Q3 2024 Kura Oncology Inc Earnings Call
Please standby we're about to begin.
Speaker Change: 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 registered to ask a question at any time by pressing star one on your telephone keypad.
Speaker Change: 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 de Spain head of Investor Relations. Please go ahead Sir.
Speaker Change: Great. Thank you Bill good afternoon, and welcome to occur oncology 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 Leoni are executive Vice President of clinical development is also with us and available.
Speaker Change: To answer your questions before.
Speaker Change: 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 managements judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to <unk> filings with the SEC, which are available from the SEC.
Troy Wilson: Or on the current oncology website for information concerning risk factors that could affect the company with that I'll now turn the call over to Troy.
Troy Wilson: 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 just a matter.
Troy Wilson: We believe <unk> is well positioned to transform the treatment of men independent AML, so that patients with cancer may lead better longer lives.
Troy Wilson: Earlier this week two abstracts reporting preliminary data from our common zero-zero seven combination trial of just a minute were posted on the website of the American society of hematology.
Troy Wilson: As of the June 21st data cut off the abstracts continue to support a potential best in class safety and Tolerability profile for just a minute as well as robust and durable activity in combination with standard of care, including Venetic Lax plus he has decided in as well as cytarabine plus Donna rubinsohn, commonly known as seven.
Troy Wilson: Three.
Troy Wilson: In the phase one dose escalation portion of the comments you were zero seven study this momentum combined with Vanessa was well tolerated and demonstrated promising activity in relapsed refractory patients no D. L T's or is it a matter of induced Q T. C. Prolongation were reported on.
Troy Wilson: Target differentiation syndrome was observed in 12% of patients, including three of 20 K M. T. Two way rearranged patients and all patients had resolution of D S with appropriate management incurred.
Troy Wilson: Encouraging clinical activity was observed at both 204 hundred milligram dose levels, including activity in previously venetic clacks exposed to M. P. M. One mutant and Kmt <unk> rearranged patients updated results, including data from the 600 milligram cohorts will be reported at ash.
Troy Wilson: In the AML frontline adverse risk population, we are very encouraged by the safety and Tolerability profile rates of complete response and rates of <unk> negativity, notably no events of differentiation syndrome were reported at 200 or 400 milligrams, including among Kmt <unk> rearranged patients.
Troy Wilson: Suggesting is if demand if it can be safely combined with induction chemotherapy.
Troy Wilson: Particularly encouraged by the fact that in the context of the very challenging seven plus three adverse risk AML patient cohorts are 100% of the 15 N. P. M. One mutant AML patients and 84% of the 19, Kmt <unk> rearranged patients remained on study as of the data cutoff one year out.
Troy Wilson: Study start here.
Troy Wilson: Here again updated results, including data from the 600 milligram cohorts will be presented at ash.
Troy Wilson: We look forward to sharing a more mature dataset, including data from more than 100 patients with N. P. M. One mutant or Kmt <unk> rearranged acute myeloid leukemia next month.
Troy Wilson: In the meantime, I'm pleased to report that all four cohorts in the phase <unk> dose escalation portion of common 007 have cleared the highest dose and advanced into the phase <unk> expansion study at 600 milligrams.
Troy Wilson: The phase <unk> expansion study includes multiple combination cohorts, most notably as if demand plus then Asia in newly diagnosed N. P. M. One mutant or Kmt <unk> rearranged AML as well as just a minute plus seven plus three in newly diagnosed N. P. M. One newton or Kmt <unk> rearranged AML, removing the requirement for <unk>.
Troy Wilson: Patients to have high risk disease.
Troy Wilson: Each combination cohort is enrolling independently and we expect to enroll at least 20 patients per cohort.
Troy Wilson: We believe the phase <unk> expansion study will continue to lay the groundwork for helping us to redefine the current standards of care for newly diagnosed patients with N. P. M. One mutant or Kmt <unk> rearranged AML in both the fit and unfit populations, we anticipate sharing preliminary data from the phase one expansion.
Troy Wilson: Steady at a medical meeting in 2025.
Troy Wilson: In addition to comments he was there seven we continue dosing patients in our ongoing comment 008 study have slipped a minute in combination with additional standards of care, including the flip three inhibitor guilty written them as well as flag Ida and low dose cytarabine roughly half of all patients with relapsed or refractory N P. M y.
Troy Wilson: In AML have co occurring slipped three mutations and the prognosis for these patients is poor preclinical data for is if demand had been combination with split three inhibitors have shown strong synergistic effects compared to either single agent alone.
Troy Wilson: When we look across the fit unfit and slipped three mutant AML frontline populations. We believe are best in class safety and efficacy profile and optimal pharmaceutical properties could enables if demand up to become a cornerstone of therapy for patients with acute leukemias ultimately our mission is to develop ziff command them across the continuum.
Troy Wilson: <unk> care for all eligible patients with acute leukemias, whose disease is driven by the men and pathway.
Troy Wilson: Critical first step toward that mission is establishing <unk> as the best in class Menin inhibitor for patients with relapsed and refractory <unk> mutant AML.
Troy Wilson: As a reminder, <unk> is the first and only investigational therapy to be granted breakthrough therapy designation for treatment of relapsed and refractory N. P. M. One mutant AML.
Troy Wilson: N P M. One mutant AML represents approximately 30% of new AML cases annually and has a disease of significant unmet need for which there is no approved targeted therapy F. D. A awarded BTB based on data from our comments here is your one trial, recognizing zip de minimus potential as an innovative medicine.
Troy Wilson: For patients with this devastating disease supporting data from the phase one portion of comments here zero. One were recently featured in a leading clinical oncology journal the lancet oncology.
Troy Wilson: We completed enrollment in the registration directed portion of common 001 earlier this year enrolling more than 85 N. P. M. One mutant patients and 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 just a minute as a monotherapy.
Troy Wilson: RFP.
Troy Wilson: Meanwhile, we've generated a growing body of preclinical data that supports opportunities for menin inhibitors beyond acute leukemias, including the potential <unk> in the treatment of certain solid tumors.
Troy Wilson: Last month at the <unk> M C. I ACR symposium on molecular targets and cancer Therapeutics in Barcelona, We reported preclinical data supporting the combination of just a minute and Matt nib for the treatment of advanced gastrointestinal stromal tumors or just the.
Troy Wilson: 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 with significantly superior to Imatinib monotherapy.
Troy Wilson: Mechanistically the data reveal a kit dependent mechanism with ziff to men had been imatinib combining to sharply reduce kid expression indoor activity effectively silencing, both the earth and a T T M towards signaling pathways and driving robust cell cycle arrest and they pop Texas.
Troy Wilson: Given that Matt Nabors, well established as the frontline standard of care in patients with chest and generic versions are available. We believe imatinib represents a promising combination partner for ziff to minutes.
Troy Wilson: In August we received FDA clearance of our investigational new drug application for <unk> for treatment of advanced Gist. We're now prepared to initiate a proof of concept study evaluating ziff demand had been imatinib in patients with advanced Gist. After imatinib failure in the first half of 2025.
Troy Wilson: If successful the potential opportunity ingest appears to be agnostic to the mutational status of kit ingest, suggesting an opportunity to explore the combination for nearly all patients including those in the frontline setting.
Troy Wilson: 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 <unk>.
Troy Wilson: First half of 2025.
Troy Wilson: Now, let's quickly turn our attention to our furnace will transfer ace inhibitor programs. Despite the success of targeted therapies are considerable need remains to drive enhanced antitumor activity, while blunting the effects of innate and adaptive resistance. We are developing our next generation Farnesol transfer Ace inhibitor K O 20, 806 to address this need.
Troy Wilson: <unk>.
Troy Wilson: $28 six was designed to improve upon the potency pharmacokinetic and physical chemical properties of earlier F. T. I drug candidates, we've generated a growing body of preclinical and clinical data that demonstrates the potential for K, a $28 six as a companion therapeutics to augment the antitumor activities targeted therapies <unk>.
Troy Wilson: <unk> tyrosine kinase inhibitors.
Troy Wilson: Ras inhibitors and Pan RAF inhibitors.
Troy Wilson: Late last year, we began dosing patients with Kayo tornado six as a monotherapy in a phase one dose escalation trial that we call fit zero-zero one.
Troy Wilson: 001 uses an innovative design that enabled us to begin dose escalation of Kayo tornado six in combination cohorts very early in the study while continuing to dose escalate concurrently as the single agent earlier.
Troy Wilson: Earlier this year, we dosed the first patient with K O 28 of six in combination with Cabozantinib in clear cell renal cell carcinoma and in August we dosed. The first patient in combination with <unk> and K rescue 12 C. Mutated non small cell lung cancer. As a reminder, the study of T. O 28, 6% at a grass is supported by our clinical <unk>.
Troy Wilson: Operations and supply agreement with Marathi now of Bristol Myers Squibb company.
If successful we believe K O 20, 806 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 TP farnam with the targeted therapy, all palisade and picked <unk> CA dependent head and neck squamous cell carcinoma.
Troy Wilson: In our study we call current day Chen.
Troy Wilson: We believe there may be a meaningful opportunity to combine on the F. T I with a PR three kinase Delta inhibitor and look forward to presenting preliminary clinical data from the current HN trial at a medical meeting in the first half of 2025.
Speaker Change: With that I'll now turn the call over to Tom for a discussion of our financial results.
Tom Doyle: 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.
Tom Doyle: Research and development expenses for the third quarter of 2024 or $41 $7 million compared to $29 3 million for the third quarter of 2023.
Tom Doyle: The increase in R&D expenses was primarily due to the increases in clinical trial costs related to our system in it and kayo 28 or six programs.
Tom Doyle: 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.
Tom Doyle: 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 noncash share based compensation expense of $8 $3 million compared to $7 1 million for the same period in 2023.
Tom Doyle: As of September 30th 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.
Speaker Change: With that I'll now turn the call back over to Troy.
Troy Wilson: Thanks, Tom.
Troy Wilson: Before closing I'd like to thank I'd like to take this opportunity to welcome Dr. Michael Vasconcellos 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 <unk>.
Troy Wilson: Your ship across both large and emerging companies are invaluable as we advance our menin inhibitor and STI 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.
Troy Wilson: For our Menin inhibitor program.
Troy Wilson: Okay.
Troy Wilson: Present updated data from the comment zero-zero seven trial or just a minute in combination with Vanessa and seven plus three at Ash in December 2024.
Troy Wilson: Report top line results from the comment Zero-zero, one registration directed trial of just a minute and N. P. M. <unk> mutant relapsed refractory AML in early 2025.
Troy Wilson: <unk> preliminary data from the phase <unk> expansion portion of comment 007 at a medical meeting in 2025.
Troy Wilson: Initiate a proof of concept study evaluating system and had been imatinib in patients with advanced Gist in the first half of 2025 and nominated next generation Menin inhibitor development candidates targeting diabetes in the first half of 2025.
Troy Wilson: For our furnace will transfer ace inhibitor programs <unk>.
Identify the maximum tolerated dose for <unk> 28, a six as a mono therapy by the end of this year.
Troy Wilson: Initiate one or more expansion cohorts for the combination of <unk> 28, or six in Cabozantinib in renal cell carcinoma in the first half of 2025 and present data from the current HN trial of <unk> in combination with <unk> and pick three CA dependent head and neck squamous cell carcinoma in the first half of 2025 with <unk>.
Troy Wilson: We're now ready for questions.
Troy Wilson: Okay.
Speaker Change: Thank you Dr. Wilson, ladies and gentlemen at this time, if you do have any questions or comments in the press Star. One you find your question has already been addressed you may remove yourself from the queue by pressing star to once again Thats star one for any questions well go first this afternoon to Lee Huastec at Cantor Li. Please go ahead.
Lee Huastec: Hey, guys congrats on the progress and thank you for taking my questions.
Speaker Change: Troy I guess, how you're thinking about the potential of using M. Rd activity as part of the frontline endpoints and then for the <unk> data and activity data that was just presented it in your ash abstract is there any difference.
Speaker Change: In the methodology used by you versus your peers.
Speaker Change: Yeah, Great question Lee.
I'll give you my my answer and then I'll ask <unk> to comment if she will if she can.
Speaker Change: So for everybody's benefit.
Speaker Change: The base case scenario for these frontline studies is that youre using survival as the endpoint.
Speaker Change: There may be an opportunity to use <unk> negativity as in as a surrogate endpoint in an accelerated design.
Speaker Change: But I wouldn't consider that the base case I think although there is good evidence.
Speaker Change: To support it that's not yet.
Speaker Change: No, it's not yet sort of the path that has been.
Speaker Change: Given the greenlight by by the health authorities. It is something that we intend on disc.
Speaker Change: Discussing with them here in the relatively near future.
Speaker Change: So I think Lee, we will 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.
Speaker Change: 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 where we're using survival as the base case in MRV negative.
Speaker Change: <unk> excuse me as the upside case ill, let Molly at her thoughts to that and Marty If you could also maybe comment.
Speaker Change: To Lee's question on how are our methodology may differ from from from others.
Speaker Change: Sure.
Speaker Change: So Troy is exactly right, while we know that we'll be able to use a survival endpoint in each of the frontline indications, where we wish to pursue <unk> negativity as 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 theres a good.
Speaker Change: Arguments to be made with the health authorities.
Speaker Change: 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 or is very much up for discussion and nothing we are able to.
Speaker Change: Confirm or deny at this point, because we have yet to have those discussions.
Speaker Change: With regards to our MRI data in our abstract.
Speaker Change: You'll notice we were more quiet about it in the relapsed refractory setting due.
Speaker Change: Due to the fact that it's we get less samples in that setting and they're much more varied.
Speaker Change: Type of methodologies to assess them as you might imagine so what our plan to do is to actually do a central analysis at those samples. So that we can actually give a uniform.
Speaker Change: The answer to what our <unk> 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 et cetera.
Speaker Change: So we did provide those does.
Speaker Change: Site based task, but we do plan also on running those essentially so that we can give them much more uniform resolved on the MLD negativity.
Speaker Change: Okay.
Speaker Change: And then for the six month data that you presented at Ash.
Speaker Change: Just wonder if you can give us a sense of the.
Speaker Change: The number of patients follow up and what types of data that we might see.
Speaker Change: Okay.
Lee Huastec: Yeah Lee Thanks for that so we've said.
Lee Huastec: We're.
Speaker Change: Anticipating showing data on more than 100 patients at this point.
Speaker Change: Well I think you can see by the abstract will kind of halfway there.
Speaker Change: You'll see additional patients at the different dose levels.
Speaker Change: We're planning on really updating every patient on the study.
Speaker Change: As of their status with respect to response as well as duration of any clinical benefit.
Speaker Change: In terms of.
Speaker Change: What to expect.
Speaker Change: Given that the activity is pretty robust at 204 hundred.
Speaker Change: We're expecting to see sort of pretty consistent activity. We get asked a lot do we expect a dose response.
Speaker Change: Not clear you one expects a dose response with these high levels of activity, but something that Youll see is.
Speaker Change: We actually do see interestingly, a dose response with respect to safety and Tolerability as you go higher in dose.
Speaker Change: Safety, and Tolerability actually improves which might seem counterintuitive.
Speaker Change: But that helps to support as you know we've moved forward now into the expansion cohorts.
Speaker Change: At 600 milligrams across all the cohorts and Thats, partly driven by activity. It is also a significant component of safety and Tolerability. So you'll see that you'll see sort of that.
Speaker Change: It will actually be I think a meaningful update even relative to.
Speaker Change: What you see in the abstracts.
Speaker Change: Got it thank you.
Speaker Change: Sure.
Speaker Change: Okay.
Speaker Change: Thank you we'll go next now to Jonathan Chang at Leerink partners.
Jonathan Chang: Hi, guys. Thanks for taking my questions.
Jonathan Chang: As we're starting to see longer term data for <unk> and other <unk> inhibitors in the space how has that impacted your thinking on what the opportunity could be for the class.
Jonathan Chang: Do you see as the key factors determining how long patients can stay on treatment in benefit. Thank you.
Jonathan Chang: Yes, Jonathan Thanks for that question that that's actually.
Jonathan Chang: While I appreciate that there you know there are a significant number of folks that sort of want to get into the scrum was comparing one relapsed refractory data set against another one of the big take home messages from from our abstract is.
Jonathan Chang: Something I think you are 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 seven plus three youll notice.
Jonathan Chang: As of the data cutoff in June <unk>.
Jonathan Chang: 15 out of 15 N P M. One mutant patients and 16 out of 19, Kmt <unk> rearranged patients remained on study on therapy as of the data cutoff in it and for some of those patients.
Jonathan Chang: That study had been going at that point for a year or so.
Speaker Change: Well, what we've said consistently Jonathan is there.
Speaker Change: 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 continued.
Speaker Change: <unk> therapy I E. They get a response they stay on <unk>.
Don't necessarily go to transplant or in the alternative.
Speaker Change: Get a response they go to transplant and then they go back on Ziff DAU in a post transplant maintenance.
Speaker Change: That's the that's what we're seeing we think beginning to emerge in the seven plus three adverse risk frontline population.
Fact that you have 90 plus percent of the patients.
Speaker Change: Again as of the data cutoff staying on study.
Speaker Change: Not even survival right that's on study.
Speaker Change: That's significant I think that.
Speaker Change: The way I've always thought about it as adverse risk seven plus three is is about as hard as it gets in the frontline setting.
Speaker Change: Hopeful that that trend continues now that we're in the expansion cohorts for the frontline seven plus three without adverse risk e-commerce as well as the frontline vent Asia. If we can take these frontline patients and keep them on in a response and keep them on therapy for a year.
Speaker Change: 18 months.
Speaker Change: Potentially even longer that's where you really begin to see significantly inflect the disease and thats what in our in our thinking and our models really helps drive the commercial case and I think we're we're excited to share with you the update for both the relapsed refractory and frontline.
Speaker Change: That frontline picture is beginning to come into focus and I think it looks pretty attractive relative to the competition.
Speaker Change: Okay.
Speaker Change: Understood. Thanks for taking the questions.
Speaker Change: Yes.
Speaker Change: Thank you.
Speaker Change: Well go next now to Jason Szymanski at Bank of America.
Speaker Change: Good evening.
Speaker Change: Congratulations on the progress and thanks, so much for taking our questions.
Speaker Change: <unk> the combination updates at ash, what should we be thinking in terms of benchmarking a win here.
Speaker Change: Safety is 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.
Speaker Change: Yeah, So, let's let's let's start with that Jason.
Speaker Change: <unk>.
Speaker Change: And Molly maybe maybe you want to take Jason's question in terms of how we think about benchmarking maybe maybe we can start with the relapsed refractory and then we can we can talk a little bit about the frontline and sort of what the benchmark would be.
Speaker Change: Sure.
Speaker Change: Realistically in the relapsed refractory setting these patients have for the most part failed venetic clocks and as we know that some extremely poor prognostic factor for doing well on any therapy.
Speaker Change: For Kmt too as you'd probably set the bar at less than 10% potential response rate for MTM on slightly higher but the data tends to suggest that overall survival would only be 2.4 months or so.
Speaker Change: And this particular subsets of patients so that that helps see how bleak the situation is.
Andy: And so 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 600 milligram dose without D. L T's Andy.
Speaker Change: And as Troy referred to see not only the ability to escalate safely, but to see improved safety as we escalate isn't extremely strong sign.
Andy: That that where we're getting good activity as we increase in doses.
Speaker Change: Troy is there anything you would add.
Troy Wilson: No not to that moly, but maybe we could.
Troy Wilson: Help set expectations for frontline and how we think about that in the adverse risk population apps absolutely. So our best comparison for the frontline is the VIX is control arm, which put the response rate of about.
Troy Wilson: For our composite response rate at about 60%.
Troy Wilson: So that would be your CR or a complete response or a complete responses partial hematologic recovery and a complete response with incomplete hematologic recovery, so about 60% there and overall survival of about six months, so again and these adverse risk patients not a good a good setting to see but again, we're seeing excellent.
Troy Wilson: Our ability to be able to escalate the dose. These patients are staying on for a very significant periods of time as Trey alluded to very few have come off study even in our 200 milligram cohort, which has been going on for well over a year.
Troy Wilson: So so far I think where we're seeing.
Troy Wilson: Signs that make us encouraged to keep moving forward.
Speaker Change: Got it that's helpful and maybe to circle back on your comments on Tolerability and safety.
Speaker Change: The team has been guiding away from a zero percent DSA, which makes sense, but I'm curious is there a level that you think would be especially encouraging in both the seven plus three and then a user settings is.
Speaker Change: Is there a ceiling here as well.
Speaker Change: Go ahead. Mike go ahead, you have to take that sure. Yeah, we have traditionally thought that as long as it was.
Speaker Change: Easily controllable.
Speaker Change: Easily addressed.
Speaker Change: Now, 20% or less D. S rate is extremely tolerable, what I always like to remind people is that for.
Speaker Change: The grading of differentiation syndrome grade three simply means that a patient with hospitalized for the event.
Speaker Change: And in these patients are extremely fragile and tend to have fevers of unknown significance and other symptoms that.
Speaker Change: That might need urgent intervention, they're hospitalized all the time.
Speaker Change: So a grade III D. S is not necessarily associated with extremely severe symptoms and what we're seeing is grades two and three D. S that are very easily controlled and what's different from the monotherapy as it doesn't even appear that we need to interrupt drug to be able to control them steroids and supportive care do seem to be sufficient so.
Speaker Change: Just to summarize you know reasonable severity level, probably about 20%.
Speaker Change: And with the ability to treat easily and quickly get these patients continued on therapy is is where we would set the bar.
Speaker Change: Great.
Speaker Change: And all of the color I'll, just add to that yes.
Speaker Change: Yes, Jason I will just add to that Youll expect to see when we give the full data the DFS rate drop to single digit percentages. So.
Speaker Change: I think I think we're encouraged we've seen it primarily as Molly indicated in the KMT two rearranged in the relapsed refractory setting seems to be.
Speaker Change: Well managed with these combinations.
Speaker Change: Okay very helpful guys. Thanks, so much.
Speaker Change: Our pleasure thank you.
Yeah.
Speaker Change: We'll go next now to Roger song with Jefferies.
Speaker Change: Great.
Speaker Change: Congrats for all the all the progress and then taking all the questions.
Speaker Change: Maybe one question related to the again back to the potential pivotal plan understanding you are discussing with the FDA right now just curious about the timing.
Speaker Change: For the.
Speaker Change: Pivotal study initiation.
Speaker Change: Initiation versus your <unk>.
Speaker Change: Expansion data already.
Speaker Change: You need to see more dose dependent efficacy at the higher dose of <unk> 600 milligram versus the others or.
Speaker Change: Brent.
Speaker Change: Most exposure or the total package sufficient for you to move into the pivotal once you finalize the design.
Speaker Change: Yeah, Roger Thanks for the question.
Speaker Change: We already have those trials designed.
Speaker Change: And are preparing to engage the health authorities in discussion. So if that helps address your question.
Speaker Change: As Mollie indicated both the clinical activity and the safety and Tolerability support that 600 milligrams.
Speaker Change: Is going to represent the dose that we recommend to FDA and other global health authorities as the dose in combination.
Speaker Change: You know that the health in addition to the dose selection as Molly indicated in an answer to one of the previous questions, we'll talk about about endpoints.
Speaker Change: The the powering the design I mean, that's really up up up to us, but the endpoints are a critical question and will want to have a have a robust discussion there. We're currently.
Speaker Change: Thinking that well will kick off those studies middle of next year.
Speaker Change: We believe there is an opportunity to combine ziff demanded in both.
Speaker Change: Seven plus three and then Asia.
Speaker Change: So we've designed trials for each of those two.
Speaker Change: Those two settings, something that I think has been an interesting surprise to us as before we had dosed a patient.
Speaker Change: I don't think we really appreciated the opportunity in the frontline seven plus three.
We sort of naively assumed patients would would would enter that cohort. They would go through a 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 a more fulsome dataset patients are.
Speaker Change: Molly indicated they are staying on therapy for prolonged periods of time many of them are not going to transplant.
Speaker Change: And we will 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 venetic clacks as decided in what's the much larger commercial opportunity.
Speaker Change: It is it is meaningful Theres no question and we will pursue that.
Speaker Change: About seven plus three plus Ziff Doe 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 thats beginning to emerge. So we are rolling all of that and think about regulatory discussions in the early part of next year.
Speaker Change: With a goal towards starting a combination study or studies middle of next year hopefully that helps answer your question.
Speaker Change: Excellent.
Speaker Change: That's very helpful and a similar in terms of the timeline regarding your.
Speaker Change: The monotherapy and Kim one data continue to be early 'twenty 'twenty fine how should we think about NDA filing.
Monica: Monica Thank you.
Speaker Change: Yeah, Yeah. Another another thank you for that question so yes.
Speaker Change: Once that once the data has been collected and cleaned and locks will be in a position to provide the top line results.
Speaker Change: Within.
Speaker Change: Some period of time as measured by you know 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.
Speaker Change: Well, 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.
Speaker Change: Okay. That's very helpful. Thank you.
Speaker Change: Sure.
Speaker Change: We'll go next now to Charles Zhou at lifestyle capital.
Speaker Change: 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 <unk> expansion cohorts, how should we be thinking about enrollment speed there.
Thank you.
Speaker Change: 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.
Speaker Change: I don't know what if anything we can say about enrollment.
Speaker Change: Sure. So you know.
Speaker Change: The way, we've defined adverse risk is older patient with that.
Speaker Change: That may also have a.
Speaker Change: <unk> set a genetic or be treatment related.
Speaker Change: So that is how we define adverse RASK and realistically it does comprise a fair amount of patients.
Speaker Change: No exact numbers, but my answer would be about 30%.
Speaker Change: 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 <unk>, where we did have the address RASK was extraordinarily breast.
Speaker Change: As you can see with the thought that where we're able to now share a 105 patients worth of data after.
Speaker Change: Just a just over a year.
Speaker Change: It is now Joseph brisk, if not more so as we move into the phase one b.
Speaker Change: So we are very encouraged by the excitement of the investigators and the desire of the patients to participate in our trials.
Speaker Change: Yeah.
Got it great. Thanks for that and regarding the ash abstract one clarifying question here is there a response deepening affect that we could be seeing at the lower 200 milligram dose given that has longer follow up versus the 400 and granted these are very small and but how should we be thinking about what it appears.
Speaker Change: To be a numerically inverse dose response between two and 400 milligrams in combination. Thank you.
Speaker Change: Well, yes.
Speaker Change: Sure I think there's a combination of reasons I think the biggest one is exactly as you point out.
Speaker Change: Small numbers and within the small numbers when I look at the demographic details there's varying.
Speaker Change: Baseline characteristics as well that can complicate the interpretation so you'll have different <unk> medians four different dose levels different numbers of priors for different dose levels.
Speaker Change: So ultimately it really does become the totality of evidence that helps us determine what the correct dose to carry forward it should be and I should clarify that we have both the safety monitoring committee and an independent data monitoring committee that have been involved.
Speaker Change: <unk> throughout the study not only in helping to decide.
Speaker Change: 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.
Speaker Change: Safety and Tolerability.
Speaker Change: The count improvement speed to response, you know a myriad of different data pieces. So we.
Speaker Change: Well it could appear to be an inverse dose response, we don't think that is actually.
Speaker Change: The reality of of this particular study.
Speaker Change: Perfect Great makes sense of humor, maybe just one last one from for me regarding the on target and men and resistance mutations that we've heard a few things from some third parties out there, but could you clarify the assay that you use.
Speaker Change: Used relative to one of your peers slash competitors assays when they reported their 38, 7% rate of mutations and how similar or different are the sensitivities of those assays and what does that mean with the rate of emergent.
Speaker Change: Resistance on Ziff Don Thank you.
Speaker Change: So I think you're referring to the difference between digital droplet PCR and RT PCR that we used to be I'll say, it's different sources.
Speaker Change: DNA versus RNA for examining that data.
Speaker Change: However, the the patients that we looked at four.
Speaker Change: Mutations wood has been detectable at even less.
Less sensitive assay.
Speaker Change: So you didn't need digital droplet PCR in order to determine if these if these mutations where there. So we do think that our data is highly reliable and that we're able to compare.
Speaker Change: To the to these other data and remember they were huge using the digital droplet PCR to determine if these were present at.
Speaker Change: President baseline them 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 analysis that our findings are extraordinarily consistent with what we presented at <unk>.
Speaker Change: Excellent. Thank you very much for taking my questions and congrats again.
Speaker Change: Thanks Charles.
Speaker Change: Thank you we'll go next now to Phil Nadeau at TD Cowen.
Phil Nadeau: Good afternoon, thanks for taking our questions as well.
Speaker Change: We were intrigued by your comments about safety improving for Cisco as the doses increase is there a mechanistic rationale as to why safety should improve with with increased exposure.
Yeah, Phil there is actually and I'll, let <unk> give you more color.
Speaker Change: Yeah.
Speaker Change: Actually a little bit more obvious the need even think we are seeing a foster count recoveries with increased dose.
Speaker Change: Obviously foster count recoveries mean, these patients have less time to be susceptible to infection talk last time to be susceptible to bleed have less need for transfusions.
So there is there does seem to be a very good basis for why we are seeing the improved safety increased dose.
Speaker Change: That is very helpful. And then second question on the next generation minute inhibitors. I think you mentioned, specifically that you will nominate a candidate for diabetes.
Speaker Change: In the first half of 2025 are there efforts underway to identify next generation of <unk> inhibitors to advance in heme malignancies as well.
Speaker Change: Yeah. Good question Phil.
Speaker Change: There could be I mean, we have molecules.
Speaker Change: It's.
Speaker Change: You always think your baby is the most beautiful right.
Speaker Change: It's hard to imagine improving on Ziff dough.
Speaker Change: 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.
Speaker Change: It's not obvious to us now that we're in combinations and as Molly said.
Speaker Change: We continue to see.
Speaker Change: Very very low rates of induction of gatekeeper mutations that that's an advantage. So at the moment I would say.
Speaker Change: We have the molecules were holding them.
Speaker Change: And really putting putting.
Speaker Change: Putting the best <unk> Ziff Dell going into combinations initially in the frontline as well as doing work for example, what's the split three inhibitors.
Speaker Change: We are we are however, looking at Menin inhibitors potentially for other solid tumors.
Speaker Change: And we put out what I think are some very nice preclinical data.
Speaker Change: Combining <unk> if demand with Imatinib ingest.
Speaker Change: We're doing the work to determine.
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 menin inhibitor for those solid tumor applications as we continue to do more work so well.
Speaker Change: We will begin to fill that picture and probably next year.
Speaker Change: That's helpful. Thank you for taking our questions.
Speaker Change: Our pleasure.
Speaker Change: We go next now to Peter Lawson at Barclays.
Peter Lawson: Great. Thank you so much.
Peter Lawson: Sure.
Speaker Change: Just as we think about expectations for kind of product.
Speaker Change: Been treated patients in the pivotal study.
How should we think about that versus what we saw in the phase one data that was published.
Speaker Change: Yeah.
Speaker Change: Molly do you want to speak to Peter's question.
Speaker Change: Sure obviously, the published data was on a very small dataset and we'll continue to analyze the monotherapy data as we.
Speaker Change: Put out our phase II data set as well and probably gain a better picture as to exactly what these patients look like post frenetic lacks failure and if we're able to re sensitize them and get these patients back able to respond to therapies in the combination setting.
We are we will be presenting more data on that as we get to ash. We do think that there is still a good potential for patients to respond post venetic flex failure again is that due to our ability to re sensitize. These patients <unk> is it.
Speaker Change: 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.
Speaker Change: Perfect. Thank you so much really interesting.
Speaker Change: On the seven plus three adverse risk patients.
Speaker Change: What was the duration of response, how could that differ between your thinking the A&P in one versus the <unk> patients.
Speaker Change: Yeah, Molly do you want to take that question as well.
Speaker Change: 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.
Speaker Change: So.
Speaker Change: Thankfully, we haven't reached our median duration of response for these for these groups.
Speaker Change: And we hope that it continues on that way and so that this question continues to be difficult to answer.
Speaker Change: Okay.
Speaker Change: Kind of.
Speaker Change: Fundamental difference do you think between the NPM one K P.
Speaker Change: Q2 80 patients.
Speaker Change: I do I think Kmt today are much harder to permanently control.
Speaker Change: They have just a much more aggressive monothetic disease that is so invasive them, but I think that's where a molecule like system. Then it becomes so important because our drug is able to actually accumulate in tissues as well and find some of these areas where the.
Speaker Change: The the Kmt <unk> rearrange cells have been able to already invade at the time of diagnosis even in the frontline.
Speaker Change: So, yes definitely a fundamental difference in the level of aggression between the two but we hope that men and becomes met inhibitors at least become the great equalizer for them.
Speaker Change: Perfect. Thank you so much thanks for taking the question.
Peter Lawson: Thanks Peter.
Speaker Change: We go next to Justin Zelman of BTG.
Justin Zelman: Hey, Thanks for taking my question and congrats on the progress.
Justin Zelman: Maybe following up on an earlier question about resistance mutations would you look to do that analysis in your combination in earlier line studies and.
Justin Zelman: Just expectations there if you think that it might differ in those settings.
Speaker Change: Molly do you want to take I mean.
Molly Leoni: Yeah, obviously, <unk> and frontline settings, we.
Molly Leoni: We don't expect to see you know at least the baseline existence of these resistant mutations although they could very well be in your relapsed refractory setting after exposure to other men inhibitors, but with regards to a differential ability to develop these mutations once you get into combination your risks kind of decrease in <unk>.
Lee Huastec: Lee, it's the mono therapy, that's really the big risk.
Lee Huastec: For developing these types of mutations because youre, just not hitting it hard enough fast enough and you're giving it time, just like with bacteria to grow out resistant colonies.
Lee Huastec: So I think that Youre, 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.
Speaker Change: Great that makes sense to me thanks for taking my question.
Speaker Change: And well go next now to Brad Canino at Stifel.
Brad Canino: Alright. Thanks for the question just one from me wondering given we've seen one of the pyramid companies initiate a frontline trial in collaboration with one of the European Cooperative groups, just what's your current thinking about.
Brad Canino: Following 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.
Brad Canino: Yeah, Thanks, Brad for the question.
Speaker Change: So cooperative groups play a really important role in the ecosystem.
Speaker Change: They do they do some terrific work.
Speaker Change: In our in our view.
Speaker Change: And you can see this reflected in the in the development plan we are establishing.
Speaker Change: Data data packages for safety Tolerability combinability clinical activity across a range of different combinations.
Speaker Change: A focus obviously in the run up to ashes around seven plus three and Vanessa but hopefully next year, we'll talk more about L O eight which as Gil to written Nib L. DAC flag Ida.
Speaker Change: So to the extent that for some of these perhaps you know either smaller opportunities are populations, where it's more difficult to treat you to identify these patients for treatment those are ideal for four cooperative groups.
Speaker Change: And I think.
Speaker Change: You really want to take full advantage of it and in that context.
Speaker Change: You probably know we have a collaboration with LLS as pedal in.
Speaker Change: In the pediatric indications because they're huge unmet need.
Speaker Change: Difficult to find those patients it's not a it's not a huge commercial opportunity, but but it is unquestionably one of the most important things you can do and we are.
Speaker Change: Very happy to be collaborating with LLS, the downside to a cooperative group study as it is.
Speaker Change: Their design, it's their timeline.
Speaker Change: They dictate data release, they dictate how the how you interpret that data any amendments you make to the study.
Speaker Change: Don't think youre going to see us using cooperative group studies for either our seven plus three or vent Asia trials, because that's where 90% of the value is to be honest right. We all we all know this the the big money here is get patients on study right right at the get go and ideally.
Speaker Change: Keep them on 12, 18, perhaps even 24 months, so you're going to see us Brad do Chris sponsored studies, but we will continue to work and have studies planned for cooperative groups, where the smaller indications may be appropriate what we will do a mix of both.
Speaker Change: Okay.
Speaker Change: Thank you.
Speaker Change: Sure.
Speaker Change: We'll go next to David dye at UBS.
Speaker Change: Hi, this is <unk> on for.
Speaker Change #100: David Thank you so much for taking our questions and congrats on the quarter.
Speaker Change #100: I guess, our first question.
Speaker Change #100: It's kind of like a PD <unk>.
Speaker Change #101: Madame pivotal data.
When last Halloween factory in <unk>.
Speaker Change #102: Or any kind of any five so just curious if you could set some expectations on the clinical meaningful efficacy.
Speaker Change #102: Your ratio bar.
Speaker Change #103: Allison I think ash.
Speaker Change #103: Ash abstract, although they've come down that path.
Speaker Change #103: Asa cohort. So we saw there were up on the F. 'twenty from my presentations.
Speaker Change #105: You may have prior Manny Hey, Peter I'm, just curious if we're going to see the efficacy profile from these set of patients.
Speaker Change #103: Presentation.
Speaker Change #106: Yes, I think it just like related to.
Speaker Change #106: Second higher activity taken some rotation resistant patient. Thank you.
Sure. Thanks for the question.
Speaker Change #107: So on with respect to the monotherapy pivotal data.
Speaker Change #106: I think you know.
Speaker Change #106: Even before we ever dose to patients we've always given the same guidance switches.
Speaker Change #106: The regulatory bar in our view the BARDA approval is 20% to 30% CR CRH.
Speaker Change #106: And four to six months median duration of response I don't think I've ever vary from from when I've been asked that question certainly at this point nothing has changed now.
Speaker Change #106: That is the that is the the bar that the agency uses.
Speaker Change #108: To consider a probability as molly's already indicated to you there are a lot of other factors so and some of those have been spoken to by by competitors of ours. So CRC rate overall response rate.
Speaker Change #108: Ah things such as that as well as safety and Tolerability all factors in but Thats, how were continuing to think about the monotherapy data as far as data on.
Speaker Change #108: Activity in in.
Speaker Change #108: Patients, who have who have experienced prior menin inhibitors, yes, there will be there will be some additional data in the.
Speaker Change #109: 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.
Speaker Change #108: Yeah.
Speaker Change #108: Because these patients are because the patient population is so heterogeneous E cogs 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 <unk>.
Speaker Change #108: Progressed on prior Menin inhibitors and learning what if anything can we do to to increase that when we treat them with just a minute.
Speaker Change #110: That's awesome. Thank you so much.
Speaker Change #110: Sure.
Speaker Change #110: Yeah.
Speaker Change #111: And we'll go next now to George Farmer at Scotia Bank.
Speaker Change #112: Hi, Good evening this is <unk>.
Speaker Change #113: George can you hear me okay.
Speaker Change #114: We can.
Speaker Change #114: Okay great.
Speaker Change #114: Yes, the balance sheet.
Speaker Change #114: Got it.
Speaker Change #114:
Speaker Change #115: And how this next gen. <unk> inhibitor is that you're going to get more information on that next year. Thank you be different from Germany and from other competitor molecules.
Critical data by by.
Speaker Change #114: By year end.
Speaker Change #114: And I guess there'll be setting the benchmark for further potential.
Speaker Change #116: In diabetes, what can we need to see from your own program eventually down the road in Walkaways are you hoping to be similar to differentiate from that.
Speaker Change #116: And then I have a follow up yeah.
Speaker Change #116: Okay.
Speaker Change #116: Yes, great Great question so.
Speaker Change #116: In our hands and when we do these experiments away from AML, whether its just whether it's diabetes.
Speaker Change #116: We should understand we evaluate not only shift a minute, but competitor compounds as well as our next generation.
Speaker Change #116: <unk> compounds in our portfolio. So we try to get a holistic picture and for example, ingest as if though is is uniquely active ingest and we think in part due to its tissue penetrance.
Speaker Change #116: In diabetes, it's also seems to be extremely active.
Speaker Change #116: Francis Burrows, who is not with us on the call who is our who is our senior Vice President of translational research. He characterized as if Doe as it hits man and as hard as you can hit it.
Speaker Change #116: It provides very potent knockdown, it's a man integrator, which is a property that is shared by some of the other compounds not all.
Speaker Change #118: We're not.
Speaker Change #118: I think we can actually say, we probably don't have to hit men quite as hard as one hits it with leukemia in order to.
Speaker Change #118: To drive the sort of pharmacology that youre seeing in the diabetes models that we showed at the Ada meeting in June as.
Speaker Change #118: As we think about the properties of the Nexgen compound.
Speaker Change #118: Yeah.
Speaker Change #118: 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 diabetic patients that's not to take anything away, but the hurdle for safety and Tolerability is much higher so youre going to see us.
Speaker Change #118: Put a real emphasis on not only activity in the appropriate animal models, but really trying to create as larger therapeutic window is as we can the other interesting thing and we benchmark. This against other compounds that you may be aware of what we see with Ziff Doe is.
Speaker Change #118: When you when you add Ziff Doe it takes several weeks for the activity to kick in when you remove ziff, though it takes several weeks for the activity to decay.
Speaker Change #119: Does that makes sense, yes. 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 Menon, and so we're going to want to make sure we understand.
Speaker Change #119: And that as well the final thing I'll say is 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.
Speaker Change #119: Again looking forward to nominating the probably the first compound maybe 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.
Speaker Change #120: Yes, yes, thank you very very helpful.
Speaker Change #121: Color there and just your current cash runway estimate.
Speaker Change #120: Early.
Speaker Change #120: Clinical work early phase one work in diabetes.
Speaker Change #120: We will enter the clinic.
Speaker Change #122: Yes, let me ask Tom actually if he can speak to that question.
Tom Doyle: Thank you it does our cash runway does include the next generation work in diabetes.
Speaker Change #123: Great. Thank you so much.
Speaker Change #124: Thank you and it appears Dr. Wilson, we have no further questions today I would like to turn the conference back to you Sir for any closing comments.
Troy Wilson: Thank you Bo and thank you all once again for joining our call today.
Troy Wilson: We'll be participating across the pond 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.
Troy Wilson: You all again and have a good evening everyone.
Speaker Change #125: Thank you Dr. Wilson again, ladies and gentlemen that will conclude the cure oncology third quarter financial results call again. Thank you so much for joining us and we wish you all a great evening Goodbye.
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