Kura Oncology Q4 2023 Earnings Call Transcript

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Provided by Quartr
February 27, 2024

There are 11 speakers on the call.

Operator

Good afternoon, ladies and gentlemen, and welcome to the Q4 2023 Cora Oncology Incorporated Financial Results Conference Call. At this time, all lines are in listen only mode. Following the presentation, we will conduct a question and answer session. Call is being recorded on Tuesday, February 27, 2024. I would now like to turn the conference over to Pete Despain, Head of Investor Relations.

Operator

Please go ahead.

Speaker 1

Great. Thank you, Eric. Good afternoon, and welcome to Kura Oncology's 4th quarter and full year 2023 conference call. Joining me on the call are Doctor. Troy Wilson, our President and CEO and Tom Doyle, our Senior Vice President of Finance and Accounting.

Speaker 1

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

Speaker 2

Thank you, Pete, and thank you all for joining us. Let's jump right in. Last month, we reported preliminary clinical data from the first 20 patients in COMET-seven, a Phase 1 dose escalation trial of our menin inhibitor, ziptomenid, in combination with standards of care in patients with NPM1 mutant and KMT2A rearranged acute myeloid leukemia. The first 20 patients were enrolled in fewer than 4 months from July to November of last year, including 5 newly diagnosed patients with adverse risk AML and 15 patients with relapsed refractory AML. Zifdomenib demonstrated a highly encouraging safety and tolerability profile in combination with cytarabine plus donorubicin or 7 plus 3 as well as with venetoclax plus azacitidine enabling continuous administration of ziptomenib while effectively mitigating the risk of differentiation syndrome.

Speaker 2

No differentiation syndrome events of any grade were reported among the first 20 patients. Furthermore, no dose limiting toxicities, QTC prolongation, drug drug interactions or additive myelosuppression were observed. As of the data cut off on January 11th, all 5 newly diagnosed patients with adverse risk NPM1 mutant or KMT2A rearranged AML treated with ziptometib in 7 +3 achieved a complete remission with full count recovery for a CR rate of 100%. The overall response rate among the 15 relapsed refractory patients treated with ziptomenab and VENAZA was 53%, including a 40% ORR among the 10 patients who had received prior venetoclax, a setting with very limited effective treatment options. Notably, the CRCRH rate among the 9 relapsed refractory patients who were menin inhibitor naive was 56%.

Speaker 2

As of the data cut off, 16 of the first 20 patients remained on trial, including all 11 NPM1 mutant patients. Continuous daily dosing of ziptomenab at 200 milligrams QD was well tolerated and the safety profile was consistent with features of underlying disease and backbone therapies. As we reported on January 30, the 200 milligram dose of ziptomenib has been cleared in both relapsedrefractory venesa cohorts and enrollment at the 400 milligram dose continues. In the meantime, I'm pleased to report we've also escalated to the 400 milligram dose of ziptomenib in the frontline adverse risk NPM1 mutant7 +3 cohort and we anticipate clearing the 200 milligram dose in the frontline KMT2A rearranged 7+3 cohort shortly. At this rate, we expect to determine the recommended Phase 2 dose for ziptomenib in combination with VENAZA and in combination with 7+3 by the middle of this year.

Speaker 2

After determination of the recommended Phase 2 dose, we plan to initiate a Phase 1b dose validation expansion with ziptomenab in Venza in newly diagnosed with patients with NTM-one mutant and KMT2A rearranged AML. In the meantime, we're now dosing patients in our COMET-eight study of ziptomatib in combination with additional standards of care, including the FLT3 inhibitor gilturitinib, flagida or LDAC, all for the treatment of relapsed refractory NPM1 mutant or KMT2A rearranged AML. Roughly half of patients with relapsed or refractory NPM1 mutant AML have co occurring FLT3 mutations and the prognosis for these patients is particularly poor. Preclinical data for ziptometib in combination with FLT3 inhibitors demonstrates strong synergistic effects compared to either single agent alone. We believe a best in class safety and activity profile and optimum pharmaceutical properties will enable Zifdomenib to become a cornerstone of therapy for patients with acute leukemias.

Speaker 2

This belief is supported by growing investigator enthusiasm as evidenced by rapid enrollment across all of our ongoing ziftomedib studies. We continue to be encouraged by the rate of enrollment in COMET-one, our Phase 2 registration directed trial of ziptomenib in patients with relapsed refractory NPM1 mutant AML and we remain on pace to complete enrollment of all 85 patients in the trial by the middle of this year. Our mission is to develop ziptomenab across the continuum of care for all patients with acute leukemias whose disease is driven by the menin pathway, including pediatrics where poor outcomes unfortunately remain. In December, we announced ziptomenib was selected for the Leukemia and Lymphoma Society's pediatric acute leukemia master clinical trial commonly known as Pedal. As part of the studies, Iftamenib will be evaluated in combination with chemotherapy in pediatric patients with relapsed refractory KMT2A rearranged, NUP-ninety eight rearranged or NPM1 mutant acute leukemia.

Speaker 2

In addition, we recently began dosing patients with KMT2A rearranged acute lymphoblastic leukemia, a relatively small group of patients, but with a very large unmet medical need, as well as a cohort of patients who have neither NPM1 mutant nor KMT2A rearranged AML. We also have a growing body of preclinical data that supports attractive opportunities for menin inhibitors beyond acute leukemias. We're now preparing to initiate a proof of concept study in an undisclosed solid tumor indication later this year. Meanwhile, we continue to make progress toward a next generation menin inhibitor, which we intend to direct to an additional soon to be disclosed indication. And with our recent financing, we remain in a strong financial position, which enables us to invest aggressively in research, development and pre commercial activities to maximize the value of ziptomenib and support our other pipeline assets.

Speaker 2

Now let's turn our attention to our farnesyltransferase inhibitor programs beginning with KO-two thousand eight hundred and six. Despite success of targeted cancer drugs such as tyrosine kinase inhibitors and KRAS inhibitors, a considerable need remains to drive enhanced antitumor activity while addressing mechanisms of innate and adaptive resistance. We are developing our next generation farnesyltransferase inhibitor KO-two thousand eight hundred and six to address this need. 2,806 was designed to improve upon the potency, pharmacokinetic and physio chemical properties of earlier FTI drug candidates. Last year, we presented compelling preclinical data supporting the rationale for combining KO-two thousand eight hundred and six with distinct classes of targeted therapies, including Tyrosine Kinase inhibitors and KRAS inhibitors.

Speaker 2

In October, we began dosing patients with KO-two thousand eight hundred and six as a monotherapy in a Phase 1 dose escalation trial that we call FIT-one. FIT-one uses an innovative design that enables us to begin dose escalation of KO-two thousand eight hundred and six in combination cohorts very early on in the study while continuing to dose escalate concurrently as a monotherapy. We're now preparing to dose the first patients with KO-two thousand eight hundred and six in combination with cabozantinib in clear cell renal cell carcinoma and in combination with atagracinib in KRAS G12C mutated non small cell lung cancer by the middle of this year. Recall in November, we announced a clinical collaboration and supply agreement with Mirati Therapeutics, now Bristol Myers Squibb to support that latter study. We're encouraged that the strong operational execution seen in the ZYPTO MEDIB trials has carried over to the FIT-one study and look forward to realizing the promise of the combinations.

Speaker 2

If successful, we believe KO-two thousand eight hundred and six could become an ideal combination partner multiple targeted therapies in large solid tumor indications. Meanwhile, we continue to evaluate our 1st generation FTI tipifarnib in combination with the targeted therapy Alpelasib building on impressive clinical benefit we observed with Tipifarnib alone in head and neck cancer. We continue to evaluate patients in the dose escalation study of Tipifarnib and Nalpelosib, which we call current HN. Given encouraging clinical activity observed at multiple dose levels, we're adding additional patients to help inform selection of the optimal biologically active dose for the combination. Once we determine the OBAD later this year, we'll determine the next steps for the program.

Speaker 2

Importantly, we are encouraged that tipifarnib continues to demonstrate a favorable safety and tolerability profile at its full dose in combination with alpelasib. We believe this significantly derisks development of our next generation FTI KO-two thousand eight hundred and six as we begin to evaluate it in combination with other targeted therapies. With that, I'll now turn the call over to Tom Doyle a discussion of our financial results. Tom? Thank you, Troy, and good afternoon, everyone.

Speaker 2

I'm happy to provide a brief overview of our financial results for

Speaker 3

the Q4 and full year 2023. Research and development expenses for the Q4 of 2023 were $32,500,000 compared to $22,700,000 for the Q4 of 2022. R and D expenses for the full year 2023 were $115,200,000 compared to $92,800,000 for the prior year. The increase in R and D expenses was primarily due to increases in clinical trial costs related to our ziptomenib and KO-two thousand eight hundred and six programs. General and administrative expenses for the Q4 of 2023 were $14,200,000 compared to $12,500,000

Speaker 2

for the Q4 of 2022.

Speaker 3

G and A expenses for the full year of 2023 were $50,600,000 compared to 47 $100,000 for the prior year. Net loss for the Q4 of 2023 was $42,800,000 compared to a net loss of $33,100,000 for the Q4 of 2022. Net loss for the full year of 2023 was 100 and $52,600,000 compared to a net loss of $135,800,000 for the prior year. Net loss for the Q4 and full year of 2023 included non cash share based compensation expense of $7,200,000 $28,100,000 respectively. This compares to $6,800,000 $26,300,000 for the same periods in 2022.

Speaker 3

As of December 31, 2023, we had cash, cash equivalents and short term investments of $424,000,000 compared to $438,000,000 as of December 31, 2022. Subsequently, on January 26, 2024, we completed an oversubscribed private placement with a select group of institutional and accredited healthcare specialist investors. As adjusted for the approximately $146,000,000 in net proceeds resulting from this private placement, Kura had on a pro form a basis $570,000,000 in cash, cash equivalents and short term investments. We believe that our cash, cash equivalents and short term investments will be sufficient to fund our current operating plan into 2027. With that, I now turn the call back over to Troy.

Speaker 2

Thank you, Tom. Before we jump into the question and answer session, let me lay out our anticipated upcoming milestones. For ziptomenib, initiate the post transplant maintenance program in the Q1 of 2024, complete enrollment of 85 patients in the COMET-one registration directed trial in NPM1 mutant AML by mid-twenty 24, determine the recommended Phase 2 dose in combination with VENAZA and initiate dose validation expansion in frontline AML by mid-twenty 24 and determine the recommended Phase 2 dose in combination with 7+3 by mid-twenty 24. For KO-two thousand eight hundred and six, dose the first patients in combination with cabozantinib in clear cell renal cell carcinoma by mid-twenty 24 and dose the first patients in combination with adagracif in KRAS G12C mutated non small cell lung cancer by mid-twenty 24. And for tipifarnib, complete enrollment of 2 expansion cohorts to support determination of the optimal biologically active dose in combination with alpelasib by the end of 2024.

Speaker 2

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

Operator

Thank you. Ladies and gentlemen, we will now begin the question and answer session. Your first question comes from the line of Jonathan Chang with Leerink Partners. Please go ahead.

Speaker 4

Hi, guys. Thanks for taking my questions. First question on zifdomenib. Can you discuss your thoughts on the combinability with Venaza and your thoughts on whether you need to adjust the dose of VEN due to drug drug interactions and potential CYP-three eighty four inhibition?

Speaker 2

Sure, Jonathan. Thanks for the question. So, I'll actually direct folks and there's a revised slide in the corporate deck. If you want to take a look at it, it has the some of the key points, Jonathan, from the 1 study. Most importantly, from the clinical data we've now generated, the human clinical data, we can say ziptomenab is not a clinically meaningful CYP3A4 substrate.

Speaker 2

We don't have to adjust its dose at all in the presence of azoles for example. And it is not also not a clinically meaningful CYP3A4 inhibitor. In other words to your specific question, we don't have to adjust the dose of venetoclax, which is a CYP3A4 substrate in the presence of Zipta Mena. Now I want to be clear, the protocol does allow for the adjustment of venetoclax dosing if a patient for example is on an nasal that is per the label of venetoclax, but there's no dose adjustment needed when venetoclax is combined with Ziftemetid. So just to underscore, it's neither a substrate nor an inhibitor of CYP3A4.

Speaker 4

Got it. Thanks for clarifying. And then just second question with the COMET-eight study starting. Can you discuss the opportunity for zifdomenib in combination with the FLT 3 inhibitor? And what are your reasons for confidence in the combinability of these drugs?

Speaker 4

Thank you.

Speaker 2

Sure. So the rationale is maybe just taking a half a step back. When you look at the various combinations of the 7 and the 8 protocols, what our team, Molly Leone, Stephen Dale and others on the team have endeavored to do is to provide a foundation where physicians can in principle combine Zivtamenib with any available standard of care, giving them maximal flexibility as they're dealing with patients in various lines of therapy. More specifically to your question about FLT3, so FLT3 mutants are represent roughly half of the NPM1 population. And you can see that for example in the gilteritinib and in the quisartinib studies.

Speaker 2

The extent of overlap between NPM1 mutants and FLT3 mutants is roughly 50%. That's number 1. Number 2 is, if we could provide those patients with an all oral targeted therapy regimen that was effective and well tolerated, we think that would be broadly embraced. In our discussions with physicians, gilterritinib is very popular and the preclinical data that we've generated admittedly it's preclinical, but the preclinical data combining FLT3 inhibitors with zifdomenib, the results are nearly curative. I mean, I'll say they're curative.

Speaker 2

I use that word carefully. But the potential, Jonathan, to have an all oral regimen that could drive such a profound clinical benefit in patients we think would be very attractive. So it's a huge slice of the population, the possibility for an all oral regimen and something approaching a cure with excellent tolerability. In terms of managing the safety, the thing that really that we just want to make sure we pay attention to is the potential for differentiation syndrome. It was observed with the FLT3 inhibitors.

Speaker 2

However, we think that by sequencing and sort of careful monitoring and mitigation, we'll be able to deal with that. We along with the field and the investigators understand differentiation syndrome much better now. And so I think we're feeling optimistic that we'll be able to find a dose and schedule that gets those 2 agents working well together. And we'll look forward to sharing our progress later this year.

Speaker 4

Understood. Thanks for taking the questions.

Speaker 2

My pleasure.

Operator

Your next question comes from the line of Jason Zumansky with Bank of America. Please go ahead.

Speaker 5

Perfect. Good afternoon and thank you for taking our questions. I'm curious about 7 as the patients continue to hopefully do well on therapy and potentially approach hematological recovery with longer duration of therapy, what are your expectations in terms of moving them off of therapy? Is the idea maybe to keep them on ZIFTO and maybe pull back on VENAZA as which usually happens? Or would you necessarily discontinue the menin inhibitor at some point?

Speaker 5

And then a follow-up if I may.

Speaker 2

Yes. Jason, thanks for the question. So importantly, when you heard it in the prepared remarks, we don't see any additive myelosuppression. And as a result, we don't have to hold the dosing of ZIFTO at all to allow counts to recover. At one time it was thought that there might be a class effect.

Speaker 2

We certainly don't see that with ZIFTO MENET. To your question, which I think is well formulated, our experience has been that physicians use, I mean obviously they use 7 plus 3 for 7 days or 3 days as indicated. For VENAZA, they're using it to really drive the clinical activity and then they're pulling back, they're keeping patients on Zifto. I think our intent and sort of what we're seeing is that these patients are staying on Zifto. If they go to transplant, they might take a break while they're conditioning for transplant, but then they're coming back on to ZYPTO MENIB monotherapy post transplant in a maintenance setting sort of using the air quotes.

Speaker 2

That's how we would expect ZIFTO to be used Jason is literally from day 8 and then really only with an interruption perhaps for transplant patients would stay on zifdomenib until disease progression or the alternative. And we haven't had patients on long enough to say, do they no longer need to be on Zifto? Have we cured them of the disease? That's a dream, but that's for some day in the future.

Speaker 5

Got it. And then looking at your timelines, thinking about the bigger commercial dynamics here, you're potentially looking at a scenario where you may be a next to market menin inhibitor in the NPM1 space with potentially better efficacy. How are you thinking about launching into this space? I guess what I'm really driving at here is at this stage, do you get the sense that the community, the prescribing community sees the 2 different menin inhibitors as more distinct versus similar? I mean, what's the feedback been like here?

Speaker 2

Yes. So look, we've done a small amount of sort of pre commercial work with physicians. And what we found is when we profile the Ziftamenib target product profile as informed by data and we put it up against the competition, we hear sort of an overwhelming preference to use ZYPTOMANIB, primarily driven by the safety and tolerability. No CYP3A4 liability, no dose limiting toxicity. And I think that's only going to continue and get amplified, Jason, as we move into combination.

Speaker 2

So and I would also say, I'm not I think we're not really willing to concede yet that we're going to be second to market in the NPM-one setting. To my knowledge neither study has yet completed enrollment. Maybe there are some updates today from the competition but our enrollment continues to be robust. I think we've got a well powered study and we intend to move very aggressively. I think we'll be well positioned.

Speaker 2

And if anything, again, I keep going back to our enrollment because all other data points, they can be shaded in various ways. Enrollment is objective. Enrollment is difficult to argue with. And we've already mentioned we continue to make progress. We're looking forward I think to being able to move into the 600 milligram cohort here before too long, that enrollment speaks for itself and we expect to see that pull through into the commercial marketplace.

Speaker 2

Got it. You had a follow-up question.

Speaker 6

But that was it, but that was the follow-up.

Speaker 5

Thank you so much for the insights and color.

Speaker 2

Our pleasure. Thank you for the questions.

Operator

Your next question comes from the line of Leigh Wlodarczak with Cantor Fitzgerald. Please go ahead.

Speaker 7

Hi, good afternoon. Congrats on the progress. Maybe just a couple of follow-up questions from me. Just wondering if you can clarify the plan for data disclosure for 7 study around midyear. Other than RP2D dose selection, would you be sharing data at higher doses?

Speaker 7

And also can you comment on if you have started to dose patients at 600 mg?

Speaker 2

Yes. So thanks Lee for the questions. Let me take them in reverse order. So as of today, no, we haven't started yet dosing patients at 600. I think you can hear from us, we're encouraged thus far by what we're seeing.

Speaker 2

And as you know from the monotherapy, there's nothing that we've seen that really gives us cause for concern, but one still has to run the experiment. In terms of what data one might expect, so obviously going back to the January update which feels like a lifetime ago, but was just about a month ago. At that point, we had 20 patients that we for which we shared data and we were focused on safety, tolerability, combinability and then some early signs of activity. The next logical update ideally you said it in your question, I think it's right is around the RP2D. Are we able to dose escalate?

Speaker 2

What does that look like from again safety, tolerability, combinability, is there any difference or are we simply giving more ZIFTHO. When we give an update, we'll give an update on all the patients on study. And you can tell everyone probably remembers each of these 4 cohorts are at least 6 patients per dose. And I want to be careful with that. There may be additional patients simply because if we get them in screening and but we're not yet ready to escalate we might tack on a couple of more patients at a given dose.

Speaker 2

So expect 6 plus patients per cohort per dose and you can hear us moving pretty aggressively through these dose cohorts. Finally, Lee, as to timing, there I think we're keeping all the options open, right. Obviously, we're going to have a presence at EHA. It's one of the most important heme meetings. In terms of the update on this study, there might be something there, there could be something in a corporate update.

Speaker 2

I think we know what people are looking for and we want to make sure we have that data rather than sort of being necessarily constrained by this precise timing of the medical meeting. We still have lots of time until that happens and we're making good progress. And we'll certainly look forward to giving a more fulsome data update on 7 a bit later this year.

Speaker 7

Okay. And then maybe a follow-up question. Troy, you mentioned about enrollment speed here. I mean, given the very strong data from 7 study last month, I guess, what is your expectation for the enrollment rate for the 8? And also in terms of clinical sites, what's the degree of overlap between these two studies?

Speaker 2

Yes, good question. So again, I appreciate it's a 2 part question. Let me take the second part first because it's a little easier. At this point, there's sort of minimal overlap between 7 and 8. We're trying not to create situations where sites are competing although the trial that they go on to is largely driven by the line of therapy.

Speaker 2

So the frontline patients obviously have frontline options for 7 once we reach the RP2D for example for VENAZA, we'll do the expansion validation in the frontline, right. So that will be self limiting. I think it's early, Lee. We've just really gotten going. We're sort of taking the first tentative steps on 8.

Speaker 2

We'll have a better sense of how that's going as the weeks months continue. 7 is going very robustly and as is 1, I think we have every expectation 8 will as well. We particularly expect to see interest in gilterritinib. The investigators fondly refer to this study as the FLT3 study. I think they're excited to see this combination and we're excited to get going on this study and begin to get some experience.

Speaker 2

So look forward to an enrollment update on 8 again the next time we have the microphone or a little later in the year.

Speaker 7

Thank you very much.

Speaker 8

Sure.

Operator

Your next question comes from the line of Peter Lawson with Barclays. Please go ahead.

Speaker 9

Great. Thank you so much. Thanks for the updates. I had a quick question on COMET-seven combo. Just why ZIFTHO starts on day 8?

Speaker 9

Is there any worries about drug drug interaction or just the rationale there?

Speaker 2

Yes. So actually the opposite Peter. So I don't know if you heard the answer to the question that Jonathan asked, but there's a new slide in our corporate presentation that I would direct everybody to that says as clearly as we can say it, ZIFTO is neither full stop, right, in anything that we've seen, either monotherapy or combo. The rationale for the day 8 start is actually pretty simple. It gives you 3 things, 3 advantages.

Speaker 2

Number 1, you debulk the patient, less disease means you have lower propensity for differentiation syndrome. You're just physically debulking the tumor. Number 2, you get a baseline safety view, so you can differentiate what are effects due to the backbone versus effects due to ZIFTA plus the backbone. And number 3, it gives you time to ensure that you're enrolling the right patients, particularly NPM1, sometimes the turnaround time takes several days. And so you want to make sure that you're not losing slots on patients who aren't who ultimately are not eligible.

Speaker 2

Those are the three reasons. And we've been extremely pleased by the results. I will say as folks know, we have Bristol Myers Squibb as an equity investor back to ASH 2022. They made a $25,000,000 equity investment and we have a continued good relationship with them. They actually encouraged us to do that staggered dosing in all of our combos for exactly the reasons that I enunciated to you.

Speaker 2

And these are folks who do research development commercialization in the market. I think that was very good advice. It has served the program well.

Speaker 9

Perfect. Thank you so much. Thanks for clarifying that. And then just on the expansion cohort, that's really interesting. So patients without AMPM1 came to 2A.

Speaker 9

Are there particular mutations you're targeting or is that kind of all comers approach? Just curious on how you're kind of focused?

Speaker 2

Yes. So thanks for the question. So to clarify for everyone, in the prepared remarks, we announced that we've dosed the first patient in an addition to 1. It's not part of the registrational study, but it's part of the 1 protocol that is looking to dose ziptomenib at its RP2D at 600 milligrams in patients who are neither KMT2A nor NPM1 mutant. Why are we doing that?

Speaker 2

Well, if you go back to the results from the Phase 1a, 1b, you'll recall we saw a number of patients, multiple patients who had evidence of clinical benefit, blast count reduction, disease stabilization. We even went so far as a patient with a SETT2 RUNX1 double mutant who had a CR at the 100 milligram dose. At that time, I don't think we understood A, how to use ZYFTO as well as we do today and B, really what to look for. And investigators confused in some cases differentiation and to progression. They're no longer making that mistake.

Speaker 2

So now it's a great time to go back into that population. It could be as much as 10% to 15% of AML and ask the question, what do we see as a monotherapy? If we see evidence of clinical benefit, we might pursue it as a monotherapy. We might pursue it in combination. It might help broaden the scope of the combinations.

Speaker 2

Peter, to your specific question, the way those patients are selected is via an algorithm that picks among selected mutants that we have evidence confer a sensitivity to menin inhibition. So it's not an all commerce population. It is enriched and it's enriched via an algorithm.

Speaker 9

Got you. Perfect. Thanks so much. Really appreciate it.

Speaker 2

Yes. Pleasure.

Operator

Your next question comes from the line of Justin Zelman with BTIG. Please go ahead.

Speaker 8

Hi, thanks for taking the questions and congrats on the progress. So Troy, you mentioned interrogating menin in other indications outside of acute leukemia, as you mentioned some solid tumor and non oncology indications. So will that be with ZYPTO or next gen molecule? And do you have an idea of when we might see some early translational data from those programs?

Speaker 2

Yes, Justin. Really good question. So let's tease those two parts apart. We really view zifdomenib as having an ideal properties for oncology applications. And I'll confess to you, it was partly by design and partly by good fortune.

Speaker 2

As you know, Zifto accumulates, it has very high tissue penetrance. Essentially you are saturating the tissues with high concentrations of menin inhibitor and there's never a time when the target isn't covered. As a consequence, that's really attractive for oncology indications where you kind of need an always on. For non oncology applications, you may actually want to have somewhat of a different profile. I will tell you we've made a significant investment in next generation compounds.

Speaker 2

We have ones for both oncology and non oncology. And we're waiting to share the translational data until we're further along toward execution of the clinical experiment because let's be honest, this is a competitive field. We view ourselves as scientific innovators. We know we're going to attract competition. So we're holding those cards a little closer to the vest, but we're quite excited.

Speaker 2

We're doing the work to prepare for that study and to share with you some of those data a bit later in the year. We'll do the oncology, the solid tumor experiment, Justin, we think with Zifto. The other applications, I think we're leaving that open and we'll use the best menin inhibitor for the job. And I think we're going to have multiple options there.

Speaker 8

Great. Looking forward to it. Thanks for taking the questions.

Speaker 2

Sure. Thank you.

Operator

Your next question comes from the line of Ren Benjamin with Citizens JMP. Please go ahead.

Speaker 6

Hey, thanks for taking the questions guys and congratulations on the progress. Maybe just two questions for me Troy. 1, in the prior data that you guys had already reported from 7, you talked about 10 patients who had already received prior venetoclax and you were still seeing a 40% ORR. And I don't know if this was asked before or not, but does this suggest that then could potentially be taken out of that regimen and a less toxic, call it, ZIFTA, ASA combination could or should be evaluated? Or does it suggest maybe something else that maybe menin inhibition is resensitizing patients to BCL-two inhibition?

Speaker 6

That's one question. The other is more from a commercial perspective. It seems you're evaluating ZIFTA throughout continuum of AML treatment and it might actually result, if I'm thinking about this right, in the cannibalization of Zifto in later lines of treatment. So how does this work in the real world as you're kind of evaluating this? Or is this are all these combination studies really more to maximize BD discussions and ultimately confirmatory studies will be run-in the hands of a partner.

Speaker 2

Right. Okay. So several questions packed in there, Ren. Maybe taking your second question, second set of questions first. So the yes, you will by design cannibalize those later lines if you're successful.

Speaker 2

Our goal, I think the goal of everyone in this field is to prevent the need for use in the relapsed refractory setting by treating patients in the upfront setting. Our goal is treat patients early in lines of therapy where the benefit, the clinical benefit is potentially much greater. Will that come at the expense of the relapsed refractory? It will. But ultimately, that's better for patients, offers them a better clinical benefit and is arguably a more compelling commercial case.

Speaker 2

The combinations that we're doing, we really are wanting to make wanting to generate safety data to give physicians freedom of choice. For example, there are fewer drugs approved in Europe than in the U. S. The LDAC combination might be very attractive in Europe. Doctor.

Speaker 2

Molly Leone, who's the clinical lead and our EVP of clinical development for Kura has said, it doesn't really matter how you get patients to a response. If you can get them there with a softer response, that's better. You don't have to use a hard chemo. Your goal is to get them to response and LZAC might be an attractive way to do that. You heard me answer the question on FLT3, that's another option.

Speaker 2

Not so much driven by BD considerations, although I will say to you, we recognize to fully maximize the value of menin inhibition in these various indications, I think we've said this before. At some point, we would likely need to engage a partner in some sort of strategic relationship because that's just what it's going to take to generate multibillion dollar sales numbers in a multiplayer market. With respect to your specific questions on the 7 study in VENAZA, I guess a couple of clarifications. So the significance of seeing responses in patients who are venetoclax failures is, these are single arm dose escalation studies. I mean you're really kind of squinting at times to say what's clinical activity, but it's pretty well established for patients who failed then, they don't respond to then retreatment.

Speaker 2

That I think most physicians will agree with that. That is a disease of high unmet need. How is that happening? Is it that we're blocking a driver mutation like an NPM1 or a KMT2A? Are we blocking MCL1?

Speaker 2

Are we interacting with BCL2 to resensitize the tumor. We're still figuring that out. What does appear to be clear is that menin inhibitors plus then are better than then alone. That seems clear. To your question, I don't think you would go meninaza.

Speaker 2

I think you might go venetoclax menin inhibitor and do the doublet. You may not need the aza. And as we've talked about in the past, we will do that experiment when the time is right. We'll actually ask the question, do we need the triplet of venazemenin or can the doublet will the doublet suffice? And that's something you just have to figure out empirically.

Speaker 2

But going back to 'seven and again, I'll acknowledge our colleagues at Syndax. We've both seen activity in venetoclax failures. And I think that's highly encouraging of the clinical benefit that these menin inhibitors can provide.

Speaker 6

Great. Thanks for taking the questions.

Speaker 3

Sure.

Operator

Your next question comes from the line of Brad Canino with Stifel. Please go ahead.

Speaker 6

Hey, good afternoon.

Speaker 8

Troy, how important does response durability become at your next combo data update?

Speaker 2

I mean it's important Brad, it's always important, but I would say I cautioned people at the time with the 200 milligram dose, we're looking at an immature data cut in a dose escalation study. So I'd be careful not to over interpret. Ideally, you should be seeing a direction of travel that is better than the monotherapy, right? Will the data be mature enough? Hard to say.

Speaker 2

We're still I mean, obviously, we haven't dosed a patient yet at 600 milligrams. So if we were to disclose in the next several months, we'll be limited in terms of what we can say about durability. I do think it's important. We have every reason to believe as we go into combinations, as we go earlier, durability will improve. There isn't anything that's suggesting there's nothing we're seeing.

Speaker 2

There's nothing we're seeing from others that would suggest that that wouldn't be the case. I wouldn't have an undue reliance on that one data point. What I would be looking for Brad is can we combine effectively at 600 mg with those standards of care. Because if you go back to the monotherapy that's the optimal dose from a monotherapy perspective it maximizes exposure after that it plateaus. It should be no different in the combos.

Speaker 2

That's the critical data point to look for. The durability will come in time and I think we're cautiously optimistic it will inform in the right direction.

Speaker 6

Okay.

Speaker 8

And then another question. We talk a lot about potential best in class drug properties on this call and in others. But as we move towards more substantial venaza triplet data from both you and other menin inhibitors that are being developed, how do you expect potential differentiation might emerge in those clinical data reported in the Phase III studies?

Speaker 2

Yes. So it's going to take the form in a couple of different ways. So there's a I would say, does one need to hold the menin inhibitor to allow counts to recover? That's question number 1. And when you get out into the real world in a broader population, If you have to hold the menin inhibitor that potentially gives the disease a chance to escape.

Speaker 2

The second is, one of our competitors presented data in a post transplant maintenance study and you can look at the rate of dose a high rate of thrombocytopenia. That is not on mechanism. That's something else. We don't see that. Couple of the other compounds don't see that, but that is a characteristic of some menin inhibitors.

Speaker 2

So I think Brad it's going to go kind of both directions. Number 1, can you keep constant pressure and constant exposure? Number 2, can you really saturate all the sites in the body on a sustained basis? I would argue to you that if you can bathe a patient in a menin inhibitor essentially indefinitely with no talks, that's probably the best thing you can do to delay recurrence. I think that's a good setup for ZIFTA because of its physical chemical properties, because of its tolerability.

Speaker 2

How that's going to manifest itself, that's going to take time. You're going to see it emerge in the form of resistance and then that's going to play out in survival, but that will take some time. Something I've said pretty consistently is if you show me a race between 2 drugs and they're equivalent on activity, the safest, most well tolerated, most combinable drug always wins, full stop. And I think ZYPTO is well positioned there. But there's not for people who are looking for some kind of knockout blow, that's not coming, right?

Speaker 2

This is going to be a multiplayer, hopefully multibillion dollar market that's really good for patients. We'll be competing out there. The more data we generate with ZIFTO, the more excited we become.

Speaker 8

Very helpful. Thank you.

Speaker 2

Sure. Thanks.

Operator

Your next question comes from the line of Eva Privetera with TD Cowen. Please go ahead.

Speaker 10

Hi, good afternoon. Thank you for taking our questions. So with escalation going really well in 7 and the RP2D expected midyear, when could ZYFTO potentially move into pivotal development with either chemo or VENASA combos? And what could be a potential design? Do you think MRD negativity could be a registrational endpoint?

Speaker 2

Yes. Eva, thanks. Saving the best questions for last. So in terms of timing for development, it's a little bit early. We recognize again it's a competitive landscape.

Speaker 2

I think realistically you probably wouldn't dose a patient in a pivotal until early next year. But you can imagine we're already putting the designs together on the basis of the data we've generated thus far, right. Based on what we're seeing in the 7 study, I think we're highly encouraged. It's a matter of dropping the data in to support it. A big part of that is the lead time to actually engage with global health authorities.

Speaker 2

You could potentially have the study up and running by the end of the year, but it would be very aggressive to dose a patient. I dare say it would be impossible to dose a patient, just because these things take time, right? And we do need to do the expansion to make sure that we validate the dose. As for your question about MRD, probably not an endpoint at this point. I think there are a number of parties that are working as part of a consortium to try to help the field move in that direction.

Speaker 2

It's not likely to be an endpoint, but it is likely to be supportive. We do think that there's likely to be an integrated design where you'd go with an accelerated endpoint probably based on response and then a full endpoint based on survival. And the agency has been pretty clear that's what they're looking for. Project Frontrunner, they want to see that as a first approval, but the themes of Project Frontrunner carry through to designs. How can we do a seamless design?

Speaker 2

And that's very much what we'll be looking at here in the various combinations.

Speaker 10

Thank you. That's helpful. And a quick follow-up on an earlier question about additional genetic subtypes where you're pursuing other activity. Does this patient selection algorithm enrich for the hoxnease transcriptional pathway? It

Speaker 2

so there is an association, Ava. I think we remain unconvinced that if you use hoxmece expression as your selection algorithm that that's going to work. What we're doing instead is mutations, which are a proxy for that. What's clear is this is a central node, right? This biology is fundamental to leukemia.

Speaker 2

It's wired into MCL1 to BCL2 to FLT3 to IDH. I don't think we fully understand all the wiring. So we're going to do our best and see if we can enrich for a signal. And I think we're particularly optimistic of what might be possible when you then go and layer that on top of say example, venetoclax or FLT3 or something. That might give you an extra oomph.

Speaker 2

Back in the 1a, 1b days people kind of shrugged. Everybody wants to see a CR, right? But actually blast count reduction sustained disease stabilization in this setting is really clinically meaningful and it's telling you like spend more time here, look here, it's giving you a little neon sign. So that's what we're doing. And we'll see where it goes.

Speaker 2

But it's associated with Hoxmeis, but it's not it's just an association. It's not going to be a direct correlation. I hope that helps.

Speaker 10

That helps a lot. Thank you.

Operator

Sure. I would now like to turn the call back over to Troy Wilson for closing remarks. Please go ahead.

Speaker 2

Thank you, Eric, and thank you all once again for joining our call today. We'll be participating in several investor conferences over the next couple of weeks and we look forward to seeing many of you there. In the meantime, if you have any additional questions, please feel free to reach out to Pete, to Tom or to me. Thank you again and have a good evening everyone.

Operator

Ladies and gentlemen, this concludes your conference call for today. We thank you for participating and ask that you please disconnect your lines.

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Earnings Conference Call
Kura Oncology Q4 2023
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