Kura Oncology Q2 2023 Earnings Call Transcript

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August 3, 2023

Key Takeaways

  • COMET-1 Trial Update: At 600 mg ziftomenib achieved a 35% complete remission rate and 45% overall response rate in relapsed/refractory NPM1-mutant AML with a median response duration of 8.2 months.
  • Phase 2 Enrollment Momentum: The registration-directed trial in relapsed/refractory NPM1-mutant AML is ahead of projections and on track to enroll 85 patients across the US and Europe.
  • Expanding Combination Studies: COMET-7 (ziftomenib + venetoclax/azacitidine or 7+3) is dosing patients with preliminary data due Q4 2023/Q1 2024, alongside planned COMET-8 and post-transplant maintenance studies.
  • Tipifarnib + Alpelisib in HNSCC: The FTI/PI3Kα inhibitor combo shows no dose-limiting toxicities and early signs of enhanced activity versus expectations, with a Phase 2 expansion in PIK3CA-mutant head and neck cancer slated for mid-2024.
  • Financial Position: Q2 2023 R&D expenses rose to $28.2 m and G&A to $11.8 m, net loss was $37.2 m, and $477 m cash runway supports operations through mid-2026.
AI Generated. May Contain Errors.
Earnings Conference Call
Kura Oncology Q2 2023
00:00 / 00:00

There are 11 speakers on the call.

Operator

Good afternoon, ladies and gentlemen, and welcome to the Q2 2023 CURA Oncology, Inc. Earnings Conference Call. At this time, all lines are in listen only mode. And following the presentation, we will conduct a question and answer session. This call is being recorded on Thursday, August 3rd, 2023.

Operator

I would now like to turn the conference call over to Mr. Pete Duisbaine, Head of Investor Relations. Please go ahead.

Speaker 1

Thank you, Kelsey. Good afternoon, and welcome to Kura Oncology's Q2 2023 conference call. Joining me on the call are Doctor. Troy Wilson, our President and Chief Executive Officer and Tom Doyle, our Senior Vice President of Finance and Accounting. Before I turn the call over to Doctor.

Speaker 1

Wilson, I'd like to remind you that today's call will include forward looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Cura's filings with the SEC, which are available from the SEC or on the Cura Oncology website for information concerning risk factors that could affect the company. With that, I'll now turn

Speaker 2

the call over to Troy. Thank you, Pete, and thank you all for joining us this afternoon. Let's jump right in. In June, we reported updated data from the COMET-one trial of our menin inhibitors at Dementin, including durable activity in patients These data were featured during a late breaking oral session at the European Hematology Association Annual Congress in Frankfurt. As of the April 12 data cut off, 7 of the 20 patients with NPM1 mutant AML who were treated at the recommended Phase 2 dose 600 milligrams achieved complete remission with full count recovery for a CR rate of 35% And an overall response rate of 45%.

Speaker 2

This represents one of the highest response rates reported for a targeted therapy in the setting of relapsed refractory leukemia. An aged patient who had a CR with partial count recovery after treatment with ziptamenib Subsequently evolved to a CR with full count recovery after transplant and remained unsteady as of the date of the EHA presentation. In addition, a patient with NPM1 mutant AML treated at 200 milligrams remained on ZYPTO MEDENT for 36 cycles as of the cutoff date. The median duration of response for all NPM1 mutant patients was 8.2 months with a median follow-up of 8.8 months. Continuous once daily dosing of ziptomenon was well tolerated in the Phase 1 study and the reported adverse event profile remains consistent with features of underlying annually and represents a disease of significant unmet need for which no approved targeted therapy exists.

Speaker 2

Once the disease becomes relapsed or refractory, the prognosis for NPM1 mutant AML patients is especially poor. NPM1 mutant AML is further compounded with co mutations such as IDH and FLT3. Notably, in our Phase 1 study, 33 And IDH co mutations achieved a CR on ziptaometib, all of whom had failed prior treatment with IDH and or FLT3 inhibitors. We remain impressed with the ability of ZYPTO MENIB to drive durable remissions as a monotherapy in this difficult to treat population, We believe these data further demonstrate its potential best in class product profile. Building on momentum generated by our EHA data, Enrollment in our Phase 2 registration directed trial of ZYPTO MENET in patients with relapsedrefractory NPM1 mutant AML continues to outperform projections, which speaks to both the size of the population and its significant unmet need.

Speaker 2

Our study is expected to enroll a total of 85 patients in the United States and Europe. In parallel with our efforts to advance ziptaminibas monotherapy, We're conducting a series of studies in combination with current standards of care in earlier lines of therapy and across multiple patient populations, Including NPM1 mutant AML and KMT2A rearranged AML. Our approach to establish ziptumetiv as a foundational therapy that can be combined safely with various commonly used regimens And then prioritize those combinations that represent the greatest unmet medical need and the greatest potential commercial value, namely venetoclax and FLT3 inhibitor containing regimens. Combination approaches also offer the potential to mitigate differentiation syndrome, Particularly in the KMT2A rearranged population as has been previously demonstrated in the development of IDH inhibitors in combination with azacitidine. In that regard, I'm pleased to report we're now dosing patients in the first of our combination studies, which we call COMET 7 in both the newly diagnosed and relapsed refractory settings.

Speaker 2

COMET 7 is a Phase 1 study Designed to assess safety, tolerability and preliminary activity of ziptomenab in combination with either venetoclax and azacitidine or standard induction cytarabine donorubicin chemotherapy, commonly known as 7+3. The study is expected to enroll patients With NTM-one mutant or KMT2A rearranged AML across sites in the U. S. And Europe, We anticipate having preliminary data from the COMET-seven study in the Q4 of 2023 or the Q1 of 2024. We're also working to initiate our COMET-eight study of ziptaminib in combination with additional standards of care, including the FLT3 inhibitor gilterritinib later this year.

Speaker 2

In addition, we expect to begin our post transplant maintenance program for ziptomenab in the Q1 of 2024. We are very excited about the potential for these studies to further demonstrate the value of our menin program And established ziptomenab as a backbone of therapy across the continuum of care for AML patients. Now let's turn our attention to our farnesyltransferase inhibitor programs beginning with Tipifarnib. We continue to work to unlock the Substantial therapeutic and commercial value of farnesyltransferase inhibition and we believe this novel mechanism is uniquely positioned to deliver Clinical benefit in multiple large solid tumor indications. The first such opportunity is in head and neck squamous cell carcinoma Through the combination of tipifarnib and the PI3 kinase alpha selective inhibitor, alpelasib, Head and neck cancer is the 7th most common cancer worldwide and it remains a significant unmet medical need with no approved small molecule targeted therapies.

Speaker 2

The objective response rate for the 3 FDA approved therapies The treatment of HNSCC in the second line range from 13% to 16% with median progression free survival of 2 to 3 months And a median overall survival of just 5 to 8 months. Recall, we previously reported the first demonstration of a durable clinical response With the combination of tipifarnib and alpelasib in a patient with PIK3CA mutated squamous cell carcinoma of the tonsil. Since that time, our dose escalation study has continued with no dose limiting toxicities to date observed for the combination. We are encouraged both by the safety profile as well as the clinical activity we're seeing in the trial, which we call current HN With continued evidence of activity at multiple doses and enhanced activity relative to our expectations for either drug alone in this population, We are now evaluating patients in the study's highest planned dose cohort to help inform selection of the optimal biologically active dose for the combination. Once we determine the OBAD, we intend to initiate a small dose expansion of patients with PIK3CA mutant HNSCC to validate the safety profile and activity of the combination at the recommended Phase 2 dose.

Speaker 2

Meanwhile, we've generated a growing body of preclinical data that Supports the combination of farnesyltransferase inhibitors with multiple classes of targeted therapies to either prevent or delay Emergence of Drug Resistance in Large Solid Tumor Indications. In April, we presented encouraging preclinical data At the American Association For Cancer Research Annual Meeting, supporting the potential use of FTIs in combination with 2 additional distinct classes of targeted therapies. The first of 2 posters revealed robust synergy Between tipifarnib and the standard of care anti angiogenic tyrosine kinase inhibitor or TKI, axitinib in cell and patient derived xenograft models of clear cell renal cell carcinoma. The 2nd poster reported regression of multiple models of KRAS inhibitor resistant non small cell lung cancer by the addition of tipifarnib to either adagrasib or satorasib therapy. These promising preclinical data illustrate the potential for FTIs to drive enhanced antitumor activity and address mechanisms of innate and adaptive generation farnesyltransferase inhibitor, which we call KO-two thousand eight hundred and six with TKIs in clear cell renal cell carcinoma and with KRAS G12C specific mutant specific inhibitors in non small cell lung cancer.

Speaker 2

Earlier this year, we received FDA clearance of the investigational new drug application for KO-two thousand eight hundred and six for treatment of advanced solid tumors. We intend to evaluate the safety, tolerability and preliminary anti tumor activity of KO-two thousand eight hundred and six in a Phase 1 dose escalation study, which we're calling FIT-one, we've begun site activation in FIT-one and look forward to dosing the first patients in the study later this year. Concurrent with the dose escalation as a monotherapy, we plan to evaluate KO-two thousand eight hundred and six in dose escalation combination cohorts and advanced solid tumors beginning with clear cell renal cell carcinoma. With that, I'll now turn the call over to Tom for

Speaker 3

a discussion of our financial results. Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the Q2 2023. Research and development expenses for the Q2 of 2023 were $28,200,000 compared to $24,300,000 the Q2 of 2022. The increase in R and D expenses was primarily due to the increases in clinical trial cost related to our ziptomenab and KO-two thousand eight hundred and six programs.

Speaker 3

General and administrative Expenses for the Q2 of 2023 were $11,800,000 compared to $11,100,000 for the Q2 of 2022. Net loss for the Q2 of 2023 was $37,200,000 compared to a net loss of of $34,800,000 for the Q2 of 2022. This includes non cash share based compensation expense $7,000,000 compared to $6,500,000 for the same period in 2022. As of June 30, we had cash, cash equivalents and short term investments of $477,000,000 compared to $438,000,000 as of December 31, 2022. This includes net proceeds of approximately $94,000,000 from our public offering completed in June of 2023.

Speaker 3

We believe that our cash, cash equivalents and short term investments will be sufficient to fund our Current operating plan to mid-twenty 26. With that, I now turn the call back over to Troy.

Speaker 2

Thank you, Tom. Before we jump into the question and answer session, let me lay out our anticipated milestones for the remainder of this year and next year. For zipta menop, dosed the first patients in the COMET-eight combination trial in the second half of twenty twenty three, Preliminary data from the COMET-seven combination trial in the Q4 of 2023 or the Q1 of 2024 And dose the first patients in the post transplant maintenance program in the Q1 of 2024. For tipifarnib, Initiate dose expansion in the current HN trial in mid-twenty 24. And for KO-two thousand eight hundred and six, dose patients in the FIT-one dose escalation trial in combination with a targeted therapy in clear cell renal cell carcinoma in the second half of twenty twenty four.

Speaker 2

With that, Kelsey, we're now ready for questions.

Operator

Thank you. Ladies and gentlemen, we'll now begin the question and answer session. You will then hear a 3 tone prompt acknowledging your request and your questions will be pulled in the order that they are received. And your first question comes from Jonathan Chang from Leerink Partners. Please go ahead.

Speaker 4

Hi, guys. Thanks for taking my questions. First question, can you give us any more color around enrollment progress and the registration directed study of zifdomenib and NPM1 mutant AML? And what do you mean by outperforming projections?

Speaker 2

Sure. Thanks, Jonathan, for the question. So We have guided or I should say, we anticipate full enrollment of the 85 patients in the study Approximately the middle of next year. And just to take a half a step back, just to remind everyone, We sized the trial at 85 patients because it was our view that for a potentially best in class therapy, the agency would We want to see approximately 100 patients worth of safety data at the recommended Phase 2 dose. It's still early days, Jonathan, but in terms of both site activation and now enrollment of patients on the study, We are ahead quite a bit ahead of where we expected to be.

Speaker 2

And we've Obviously, have enrollment curves under different scenarios. We haven't yet made any adjustments To our guidance in terms of timing of overall enrollment, we want to see how the rest of the summer goes and a little bit into the fall. Sometimes you see a slowdown in the late summer, so we want to just be mindful of that. But what we want to communicate is there's very strong interest Among both physicians and patients and that seems to be translating directly into enrollment. There also Jonathan appeared to be More patients than I think we had anticipated, both from potential competitors and other folks who've tried to enroll trials in the NPM1 space.

Speaker 2

There was some sort of anecdotal comments out there that it might be challenging to enroll. That hasn't been our experience at all. In fact, quite the opposite. Since through EHA and now on the other side of EHA, we're seeing very, very, very strong interest, which is translating into enrollment. And I think that's driven, Jonathan, in part because of the data that I just very summarily walked through.

Speaker 2

The fact that we're seeing activity in patients who failed FLT3, patients who failed IDH, patients with various co mutations, I don't think we're seeing a siphoning off of patients to those other trials. Instead, they we're seeing very Strong interest in putting them on the ZYPTO MENIB monotherapy study and we have every expectation that's going to translate into the combos, Which is it's even earlier days there, but I think we're quite encouraged.

Speaker 4

Got it. Thank you. And second question, can you discuss the post transplant maintenance opportunity for ZYPTO MENA?

Speaker 2

Sure. Yes. And let me just clarify there. We're actually going to do both a post transplant maintenance as well as Just a maintenance without requiring transplant and let's talk about how those are different. So first of all, without needing to get to transplant, Our protocols have made allowances for patients to be able to stay on study.

Speaker 2

So for example, patients who are enrolled in 7 plus 3 plus Zifto can stay on Zifto in a maintenance type of setting. But and that's And we've built that in everywhere we can. So that's obviously important and I think has the potential to drive value. Our team I think is thinking very cleverly of the post transplant setting Jonathan and what we're shooting for is To be able to capture patients no matter how they get to transplant, whether they've had a prior menin inhibitor Or not, no matter where they've gotten, if they meet the entry criteria and they're on the other side of transplant, they'll be eligible to go into that study. It's our view, Jonathan, that given we have such a favorable safety profile, we have no QT prolongation, we have no evidence Drug induced myelosuppression, we just have a very, very attractive safety profile.

Speaker 2

We really have To be a preferred agent in the maintenance setting and we've heard from sophisticated parties that's a very attractive commercial opportunity. If you can keep patients on there for a year or 2, that has the potential to drive really significant value, Both for the patients as well as for the value of the overall enterprise. So and then the final thing, Jonathan, I'll comment on is, We're trying if people have been paying attention to the way we've laid these studies out, thus far, all the studies we've undertaken are Kura specific studies, Cura sponsored studies, so that we can drive the timing, and they're all sort of very much value creating. With The maintenance study will do an initial Phase 1 study as an investigator sponsored study to gather enough data and then we'll flip it over into a CURRA sponsored study, if it makes the transition into a Phase twothree. So we're trying as much as we can to retain control of the studies To be able to drive timelines and execution and thus far that's working quite well.

Speaker 4

Understood. Thanks for taking the questions.

Speaker 2

Our pleasure. Thank you.

Operator

Thank you. And your next Question comes from Roger Song from Jefferies. Please go ahead.

Speaker 5

All right. Congrats for all the progress and Thanks for taking the question. I think you mentioned you already start to dose the first combo combo trial, which is very encouraging. Maybe, Troy, you can give us some color around the enrollment progress so far And how should we think about the expectation for the initial data later this year, early next year in terms of the Maybe the activity you are looking for and also when you will potentially decide the IP-2D? Thank you.

Speaker 5

Multiple parts, sorry.

Speaker 2

Yes, that's okay. I'll take each of them, Roger. And if I miss one, please remind me or correct me. So first of all, just a comment on the design of the trials. So these are dose escalation trials.

Speaker 2

Each of the genotypes is being treated separately with standard of care. So in the context of 7+3, we have KMT2A cohort, we have an NPM1 cohort. These are typically 6 patient escalation cohorts, and we're starting at an N-two dose, 200 milligram dose, similarly for the venetoclax containing regimen. I'll remind you that in the Phase 1, There really was no dose dependence within between 206 100 milligrams as it pertained to differentiation syndrome. And that's important because you talked about kind of how do we think about data and RP2D.

Speaker 2

So as with any study, 1st and foremost, what we're going to focus on, I think, and we're guiding to Q4 this year Or at the latest Q1 next year is safety and tolerability, specifically with respect to differentiation syndrome. So can we safely combine with the current standards of care? We believe we can. And importantly, do those standards of Care helped mitigate the differentiation syndrome that was seen in the KMT2A population. And the question of activity, Roger, is a good one.

Speaker 2

However, as you appreciate, the backbone therapy has a meaningful level of clinical activity. So that really isn't going to be anything I think we Speak to, that's really when you get further on and you take once you're at a dose that is Optimum biologically active dose or the RP2D, you'll take it potentially into an expansion cohort and then we can get a better sense of Clinical activity relative to the backbone alone. The update as it pertains The end of this year or early next, although we fully expect there will be clinical activity, I think we want to make sure we step through it. Safety and tolerability, can we mitigate differentiation syndrome and then how are we making progress in the dose escalation. And it's We expect Roger ultimately to have 40 U.

Speaker 2

S. Sites in the Phase 1a. We have a handful of them that are open now and Enrolling patients that number will increase in the weeks months ahead. But thus far, again, interest has been very robust And we have a philosophy, Roger, with this trial and the accompanying 8 trial of what we've sort of called no patient left behind, right? A patient who presents at a physician's office, if he or she needs a venetoclax containing regimen, they can go on VEN plus ZIFTO.

Speaker 2

If they need if they are more or they're better suited for 7 plus 3, they can go on 7 plus 3 plus ZIFTA. When we get to 8, there's a lot of interest in combining with gilteritinib. Those of you who saw The data from quizartinib that supported the recent FDA approval, you saw that half of those FLT3 patients in the quiz trial We're NPM1 co mutant, fully 50%. So there's a lot of interest in combining menin inhibitors with FLT3 inhibitors and our team Is moving as aggressively as possible to get 8 open as soon as we can. So I hope that gives you some color, Roger.

Speaker 2

And I think I addressed all the components of your question, but let me know if I need to follow-up on anything.

Speaker 5

No, that's great. That's great. Okay. So that's very clear now. Maybe just shift gear to the Tippie.

Speaker 5

So understanding you're Figuring out the RP2D for them and but in the past, you seems to kind of guide towards The data released around the mid year for the RP2D and now you're kind of guiding towards The expansion cohort second half next year. So maybe just to let us know what's the current thinking around the TIPI? Thank you.

Speaker 2

Yes. It's a good question. And I think it's the reasonable question and the right question. So In short, Roger, the combination is both better tolerated and more active than we expected. That's the short answer.

Speaker 2

We had so if we take a step back, before we ever dosed a patient, when Investors and analysts asked me what's the greatest risk. I said from my perspective, the greatest risk is The challenges with combining tipifarnib and alpelasib. Particularly, we as an industry have not had good success And combining inhibitors of the MAP kinase pathway and inhibitors of the PI3 kinase pathway. We have been, I think very pleasantly surprised at the safety and tolerability that we've seen with this combination. We have seen evidence of hyperglycemia, but it hasn't been dose limiting.

Speaker 2

It hasn't inhibited in any way Our ability to escalate both tipi and elpelasib and just to put a point on that, now this final escalation cohort is a full dose of tipi, 600 milligrams twice a day and a full dose of alpelasib 300 milligrams daily. Honestly, I was Surprised. I wouldn't say shocked, but pleasantly surprised. The other thing, Roger, is we're seeing evidence of clinical activity. Now in this population, That's why I cited to you second line head and neck, you're typically seeing response rates in the teens, 13% to 16% And really challenging PFS and OS, PFS of 2 to 3 months.

Speaker 2

You can assume we are seeing Responses. I don't want to get into the granularity of the data, but we're seeing activity at and we're seeing, 1st of all, good safety and tolerability. We're seeing activity at different dose levels. We do need to make sure that we select The optimum biologically active dose and that's the lowest dose at which we have full activity and acceptable safety. So we're sorting that out.

Speaker 2

I think the critical questions and the reason we're guiding to next year is What dose is that? And then importantly, what level of activity are you seeing at that dose to help inform what a Phase twothree trial might look like? Just to remind everyone, HRAS mutant is 4% to 6% of the population, PIK3CA mutant is 15% to 20% of the population, we've seen that reflected in the enrollment curves and the enrollment on this study. We could potentially be treating up to a quarter of And neck cancer, Roger, but we want to make sure we get it right. And we've already shown we showed the example of the patient with The tonsil, the metastatic head and neck cancer from the tonsil, an 85% tumor reduction after 1 cycle and a durable So the next critical question is what's the dose and then how do you think about the safety, tolerability and activity To frame the opportunity for a registrational trial in a disease where there's been no approved small molecule targeted therapy.

Speaker 2

That's the work we have to do And the teams cranking as fast as they can. We think reasonable guidance is on that expansion cohort is sort of middle of next year.

Speaker 5

Excellent. Thanks, Troy, for all the comments. That's it from us. Thank you.

Operator

Thank you. Your next question comes from Peter Lawson from Barclays. Please go ahead.

Speaker 6

Thanks so much for taking the questions. Just kind of a firstly a follow-up around the maintenance setting, whether resistance mutations could preclude ZIFTHO from being in using that maintenance setting. And then Another question just around moving ZIFTA beyond AML and ALL into other heme indications, So tumors or other diseases? Thank you.

Speaker 2

Sure. Yes. Thanks, Peter, for the question.

Speaker 7

So

Speaker 2

We don't think resistance mutations are going to be a big threat to using ZYFTO in the maintenance setting. We've only ever seen one patient of the ones we've tested, the 29 or so we've tested who had a who Developed a resistance mutation while on ZIFTO. And people might ask the question, well, was your assay sensitive enough? And my answer would be, we don't see any evidence of resistance mutations driving progression Or resistance to ZIFTO. Patients do develop resistance.

Speaker 2

They do progress, It doesn't appear to be due to these resistance mutations. That's part number 1. We've got about a 3% to 4% Rate of resistance mutations in the data that we've sampled thus far, Peter. But the other important point is Zifdomenib is fully active on 2 of the 3 mutants and it retains meaningful activity on the 3rd, the 3 27 mutant. So and that's in contrast to a number of the other inhibitors in the class.

Speaker 2

And we've actually seen that as we spoke to around EHA, We've seen that when we treated patients who have come to our study having failed another menin inhibitor, we do have a measure of clinical activity. Long story short, Peter, I don't think it's we don't think it's going to make a difference. We think ZYFTO is very well positioned for the maintenance setting. And importantly, Peter, even probably more importantly, it's very easy to use. It doesn't have Any other toxicities that thus far that have revealed themselves that would require sort of extra Detection or extra vigilance in that setting.

Speaker 2

So I think we're looking forward to using ZYPTO in the maintenance setting. And forgive me, Peter, the second part of your question is? Yes. Oh, additional indications.

Speaker 6

The question was expanded outside, heme indications or other heme indications into solid tumors and other diseases.

Speaker 2

Sure. So I think there, Peter, You want to be data driven. There are other opportunities that we see beyond acute leukemia for menin inhibitors. I think one needs to be very mindful of the potential impact of the Inflation Reduction Act. And Long story short, the best analysis we have and we've talked to all the experts including CMS Is that we can do anything within AML and we stay out of the Inflation Reduction Act By virtue of having an orphan designation that covers AML.

Speaker 2

Once you go to another indication, be it ALL, be it any of the others, You potentially put your program at risk of being included in the IRA. And I think we think, Peter, the appropriate way to mitigate that risk We have a next generation menin inhibitor program. We've taken everything about ZYPTO that we think can be improved and the team Is, has a very attractive compound. It that would be the one we would probably take into additional indications. Be those other solid or liquid tumors, be that potentially diabetes, we've got multiple opportunities for Additional menin inhibitors and just given the evolving sort of legal and regulatory and pricing landscape, I think one wants to be thoughtful there.

Speaker 2

We think we can drive significant value just in AML alone and you hear us, right? We're talking about Frontline relapsedrefractory maintenance, we really think you can transform the standard of care and transform the market. And we're going to do everything we can with ZYFTO in that setting. If there's additional opportunities, I think we might do some early exploration, but we'd likely Pick those up with a 2nd generation compound. And that way you can really drive the full commercial value for the franchise.

Speaker 6

Great. Thank you so much. Really appreciate it.

Speaker 2

Pleasure.

Operator

Thank you. And your next question comes from Lee Wasek from Cantor. Please go ahead.

Speaker 7

Hey, congrats on the And thank you for taking our questions. I guess first one is on the Phase 2 pivotal study of ZYPTO. Troy, can you maybe just clarify if you have seen greater traction in terms of patient enrollment after Your EHA update in June, I mean especially for some of the EU sites that you have. And also for the potential combo data later this year or early next year, can you give us a Since the variables here, is it just a matter of enrollment speed or you want to reach a certain number of patients or certain period of follow-up before you disclose the data?

Speaker 2

Yes, Leith. Thanks for the question. So on the first question, it's When you do this with any trial, you do feasibility studies and you have An enrollment curve. And that enrollment curve is driven by the feedback that you get from the sites. How many patients do they see?

Speaker 2

How many do they think they can put on, etcetera? And our clinical operations group has done that very well with the 1 study. We are ahead of our projections, Lee. And I think there are a lot of reasons for that. I think it's physician excitement.

Speaker 2

I think it's the data itself. I think there's more patients than perhaps we expected and there we're not losing them to other studies. It's hard to say kind of it's hard to isolate one variable. What we're communicating is for people who think There's going to be a big gap in terms of time to market. I think we have a different view that's perhaps informed by data, Particularly in that NPM1 setting.

Speaker 2

And you fully expect, if the combination trials go well and we have good safety and tolerability, That you would expect that traction to continue because everyone acknowledges that as these molecules Eventually go in front of the FDA and potentially come to market. We're still AML is a disease of combination therapy. So the party that can get to the combinations with the highest, the best safety, best tolerability, combinability and activity Is ultimately going to be the market leader and we think that sets up very nicely for ZIFTO. So I expect that that excitement and enthusiasm will pull through Into the combo studies. With respect to the second part of your question, Lee, In terms of how we think about data release, so we understand that one of the questions in the minds of all of the analysts and the investors is, can we mitigate differentiation syndrome, Can we mitigate differentiation syndrome through co administration of the standard of care regimens?

Speaker 2

And does that unlock The activity of ZYPTO MEDIM more fully, particularly in the KMT II A set, rearranged population. It's a Every indication, everyone we talk to tells us that that's likely the appropriate path forward, But you have to do the work. You have to actually do it. That's why I'm focusing initially safety, tolerability, Mitigation of DS. DS is typically something you see in between cycle 1 cycle 3.

Speaker 2

Once the leukemia Is eliminated, there's no risk of DS. And if you're not eliminating the leukemia, the patient's likely going to progress and leave the study anyway. So You know relatively early on if you've mitigated DS. I don't think we're going to share data. We're not going to Dribble the data out with an eyedropper on a patient by patient basis.

Speaker 2

We want to get a sufficient number of patients on study that we can come to you and say, Here's the data and we can draw some meaningful conclusions. And I've indicated to you, these are 6 patient dose escalation cohorts. So the numbers get to be meaningful pretty quickly, even when we're in the first dose escalation or 2. We don't know yet will each of the Will, are the genotypes and the various combinations going to enroll at different rates? We don't have enough clarity into that yet.

Speaker 2

What we've been encouraged by is that, just as with L1, physicians are finding patients, screening, Patients are coming on study. The machine is working. And I think as we look toward our next earnings call, Lee, in November, as we look toward ASH At the end of the year, I think we'll be in a position to possibly give a meaningful update on why we think ZIFTO has A best in class profile. Hope that helps.

Speaker 7

Yes. Okay. Thank you. I have a second question. So in terms of the patient that you're enrolling into the pivotal study with co mutation, Do you have a sense of the in terms of the breakdown for FLP3 versus IDH co mutation?

Speaker 2

No, at least I don't think so. The you're talking, Lee, about The breakdown of co mutations in patients enrolled on the study, is that what you're asking?

Speaker 5

Yes.

Speaker 2

We are seeing so I think it's early days. We're seeing very high levels of co mutation. That's why I highlighted for you, If you go pull the quizartinib label, 50% of the FLT3 are NPM1 co mutated, right. So you need to be able at some point to combine with the FLT3 inhibitor You've given up 15% of the population. We're seeing that as well Lee, both FLT3, IDH, DNMT IIIA, all the central actors.

Speaker 2

It's exact it's very similar to what we've seen in the 1b. I don't have I don't think we have specific breakdowns yet in terms of the co mutational content in the population.

Speaker 7

Okay. Thank you.

Speaker 2

Sure.

Operator

Thank you. And your next question comes from Bradley Canino from Stifel. Please go ahead.

Speaker 8

Hi, this is Bijan on for Brad Canino. Congrats on the progress. So first question is on Tipifarnib. Glad you're seeing responses and some limited safety issues. How should we be thinking about the contribution of parts For TIPIA and PIKRae in the next data and then will we be getting data in both the HRAS overexpressed population and PIK3CA?

Speaker 2

Yes, Bijan. So thank you. So let's if I may, let's take those in opposite order. So Earlier this year, we announced that we were not going to continue enrolling in the HRAS over expressing cohort, we were going to focus our effort in the PIK3CA mutant. And that was really for a couple of reasons.

Speaker 2

Number We as with every company, we have finite resources and we have more things we can invest in than we have Funds with which to invest. So particularly as you hear us articulate everything we're doing with Zifdomenib. If one wants to identify the OBAD, the best place in our experience to go is In those patients who have driver mutations in the target oncogene, whether they be HRAS mutant in the case of the RUN and the AIM studies Or PIK3CA mutants in the case of the current studies. If you're going to define the OBAD, go there because that's where you're going to Have the potential of the greatest level of activity because the closer you get to a driver mutation or I should say a Gain of function mutation in a driver oncogene, typically that's where you see the highest activity. That doesn't, Bijan, preclude That once we get the OBAD, we would come back and investigate either HRAS overexpressed or PIK3CA amplified.

Speaker 2

We just want to do it in stages And we want to be good stewards of capital, good fiduciaries and be smart about doing drug development. So we are The picture is coming into focus in the PIK3CA mutant. Your question around contribution of parts, there So tipifarnib, you would expect it has no ability to drive responses in a PIK3CA mutant population As a monotherapy, that I can say with great confidence. Alpelasib in the experience Novartis has had a very limited ability to drive responses and those responses typically I'm aware of only one They are typically not durable. What you're seeing here, we have some very nice preclinical work That our translational research team published showing that the mechanistic rationale for why this combination is so effective in this disease, and how TOR and particularly REV Allows you potentially to drive more activity on PIK3CA.

Speaker 2

It's clear to us that the combo is doing has better clinical activity than Your drug is a monotherapy. At this point now, we're just continuing to gather data and gather confidence. I will say something. I didn't get a chance to address it with Roger's question. But The other thing this gives us great confidence in is as we look to 2,806 and we've already given you a heads up, Look at TKIs and renal cell, look at mutant selective inhibitors in KRAS, the fact that we can safely combine TPI and elpasib And to get data that get activity that is at a minimum additive, possibly better than additive, maybe synergistic, I think bodes very well for As we are now preparing to advance 2,806 into the clinic.

Speaker 2

Because if you look at second line RCC, Again, you're talking about a response rate with TKIs that's in the teens. And the activity in KRAS inhibitors is impressive, But the resistance happens pretty rapidly and I think that entire field is looking for the preferred combination partner. Is it Ship 2? Is Sauce, what do you do? I'm going to tell you, we think FTI stands a very strong Chance of being a preferred partner in both of those settings and the tipi alpelsib data potentially gives us an opportunity into head and neck And it also then I think again bodes well for 2,806, but let's start dosing patients on that study and see if that's correct.

Speaker 8

Got it. Great. Thanks for the comments there.

Speaker 2

Sure. Appreciate the question.

Operator

Thank you. And your next question comes from Fin Zelman from BTIG. You may go ahead.

Speaker 9

Yes, hi. Yes, hi. This is Jeet on for Justin. Thanks for taking our questions. Just looking to get your take on your view on Menin for diabetes based on recent competitor data at ADA and I had a follow-up question.

Speaker 2

Sure. So we're following as many are, we're following that data with interest. There's certainly a relationship between menin inhibition and beta cell regeneration. I think In our minds, there's still a lot of gaps and questions, as to what exactly is going on there. What we've decided to do is to we'll continue to watchfully weight that data set.

Speaker 2

We're actually evaluating ziptomenab As well as a number of other menin inhibitors in the appropriate models of diabetes, both as monotherapy and in combination. And I'm hopeful that we'll have some data later this year to make an assessment as to do we see an opportunity and if So how do we make sure we take advantage of it? If there's an opportunity for menin inhibitors in diabetes, I'll tell you today, we'll find a way to maximize that value for shareholders, either through a partnership or an out licensing, I doubt we'll become Kura Diabetes, but we'll find a way to get the value in it. But importantly, and this is an answer I gave previously, our view is you probably want to do that with another menin inhibitor, Both because you don't necessarily want your diabetes compound and your oncology compounds to have the same safety database. And number 2, from the standpoint of the Inflation Reduction Act, you've kind of shot yourself in the foot.

Speaker 2

We have, as I said, a next generation menin inhibitor that we've been bringing along. That may if the data supports it and We're going to look for the recommendation from our translational research and clinical colleagues. That's how you'll see us Generate value with menin inhibitors in diabetes is through a next generation compound. And I'll tell you this, if it's there, I have no doubt we can generate a best It's just a matter of let's be disciplined, let's do the right experiments, and let's generate the data and see.

Speaker 9

Makes sense. And just as a follow-up, I was hoping you could maybe just clarify the number of patients Being treated for the head and neck expansion cohort for tipifarnib? And secondly, what other indications outside of head and neck and RCC are most promising for FTIs in your deal?

Speaker 2

Yes, great question. So within head and neck, you probably want an expansion cohort of sort of And I'm just spitballing here sort of 6 to 12 patients. Similar to what we did with ziptomanab in the Phase 1b, you want to have Enough clinical data there that you've got a strong steer on how to think about future development. So that's that. In terms of other indications, We've got, I think, very good and evolving clinical data, both with tipifarnib as a monotherapy And increasingly tipifarnib and alpelasib.

Speaker 2

Although we terminated enrollment in our AIM study, We terminated it for operational feasibility. The compound is active. It's actually quite active. But again, in a world of limited resources, you have to make some difficult choices. And we would do our best to try to capture both the HRAS mutant And the PIK3CA mutant population, which is about a quarter of head and neck.

Speaker 2

For that, I would think about tipifarnib and dalpelasib. You would then want to come with a second and possibly a third FTI and think about RCC And how you crack the KRAS riddle. At this point, you want to generate data, you want to make sure you have optionality. But there have been questions about Tippie, the composition of matter patent has expired. But once you bundle it up with alpelasib, our IP colleagues have done a great job of building a strong patent estate Around FTIs in head and neck cancer that we can leverage.

Speaker 2

And if we could beat it, if we could get Tippi and alpelasib to market for patients, like that would be an amazing accomplishment. There's no targeted no small molecule Targeted therapy approved. If you then wanted to come along with another FTI and try to beat it, great. But I always joke, Walk then run then run the 4 minute mile. So let's keep Tipia and alpelisib moving along.

Speaker 2

You'll see us Put increasing resources on 2,806. And at this point, we don't have to make a decision. We want to generate data in both RCC and KRAS And continue to mine the chemical space for more FTIs and see where we go. Those are 3 very significant solid tumor indications. And I think the data set is coming together nicely.

Speaker 2

It's turning out to be who knew that the killer application of FTIs was going to be back to KRAS where it all started, but just as a combination therapy. That would be sort of coming home, if you will. I hope that's where we end up.

Speaker 9

Makes sense. Thank you so much.

Speaker 2

Sure.

Operator

Thank you. And our last question comes from Ren Benjamin from JMP Securities. Please go ahead.

Speaker 10

Hey guys, thanks for taking the questions. Troy, can you talk to us a little bit about maybe the strategic rationale Starting off with RCC and what's the unmet need there versus starting off with KRAS and KRAS mutant and NSCLC. And then A question for kind of all your combination programs. Are you in any sort of discussions with the companies that are marketing the approved drugs that you're combining Either Zifto or TipiWizz in order to set up an MTA or try to get some free drug, I mean how important is that Or kind of cost mitigation and maybe enrolling patients quickly and getting the clinical trials off the ground?

Speaker 2

Sure. It's a great question, Ren, and let me take it in parts. So with respect to RCC going first, We are improving as an organization, Fundamentally different than where we were just a few years ago and really have a great cross functional effort as we think about Going from sort of preclinical R and D all the way through to lifecycle management. And so we've done the work On renal cell carcinoma, we've talked to the KOLs, we've done the market research, we understand the landscape And we'll speak more to our specific partner in RCC probably a little later this year, but that's ran a relatively more mature space. We know what it's still evolving, but it's relatively more mature.

Speaker 2

So for example, the docs were very clear, If they could if we could enable them to use TKIs in the second line, that would be phenomenal. And if you look at the preclinical data that Francis' group has generated, there's really potent synergy between tipifarnib And TKI is most notably axitinib in that setting. So it's a great setup. The docs love it. In my view, we can't get there fast enough.

Speaker 2

Now take KRAS. KRAS is an emerging area. It's I know it's got a lot of heat, a lot of light. It is a rapidly evolving area. It's clear that resistance It's going to be something that everybody is going to have to contend with and TOR target of rapamycin, Which is what we one of the targets that we deal with, with TIPI and 2,806 that seems to be a central actor in driving resistance To KRAS inhibitors across the board, whether they're mutant selective, whether they're RAS on, whether they're G12C or G12D, Yes.

Speaker 2

If you hit KRAS, TOR gets engaged and tries to develop resistance. The tumor tries to find a workaround. So it's taking we're just being Ren very deliberate and making sure that we're making the right decisions. With respect to your last question, are we Trying to build clinical collaboration or supply agreements? The answer is yes.

Speaker 2

Ideally, You either want the drug to be reimbursed or you want to work with the sponsor to try to get Yes. A drug sharing agreement or a clinical collaboration. We did that of course with Novartis initially with the With the tipifarnivalpelasib trial and you can assume we are taking a similar strategy as we think about The opportunities for 2,806.

Speaker 10

Perfect. Thanks for taking the questions.

Speaker 3

Sure.

Operator

Thank you. There are no further questions at this time. Mr. Troy Wilson, you may proceed with closing remarks.

Speaker 2

Thank you. And thank you all for joining our call today. We'll be participating in the Cantor Healthcare Conference next And hope to see a number of you there. In the meantime, if you have any additional questions, please contact Pete, Tom or me. Thank you again for attending our call and have a good evening everyone.

Operator

Ladies and gentlemen, this concludes your conference call for today. We thank you very much for participating and ask that you please disconnect your lines. Have a great day.

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