Good afternoon, ladies and gentlemen, and welcome to the Q4 2023 Kura Oncology, Inc. 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. [Operator Instructions] This call is being recorded on Tuesday, February 27, 2024.

I would now like to turn the conference over to Pete De Spain, Head of Investor Relations. Please go ahead..

Great, thank you, Eric. Good afternoon and welcome to Kura Oncology's fourth quarter and full-year 2023 conference call. Joining me on the call are Dr. Troy Wilson, our President and CEO and Tom Doyle, our Senior Vice President of Finance and Accounting. Before I turn the call over to Dr.

Wilson, I'd like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results.

Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company. With that, I'll now turn the call over to Troy..

Thank you, Pete, and thank you all for joining us. Let's jump right in. Last month we reported preliminary clinical data from the first 20 patients in KOMET-007, a Phase 1 dose escalation trial of our Menin inhibitor, Ziftomenib 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 four months from July to November of last year, including five newly diagnosed patients with adverse risk AML and 15 patients with relapsed refractory AML.

Ziftomenib demonstrated a highly encouraging safety and tolerability profile in combination with cytarabine plus daunorubicin or 7+3 as well as with Venetoclax plus Azacitidine enabling continuous administration of Ziftomenib while effectively mitigating the risk of differentiation syndrome.

In fact, 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 cutoff on January 11, all five newly diagnosed patients with adverse risk NPM1 mutant or KMT2A rearranged AML treated with Ziftomenib 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 Ziftomenib and Ven/Aza 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 CR/CRh rate among the nine relapsed refractory patients who were Menin inhibitor naive was 56%. As of the data cutoff, 16 of the first 20 patients remained on trial, including all 11 NPM1 mutant patients.

Continuous daily dosing of Ziftomenib 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 Ziftomenib has been cleared in both relapsed refractory Ven/Aza 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 Ziftomenib in the frontline adverse risk NPM1 mutant 7+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 Ziftomenib in combination with Ven/Aza and in combination with 7+3 by the middle of this year.

After determination of the recommended Phase 2 dose, we plan to initiate a Phase 1b dose validation expansion with Ziftomenib in Ven/Aza in newly diagnosed with patients with NPM1 mutant and KMT2A rearranged AML.

In the meantime, we're now dosing patients in our KOMET-008 study of Ziftomenib in combination with additional standards of care, including the FLT3 inhibitor, Gilteritinib, FLAG-IDA 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 cooccurring FLT3 mutations and the prognosis for these patients is particularly poor.

Preclinical data for Ziftomenib 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 Ziftomenib to become a cornerstone of therapy for patients with acute leukemias.

This belief is supported by growing investigator enthusiasm as evidenced by rapid enrollment across all of our ongoing Ziftomenib studies.

We continue to be encouraged by the rate of enrollment in KOMET-001, our Phase 2 registration directed trial of Ziftomenib 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 Ziftomenib 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 Ziftomenib was selected for the Leukemia and Lymphoma Society's Pediatric Acute Leukemia Master Clinical Trial commonly known as PedAL.

As part of the study, Ziftomenib will be evaluated in combination with chemotherapy in pediatric patients with relapsed refractory, KMT2A rearranged, NUP98-rearranged or NPM1-mutant acute leukemia.

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 precommercial activities to maximize the value of Ziftomenib and support our other pipeline assets. Now let's turn our attention to our Farnesyl Transferase Inhibitor Programs beginning with KO-2806.

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 Farnesyl Transferase Inhibitor KO-2806 to address this need.

2806 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-2806 with distinct classes of targeted therapies, including Tyrosine Kinase inhibitors and KRAS inhibitors.

In October, we began dosing patients with KO-2806 as a monotherapy in a Phase 1 dose escalation trial that we call FIT-001. FIT-001 uses an innovative design that enables us to begin dose escalation of KO-2806 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-2806 in combination with Cabozantinib in clear cell renal cell carcinoma and in combination with Adagrasib 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 Ziftomenib trials has carried over to the FIT-001 study and look forward to realizing the promise of the combinations.

If successful, we believe KO-2806 could become an ideal combination partner for multiple targeted therapies in large solid tumor indications.

Meanwhile, we continue to evaluate our first generation FTI Tipifarnib in combination with the targeted therapy Alpelisib, 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 Alpelisib, which we call KURRENT-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.

Importantly, we are encouraged that Tipifarnib continues to demonstrate a favorable safety and tolerability profile at its full dose in combination with Alpelisib. We believe this significantly derisks development of our next generation FTI KO-2806 as we begin to evaluate it in combination with other targeted therapies.

And with that, I'll now turn the call over to Tom Doyle for a discussion of our financial results.

Tom?.

Thank you, Troy, and good afternoon everyone. I'm happy to provide a brief overview of our financial results for the fourth quarter and full-year 2023. Research and development expenses for the fourth quarter of 2023 were $32.5 million compared to $22.7 million for the fourth quarter of 2022.

R&D expenses for the full-year 2023 were $115.2 million compared to $92.8 million for the prior year. The increase in R&D expenses was primarily due to increases in clinical trial costs related to our Ziftomenib and KO-2806 programs.

General and administrative expenses for the fourth quarter of 2023 were $14.2 million compared to $12.5 million for the fourth quarter of 2022. G&A expenses for the full-year of 2023 were $50.6 million compared to $47.1 million for the prior year.

Net loss for the fourth quarter of 2023 was $42.8 million compared to a net loss of $33.1 million for the fourth quarter of 2022. Net loss for the full-year of 2023 was $152.6 million compared to a net loss of $135.8 million for the prior year.

Net loss for the fourth quarter and full-year of 2023 included non-cash share based compensation expense of $7.2 million, and $28.1 million respectively. This compares to $6.8 million and $26.3 million for the same periods in 2022.

As of December 31, 2023 we had cash, cash equivalents and short-term investments of $424 million compared to $438 million 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 million in net proceeds resulting from this private placement, Kura had on a pro form basis $570 million 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'd now like to turn the call back over to Troy..

Thank you, Tom. Before we jump into the question-and-answer session, let me lay out our anticipated upcoming milestones.

For Ziftomenib, initiate the post-transplant maintenance program in the first quarter of 2024, complete enrollment of 85 patients in the KOMET-001 registration directed trial in NPM1 mutant AML by mid-2024, determine the recommended Phase 2 dose in combination with Ven/Aza and initiate dose validation expansion in frontline AML by mid-2024 and determine the recommended Phase 2 dose in combination with 7+3 by mid-2024.

For KO-2806 dose the first patients in combination with Cabozantinib in clear cell renal cell carcinoma by 2024 and dose the first patients in combination with Adagrasib in KRAS G12C mutated non-small cell lung cancer by mid-2024.

And for Tipifarnib, complete enrollment of two expansion cohorts to support determination of the optimal biologically active dose in combination with Alpelisib by the end of 2024. With that Eric, we are now ready for questions..

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

Hi, guys. Thanks for taking my questions. First question on Ziftomenib. Can you discuss your thoughts on the combinability with Ven/Aza.

And your thoughts on whether you need to adjust the dose of ven due to drug, drug interactions and potential CYP3A4 inhibition?.

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 exposure curve by dose on the right side, and on the left side some of the key points Jonathan from the 001 study. Most importantly, from the clinical data we've now generated.

The human clinical data, we can say Ziftomenib is not a clinically meaningful CYP3A4 substrate. We don't have to adjust its dose at all in the presence of azoles for example. And it is 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 Ziftomenib.

Now want to be clear the protocol does allow for the adjustment of Venetoclax dosing, if a patient for example is on an azole, that is per the label of Venetoclax, but there is no dose adjustment needed when Venetoclax is combined with Ziftomenib. So just to underscore its neither a substrate nor an inhibitor of CYP3A4..

Got it. Thanks for clarifying. And then just second question with the KOMET-008 study starting. Can you discuss the opportunity for Ziftomenib in combination with the FLT3 inhibitor? And what are your reasons for confidence in the combinability of these drugs? Thank you..

Sure. So the rationale is maybe just taking a half a step back.

When you look at the various combinations of the 007 and the 008 protocols, what our team Mollie Leoni, Stephen Dale and others on the team have endeavored to do is to provide a foundation where physicians can in principle combine Ziftomenib 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 Quizartinib studies. The extent of overlap between NPM1-mutants and FLT3-mutants is roughly 50%. That's number one.

Number two 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, Gilteritinib is very popular and the preclinical data that we've generated admittedly it's preclinical, but the preclinical data combining FLT3 inhibitors with Ziftomenib, the results are nearly curative. I mean, I'll say they're curative. 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. 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 two agents working well together. And we'll look forward to sharing our progress later this year..

Understood. Thanks for taking the questions..

My pleasure..

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

Perfect. Good afternoon and thank you for taking our questions. I'm curious about 007 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 Ven/Aza as which usually happens? Or would you necessarily discontinue the menin inhibitor at some point? And then a follow-up if I may..

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, we certainly don't see that with Ziftomenib.

To your question, which I think is well formulated, our experience has been that physicians use, I mean obviously they use seven plus three for seven days or three days as indicated. For Ven/Aza 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 Ziftomenib monotherapy, post-transplant, in a maintenance setting sort of using the air quotes.

That's how we would expect Zifto to be used, Jason, is literally from day eight. And then really only with an interruption perhaps for transplant, patients would stay on Ziftomenib 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..

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 two different menin inhibitors as more distinct versus similar? I mean, what's the feedback been like here?.

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 Ziftomenib target product profile as informed by data and we put it up against the competition, we hear sort of an overwhelming preference to use Ziftomenib, 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. 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 NPM1 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. 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..

Got it..

You had a follow-up question. Yes, sure..

That was it, but that was the follow-up. Thank you so much for the insights and color..

Our pleasure. Thank you for the questions..

Your next question comes from the line of Li Watsek with Cantor Fitzgerald. Please go ahead..

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 007 study around midyear.

Other than RP2D dose selection, would you be sharing data at higher doses? And also can you comment on if you have started to dose patients at 600 mg?.

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

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? What does that look like from again safety, tolerability, combinability? Is there any difference or are we simply giving more Zifto? 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 four cohorts are at least six patients per dose.

And I want to be careful with that. There may be additional patients simply because if we get them in screening, but we're not yet ready to escalate we might tack on a couple of more patients at a given dose. So expect six plus patients per cohort per dose and you can hear us moving pretty aggressively through these dose cohorts.

Finally, Li, 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.

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 007 a bit later this year..

Okay. And then maybe a follow-up question. Troy, you mentioned about enrollment speed here.

I mean, given the very strong data from 007 study last month, I guess, what is your expectation for the enrollment rate for the 008? And also in terms of clinical sites, what's the degree of overlap between these two studies?.

Yes. Good question. So again, I appreciate it's a two 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 007 and 008. 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.

So the front line patients obviously have front line options. For 007, once we reach the RP2D, for example, for Ven/Aza, we'll do the expansion validation in the front line, right? So that will be self-limiting. The -- I think it's early. Li, we've just really gotten going. We're sort of taking the first tentative steps on 008.

We'll have a better sense of how that's going as the weeks and months continue. 007 is going very robustly and as this 001, I think we have every expectation 008 will as well. We particularly expect to see interest in Gilteritinib. 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. So look forward to an enrollment update on 008 again the next time we have the microphone or a little later in the year..

Thank you very much..

Sure..

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

Great. Thank you so much. Thanks for the updates. I had a quick question on KOMET-007 combo.

Just why Zifto starts on day 8? There's any worries about drug, drug interaction or just the rationale there?.

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 a CYP3A4 substrate nor a CYP3A4 inhibitor. There is no to date, no observed drug.

drug interaction 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 three things, three advantages. Number one, you debulk the patient. Less disease means you have lower propensity for differentiation syndrome. You're just physically debulking the tumor.

Number two, you get a baseline safety view, so you can differentiate what are effects due to the backbone versus effects due to Zifto 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 ultimately are not eligible. 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 million 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 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..

Perfect. Thank you so much. Thanks for clarifying that. And then just on the expansion cohort, that's really interesting. So patients without NPM1 came to 2A.

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

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 001. It's not part of the registrational study, but it's part of the one protocol that is looking to dose Ziftomenib at its RP2D at 600 milligrams in patients who are neither KMT2A nor NPM1 mutant.

Why are we doing that? 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 SETD2/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 Zifto 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. 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.

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-comer's population. It is enriched, and it's enriched via an algorithm..

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

Yes. Pleasure..

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

Hi, thanks for taking the questions and congrats on the progress. So Troy, you mentioned interrogating Menin in other indications outside of acute leukemias. You mentioned, some solid tumor and, non-oncology indications.

So will that be with Zifto or NextGen molecule? And do you have an idea of when we might see some early translational data from those programs?.

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

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

Sure. Thank you..

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

Hey, thanks for taking the questions guys and congratulations on the progress. Maybe just two questions for me, Troy. One, in the prior data that you guys had already reported from 007, you talked about 10 patients who had already received prior [indiscernible] 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, Zifto, ASA combination could or should be evaluated? Or does it suggest maybe something else that, maybe Menin inhibition is resensitizing patients to BCL 2 inhibition? That's one question.

The other is more from a commercial perspective. It seems you're evaluating Zifto throughout the 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..

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.

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. 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. Dr. Mollie Leoni, 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 LDAC might be an attractive way to do that. You heard me answer the question on FLT3. That's another option.

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 007 study in Ven/Aza, 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. 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? Are we interacting with BCL2 to re-sensitize the tumor. We're still figuring that out. What does appear to be clear is that menin inhibitors plus ven are better than ven alone. That seems clear.

To your question, I don't think you would go menin aza. 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 Ven/Aza menin or can the -- will the doublet suffice? And that's something you just have to figure out empirically. But going back to 007, 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..

Great. Thanks for taking the questions..

Sure..

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

Hey, good afternoon.

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

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. 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 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 milligrams 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. That's the critical datapoint to look for.

The durability will come in time, and I think we're cautiously optimistic it will inform in the right direction..

Okay. 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 Ven/Aza 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 1, 2 studies?.

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 one.

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. The second is, one of our competitors presented data in a post-transplant maintenance study, and you can look at the rate of dose reduction or interruption or discontinuation due to AEs.

And with several menin inhibitors we're seeing a high rate of Thrombocytopenia that is not on mechanism. That's something else. We don't see that a couple of the other compounds don't see that, but that is a characteristic of some menin inhibitors. So I think, Brad, it's going to go kind of both directions.

Number one, can you keep constant pressure and constant exposure? Number two, 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 Zifto, because of its physical chemical properties, because of its tolerability. 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 two drugs and they're equivalent on activity, the safest, most well tolerated most combinable drug always wins.

And I think Zifto is well positioned there, but there's not for people who are looking for some kind of knockout blow, that's not coming, right? This is going to be a multi-player, hopefully multi-billion 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..

Very helpful. Thank you..

Sure. Thanks..

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

Hi, good afternoon. Thank you for taking our questions.

So with escalation going really well in 007 and the RP2D expected mid-year, when could Zifto potentially move into pivotal development with either chemo or Ven/Aza combos? And what could be a potential design? Do you think MRD negativity could be a registrational endpoint?.

Yes. Eva, thanks. You 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. 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 007 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.

You could potentially have the study up and running by the end of the year, but it would be very aggressive to dose the 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. 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 end point 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? And that's very much what we'll be looking at here in the various combinations..

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 HOX/MEIS transcriptional pathway?.

It -- so there is an association, Eva. I think we remain unconvinced that if you use HOX/MEIS 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.

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 on.

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.

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

That helps a lot. Thank you..

Sure..

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

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..

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