Kura Oncology, Inc. Q3 FY2024 Earnings Call

Good afternoon, ladies and gentlemen. Welcome to the Kura 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. Also, today's call is being recorded. Now at this time, I’ll turn things over to Mr. Pete De Spain, Head of Investor Relations. Please go ahead, sir.

Great. Thank you, Bo. Good afternoon, and welcome to Kura Oncology’s third quarter 2024 conference call. Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer; Tom Doyle, our Senior Vice President of Finance and Accounting; and Dr. Mollie Leoni, 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 Kura’s filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company. With that, I’ll now turn the call over to Troy.

Thank you, Pete, and thank you all for joining us. We continue to generate what we believe is a robust clinical data package to support the broad development of our menin inhibitor program, beginning with ziftomenib. We believe ziftomenib is well positioned to transform the treatment of menin-dependent AML so that patients with cancer may lead better, longer lives. Earlier this week, two abstracts reporting preliminary data from our KOMET-007 combination trial of ziftomenib were posted on the website of the American Society of Hematology. As of the June 21 data cutoff, the abstracts continue to support a potential best-in-class safety and tolerability profile for ziftomenib, as well as robust and durable activity in combination with standards-of-care, including venetoclax plus azacitidine, as well as cytarabine plus daunorubicin, commonly known as 7+3. In the Phase 1a dose escalation portion of the KOMET-007 study, ziftomenib combined with ven/aza was well tolerated and demonstrated promising activity in relapsed/refractory patients. No dose-limiting toxicities or ziftomenib-induced QTc 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 differentiation syndrome with appropriate management. Encouraging clinical activity was observed at both 200-milligram 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 milligrams or 400 milligrams, including among KMT2A rearranged patients, suggesting ziftomenib can be safely combined with induction chemotherapy. We’re particularly encouraged by the fact that in the context of the very challenging 7+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 KOMET-007 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, ziftomenib plus ven/aza in newly diagnosed NPM1-mutant or KMT2A rearranged AML, as well as ziftomenib plus 7+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 KOMET-007, we continue dosing patients in our ongoing KOMET-008 study of ziftomenib in combination with additional standards-of-care, including the FLT3 inhibitor gilteritinib, as well as FLAG-IDA and low-dose cytarabine. Roughly half of all patients with relapsed/refractory NPM1-mutant AML have co-occurring FLT3 mutations, and the prognosis for these patients is poor. Preclinical data for ziftomenib in combination with FLT3 inhibitors has shown strong synergistic effects compared to either single agent alone. When we look across the fit, unfit and FLT3-mutant AML frontline populations, we believe a best-in-class safety and efficacy profile and optimal pharmaceutical properties could enable ziftomenib to become a cornerstone of therapy for patients with acute leukemias. Ultimately, our mission is to develop ziftomenib across the continuum of care for all eligible patients with acute leukemias whose disease is driven by the menin pathway. A critical first step toward that mission is establishing ziftomenib as the best-in-class menin inhibitor for patients with relapsed and refractory NPM1-mutant AML. As a reminder, ziftomenib 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. The FDA awarded Breakthrough Therapy Designation based on data from our KOMET-001 trial, recognizing ziftomenib’s potential as an innovative medicine for patients with this devastating disease. Supporting data from the Phase 1 portion of KOMET-001 were recently featured in a leading clinical oncology journal, The Lancet Oncology. We completed enrollment in the registration-directed portion of KOMET-001 earlier this year, enrolling more than 85 NPM1-mutant patients in fewer than 16 months. We look forward to sharing topline results from this pivotal study next year as we continue to work closely with the FDA to expedite development and review of ziftomenib as a monotherapy. Meanwhile, we’ve generated a growing body of preclinical data that supports opportunities for menin inhibitors beyond acute leukemias, including the potential for ziftomenib in the treatment of certain solid tumors. Last month, at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, we reported preclinical data supporting the combination of ziftomenib and imatinib for the treatment of advanced gastrointestinal stromal tumors, or GIST. The combination showed unexpectedly robust and durable antitumor activity in both imatinib-sensitive and imatinib-resistant GIST patient-derived xenograft models, and in all cases, the combination was significantly superior to imatinib monotherapy. Mechanistically, the data revealed a KIT-dependent mechanism with ziftomenib and imatinib combining to sharply reduce KIT expression and/or activity, effectively silencing both the ERK and AKT/mTOR signaling pathways and driving robust cell-cycle arrest and apoptosis. Given that imatinib is well established as the frontline standard-of-care in patients with GIST and generic versions are available, we believe imatinib represents a promising combination partner for ziftomenib. In August, we received FDA clearance of our investigational new drug application for ziftomenib for treatment of advanced GIST. We’re now prepared to initiate a proof-of-concept study evaluating ziftomenib and imatinib in patients with advanced GIST after imatinib 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 antitumor activity while blunting the effects of innate and adaptive resistance. We’re developing our next-generation farnesyl transferase inhibitor, KO-2806, to address this need. KO-2806 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 KO-2806 as a companion therapeutic to augment the antitumor activities of targeted therapies, including tyrosine kinase inhibitors, KRAS inhibitors and pan-RAS inhibitors. Late last year, we began dosing patients with KO-2806 as a monotherapy in a Phase 1 dose escalation trial that we call FIT-001. FIT-001 uses an innovative design that enabled us to begin dose escalation of KO-2806 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 KO-2806 in combination with cabozantinib in clear cell renal cell carcinoma. And in August, we dosed the first patient in combination with adagrasib in KRAS G12C-mutated non-small cell lung cancer. As a reminder, the study of KO-2806 and adagrasib is supported by a clinical collaboration and supply agreement with Mirati, now a Bristol Myers Squibb company. If successful, we believe KO-2806 could drive enhanced antitumor activity and become a combination partner to multiple targeted therapies in large solid tumor indications. Meanwhile, we continue to evaluate the combination of tipifarnib with the targeted therapy alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma in a study we call KURRENT-HN. 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 KURRENT-HN 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 increases in clinical trial costs related to our ziftomenib and KO-2806 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 share-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 Vasconcelles to our Board of Directors. Mike is an accomplished biopharmaceutical executive with more than 25 years of oncology drug development 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 menin 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 menin-inhibitor program: present updated data from the KOMET-007 trial of ziftomenib in combination with ven/aza and 7+3 at ASH in December 2024; report topline results from the KOMET-001 registration-directed trial of ziftomenib in NPM1-mutant relapsed/refractory AML in early 2025; present preliminary data from the Phase 1b expansion portion of KOMET-007 at a medical meeting in 2025; initiate a proof-of-concept study evaluating ziftomenib and imatinib in patients with advanced GIST in the first half of 2025; and nominate a next-generation menin 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 cabozantinib in renal cell carcinoma in the first half of 2025; and present data from the KURRENT-HN trial of tipifarnib in combination with alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma in the first half of 2025. With that, Bo, we’re now ready for questions.

Thank you, Dr. Wilson. We will go first this afternoon to Li Watsek at Cantor. Li, please go ahead.

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

Great question, Li. I’ll give you my answer, and then I’ll ask Mollie to comment. For everybody’s benefit, 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. Although there’s good evidence to support it, that’s not yet a path that has been given the green light by health authorities. It is something we intend to discuss with them in the relatively near future. We expect to 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. Mollie, could you add your thoughts and comment on how our methodology may differ from others?

Sure. Troy is exactly right. While we know that we’ll be able to use a survival endpoint in each of the frontline indications we wish to pursue, MRD negativity is a clear and obvious way to look at benefit for these patients. We’ve seen MRD function as an excellent surrogate in other studies. We do think there’s a good argument to be made with health authorities to use it as part of the study, but how we can use it and to what extent it would be allowed as an endpoint is very much up for discussion and nothing we can confirm at this point because we have yet to have those discussions. Regarding our MRD data and our abstracts, you’ll notice we were more quiet about it in the relapsed/refractory setting due to fewer samples in that setting and more varied methodologies used to assess them. Our plan is to do a central analysis of those samples so that we can give a uniform answer to MRD negativity in those patients. In the frontline setting, we provided the local test results. They are done more consistently because they’re used to make standard-of-care decisions regarding transplant, etc. We did provide those site-based tests, but we also plan to run them centrally so we can give a much more uniform result on MRD negativity.

Okay. And then for the 600-milligram data that you’ll present at ASH, can you give us a sense of number of patients, follow-up and what types of data we might see?

We’re anticipating showing data on more than 100 patients at this point. That will include additional patients at the different dose levels. We’re planning on updating every patient on the study as of their status with respect to response, as well as duration of any clinical benefit. Given that activity is pretty robust at 200 milligrams and 400 milligrams, we’re expecting to see consistent activity. We get asked a lot whether we expect a dose response; it’s not clear given these high levels of activity. Interestingly, we do see a dose response with respect to safety and tolerability: as you go higher in dose, safety and tolerability actually improve, which might seem counterintuitive. That helps to support why we’ve moved into the expansion cohorts at 600 milligrams across all cohorts; that decision is driven partly by activity but also significantly by safety and tolerability. You will see a meaningful update relative to what was in the abstracts.

Got it. Thank you.

Sure.

We go next now to Jonathan Chang at Leerink Partners. Jonathan, please go ahead.

Hi, guys. Thank you for taking the questions. As we’re starting to see longer-term data for ziftomenib and other menin 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.

Thanks, Jonathan. While many want to compare relapsed/refractory data sets against one another, one of the big takeaways from our abstract is the emerging frontline picture. In the frontline 7+3 adverse risk cohorts, as of the data cutoff in June, 15 of 15 NPM1-mutant patients and 16 of 19 KMT2A rearranged patients remained on study as of the data cutoff, and some of those patients had been on study for a year. We’ve always said there is significant unmet need in the relapsed/refractory population, but from a commercial perspective, intercepting patients earlier in their treatment journey could be more impactful. If we can treat frontline patients and keep them on therapy—either they remain on ziftomenib in response without transplant, or they go to transplant and then resume ziftomenib as maintenance—then you begin to see meaningful commercial and patient impact. The frontline data is beginning to come into focus and looks attractive relative to alternatives.

Understood. Thanks for taking the questions.

We will go next now to Jason Zemansky at Bank of America. Jason, please go ahead.

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 a 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.

Let’s start with that, Jason. Mollie, perhaps you can help set expectations and benchmarks, starting with the relapsed/refractory setting and then the frontline.

Realistically, in the relapsed/refractory setting, most patients have failed venetoclax, which is an extremely poor prognostic factor. For KMT2A, you should set the bar at less than 10% potential response rate post-venetoclax; potential response rate for NPM1 is slightly higher, but overall survival in these subsets would be roughly two to three months historically, which highlights how bleak the situation is. So any improvement would be significant. But with Phase 1 dose escalation, the primary goal is safety and tolerability. The fact that we’ve been able to safely escalate through 600 milligrams without DLTs, and to see improved safety as we escalate, is a strong sign. That supports moving forward with expansion cohorts at 600 milligrams. In terms of frontline, our best comparator for the adverse risk setting is Vyxeos control arm data, with a composite response rate around 60% and overall survival around six months in that population. In our data, patients are staying on therapy for significant periods, and very few have come off study even in the 200-milligram cohort, which has been going on for well over a year. So far, the data are encouraging and support continued development.

Got it. That’s helpful. And maybe to circle back on your comments on tolerability and safety: the team has been guiding away from a zero percent differentiation syndrome rate, which makes sense. Is there a level that you think would be especially encouraging in both the 7+3 and ven/aza settings, and is there a ceiling here as well?

We traditionally thought that as long as differentiation syndrome was easily controllable, a rate around 20% or less would be extremely tolerable. It’s important to understand grading: Grade 3 can mean a patient was hospitalized for the event, and in these fragile patients, hospitalization is not uncommon for fever or other symptoms. A Grade 3 differentiation syndrome is not necessarily associated with extremely severe symptoms. What we’re seeing are Grade 2 and Grade 3 events that are very easily controlled. Unlike monotherapy, it does not appear we need to interrupt drug to control them; steroids and supportive care seem sufficient. So a reasonable bar is around 20% with events that are readily treatable and allow patients to continue therapy.

I’ll just add that when we present the full data, you should expect to see the differentiation syndrome rate drop to single-digit percentages. We’re encouraged by what we’ve seen, primarily in the KMT2A rearranged patients in the relapsed/refractory setting, and it seems well managed in combinations.

Very helpful, guys. Thanks so much.

We will go next now to Roger Song at Jefferies. Roger, please go ahead.

Great. Congrats for all the progress and thank you for taking my question. Related to the potential pivotal plan and understanding you’re discussing with the FDA now: what is the timing for pivotal study initiation versus your expansion data release? Do you need to see more dose-dependent efficacy at the higher 600-milligram dose versus the others, or is the current total package sufficient for you to move into the pivotal once you finalize the design?

Thanks, Roger. We already have those trials designed and are preparing to engage health authorities. Both the clinical activity and the safety and tolerability support 600 milligrams as the dose we would recommend to the FDA and other regulators in combination. In addition to dose selection, endpoints are a critical question and will be part of our discussions. We are currently thinking we’ll kick off those studies in the middle of next year. We believe there’s an opportunity to combine ziftomenib with both 7+3 and ven/aza, so we’ve designed trials for each of those settings. Before dosing a patient, we didn’t fully appreciate the opportunity in frontline 7+3: patients are staying on therapy for prolonged periods and many are not going to transplant. That led us to appreciate that 7+3 plus ziftomenib appears to be nearly equally important commercially to ven/aza plus ziftomenib. We’re rolling all of that into regulatory discussions early next year with the goal of starting combination studies mid-next year.

Excellent. That’s very helpful. And similar in terms of the timeline regarding your monotherapy NPM1 data: topline should be early 2025 and how should we think about the NDA filing for that monotherapy?

Yes. Once the data have been collected, cleaned and locked, we’ll be in a position to provide topline results. Within a few months after that, we would be ready to submit the NDA. If all goes well with submission and review, we would be looking for potential approval in the second half of next year. We’ll be in a better position to guide more specific timing next year when we are closer, but that gives a rough idea.

We will go next now to Charles Zhu at LifeSci Capital. Charles, please go ahead.

Good afternoon, guys. Thanks for taking the questions and congrats on the progress. First, could you remind us what proportion of patients are 'adverse risk'? And if you’re including a broader population beyond adverse risk in your Phase 1b expansion cohorts, how should we think about enrollment speed there? Thank you.

Mollie, can you speak to adverse risk versus broader populations and what that means for enrollment?

We define adverse risk as older patients who may also have complex cytogenetics or treatment-related AML. That comprises a fair amount of patients—my estimate would be about 30%. Regarding enrollment speed, our enrollment in Phase 1a, where we did have adverse risk, was extraordinarily brisk, as reflected by the fact that we shared 105 patients' worth of data after just over a year. Enrollment remains brisk as we move into Phase 1b. We are very encouraged by the interest from investigators and patients.

Got it. Great. Thanks for that. Regarding your ASH abstract, one clarifying question: is there any response deepening at the lower 200-milligram dose given longer follow-up versus the 400-milligram dose? How should we think about the numerically inverse dose response between 200 milligrams and 400 milligrams in combination?

Mollie, do you want to take that?

There are a combination of reasons. The biggest is small numbers, and within those small numbers there are differing baseline characteristics that complicate interpretation—different ECOG medians, different numbers of prior therapies, etc. The totality of evidence helps determine the correct dose to carry forward. We have both a safety monitoring committee and an independent data monitoring committee involved throughout the study. Both committees agreed that 600 milligrams should be taken into the expansion cohorts based not just on response rates but also on baseline characteristics, safety and tolerability, count improvements, speed to response and other data pieces. So while it may appear there is an inverse dose response, we don’t believe that is the reality.

Perfect. Makes sense. One last question: regarding on-target menin resistance mutations, could you clarify the assay you used relative to a peer’s assay that reported a 38.7% rate of mutations? How similar or different are the sensitivities, and what does that mean for the rate of emergent menin resistance on ziftomenib?

I think you’re referring to the difference between digital droplet PCR and RT-PCR. We also use different sources, DNA versus RNA, for examining that data. However, the patients we looked at for mutations would have been detectable even with a less sensitive assay, so we didn’t need digital droplet PCR to determine if these mutations were present. We believe our data is highly reliable and comparable to others. Remember that some peers used digital droplet PCR to determine if mutations were present at baseline rather than mutations that developed over time. We’ve continued to work on this topic and have confirmed through increasingly sensitive analyses that our findings are consistent with what we presented at EHA.

Excellent. Thank you very much for taking my questions and congrats again.

Thanks, Charles.

We will go next now to Phil Nadeau at TD Cowen. Phil, please go ahead.

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

There is, Phil. Mollie, would you give more color?

It’s a little more obvious than one might think. We’re seeing faster count recoveries with increased dose. Faster count recovery means patients have less time to be susceptible to infections, less time to be susceptible to bleeding, and less need for transfusions. So there is a good basis for why safety improves at increased dose.

That is very helpful. And then a second question on next-generation menin inhibitors: you mentioned you will nominate a candidate for diabetes in the first half of 2025. Are there efforts underway to identify next-generation menin inhibitors to advance in hematologic malignancies as well?

Good question. We do have molecules. It’s always hard to imagine improving on ziftomenib, which is highly potent. One potential advantage for next-generation molecules could be activity against known gatekeeper mutations; we do have such molecules. Right now, given ziftomenib’s performance in combinations and the low rates of induction of gatekeeper mutations, our focus is to move ziftomenib into combinations initially in the frontline as well as with FLT3 inhibitors. We are, however, exploring menin inhibitors for solid tumors. For example, we published strong preclinical data combining ziftomenib with imatinib in GIST. We’re evaluating whether that is an isolated example or if there are other solid tumor applications. If other applications emerge, having a distinct next-generation menin inhibitor for those indications could be valuable. We’ll continue to fill in that picture next year.

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

We will go next now to Peter Lawson at Barclays. Peter, please go ahead.

Thanks. As we think about expectations for patients previously treated in the pivotal study, how should we think about that versus what we saw in the Phase 1 published data?

Mollie, do you want to speak to that question?

The published data was on a very small data set. We will continue to analyze monotherapy data as we put out our Phase 2 data set and gain a better picture of patients post-venetoclax failure and whether we can resensitize them. In the combination setting, we will present more data at ASH. There is potential for patients to respond post-venetoclax failure, but whether that is resensitization or synergy between the two molecules is too early to say. We continue to be encouraged.

On the 7+3 adverse risk patients, how might the duration of response differ between NPM1 and KMT2A patients?

We don’t know yet because most of these patients are still ongoing therapy, so we haven’t reached a median duration of response for these groups. I will say there is a fundamental difference: KMT2A patients tend to be more aggressive with more invasive monocytic disease, which makes them harder to control. Ziftomenib’s tissue accumulation may help address areas where KMT2A cells have invaded at diagnosis. We hope menin inhibitors can help equalize outcomes.

Perfect. Thanks so much.

Thanks, Peter.

We will go next now to Justin Zelin of BTIG. Justin, please go ahead.

Hey. Thanks for taking the question and congrats on the progress. Following up on resistance mutations: would you analyze that in your combination and earlier-line studies? Do you expect it might differ in those settings?

Yes. In frontline settings, we don’t expect baseline existence of resistance mutations, though they could appear in relapsed/refractory patients after exposure to other menin inhibitors. The risk of developing these mutations will likely decrease substantially in combination settings. Monotherapy is the larger risk for developing such mutations because you may not be hitting the pathway hard enough or fast enough, allowing resistant clones to emerge. Overall, combinations should reduce the likelihood of mutation-driven resistance.

Great. That makes sense. Thanks for taking our question.

We will go next now to Brad Canino at Stifel. Brad, please go ahead.

Hi. Thanks for taking the question. Given that one peer initiated a frontline trial in collaboration with a European cooperative group, what is your current thinking about using a similar strategy? How do you weigh the pros and cons of a cooperative group collaboration versus doing a fully company-sponsored trial?

Cooperative groups play an important role and do excellent work. In our view, they are ideal for smaller opportunities or populations where identifying patients is more difficult. For example, we have a collaboration with LLS for pediatric indications where patient identification is challenging and the need is great. The downside of cooperative group studies is they’re their design, timeline and data release schedule; they dictate amendments and interpretation. For large, high-value indications like frontline 7+3 and ven/aza, where 90% of the commercial value is, we plan to run company-sponsored studies to control design and timelines. We will, however, continue to use cooperative groups where appropriate for niche indications.

Thank you.

We will go next now to UBS. This is Ihan on for David Dai. Ihan, please go ahead.

Hi. Thank you so much for taking our question and congrats on the quarter. First, for the pivotal ziftomenib data in relapsed or refractory NPM1-mutated AML expected in early 2025, can you set expectations on clinically meaningful efficacy and duration? Second, in your ASH abstract for the ziftomenib plus azacitidine cohort, around 25% of patients had prior menin inhibitor exposure. Will we see efficacy data for that subgroup at the presentation, and do you expect different activity against resistant mutations in those patients?

For the monotherapy pivotal data, our regulatory bar has consistently been about a 20% to 30% CR/CRh rate and a median duration of response of approximately four to six months. That’s the benchmark we believe the agency will use to consider approvability. Other factors like overall response, safety and tolerability also factor in. Regarding activity in patients with prior menin inhibitor exposure, we will include some additional data at ASH that covers that subgroup. The relapsed/refractory population is heterogeneous—ECOG status, prior lines of therapy, and prior exposures vary—so we’re still learning the rules of the road. We are encouraged to see activity in patients who progressed on prior menin inhibitors and are analyzing what, if anything, can increase activity in those settings.

That’s great. Thank you so much.

We will go next now to Scotiabank. This is Koli on for George Farmer. Koli, please go ahead.

Hi. Can you hear me okay? Curious about the diabetes program and how the next-generation menin inhibitor you’ll nominate next year will differ from ziftomenib and from another competitor molecule expected to have Phase 2 data by year-end. How will you differentiate your program versus theirs, and what will you need to see to set the benchmark for menin inhibition in diabetes?

Great question. When we evaluate non-AML applications like GIST or diabetes, we test ziftomenib, competitor compounds and next-generation compounds to get a holistic picture. In GIST, ziftomenib is uniquely active, likely due to tissue penetrance. In diabetes models, ziftomenib also shows strong activity. Francis Burrows, our SVP of Translational Research, characterizes ziftomenib as hitting menin very potently and it functions as a menin degrader—a property shared by some, but not all, competitors. Importantly, the pharmacology we see with ziftomenib develops over several weeks and decays over several weeks after stopping drug, consistent with an epigenetic mechanism. Some competitor compounds show immediate loss of effect after removal, which raises questions about whether they act entirely via menin. For next-generation diabetes compounds, safety and tolerability are critical because type 2 diabetes patients are not as sick as AML patients, so the therapeutic window must be large. We benchmark against other compounds and consult external experts on what preclinical and clinical data would be required. We expect to nominate our first next-generation candidate in diabetes in the first half of 2025 and will provide more details then.

Thanks. Does your current cash runway estimate include the early clinical work in diabetes as you enter the clinic?

Let me ask Tom to comment on that.

Yes. Our cash runway does include the next-generation menin inhibitor work in diabetes.

Great. Thank you so much.

It appears we have no further questions today. I’d like to turn the conference back to Dr. Troy Wilson for any closing comments.

Thank you, Bo, and thank you all once again for joining our call today. We’ll be participating at the Jefferies London Healthcare 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.

Thank you, Dr. Wilson. That will conclude the Kura Oncology third quarter financial results call. Thank you for joining and we wish you a great evening. Goodbye.