Q3 2022 Kura Oncology Inc Earnings Call

Speaker 1: improved anti-tumor activity relative to inhibition of either target alone. The initial cohort of the current head and neck study is comprised of patients with PIK3CA-dependent HNSCC. In August , we announced the first patient dosed in a second cohort comprised of patients with HRAS overexpression. Last week at the EORTC NCI AACR Molecular Targets and Cancer Therapeutics Symposium in Barcelona, we reported the first demonstration that the combination of tififarnab and alpelosib

Speaker 1: can induce a durable clinical response in a PIK3CA-dependent HNSCC. A patient with stage 3 squamous cell carcinoma of the tonsil with a PIK3CA mutation and HRS overexpression has achieved a durable partial remission in current HN. The 35-year-old patient enrolled in the study after failing two prior treatments and experienced an 81% reduction in target lesions after just one cycle of tippy farnebin delpelosib.

Speaker 1: followed by an 84% reduction after three cycles. The patient continues on study for more than 27 weeks as of last week's presentation. Treatment-related adverse events in current HN have been consistent with the known safety profiles of each drug and are manageable with no dose limiting toxicities reported to date.

Speaker 1: Our team is now working to identify a recommended phase two dose and schedule for the combination with a goal of determining the optimum biologically active dose for the PIK3CA cohort in mid-2023.

Speaker 1: Meanwhile, we've continued our efforts to demonstrate the potential for tippy farnum to drive durable responses as a monotherapy in recurrent and metastatic HRS mutant, HNSCC, through our AMHN registration-directed trial. Although we continue to observe evidence of meaningful clinical activity in patients enrolled with AMHN, we've elected to close the trial to further enrollment due to significant feasibility challenges. We're currently evaluating the best way to harvest and use the clinical data.

Speaker 1: from runHN, which formed the basis of our breakthrough therapy designation, along with the data from aimHN to inform future development of the program. We'd like to take this opportunity to thank the patients, investigators, and study teams who have participated in the aimHN study. It's important to note that given the significant overlap between patients with HRAAS overexpression and HRAAS mutation, HRAAS mutant HNSCC patients in the United States...

Speaker 1: may be eligible to enroll in the ongoing current HN study. Beyond HNSCC, we continue to elucidate the roles of FTIs in preventing or delaying the emergence of resistance for certain classes of targeted therapy with potential to drive deeper and more durable responses in large solid tumor indications.

Speaker 1: One of these emerging combination opportunities was unveiled earlier this year at the American Association for Cancer Research annual meeting. The preclinical data generated through a collaboration with NSIRM support the potential of TIPIFARNIB to prevent emergence of resistance to osimertinib and other potent EGFR inhibitors. Motivated by this significant opportunity, we've initiated a phase 1 study of TIPIFARNIB in combination with osimertinib in EGFR mutant non-small cell lung cancer.

Speaker 1: and expect to dose the first patient later this quarter. We intend to perform initial clinical evaluation of TIPIFARNA-binosimertinib to gather valuable experience and data while in parallel advancing KO2806, the lead development candidate in our next-generation FTI program through IND-enabling studies. Last week at the triple meeting, our collaborators at NSIRM presented a follow-up poster which extended their findings from EGFR to other oncogenic drivers. Thank you.

Speaker 1: a copy of the poster is available on the CURA website. Based on these recent findings, as well as our own internal translational research efforts, we continue to investigate combinations of FDIs with other potent targeted therapies in preclinical studies.

Speaker 1: We intend to evaluate KO 2806 in several of these combinations and we remain on track to submit an investigational new drug application for KO 2806 later this quarter. With that I'll now turn the call over to Tom Doyle for a discussion of our financial results.

Speaker 2: Thank you, Troy, and good morning, everyone. I'm happy to provide a brief overview of our financial results for the third quarter of 2022.

Speaker 2: Research and development expenses for the third quarter of 2022 were $25 million compared to $22.4 million for the third quarter of 2021. The increase in R&D expenses was primarily due to the increases in personnel cost and Discovery Stage programs.

Speaker 2: General and administrative expenses for the third quarter of 2022 were $11.6 million compared to $11.3 million for the third quarter of 2021.

Speaker 2: The increase in G&A expenses was primarily due to increases in personnel costs.

Speaker 2: Net loss for the third quarter of 2022 was $35.5 million compared to a net loss of $33.4 million for the third quarter of 2021.

Speaker 2: As of September 30, 2022, we had cash, cash equivalent, and short-term investments of $427.8 million compared to $518 million as of December 31, 2021.

Speaker 2: As adjusted for the $25 million equity investment from Bristol-Myers Squibb and the $10 million initial draw from the Hercules Loan Facility, Cura had, on a pro forma basis, $462.8 million in cash, cash equivalent, and short-term investments as of September 30, 2022.

Speaker 2: We believe that our cash, cash equivalents, and short-term investments, plus cash from our terminal facility from Hercules, if fully drawn, will be sufficient to fund our current operating plan into 2026, placing us in a position to deliver meaningful value inflection from each of our three programs.

Speaker 2: With that, I now turn the call back over to Troy. Thank you, Tom.

Speaker 1: Before we jump into the question and answer session, let me lay out our anticipated milestones for the remainder of 2022 and the first half of 2023. For Zifto Manib, oral presentation of the Phase 1 data from Comet 001 at ASH in December .

Speaker 1: and initiation of the phase two registration directed portion of COMET001 and a phase one combination study in frontline and relapsed refractory AML in the first half of 2023, pending FDA review of the recommended phase two dose and protocol.

Speaker 1: For tibifarnib, the first patient dosed in the phase 1 current lung study in combination with osomertinib in the fourth quarter of 2022, and determination of the optimum biologically active dose, or OBAD, for the PIK3CA cohort in the phase 1 current head and neck study in combination with alpilosib in mid-2023. And for KO2806, submission of the IND application later this quarter. With that operator, we're now ready for questions.

Speaker 1: Ladies and gentlemen, if you would like to ask a question, please signal by pressing star one on your telephone keypad. Keep in mind if you are using a speakerphone, please make sure the mute is released so that signal can reach our equipment. Once again, for questions, star one. We'll pause for just a moment to assemble the cue.

Speaker 1: And we will begin first with Jonathan Chang with SVP Securities.

Speaker 3: Hi guys, good morning and thanks for taking my questions. First question on ZYFTO-MANiB, can you provide any color on the latest status of your regulatory interactions and then the next steps here?

Speaker 1: Sure, Jonathan, good morning and thank you. So at this point, the agency has everything that it needs from us. We're awaiting alignment with them on, as I indicated in the prepared remarks, the recommended phase two dose and the forward plan and protocol for the registration enabling portion of the study. We're on track. We're just in the holding period before the formal type C meeting. We have not yet.

Speaker 1: had our Type C meeting. It's upcoming. We're not giving specific guidance on the date of the meeting, but from our perspective, we're well prepared and everything's on track.

Speaker 3: Got it. And second question, can you give us any color on how we should be thinking about data in the full ASH presentation versus data coming up in the abstract this morning? And I guess the decision to include the preliminary data on the 18 additional patients in the full ASH presentation.

Speaker 4: Sure, so.

Speaker 1: Let's take those two questions. They're related, but let's take them separately. So the data that you'll see in the abstract, as I indicated in the prepared remarks, is data from the Phase 1a dose escalation portion, which was in all comers, and the initial 24 patients in the dose optimization portion of the Phase 1b. That's what's in the abstract, and that data is relatively immature. It's as of an early summer cutoff.

Speaker 1: It'll show you clearly, as we've indicated, we continued dosing at 600 milligrams. I think you'll see clear activity, clear definition around the only safety and tolerability is going to be differentiation syndrome. For the ASH presentation, Jonathan, that's gonna be a much more comprehensive update. There, we will have rolled those initial patients on.

Speaker 1: and included an additional 18 patients from the Phase 1B extension. What that gives us then is the initial 12 patients plus an additional 18 at the dose that we believe is going to be the recommended Phase 2 dose for the Phase 2 monotherapy registrational study. And as I've said in the past, our ability to use Ziftiminib both from an ability to drive clinical activity as well as our ability...

Speaker 1: And we were delighted that the conference organizers gave us an oral spot to be able to tell that story along with the investor meeting that will come immediately afterwards.

Speaker 3: Understood. Thank you. And just third question, if I may. Can you discuss the rationale and considerations around the BMS purchase agreement and loan agreement that was announced this morning?

Speaker 1: Sure, yeah, so we've been.

Speaker 1: We've been actively engaged in discussions with

Speaker 1: with large pharma about our programs for quite some time now. And there's a significant amount of interest in both programs. Obviously, we have an upcoming data inflection point with Zipto Manabed-Ash. We have been in discussions with our colleagues at BMS for some time now. They indicated a desire to draw closer. And as we fleshed out what that would look like, we didn't feel it was an appropriate time yet to.

Speaker 1: to potentially partner, but we did really like the idea of bringing, you know,

Speaker 1: we've got really sophisticated expertise on the BMS side in both solid tumors and liquid tumors and bringing that into our what is essentially our global steering committee, not a governance body, but an advisory body allows us to make we think better decisions. And so what it does, Jonathan, is it it, you know, it further strengthens the relationship between between Cura and BMS.

Speaker 1: We were very clear, and as I said again in the prepared remarks, we maintain full ownership of the programs, we maintain full control, but it really allows us to continue to deepen that relationship. The reason for the BMS investment and then putting the facility in place is we're looking at making investments across the portfolio. In Zift Omenib, we talked about it, the registrational study, we've got an extensive program planned in combinations. It's clusters of these things, the

Speaker 1: We have the current HN study ongoing. We're gonna be moving 2806 very shortly into phase one with an expansive combination strategy behind that. And we wanted to give ourselves the flexibility to be able to make development decisions that we think can create value for patients and ultimately shareholders. And to do that, we wanna be obviously at all times in the very strongest position. So, we run the company pretty conservatively. We've said that consistently. This gives us...

Speaker 1: cash into 2026 and yet it allows us to fully fund everything we've just walked through across those three different pillars of the business. It was a good time, we thought, with the engagement with BMS, it was a good time to make sure we could shore up the company's capital resources as we look into 2023.

Speaker 3: Understood. Thanks for taking my questions.

Speaker 5: Pleasure, thank you John .

Speaker 5: We'll now hear from Peter Lawson with Barclays. Please go ahead.

Speaker 6: Thanks for taking my questions. Troy, I don't know how much you can say, but this type C meeting with the FDA, is that a year-end event, a 2022 event, and then on the Brisbane... Yeah.

Speaker 7: Of.

Speaker 6: financing did they see all the men in data so what we see at the Ash oral presentation for instance

Speaker 1: Yeah, Peter, two good questions and I think top of mind for a lot of folks. While not being specific as to the date, I can tell you it is our goal to try to have all of this wrapped up by Ash. So, it we're not, you know, again.

Speaker 1: Part of the reason we've been guarded about the FDA engagement is, we're one of the first companies through Project Optimus and the FDA is going to make its own determination, but we think we're in a very strong position. If things go as we hope they will, we should have everything we need by ASH. That would be our goal. I can't be more specific than that, but it's not clear.

Speaker 1: from a timing perspective, and right now it's just, we're just literally waiting for the calendar. We're not expecting that we would move into 2023. We'd be able to give you an updated dash. As far as what did BMS see, you can assume that BMS saw a comprehensive data set, including both the rationale for the recommended phase two dose, as well as the full data set, which will be...

Speaker 1: profile that ash. Yes, you can assume that they saw that.

Speaker 3: Yes, you can assume that they saw that. Great, thank you so much. Thanks for the...

Speaker 8: Thank you.

Speaker 1: Our pleasure. Thank you, Peter.

Speaker 5: Next question will come from Roger Song with Jeffries.

Speaker 9: Great. Thank you for taking the question. Congrats for that.

Speaker 9: for the update. So a couple of comments, I understand you won't have the, won't be able to talk about the real data, but just the high level, given you have been guided this efficacy is as good, if not better, being a competitor and we also know,

Speaker 9: index will have updated data at ASH as well. Just curious your comments around this guidance for both abstract and the presentation and particularly how do you anticipate your competitor data at ASH as well.

Speaker 1: Yeah, Roger, I want to be careful, particularly within an hour or so of abstracts dropping, not to comment too much on our competitors' data. Let's let their data speak for themselves. With regard to our data, I think the most important point will be...

Speaker 1: The point that I made about, at ASH, you'll see N equals, you know, potentially N equals 30 patients at the recommended phase two dose. As the trial has gone on, you know, initially we started with, by seeing a higher percentage of KMT2A patients in the trial versus NPM1, relative to the epidemiology that we would have expected. As the trial has gone on, that has tilted...

Speaker 1: such that we've seen an enrichment in NPM-1 as we've moved from early in the 1B on into sort of later in the 1B. And I think in particular, again, I'll reiterate what I've said. The goal for registration is a 20 to 30% CRCR rate, four to six months median duration of response, transfusion independence as a key secondary endpoint. What we'll show you, I think, is a comprehensive data set at what we believe and what we have proposed is a comprehensive data set

Speaker 1: you know, we're really directing people toward the full data presentation at ASH. I think our data set, Roger, will be, as I've said before, I would challenge anyone else to put out as much data at their recommended phase two dose as we intend to. I think Zipto-Menop will, you know, we hope will look good in that context, in the context of a comprehensive data presentation.

Speaker 1: It'll look good in the abstract as well, I think, but obviously as the numbers go up, as the denominator increases, your confidence that you're going to translate into a registration study goes up as well.

Speaker 9: That's great. Thanks for the comment. And I think you raised a point in terms of the genotype kind of between the KMT2A and the MPM1. Maybe question is, do you see the consistent efficacy between those two genotypes and how does that compare to the current therapy given you may start to see some different...

Speaker 9: CRH and the implication for this is would FDA will require different null hypothesis for those two genotypes for the registration trial.

Speaker 1: Yeah, it's a good question. So let me take your question in reverse, your questions in reverse. To the best of our understanding, the FDA can use, you know, perhaps not identical, but a very similar null hypothesis in the two genotypes. And we've given a range of 10 to 15% CRCRH. That's probably even being a bit, you know, a bit generous. But the reason for that, Roger, is there's no effective therapy.

Speaker 1: for either of these two genotypes in the relapse refractory setting. So then if you're looking for a CR CRH rate that is 20 to 30 percent, that gives you adequate powering to be able to detect the difference between the sample population and the null hypothesis so that you can distinguish the two. In a monotherapy study, you wouldn't expect those designs to look substantially different. In our experience, and we've commented on this along the way, the dose is the same for the two populations.

Speaker 1: Now, we've developed strategies to mitigate that, first of all, to detect it, to see it coming, and then to mitigate it, and we'll talk about that at ASH. I don't think we're gonna talk, it's not in the context of the abstract, you won't see it there, but you will see it. You will see our strategies both in monotherapy, Roger, as well as in combination therapy at ASH.

Speaker 9: Excellent. Thanks for the. Extensive comment on those 2 questions. I appreciate that. That's all from us.

Speaker 2: Our pleasure, happy to do it.

Speaker 5: Our next question will come from Lee Wozzeck with Kentar Fitzgerald.

Speaker 10: Hi, good morning. Thank you for taking my questions Troy. It was just 1st on data update. Can you give us a sense of maybe the medium follow up for the 24 patients and those 18 additional patients. And then, you know, in terms of the combination trials, and can you sort of talk about how quickly you may be able to move into the clinic in, you know, 1st, half of next year in both the refractory.

Speaker 1: dosing and the phase 1b dose optimization, we announced that on our May earnings call. This abstract is as of an early summer data cut. For the additional 18 patients, those patients were dosed between May and August . And we have a number of patients on study. You can just kind of roll it forward. We're still at a point, I mean we have a significant phase 1 study here.

Speaker 1: when you look at the 1A, the 1B optimization, and the 1B extension. But that being said, it's still a phase one study. So I think the duration of response is still kind of coming into view. It's going to be an evolving number as patients stay on study. What I can tell you is we're not, we're I would say optimistic, somewhere between optimistic and confident. I want to be careful which word I choose.

Speaker 1: that that four to six months median duration of responses is achievable with ZYFTOMEDM, right? We're not seeing any warning signs that tell us that patients are rolling off. To the contrary, when we see responses, they're typically pretty durable in duration. But we're still talking about an anecdotal number of patients. In terms of starting the trials, that was your second question. If we get the green light from the agency here in the fourth quarter, you're really looking at three to four months before you probably dose the first patient.

Speaker 1: We have a great team, they're doing everything they can at risk to position the sites to be ready to go. But just to set expectations, that's why we're guiding to sort of first half of 2023. And then the final question on the competition, you know, there's no question, at least if we talk about about Syndex, there's no question we're behind. And I've said this before, I think ZYFTO menib potentially represents the most potent, cleanest.

Speaker 1: most combinable menin inhibitor that we have thus seen clinical data for. We will do everything we can to catch up, but as we've seen with KRAS, as we've seen with other agents where ultimately you're going to end up in combination, what matters is who can get to the combinations, who can drive the best activity with the best safety. And I think what you'll see at ASH is...

Speaker 1: Zifto men have very well positioned in that regard. So we'll do everything we can to catch up to syndex and to stay abreast or ahead of our competitors. But at the end of the day, the best date is gonna win. And I hear people get agitated about this and they're not really following history. Look at the KRAS story, look at how that's rolling out. Like history just keeps repeating itself with these targeted therapies. Men and inhibitors, yes, they show remarkable activity as monotherapy.

Speaker 1: But if you want to offer patients the promise of a long-term durable remission, you want to put them into some form of combo, whether it's Venetoclax, whether it's chemo, that's going to really give them the best chance for something approximating a cure. And I think you'll see where, I think Ziptiminib stacks up very nicely in that regard.

Speaker 10: Okay, great. Maybe just a quick question on TP, I guess, model therapy. Can you just give us a sense of how many patients that you've been role so far and what proportion of those patients that you can potentially, I guess, enroll into the current action study.

Speaker 1: Yeah, so we're not being specific. Lee. It's a good question and we're being a little bit vague in terms of what we're doing.

Speaker 1: We do see compelling activity in the AMHN study. The challenge, as we've been clear with folks, is it's a rare population and the vast majority of patients with HRAZ mutations are too sick to even enroll in the trial. So we face significant feasibility challenges, but it's about enrollment. It's not about either safety or activity of the drug. We've enrolled a significant number of patients, significant enough that we can confidently say we're seeing.

Speaker 1: can to harvest that data. We've got a strong run HN data set, and we're going to see if there are potentially paths forward from a development and regulatory perspective. I don't want to say too much because I don't want to set expectations inappropriately. But our team is focused and knows what they have to do. And if and when it's appropriate, we'll come back to you with more information on the path forward for the monotherapy. You raise an important point, and that is,

Speaker 1: We were really pleased to see the patient who was profiled at the triple meeting. I can tell you our experiences given that

Speaker 1: Excuse me, given that.

Speaker 1: PIK3CA dysregulation is a mechanism of resistance to patients with H-RAS mutations. The combination is a logical next step.

Speaker 1: Current HN is actually enrolling very nicely. Not surprisingly, you significantly expand the patient population, you're going to drive enrollment. We want to make sure that these patients have, particularly those in the U.S., have a place to go. And there's about an 80% overlap lead between HRAAS overexpression and HRAAS mutation. So it's our hope that for patients who have HRAAS mutations, if they also qualify for overexpression, they will be eligible potentially to be included in the current HN study.

Speaker 1: Because ultimately, you know, the way we win as you put patients first, you have to be a good fiduciary, but we're trying to be very responsible and make sure that we can find a way to provide these patients appropriate care.

Speaker 8: Thank you so much.

Speaker 7: My pleasure.

Speaker 5: Tiago Fox with Credit Suisse has the next question.

Speaker 2: Just a quick follow-up from you on ZYTO. So, as you look at the mix of patients between NPM1 mutant or KM2 to a range, there's still some skepticism of the feasibility or the amount of patients on the NPM1 bucket, which would be potentially a little bit bigger. But it sounds like you're actually seeing a relatively healthy mix. Like, what are the implications for that on building registration cohorts? We still get some questions around the commercial opportunities there. So it'd be good to get any color.

Speaker 1: but let's not get too far ahead of the data. But we feel confident in the feasibility of enrolling an NPM-1 mutant cohort. We also feel confident that we're seeing a favorable benefit risk for the patients. And again, you'll get a glimpse of this in the abstract. It's definitely going in the right direction. It's encouraging. You'll get a much more comprehensive update with those N equals 30 denominator patients at ASH.

Speaker 7: Thanks for taking the question.

Speaker 7: Thanks for taking the question. Sure.

Speaker 5: Moving on to Phil Nadeau with Cowen.

Speaker 2: Good morning. Congrats on the progress. Thanks for taking our questions. We have two on ZIFTO and then one follow-up on AMHN. First on ZIFTO, we're curious about the Type C meeting. Why do you feel a Type C meeting is necessary? Had you always expected to have one? It seems like...

Speaker 2: to sign off on a phase two dose in a protocol, maybe a meeting wouldn't have been necessary. And then second on the DS, sounds like you're basically suggesting that the DS is gonna look better at ASH than maybe where we see the abstract. And you've given, I think, two reasons why that could be. One is better management, and the other is different patient mix with more NPM1 patients.

Speaker 2: what would be the relative contribution in your mind to the improving DS rates that you're seeing over time.

Speaker 1: Yeah, Phil, thanks for the two questions. So on the DS, you know, DS is an on-mechanism effect, it's an on-mechanism adverse event, obviously. Our ability to detect it, to see it coming, has greatly improved in terms of looking at inflammatory markers. And these were measures that we put in place as we came off clinical hold. Those measures have been.

Speaker 1: effective, and it also, you know, the physicians, I think, have gotten more comfortable with their ability to manage differentiation syndrome. The differentiation syndrome is qualitatively different between the two genotypes. The NPM1 is more, in our minds, what people would characterize typical DS with other targeted therapies. The KMT2A is a bit of a different animal, and as I said, we think that's really due to two reasons.

Speaker 1: One is the nature of the disease and the second is the nature of Zifdomenin. Zifdomenin in our experience is highly tissue-penetrant. It really is able to get into all of the, I call it the nooks and crannies of the patients and find those tumor cells in the tissue, in the lymphatic system, in the joints. And ultimately the reason that may be important is...

Speaker 1: If patients are relapsing, often they may be relapsing because there's residual AML hiding in their tissue. So that has implications for treatment. I think it's improving, Phil, frankly, because our ability to detect it and manage it has improved over time. With respect to your question about the FDA meeting, so we had a meeting with the agency for the 30- America Fair today. I think, after bloom, there hasn't been as much controversy throughout theUSB. So we came up with the P library as a deaf and hearingStar. It has enriching streams and graphically applied Spiegel's TH stained fragment and sustainability across this conference.

Speaker 1: to discuss the phase 1b dose optimization. The agency considered that a type B meeting, our one type B meeting for an end of phase one. So by default, if we were going to request a meeting, it was going to be a type C meeting. We specifically requested a type C meeting for the reason that if we don't, there really isn't any timeframe that the agency has to get back to us. A type C meeting is a very, as people may know, it's a bounded...

Speaker 1: you know, choreographed engagement with the agency. You schedule a meeting in advance, you provide a briefing book, you know, typically the agency responds to the questions you've posed. So we did it really, Phil, to ensure that we would get questions on both the recommended phase 2 dose and the protocol in a timely manner. And I'll just remind people, because people really focus on the RP2D, it's not just the RP2D.

Speaker 1: Yes, that's important. It's probably one of the more important elements for moving forward, but this is our last opportunity before we have a pre-NDA meeting to engage with the agency, with the exception of maybe getting breakthrough therapy designation or something like that. You want to make sure you've got all your ducks in a row. Does the agency agree with you on the statistical plan? Do they agree with you on the companion diagnostics? We want to make sure that the agency is fully aligned with us.

Speaker 1: on the design and execution of the phase two trial, because after that it's go, you know, go, go, go. So this is really serving a dual purpose of closing out the very productive exercise on Project Optimus and then making sure that we have alignment from the various directorates within the FDA on the design and execution of the phase two monotherapy study, and then that rolls forward into the combination studies and so forth. So that's the reason for the type C.

Speaker 1: And, you know, the agency wants to help sponsors. So, we, you know, they have been very good partners throughout the process of development of ZiptomeneB. They were extremely helpful in helping us get the program off clinical hold. And we're very much looking forward to wrapping this phase of it up and moving on into phase two.

Speaker 2: That's very helpful. And then just last follow-up question on AMHN. Do you think there's sufficient power, given the number of patients that you've enrolled or a sufficient number of patients enrolled for meaningful power on the trial's endpoint? Is it possible that you could unblind the data and we actually get a positive result that supports violin?

Speaker 1: Yeah, I want to, and I, so the short answer, the short answer to your question, Phil, is we wouldn't have phrased it as spending time harvesting the data for AIM and RUN if we didn't feel that there was potentially a path forward. didn't feel that there was potentially a path forward. Because of, you know, obvious, there are development and regulatory to kind of stay behind the curtain to kind of stay behind the curtain, I don't want to say too much. But, you know,

Speaker 1: And I also want to be careful. I mean, we did close a trial prior to completion of enrollment for lack of feasibility. So I would say it's challenging, but potentially there's a way to harvest that data and let us, we have some more work we need to do. Let us come back to you likely next year with some more information. Our team is working internally.

Speaker 1: And I'll have more to say. I appreciate that may be a little bit unsatisfying, but because of the strong signal we saw in RUN, because of the meaningful clinical activity we've seen in AIM, you know, potentially there's a way to harvest this data for patients. And that's really ultimately going to be our number one goal.

Speaker 2: That's helpful. Thanks again for taking our questions.

Speaker 7: Sure, our pleasure.

Speaker 5: And once again ladies and gentlemen for question star one we'll now move to Ren Benjamin with JMP Securities.

Speaker 2: Hey, good morning guys. Thanks for taking the questions and congrats on the progress. I thought that the confirmatory trial design was more or less largely agreed upon with the FDA in the past. I think you had given parameters around what the confirmatory study could look like. Am I remembering that right? And I mean, has there been any changes to those parameters that you had originally spelled out?

Speaker 1: I'm sorry, Ren, the confirmatory study for which study are we talking about? For ZIFTO. Oh, for ZIFTO. I remember. No. Yes.

Speaker 1: Yeah, yeah, yeah, yeah. So no, no, no.

Speaker 1: So if I left folks with that impression, then that was my error. So what we gained alignment from in the meeting where we discussed and agreed upon the phase 1B dose optimization was that we would use endpoints in the phase 1B optimization that were consistent with endpoints that would be used in a registration enabling study. And that's exactly what we've done. And that's why I say, you know, I keep saying it over.

Speaker 1: you know, to the question that Phil asked previously, you can always send your protocol to the agency, but the agency is not obligated to respond to you in 30 days. So if you really want to make sure that you're pushing timelines, it's important to go through the formal process and schedule the meeting. And this is probably the most significant interaction, you know, on this program. And so we really also wanna get the FDA's buy-in and make sure we do it right.

Speaker 1: because the decisions that we've made that we're recommending to the FDA, they set the foundation for every future study, not only the dose, but how we're handling DS, what we're seeing. The agency will look back on this Phase 1 data package as foundational for the future development of Ziftim-NEP. It's just good practice for sponsors to take time. If the FDA is willing to engage with you, take the time and do it. In my experience, having done this for a while...

Speaker 1: It might take you a month or two longer, but you may save yourself considerable pain and heartache down the road. So it's good to get the FDA's buy-in and that's exactly what our team is doing.

Speaker 2: Got it. Just switching gears to current HN. Can you talk or provide a little bit more color on this patient with a durable response? How do you, you know, have you evaluated or is there a way to evaluate the relative contribution of...

Speaker 7: of TIPI versus Appellasib, you know, just any additional data.

Speaker 1: Yeah, it's a good question, Ren, and the short answer is no. It is anecdotal. I think the reasons that we are encouraged, we are encouraged first and foremost because we have been able to combine tififarne and nalpelosib in a heavily pretreated population with thus far, it's manageable safety. is — but the main purpose of this is automatically to Bye-bye and to THAT the individual, not only to all!

Speaker 1: and expected adverse events. We're not seeing overlapping or cumulative toxicity. That was a big question mark. We shouldn't skip over that. Most of the time that people have tried to combine inhibitors of the MAP kinase pathway with inhibitors of the pH-3 kinase pathway, they found it's nearly impossible to combine because of the overlapping toxicity. Hitting farnesyl transferase is not the same as hitting a MAP kinase pathway target, in our experience.

Speaker 1: So that's encouraging. We are seeing evidence of sort of clinical activity, clinical benefit in other patients. We're right in the midst of dose optimization. And as we indicated in the poster, one of the challenges we have to address is the hyperglycemia that is induced by Alpelosib. It's well-known, it's seen in their labeled indication of breast cancer, but there are a number of mitigating steps that one can take that we really haven't done yet.

Speaker 1: Those include potentially scheduled changes using rapid onset anti-hyperglycemic, you know, those sorts of things. I think this, you know, the good news is we're seeing sort of as one of our physicians in the company says we're seeing green shoots of activity. We just have work to do on dose optimization to see if we can identify an optimal biologically active dose that gives us a response rate.

Speaker 1: that gives us a path forward then into registration of the combo. At that point, Ren, then I think we can do the proper study that identifies the individual contribution of the two components. But on a patient-by-patient basis, it's really... That's sort of too big an ask. Got it. And then just finally for us with 2806, how are you guys going to go about selecting the ideal...

Speaker 7: indications, let alone the ideal combinations to initially evaluate. And I remember we've talked in the past about a biomarker program, either within Corel or just that you guys continue to evaluate that. Is that still kind of moving forward and is that being used?

Speaker 1: Yeah, so two questions there, Ren, and let me answer them both and then peel them apart slightly. So, in terms of identifying the optimal biologically active dose for 2806, we will do that in a biomarker-selected population consistent with Project Optimus. You'll look at PK and exposure, you'll look at pharmacodynamics, you'll look at safety and tolerability, and you'll look at any evidence of clinical activity.

Speaker 1: that the FDA has been super clear about that, and we're going to make sure that we follow their guidance as they're expecting every sponsor to do. For your second question, it actually gets easier because we're positioning 2806 as an ideal combination agent for certain classes of targeted therapies. And let's just take the two that are visible to you right now. They are EGFR inhibitors and PS3-kinase alpha inhibitors.

Speaker 1: The good news, Ren, is we know those populations, right? You can look for T790M mutant. You can potentially look for exon 20 mutant. You can look for PI3 kinase alpha mutant. If you look at the InSIRM poster, they have preclinical data that suggests the same synergy, the same ability of FTIs to blunt adaptive resistance also exists with ALK, with BRAF, and potentially with KRAS. Again, we know what those markers are. So as soon as we're able to determine the...

Speaker 1: It makes that aspect of the development easier. And you can imagine a phase one that goes from a rapid monotherapy then into multiple combination cohorts.

Speaker 11: Great, thanks for taking the questions.

Speaker 12: Our pleasure.

Speaker 5: And ladies and gentlemen, this will conclude your question and answer session. I'll turn the call back to Tory Wilson for closing remarks.

Speaker 1: Great. Thank you, operator. Thank you all once again for joining our call today. We'll be participating in the Credit Suisse healthcare conference next week, and we look forward to seeing many of you there. In the meantime, if you have any additional questions, please feel free to contact Pete, Troy, or me. Have a good day, everyone. Thank you.

Speaker 5: And ladies and gentlemen, this does conclude your conference for today. We do thank you for your participation and you may now disconnect.

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No ly will main tain fourll owner ship and conro of our progrs and oations. We have very preciiated engagagement and Fe from our M's colleag were leaders in the disco development of trans formation ANS treatments. Equity investment strengthens the relation ship between ororg an ization and proves with C per T pleas to have the comfidence of the B M's working with deli innoate ence with the potential to benef patiations. The morning we also announced to term one facility for her capitalal proving loan proceed to one hundred 20, fivemillion dollars. one million doll will D immediate after cloing has a long three of investing in novated noleglogy company and we are great FUL for their courort. 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Meanwhile we eight Fe back F D a on the recommended Phase two dose if, as well as the protocall for the Phase two registration directed portion of comment zero zero 1, we also intend to itiate studies of if end in combination with stand care in earli L of therapy in a M patationations. We have designed Phase one studies to the Fe ll ability and therappeut activity of end in combination with regimments including clos, CED three inhibtors and the combination of 7, three very exced about the tential combination studies to further on law the valueof for patients. The we icip, ated initiate, initiated the Phase two registration direct ort of comment zero zero one and the first in a C IES Phase one combinationations studies in fron line and re fract a M L in the first half of 20 20, three pending F D a revie of our recommended Phase two dose protocols. The continue to have strong conviction in end and tential to be vest class inhiitor, our combidence supported by a? 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We end to pro Form initial clin evaluation of to valueuable experi and data law per Van ING K 20, eight o, six the lead development ATE in our next generation F program, the enabable studies. Last we the triple meeting. Our co aborators presented a follow POS which exended their finding G to other driersars. Com of the St ailable, the Webs Ed. These recent ING well as our own Al translation research efforts continue to investigateeight combination of F? D with other T target therapies in pre clinical studies. We intend to evalueuateeight twentyeight o six in sever of bination. We remain on tract to submit and investigation new ug application for o? Y eight o six later. This courarter that the call to M? Il discussion of our financial resul? morningy everyy one to over vie pri? cial results. For the third quarter of two thousand: andtwent: Y two research development expenses: the third quarter of two thousand and 22 2, 25 mill compared two 2, 22 point four million dollars. For the third quarter of two thousand and 20. the increase expenses: primar ly two to the increases personal co and disco state programs general. The ministrated expens: third quarter two thousand and 2, 22 point six million dollars compared point three million dollars. The third quarter of two thousand and 20. the increase G expenses: priimar two increases, personal cos laws for the third quarter of two thousand twent 2, thirtwenty five point five million dollars ared to laws: 20, three point four million dollars. For the third quarter of two thousand, 20 as 30, two thousand 22 cash cash quival term investments of four hundred 2, twent point eight million dollars. five hundred, eight million dollars as of the subber 20 first, two thousand and 20. as just for the 2, 25 million dollar investment from and the one million ititional raw from the facility four of for hundred sixtyy two point eight million dollars cash ort ter investment as 30, two thousand and 22. we lead our cash cash quivalence ort term investments plus C from term facility fully D will be office Ion to current pery in two thousand twent six place ING position value leion from eight of three programs with Thank before we to the Ion and ANS session out or ated mil St for the remain two thousand, 22 and the first half of two thousand and 20, three for if end oral presentationof thepe one data from comment zero zero one in cember and initiation of Phase two registration directpected portion of comment zero zero one and hase one combination stud in line and re? 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