily, as Molly indicated in the KMT-2 rearranged in the relapsed refractory setting, seems to be well managed with these combinations.

Very helpful, guys. Thanks so much.

Our pleasure. Thank you.

We'll go next now to Roger Song with Jeffreys.

Great. Congratulations for all the progress and then taking our question. Maybe one question related to the, again, back to the potential pivotal plan, understanding you are discussing with DFDA right now. Just curious about the timing for the pivotal studies initiation versus your expansion data release. Do you need to see more dose dependent efficacy at the higher dose or RP2D dose, 600 milligrams versus the others, or the current dose exposure or the total package sufficient for you to move into the pivotal once you finalize the design? Thank you.

Yeah, Roger. Thanks for the question. We already have those trials designed and are preparing to engage the health authorities in discussion. So if that helps address your question, as Molly indicated, both the clinical activity and the safety and tolerability support that 600 milligrams is going to represent the dose that we recommend to FDA and other global health authorities as the dose in combination. You know, in addition to the dose selection, as Molly indicated in an answer to one of the previous questions, we'll talk about endpoints. The powering, the design, I mean, that's really up to us, but the endpoints are a critical question and we'll want to have a robust discussion there. We're currently thinking that we'll kick off those studies middle of next year. We believe there's an opportunity to combine Zift-Amanib in both 7 plus 3 and Venaza, and so we've designed trials for each of those two, you know, those two settings. Something that I think has been an interesting surprise to us is before we had dosed a patient, I don't think we really appreciated the opportunity in the frontline 7 plus 3. We sort of naively assumed patients would enter that cohort, they would go through two or three cycles, go to transplant, and then we might or might not get them back. That's really not what we're seeing and you don't necessarily see it in the abstract, but you'll see it in the more fulsome data set. Patients are, as Molly indicated, they're staying on therapy for prolonged periods of time. Many of them are not going to transplant and we'll obviously you need to see the data to understand this, but what that's led us to is an appreciation that whereas we may have thought that Xanetoclaxase acetidine was the much larger commercial opportunity, it is meaningful, there's no question, and we'll pursue that, but 7 plus 3 plus ZIFTO appears to be nearly equally important and we can see that in terms of enrollment. We can also see that just in terms of the clinical benefit profile that's beginning to emerge. So we're rolling all of that in, think about regulatory discussions in the early part of next year with a goal towards starting a combination study or studies middle of next year. Hopefully that helps answer your question.

Excellent. That's very helpful. And similar in terms of the timeline regarding your the monotherapy, MPM1, the data continued to be early 2025, and how should we think about the fighting for that monotherapy? Thank you.

Yeah,

another thank you for that question. So yes, once the data has been collected and cleaned and locked, we'll be in a position to provide the top line results. Within some period of time, measured by a few months, we'll be ready to submit that NDA to the agency. We would be looking for ideally if all goes well with the submission and review for an approval in the second half of next year. We'll be in a better position, Roger, to guide on that more specific timing next year when we're a little bit closer, but that should give you a rough idea of how to think about it.

Excellent.

That's very helpful.

Thank you. Thank you, Troy. Sure.

We'll go next now to Charles Zhu at Lifesize Capital.

Good afternoon, guys. Thanks for taking the questions and congrats on the progress. A couple from us. First, could you remind us what proportion of patients are quote adverse risk? And if you're including this, a broader population beyond adverse risk in your phase 1B expansion cohorts, how should we be thinking about enrollment speed there? Thank you. Sure,

Charles. Thanks for the questions. Molly, can you speak to that, sort of how we think about adverse risk versus the broader population? And then what if anything, I

don't know, what if anything we can say about enrollment?

Sure. So, you know, the way we've defined adverse risk is older patients with, that may also have a complex cytogenetic or B treatment related AML. So that is how we define adverse risk. And realistically, it does comprise a fair amount of patients. I don't know exact numbers, but my estimate would be about 30%. And with regards to, you know, how that affects enrollment, being able to open it up, I can tell you that our enrollment in the 1A where we did have the adverse risk was extraordinarily brisk. As you can see with the fact that we're able to now share 105 patients' worth of data after, you know, just over a year. It is now just as brisk, if not more so, as we move into the phase 1B. So we are very encouraged by the excitement of the investigators and the desire of the patients to participate in our trials.

Great. Thanks for that. And regarding your ASH abstract, one clarifying question here, is there a response deepening effect that we could be seeing at the lower 200-milligram dose, given that it has longer follow-up versus the 400? And granted, these are very small ends, but, you know, how should we be thinking about what appears to be a numerically inverse dose response between 200 and 400 milligrams in combination? Thank you. Molly? Yeah, I think,

sure, I think there's a combination of reasons. I think the biggest one is exactly as you point out, small numbers. And within those small numbers, when I look at the demographic details, there's varying baseline characteristics as well that can complicate the interpretation. So you'll have different ECOG medians for different dose levels, different numbers of priors for different dose levels. So ultimately, it really does become the totality of evidence that helps us determine what the correct dose to carry forward should be. And I should clarify that we have both a safety monitoring committee and an independent data monitoring committee that have been involved consistently throughout this study, not only in helping to decide when and if we should dose escalate, but also helping to decide what the totality of data tells us about the right dose for these patients. And ultimately, both of those committees agreed that it is 600 milligrams that should be taken into the expansion cohort based upon not just the response rates, taking into account the baseline characteristics, especially the safety and tolerability, the count improvements, the speed to response, you know, a myriad of different data pieces. So while it could appear to be an inverse dose response, we don't think that is actually the reality of this particular study.

Perfect. Great. Makes sense. If you could humor maybe just one last one from me. Regarding the on-target men and resistance mutations, we've heard a few things from some third parties out there, but could you clarify the assay that you used relative to one of your peers slash competitors assays when they reported their 38.7 percent rate of mutations and how similar or different are the sensitivities of those assays and what does that mean with the rate of emergent men resistance on ZIFTO? Thank you.

So I think you're referring to the difference between digital droplet PCR and RT-PCR that we used. We also use different sources, DNA versus RNA for examining that data. However, the patients that we looked at for mutations would have been detectable at even a less sensitive assay. So we didn't need digital droplet PCR in order to determine if these mutations were there. So we do think that our data is highly reliable and that we're able to compare to these other data. And remember, they were using the digital droplet PCR to determine if these were present at baseline rather than things that developed over time. In addition, we've obviously continued to do our work on this topic and we have continued to confirm through more and more sensitive analyses that our findings are extraordinarily consistent with what we presented at EHA.

Excellent.

Thank you very much

for taking our questions and congrats again. Thanks Charles. Thank you. We go next now to Phil Nadeau at TD

Cowan. Good afternoon. Thanks for taking our questions as well. We were intrigued by your comments about safety improving for ZIFTO as the doses increase. Is there a mechanistic rationale as to why safety should improve with increased exposure?

Yeah, Phil, there is actually and I'll let Molly give you more color.

Yeah, it's actually a little bit more obvious than you'd even think. We are seeing faster count recoveries with increased dose. Obviously faster count recoveries means patients have less time to be susceptible to infections, have less time to be susceptible to bleeds, have less need for transfusions. So there does seem to be a very good basis for why we are seeing the improved safety at increased dose.

That is very helpful. And then a second question on the next generation men and inhibitors. I think you mentioned specifically that you will nominate a candidate for diabetes in the first half of 2025. Are there efforts underway to identify next generation men inhibitors to advance in hemalignancies as well?

Yeah, good question, Phil.

There could be. I mean, we have molecules, you know, it's, you always think your baby is the most beautiful, right? It's hard to imagine improving on ZIFTO the one thing you might say is could we actually develop a molecule that was active against all the known gatekeeper mutations? We have such molecules. It's not obvious to us now that we're in combinations. And as Molly said, we continue to see, you know, very, very low rates of induction of gatekeeper mutations that that's an advantage. So at the moment, I would say, you know, we have molecules, we're holding them and really putting the bets on ZIFTO going into combinations initially in the front line and as well as doing work, for example, with the three inhibitors. We are, however, looking at men and inhibitors potentially for other solid tumors. And, you know, we put out what I think was some very nice preclinical data combining ZIFTO with a matenib and gist. We're doing the work to determine, you know, is that an isolated example or are there other solid tumor applications? And if there are, you want the optionality of having a distinct next generation men and women inhibitor for those solid tumor applications. As we continue to do more work, Phil, we'll begin to fill that picture in probably next year.

That's helpful. Thank you for taking our questions.

Our pleasure.

We go next now to Peter Lawson at Barclays.

Great. Thank you so much. Just as we think about expectations for kind of prior ventreated patients in the pivotal study, how should we think about that versus what we saw in the phase one data that was published?

Yeah. Molly, do you want to speak to Peter's question?

Sure. Obviously, the published data was on a very small data set and we'll continue to analyze the monotherapy data as we, you know, put out our phase two data set as well and probably gain a better picture as to exactly what these patients look like post-venetoclax failure and if we're able to resensitize and get these patients back able to respond to therapies. In the combination setting, we will be presenting more data on that as we get to ASH. We do think that there is still the good potential for patients to respond post-venetoclax failure. Again, is that due to our ability to resensitize these patients to venetoclax? Is it, you know, a synergistic effect between the two molecules? We don't know. It's too early. But we'll continue to analyze the data. All I can say is we continue to be encouraged. Perfect. Thank

you so much. Really interesting. On the 7 plus 3 adverse risk patients, what would the duration response, how could that differ between, you think, the MPM1 versus the KM228 patients?

Yeah. Molly, do you want to take that question as well?

What's nice is that the answer to this question is we don't know yet because all of these patients are realistically still ongoing therapy. So, thankfully, we haven't reached our median duration of response for these groups. And we hope that it continues on that way and so that this question continues to be difficult to answer.

There's no kind of fundamental difference, you think, between the MPM1 and KMT2A patients?

I do. I think KMT2A are much harder to permanently control. They have just a much more aggressive monocytic disease that is so invasive. But I think that's where a molecule like Ziftamene becomes so important because our drug is able to actually accumulate in tissues as well and find some of these areas where the KMT2A rearranged cells have been able to already invade at the time of diagnosis even in the front line. So, yes, definitely a fundamental difference in the level of aggression between the two. But we hope that Menin inhibitors at least become the great equalizer for them.

Thank you so much. Thanks for taking the question.

Thanks,

Peter.

We go next now to Justin Zelen of BTIG.

Hey, thanks for taking the question and congrats on progress. Maybe following up on an earlier question about resistance mutations, would you look to do that analysis in your combination and earlier line studies and just expectations there if you think that it might differ in those

settings? Molly, do you want to take that?

Yeah, obviously in front line settings, we don't expect to see, you know, at least a baseline existence of these resistance mutations, although they could very well be in your relapse refractory setting after exposure to other Menin inhibitors. But with regards to a differential ability to develop these mutations, once you get into combination, your risks are going to decrease enormously. It's the monotherapy that's really the big risk for developing these types of mutations because you're just not hitting it hard enough, fast enough, and you're giving it time just like bacteria to grow out resistant colonies. So I think that you're just going to see a decrease overall in these mutations becoming an issue for patients that are able to have successful outcomes on the combinations.

Great, that makes sense to me. Thanks for taking our question. And we'll go next now to Brad Canino at Stiefel.

Hi, thanks for the question. Just one for me, wondering given we've seen one of the peer MEN and companies initiate a front line trial and collaboration with one of the European cooperative groups, just what's your current thinking about employing a similar strategy? How do you think about the pros and cons of using such a collaboration versus say doing a full company sponsored one? Thank you.

Yeah, thanks Brad for the question. So cooperative groups play a really important role in the ecosystem. They do some terrific work. In our view, and you can see this reflected in the development plan, we are establishing data packages for safety, tolerability, combinability, clinical activity across a range of different combinations. Much of the focus obviously in the run up to ASH is around seven plus three in Venasa, but hopefully next year we'll talk more about 008, which is GILTA, RITNIB, LDAC, FLAG-IDA. And so to the extent that for some of these perhaps either smaller opportunities or populations where it's more difficult to identify these patients for treatment, those are ideal for cooperative groups. And I think you really want to take full advantage. And in that context, you probably know we have a collaboration with LLS's pedal in the pediatric indications because they're huge unmet need, difficult to find those patients. It's not a huge commercial opportunity, but it is unquestionably one of the most important things you can do. And we are very happy to be collaborating with LLS. The downside to a cooperative group study is it's their design, it's their timeline. They dictate data release, they dictate how you interpret that data, any amendments you make to the study. I don't think you're going to see us using cooperative group studies for either our seven plus three or Venasa trials, because that's where 90% of the value is, to be honest. We all know this. The big money here is get patients on study right at the get go and ideally keep them on 12, 18, perhaps even 24 months. So you're going to see us, Brad, do Cura sponsored studies, but we'll continue to work and have studies planned for cooperative groups where those smaller indications may be appropriate. We'll do a mix about.

Thank

you.

Sure.

We go next now to David Dai at UBS.

Hi, this is Yihan Alpha David. Thank you so much for taking our question and congrats on the quarter. So I guess our first question is kind of like for the PIVO data in the abstract. I'm just curious if you could set some expectations on the clinical meaning of efficacy as well as duration bar. And the same one, I think for your abstract, the zip to manage plus ASA cohort, so we saw there were around 25% patients who actually have prior Manny inhibitor. I'm just curious if we're going to see the efficacy profile from these set of patients at the presentation. Yeah, I think it's just like related to potentially like higher activity against some patients, resistance to patients. Thank you.

Sure. Thanks, Yihan, for the question. So on with respect to the monotherapy pivotal data, I think, you know, even before we ever go to patient, we've always given the same guidance, which is the regulatory bar in our view, the bar to approval is 20 to 30% CRCRH and four to six months median duration of response. I don't think I've ever varied from when I've been asked that question. Certainly to this point, nothing has changed. Now, you know, that is the bar that the agency uses to consider approvability. As Molly's already indicated to you, there are a lot of other factors. So, and some of those have been spoken to by competitors of ours. So CRC rate, overall response rate, you know, things such as that, as well as safety and tolerability, all factors in. But that's how we're continuing to think about the monotherapy data. As far as data on activity in patients who have experienced prior men and inhibitors, yes, there will be some additional data in the materials that are presented at ASH that in the relapsed refractory setting, it's part of the story. It is, as Molly indicated, still kind of an evolving part of the story. Because these patients are, because the patient population is so heterogeneous, i.e. ECOG status, lines of therapy, what they've seen previously. I don't think we can, I don't think we yet fully have the rules of the road. But we are encouraged to see activity in patients who have progressed on prior men and inhibitors and learning what, if anything, can we do to, you know, to increase that when we treat them with Zipto-Menin.

That's awesome. Thank you so much.

Sure.

And we'll go next now to George Farmer at Scotia Bank.

Hi, good evening. This is Chloe on for George. Can you hear me okay?

We can.

Okay, great. Curious about your

diabetes program and how this next-gen men and inhibitor that we're going to get more information on next year, going to be different from Zipto-Menin and from other competitor molecules from which we expect some critical phase two data by your end. And I guess they'll be setting the benchmark for the potential of men inhibition in diabetes and what you'll need to see from your own program eventually down the road. In what ways are you hoping to be similar or differentiate from that other program? Then I have a follow up.

Yeah. Okay. Yeah, great question. So in our hands and when we do these experiments away from AML, whether it's, you know, gist, whether it's diabetes, folks should understand we evaluate not only Zipto-Menin but competitor compounds as well as next-generation compounds in our portfolio. We try to get a holistic picture. For example, in gist, Zipto is uniquely active in gist. We think in part due to its tissue penetrance. In diabetes, it also seems to be extremely active. Francis Burroughs, who is not with us on the call, who is our senior vice president of translational research, he characterizes Zipto as it hits men in as hard as you can hit it. Provides very potent knockdown. It's a men and degrader, which is a property that is shared by, you know, some of the other compounds, not all. We're not, you know, we, I think we can actually say we probably don't have to hit men in quite as hard as one hits it with leukemia in order to, to drive the sort of pharmacology that you're seeing in the diabetes models that we showed at the ADA meeting in June. As we think about the properties of a next-gen compound, most important is safety, safety and tolerability. In the type two setting, honestly, these patients are not that sick, right? These, they are, we're not talking about leukemia patients. We're talking about, you know, diabetic patients. That's not to take anything away, but the hurdle for safety and tolerability is much higher. So you're going to see us put a emphasis on not only activity in the appropriate animal models, but really trying to create as large a therapeutic window as we can. The other interesting thing, and we've benchmarked this against other compounds that you may be aware of. What we see with ZIFTO is when you, when you add ZIFTO, it takes several weeks for the activity to kick in. When you remove ZIFTO, it takes several weeks for the activity to decay. Does that make sense? Yeah, it does, because this is an epigenetic mechanism. With certain other competitor compounds, you do not see that. As soon as you remove the competitor compounds, the pharmacology goes away almost immediately, suggesting that maybe that's not acting entirely via Menin. And so we're going to want to make sure we understand that as well. The final thing I'll say is, you know, there are very sophisticated parties out there that know this space, and we are not shy about consulting them on what they would want to see as far as preclinical and clinical data that would ultimately allow you to do the right sort of diabetes study. So we'll have much more to talk about that. Again, looking forward to nominating probably the first compound, maybe of a couple, in diabetes first half of next year, and then happy to walk people through that data as it continues to evolve. And you said you had a follow-up.

Yes, thank you. Very, very helpful color there. Does your current cash runway estimate include this early clinical work, early phase one work in diabetes as you enter the clinic?

Yeah, let me ask Tom actually if he can speak to that question.

Yeah, thank you. It does, our cash runway does include the Menin next generation work in diabetes.

Great, thank you so much.

Thank you. And it

appears, Dr. Wilson, we have no further questions today. I'd like to turn the conference back to you, sir, for any closing comments. Thank you, Bo.

And thank you all once again for joining our call today.

We'll be participating across the pond at the Jeffries London Health Care Conference in a couple of weeks, and 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 all again, and have a good evening, everyone.

Thank you, Dr. Wilson. Again, ladies and gentlemen, that will conclude the Cura Oncology third quarter financial results call. Again, thanks so much for joining us, and we wish you all a great evening. Goodbye.