Full Year 2023 Kura Oncology Inc Earnings Call

Operator: Good afternoon, ladies and gentlemen, and welcome to the Q4 2023 Kura Oncology Incorporated Financial Results Conference. At this time, all lines are in listen-only mode.

Good afternoon, ladies and gentlemen, and welcome to the Q4 2023, Kura oncology incorporated financial results Conference call.

At this time all lines are in listen only mode.

Operator: Following the presentation, we will conduct a question and answer session. If at any time during this call you require immediate assistance, press star zero for the. This call is being recorded on Tuesday, February 26th. I would now like to turn the conference over to... Spain, Head of Investor Relations. Great. Thank you, Eric.

Following the presentation, we will conduct a question answer session.

But any time during this call you require immediate assistance. Please press star zero for the operator.

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 occur oncology 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.

Pete: 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.

Pete: 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 those expected. 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.

Before I turn the call over to Dr. Wilson I would like to remind you that today's call will include forward looking statements based on current expectations such statements represent managements judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to <unk> filings with the SEC, which are available from.

The SEC or on the Kerr 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 comment zero-zero seven phase one dose.

Troy Wilson: 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-007, the phase one dose escalation trial of our menin inhibitor, Zifto-Menin, 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 Ziftomenib demonstrated a highly encouraging safety and tolerability profile in combination with Cytarabine plus Donorubicin or 7 plus 3, as well as with Benetoclax 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.

Collation trial, if our Menin inhibitor <unk> in combination with standards of care in patients with N. P. M. One meeting and K M. Teach you a 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 <unk>.

<unk> patients with relapsed refractory AML zip.

<unk> demonstrated a highly encouraging safety and tolerability profile in combination with cytarabine, plus down a ribbon or seven plus three as well as with Venetic lax plus as decided in enabling continuous administration of lift a minute while effectively mitigating the risk of differentiation syndrome in fact no.

<unk> syndrome events of any grade were reported among the first 20 patients. Furthermore, no dose limiting toxicities Q T C prolongation drug drug interactions or additive Milo suppression were observed.

Troy Wilson: 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 Ziftometab and 7 plus 3 achieved a complete remission with full count recovery for a CR rate of 100 percent. The overall response rate among the 15 relapsed refractory patients treated with Ziptomenib and Veneza was 53 percent, including a 40 percent ORR among the 10 patients who had received prior Venetoclax, a setting with very limited effective treatment options. Notably, the CRCRH rate among the nine relapsed refractory patients who were menin inhibitor nave 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 mg QD was well tolerated, and the safety profile was consistent with features of the underlying disease and backbone therapy.

As of the data cutoff on January 11th all five newly diagnosed patients with adverse risk N. P. M. One Newton are Kmt to a rearranged AML treated with Ziff demand had been seven plus three 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 <unk> had been venues that with 53%, including a 40% or are among the 10 patients who had received prior venetic lacks a setting with very limited effective treatment options, notably to see our CRH rate among the nine relapsed refractory.

Patients who were menin inhibitor naive was 56%.

As of the data cut off 16 of the first 20 patients remained on trial, including all 11 N P. M. One mutant patients.

Continuous daily dosing of <unk> Ziff demanded at 200 milligrams QD was well tolerated and the safety profile was consistent with features of underlying disease and backbone therapies.

Troy Wilson: As we reported on January 30th, the 200 mg dose of Zyptominib has been cleared in both relapsed refractory venasa cohorts and enrollment at the 400 mg dose continues. In the meantime, I'm pleased to report we've also escalated to the 400 mg dose of Zifcominib in the frontline adverse risk NPM1 mutant 7 plus 3 cohort, and we anticipate clearing the 200 mg dose in the At this rate, we expect to determine the recommended phase 2 dose for ziftominib in combination with venasa and in combination with 7 plus 3 by the middle of this year. After determining the recommended phase 2 dose, we plan to initiate a phase 1b dose validation expansion with ziftominib and venasa in newly diagnosed patients with NPM1 mutant and KMT2A rearranged AML.

As we reported on January 30th the 200 milligram dose and zipped a minute has been cleared in both relapsed refractory then Asia 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 doses if demand had been the frontline adverse risk N P. M. One mutant.

Seven plus three cohorts.

And we anticipate clearing the 200 milligram dose in the frontline K M. T. Two a rearranged seven plus three cohort shortly.

At this rate, we expect to determine the recommended phase two dose for <unk> in combination with than Asia and in combination with seven plus three by the middle of this year. After determination of the recommended phase two dose we plan to initiate a phase one b dose validation expansion, which if demand had been venues that in.

Newly diagnosed with Ah patients with MTM, one mutant and K M T. Two a rearranged AML.

Troy Wilson: In the meantime, we're now dosing patients in our COMET-008 study of zyptomimib in combination with additional standards of care, including the FLIP3 inhibitor giltirritinib, 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 FLIP3 mutations, and the prognosis for these patients is particularly poor.

In the meantime, we're now dosing patients in our comment 008 study of <unk> in combination with additional standards of care, including the flip three inhibitor Gil to written nib flag Ida or L. DAC all for the treatment of relapsed refractory M. P. M. One mutant or K M. T. Two a rearranged AML roughly half.

Patients with relapsed or refractory N P. M. <unk> mutant AML have co occurring slipped three mutations and the prognosis for these patients is particularly poor.

Troy Wilson: Preclinical data for ziftominib in combination with FLIP3 inhibitors demonstrate 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 Ziftamedib to become a cornerstone of therapy for patients with acute leukemia. This belief is supported by growing investigator enthusiasm, as evidenced by rapid enrollment across all of our ongoing zyptomimib studies. We continue to be encouraged by the rate of enrollment in COMET-001, our Phase II registration-directed trial of ziftominib in patients with relapse, 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 Zyptomenib was selected for the Leukemia and Lymphoma Society's Pediatric Acute Leukemia Master Clinical Trial, commonly known as PETL. As part of the studies, Defdomenib will be evaluated in combination with chemotherapy in pediatric patients with relapsed refractory, KMT2A rearranged, NUP98 rearranged, or NPM1 mutant acute leukemia.

Preclinical data for Ziff demand had been combination was slipped three inhibitors demonstrate strong synergistic effects compared to either a single agent alone.

We believe a best in class safety and activity profile and optimum pharmaceutical properties will enable <unk> to become a cornerstone therapy for patients with acute leukemias. This belief is supported by growing investigator enthusiasm as evidenced by rapid enrollment across all of our ongoing Zip de minimus studies.

We continue to be encouraged by the rate of enrollment and comment 001.

Our phase II registration directed trial of Ziff demanded in patients with relapsed refractory N. P. M. One 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 ziff demanded but across the continuum of care for all patients with acute leukemias, whose disease is driven by the men and pathway, including pediatrics, where poor outcomes. Unfortunately remain.

In December we announced zipped amended was selected for the leukemia and lymphoma society pediatric acute leukemia master clinical trial, commonly known as pedal as.

As part of the studies if demand it will be evaluated in combination with chemotherapy in pediatric patients with relapsed refractory Kmt <unk> rearranged net 98 rearranged or M. P. M. One mute in acute leukemia.

Troy Wilson: 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 an 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 are 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 Zift Amenib and support our other pipeline assets. Now, let's turn our attention to our farnesyl transferase inhibitor programs, beginning with KO-2806. Despite the success of targeted cancer drugs, such as tyrosine kinase inhibitors and KRAS inhibitors, a considerable need remains to drive enhanced anti-tumor activity while addressing mechanisms of innate and adaptive resistance.

In addition, we recently began dosing patients with Kmt chewy 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 N. P. M. One mutant nor K M T. Two a 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 lift Amanda and support our other pipeline assets now lets turn our attention to our Farnesol transfer Ace inhibitor programs beginning with.

K O 28 of six <unk>.

Despite success of targeted cancer drugs, such as tyrosine kinase inhibitors, and K Ras inhibitors, a considerable need remains.

To drive enhanced antitumor activity, while addressing mechanisms of innate and adaptive resistance. We are developing our next generation Farnesol transfer Ace inhibitor K O 20, 806 to address this need.

Troy Wilson: We are developing our next-generation farnesyl transferase inhibitor, KO2806, to address this need. 2806 was designed to improve upon the potency, pharmacokinetic, and physiochemical properties of earlier FTI drug candidates. Last year, we presented compelling preclinical data supporting the rationale for combining KO2806 with distinct classes of targeted therapies, including tyrosine kinase inhibitors and KRAS inhibitors. In October, we began dosing patients with KO-2806 as monotherapy in a Phase I 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 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 adigrassib in KRAS-G12c mutated non-small cell lung cancer by the middle of this year.

$28 six was designed to improve upon the potency pharmacokinetic and Physiochemical properties of earlier F. T. I drug candidates last year, we presented compelling preclinical data supporting the rationale for combining K O 20, 806 with distinct classes of targeted therapies, including tyrosine kinase inhibitor.

N K Ras inhibitors in October we began dosing patients with K O 28, a six as a monotherapy in a phase one dose escalation trial that we call fit 001001 uses an innovative design that enables us to begin dose escalation of K O 26 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 <unk> 28, a six in combination with Cabozantinib in clear cell renal cell carcinoma and in combination with <unk> in <unk> mutated non small cell lung cancer by the middle of this year.

Troy Wilson: Recall that 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 ZIF-DOMINIB trials has carried over to the FIT-001 study and look forward to realizing the promise of the combinations. If successful, we believe KO2806 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 alpelesib, building on the impressive clinical benefit we observed with tipifarnib alone in head and neck cancer.

In November we announced a clinical collaboration and supply agreement with Marathi Therapeutics now Bristol Myers Squibb to support that ladder study.

We're encouraged that the strong operational execution seen in the <unk> trials has carried over to the fit of one study and look forward to realizing the promise of the combination if successful we believe K O 28, or six could become an ideal combination partner for multiple targeted therapies and large solid tumor indications.

Meanwhile, we continue to evaluate our first generation F T I tip of foreign it in combination with targeted therapy I'll palisade building, an impressive clinical benefit we observed with <unk> alone in head and neck cancer. We continue to evaluate patients in the dose escalation study of tip. Your foreign had been now palisade, which we call current agent.

Tom Doyle: We continue to evaluate patients in the dose escalation study of tipifarnab and nalpelisib, which we call current HN. Given the 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 tibifarnib continues to demonstrate a favorable safety and tolerability profile at its full dose in combination with alpelasib. We believe this significantly de-risks the development of our next-generation FTI, KO2806, as we begin to evaluate it in combination with other targeted therapies. With that, I'll now turn the call over to Tom Doyle for a discussion of our financial results. Tom?

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 aubade later this year will determine the next steps for the program importantly, we are encouraged that to be foreign it continues to demonstrate.

A favorable safety and Tolerability profile at its full dose in combination with our policy. We believe this significantly de risks development of our next generation F. T. I K a 28 six as we begin to evaluated in combination with other targeted therapies and with that I'll now turn the call over to Tom Doyle for a discussion.

One of our financial results Tom.

Tom Doyle: 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 Zipto-Menib 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.

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 of 2023 for $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 ours. If the amended 10-K O 22 six 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.

Tom Doyle: G&A expenses for the full year of 2023 were $50.6 million compared to $47.1 million for the prior year. The 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. The 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. The 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.

G&A expenses for the full year of 2023 were $56 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 noncash 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.

Okay.

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.

Tom Doyle: 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 investigators. As adjusted for the approximately $146 million in net proceeds resulting from this private placement, Kura had, on a pro forma basis, $570 million in cash, cash equivalents, and short-term investments.

Subsequently on January 26, 2024, we completed an oversubscribed private placement with a select group of institutional and accredited healthcare specialists investors.

As adjusted for the approximately 146 million in net proceeds resulting from this private placement, perhaps on a pro forma 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'll now 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 <unk> initiate the post transplant maintenance program in the first quarter of 2024 complete enrollment of 85 patients in the comment 001 registration directed.

Troy Wilson: 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 Tom. Thank you, Tom. Before we jump into the question and answer session, let me lay out our anticipated upcoming milestones. For Zift Amenib, we will initiate the post-transplant maintenance program in the first quarter of 2024. Enrollment of at least 85 patients in the Comet-001 registration-directed trial in NPM1 mutant AML by mid-2024.

Trial in N P. M. One mutant AML by mid 2024 determined the recommended phase two dose in combination with Ven Asa and initiate dose validation expansion in frontline AML by mid 2024 and determined the recommended phase two dose in combination with seven plus three by mid 2024 for Kayo Twenty-eight Oc.

Six dose the first patients in combination with Cabozantinib in clear cell renal cell carcinoma by mid 2024 and dose the first patients in combination with that aggressive NK rescue 12 C mutated non small cell lung cancer by mid 2024.

Troy Wilson: Determine the recommended phase 2 dose in combination with Venasa and initiate dose validation expansion in frontline AML by mid-2024. And determine the recommended phase 2 dose in combination with 7 plus 3 by mid-2024. For KO2806, dose the first patients in combination with cabizantinib in clear cell renal cell carcinoma by mid-2024.

And for TP foreign to complete enrollment of two expansion cohorts to support determination of the optimal biologically active dose in combination with our Palo said by the end of 2024 with that Eric We're now ready for questions.

Yeah.

Thank you.

Ladies and gentlemen, we will now begin the question and answer session should you have a question. Please press the star followed by the one on your Touchtone phone.

Operator: And dose the first patients in combination with adagrassib in KRAS G12C mutated non-small cell lung cancer by mid-2024. And for Tippi Farnab, complete enrollment in two expansion cohorts to support determination of the optimal biologically active dose in combination with alpelicib by end-2024. With that, Eric, we're now ready for questions. Thank you. Ladies and gentlemen, we will now begin the question and answer session. If you have a question, please press the star followed by the 1 on your touch screen. You will hear a three-tone prompt acknowledging your request.

You'll hear three torn prompt acknowledging your request and the questions will be pulled in the order their receipt.

Should you wish to decline from the polling process. Please press the star followed by the two.

If you are using a speaker phone please lift the handset before pressing any keys.

Your first question comes from the line of Jonathan Chang with Leerink partners.

Please go ahead hi, guys.

Oh, Hey, guys. Thanks for taking my questions.

First question on <unk> can you discuss your thoughts on the combinability with Vanessa.

Your thoughts on whether you need to adjust the dose of <unk> due to drug drug interactions and potential <unk> four inhibition.

Yeah.

Sure Jonathan Thanks for the question.

So I'll actually direct folks.

And Theres a revised slide in our corporate deck, if you want to take a look at it.

Operator: Questions will be pulled into the ordered area. Do you wish to decline from the polling process? Press the star followed by the, If you are using a speakerphone, please lift the handset before pressing the button.

Has the 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.

Jonathan Chang: The first question comes from the line of Jonathan Chang with Lyrinc Partners. Please go ahead. Hi guys, thanks for taking my question. First question on Zift-O-Menib: 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 interaction and potential CYP3A4 inhibition? Sure, Jonathan, thanks for the question. So I'll actually direct folks to, 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, you know, from the clinical data we've now generated, the human clinical data, we can say zyptomenib 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.

Most importantly from the clinical data, we've now generated the human clinical data, we can say ZIP demand. It is not a clinically meaningful sip three four in substrate we.

We don't have to adjust its dose at all in the presence of <unk> for example, and it is not also not a clinically meaningful Sip three <unk> four inhibitor.

In other words to your specific question, we don't have to adjust the dose of venetic lax, which is a sip three eight for substrates in the presence of uplift a minute now I want to be clear. The protocol does allow for the adjustment of venetic lacks dosing if a patient for example is on the nasal that is per.

The label of Venetic, lax, but theres no dose adjustment needed when venetic classes combined with symptomatic. So just to just to underscore it's neither a substrate nor an inhibitor of <unk> three or four.

Okay.

Got it thanks for clarifying.

And then just second question with the comment 008 study starting.

Jonathan Chang: 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 zyptomenib. Now, I 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 So just to emphasize, it's neither a substrate nor an inhibitor of CYP3A4. Got it.

Can you discuss the opportunity for just a minute in combination with a <unk> inhibitor.

And what are your reasons for confidence in the combinability of these drugs. Thank you.

Yeah.

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.

But our team Molly Leontes, Stephen Dale and others on the team I have endeavored to do is to provide a foundation where physicians can in principle combined zip demanded with any available standard of care, giving the maximal flexibility as they're dealing with patients in various lines of therapy.

Troy Wilson: Thanks for clarifying. And then just a second question, with the COMET008 study starting, can you discuss the opportunity for ZIF-dominib in combination with a FLT3 inhibitor? And what are your reasons for confidence in the combinability of, Thank you.

More specifically to your question about flit three so flip three mutants are represent roughly half of the NPM one population.

Troy Wilson: Sure, so... The rationale is, maybe just taking a half step back, when you look at the various combinations of the 007 and the 008 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 Zip2Medib with any available standard of care, giving them maximal flexibility as they're dealing with patients in various So, FLIP3 mutants represent roughly half of the NPM1 population. And you can see that, for example, in the giltaritinib and quisartinib studies. The extent of overlap between NPM1 mutants and FLIP3 mutants is roughly 50 percent.

You can see that for example in the in the Gilts written they have been in the <unk> studies.

To the extent of overlap between N P. M. One mutants and flood three 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 Rx and in our discussions with physicians Gil to written there is very popular and the preclinical data that we've generated admittedly, it's preclinical, but the preclinical data combining flip three inhibitors with ziff demand Ed. The results are are nearly curative.

Say theyre 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.

Troy Wilson: That's number one. Number two is, if we could provide those patients with an all-oral, you know, targeted therapy regimen that was effective and well-tolerated, we think that would be broadly embraced. In our discussions with physicians, giltaritinib is very popular, and the preclinical data that we've generated, admittedly, it's preclinical, but the preclinical data combining FLIP3 inhibitors with ziftominib, the results are nearly curative. I mean, I'll say they're curative. But I use that word, you know, carefully.

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 flip three inhibitors. However, we think that by sequencing and sort of careful monitor.

Ring and mitigation, we will 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 we're feeling optimistic that we'll be able to to find a dose and schedule that gets those two agents are working well together and we'll look forward.

Troy Wilson: But the potential, Jonathan, to have an all-oral regimen that could drive such profound clinical benefit in patients, we think would be very attractive. So, it's a huge slice of the population. The possibility of an all-oral regimen and something approaching, you know, a cure with, you know, excellent tolerability. In terms of managing safety, the thing that really that we just want to make sure we pay attention to is the potential for differentiation syndrome, which was observed with the FLIP3 inhibitors.

Sharing our progress later this year.

Understood. Thanks for taking the questions.

My pleasure.

Okay.

Okay.

Your next question comes from the line of Jason Domanski.

With bank of America.

Please go ahead.

Perfect. Good afternoon, and thank you for taking our questions.

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 of maybe to keep them on ziff toe and maybe pull back on van Asos, which usually happens.

Troy Wilson: However, we think that, you know, 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, you know, 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, you know, sharing our progress later this year. Understood. Thanks for taking the time to ask the question. My pleasure. My next question comes from the line of Jason Zemansky. Bank of America, Good afternoon.

Hum.

Would you necessarily discontinue the menin inhibitor at some point and then a follow up if I may.

Yeah, Jason Thanks for the questions. So.

Importantly.

And you heard it in the prepared remarks, we don't see any additive Milo suppression and.

And as a result, we don't have to hold the dosing of Ziff deal at all to allow counts to recover.

Jason Zemansky: I'm curious about 007, as the patients continue to hopefully... In the past, we have seen people 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 Xifto and maybe pull back on Venaza, which usually happens? Would you necessarily discontinue the menin inhibitor at some point?

At one time it was thought that there might be a class effect. We certainly don't see that was just a minute to your to your question, which I think is the well formulated our experience has been that physicians use I mean, obviously they use seven plus three.

Four seven days or three days at has indicated for van as they're using it to really drive the clinical activity and then they are pulling back their keeping patients on ziff dough I think our intent and sort of what we're seeing is that these patients are staying on ziff do if they go to transplant they might take.

Troy Wilson: Yeah, Jason, thanks for the question. So, importantly, as you heard 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, you know, there might be a class effect; we certainly don't see that with ZIFTO-MENIP.

Break while they are conditioning for transplant, but then they are coming back on to <unk> monotherapy.

Post transplant.

And Ah.

In a maintenance setting sort of using the air quotes that's how we would expect ZIP code to be used Jason is is literally from day eight and then really only within interruption, perhaps for transplant patients would stay on ziff demanded until disease progression or.

Troy Wilson: To your question, which I think is well formulated, our experience has been that physicians use, I mean, obviously, 7 plus 3, you know, for 7 days or 3 days, as indicated. For Veneza, 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, you know, conditioning for transplant, but then they're coming back on ZIFTO. But then they're coming back on to ZIFTO-MENIP monotherapy post-transplant, you know, in a maintenance setting, you know, sort of using the air quotes. That's how we would expect ZIFTO to be used, Jason, literally from day 8, and then, perhaps, for transplant, patients would stay on ZIFTO-MENIP, you know, until disease progression or, you know, or the alternative. And we haven't had patients on long enough to say, you know, do they no longer need to be on ZIFTO? Have we cured them of the disease?

Or the alternative and we haven't had patients on long enough to say do they no longer need to be on Ziff Dow have we cured them of the disease.

That's a dream but.

That's that's for someday in the future.

Got it and then looking at your timelines.

Thinking about the bigger commercial dynamics here youre potentially looking at a scenario, where you may be next to market Menin inhibitor and the N P M one space with potentially better efficacy.

Or 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 minute inhibitors as more distinct versus similar I mean, what what's the feedback then like here.

Troy Wilson: That's a, you know, that's a dream, but, you know, that's for some day in the future, 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 metenin inhibitor in the NPM1 space with potentially better efficacy. How are you thinking about launching into this space?

Yeah. So look we've done a small amount of.

Sort of pre commercial work with with physicians and what we found is when we profiled the Ziff day minute target product profile is informed by data and we put it up against the competition, we hear sort of an overwhelming preference to use if demand is primarily driven by baidu.

Troy Wilson: I guess what I'm really driving at here is, at this stage, do you get the sense that the community sees the two different menin inhibitors as more distinct versus similar? I mean, what's the feedback been? Yeah, so, you know, we've done a small amount of sort of pre-commercial work with physicians, and what we found is when we profile the ZIF-dominant target product profile as informed by data, and we put it up against the competition, we hear sort of an overwhelming preference to use ZIF-dominant, primarily driven by safety and tolerability. No, you know, no CYP3A4 liability, no dose- So, and I'm, you know, 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.

The safety and Tolerability no no Sip three eight for liability no dose limiting toxicity and I think that's only going to continue and get amplified Jason as we 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 NPM one setting.

To my knowledge, neither study has yet completed enrollment.

Maybe there are some updates today from 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 enrolment is objective and in rock enrolment 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.

Troy Wilson: To my knowledge, neither study has yet completed enrollment. I, you know, 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, you know, again, I keep going back to our enrollment because all other data points, you know, they can be shaded in various ways. Enrollment is the objective.

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.

Sure that was it but but.

That was the follow up thank you so much for that and the insights and color.

Our pleasure thank you for the questions.

Okay.

Your next.

Troy Wilson: Enrollment is difficult to argue with, and we've already, you know, 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. Enrollment speaks for itself, and we expect to see that pull through into the commercial marketplace.

Comes from the line of Lee <unk> with Cantor Fitzgerald. Please.

Please go ahead.

Hey, good afternoon, congrats on the progress.

Maybe just a couple follow up questions from me.

I'm just wondering if you can clarify the plans for data disclosure for instance, there was seven around next year.

Lee Watek: You had a follow-up question. Yeah, sure. That was the follow-up. Thank you so much for the insights and comments. Our pleasure. Thank you for the question. Your next question comes from the line of Lee Watek with Cantor Fitzgerald. Hi. Good afternoon.

Other than RP QD dose selection when can be sharing data at higher doses and also can comment on if you have started to dose patients at cat 600 Meg.

Troy Wilson: Congratulations on the progress. Maybe just a couple follow-up questions from me. You know, just wondering if you can clarify the plan for data disclosure for the 007 study around mid-year. You know, other than RP2D dose selection, would you be sharing data at higher doses? And also, can you comment on whether you have started to dose patients at 600 milligrams? Yeah. So thanks, Lee, for the questions. Let me take them in reverse order.

Yeah. So thanks Lee for the question, let me take them in reverse order. So as of today no. We havent started yet dosing patients at 600 I think you can you can hear from US we're encouraged thus far by what we're seeing and as you know from the mono therapy. 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 it was just about a month ago.

Troy Wilson: So as of today, no, we haven't yet started dosing patients at 600. 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.

Safety Tolerability Combinability, and then some early signs of activity.

The next logical update ideally you you said it in your question I think it's right is around the RP two D are we able to dose escalate.

What does that look like.

Again safety Tolerability Combinability is there any difference or are we simply giving more ziff Dell.

Troy Wilson: At that point, we had 20 patients 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 the safety, tolerability, and combinability perspectives? 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.

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 moving pretty pretty aggressively through these dose cohorts finally, lee as to timing.

Troy Wilson: When we give an update, we'll give an update on all the patients in the study. And you can tell, everyone probably remembers, each of these four cohorts has at least six patients per dose. And I want to be careful with that.

There I think we're keeping all the options open I, obviously, we're going to have a presence at ehealth. It's it's one of the most important he 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 right.

Troy Wilson: 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, Lee, as to timing, I think we're keeping all the options open. Obviously, we're going to have a presence at EHA.

Other than sort of being necessarily constrained by the precise timing of a medical meeting.

We still have lots of time until that happens and we're making good progress.

And we will certainly look forward to giving a more fulsome data update on O seven a bit later this year.

Okay, and then maybe a follow up question.

Troy Wilson: 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.

Joey you mentioned about enrollment speed here I mean, given the very strong data from seven study last month I guess, what is your expectation for taking problem then for the Gen.

Troy Wilson: I think we know what people are looking for, and we want to make sure we have that data rather than being necessarily constrained by the 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 O07 a bit later this year. Okay, and then maybe a follow-up question. Sure.

Eight and also in terms of when call sites, what's the degree of overlap between these two study.

Yeah. Good question. So again I appreciate it's a two part question, let me take the second part first because its a little easier.

At this point theres sort of minimal overlap between <unk> seven and OE.

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

We're trying not to create situations, where where sites are are competing although the trial that they go onto is largely driven by the line of therapy. So the frontline patients. Obviously are frontline options 4007, once we reach the <unk> for example for <unk>, we will do the expansion validation.

Troy Wilson: Yeah, good question. So again, I understand it's a two-part question. Let me take the second part first, because it's a little easier.

The frontline right, so that that will be self limiting.

Troy Wilson: At this point, there's sort of minimal overlap between 007 and 008. You know, 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 frontline patients obviously have frontline options. For 007, once we reach the RP2D, for example, for Veneza, we'll do the expansion validation in the front line, right? So that will be self-limiting. I think it's too early.

The.

I think it's early we've we've just really.

<unk> gotten going we're sort of taking the first tentative steps on 008, we'll have a better sense of how that's going is as you know.

The weeks and months continue Oh, seven is going very robustly and as is <unk>.

One I think we have every expectation, we'll as well, we particularly expect to see interest in Gil to retina.

Troy Wilson: You know, Lee, 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, as is 001. I think we have every expectation that 008 will do so as well.

The investigators fondly referred to.

To do this study is as you know the flit three study.

I think they are excited to see this combination and we're excited too.

Troy Wilson: We particularly expect to see interest in giltaritinib. 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, you know, again, the next time we have the microphone or a little later in the year. Thank you very much.

To get going on this study and begin to get some experience. So look forward to an enrollment update on O. Eight again. The next time, we have the microphone or a little later in the year.

Thank you very much.

Sure.

Yeah.

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

Please go ahead.

Great. Thank you so much thanks for the updates.

Peter Lawson: Thank you for your time. Thank you. Your next question comes from the line of Peter Lawson with Barclays. Great, thank you so much.

I had a quick question on <unk> com.

Just why is if those stops on day eight.

Troy Wilson: I had a quick question on, Thank you. Thank you. Yeah. So, actually, the opposite, Peter.

Any worries about drug drug interaction.

The rationale.

Yeah. So so actually the opposite Peter So I don't know if you heard the answer to the question that Jonathan asked but there is a new slide in our corporate presentation that I would do.

Troy Wilson: 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, to date, no observed drug-drug interaction, full stop, right, in anything that we've seen The rationale for the day eight start is actually pretty simple.

Direct everybody to that says as clearly as we can say it.

<unk> is neither a sip 384 substrate, nor a <unk> four inhibitor. There is no to date no observed drug drug interaction.

Full stops right in anything that we've seen either monotherapy or combo. The rationale for the day eight start is actually pretty simple.

Troy Wilson: It gives you three things, three advantages. Number one, you debulk the patient. Less disease means you have, you know, a 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.

It gives you. It gives you three things three advantages number one you'd debulk the patient less disease means you have.

Lower propensity for differentiation syndrome.

Physically de bulking, the tumor number two you get a baseline safety view.

So you can differentiate what's what are effects due to the backbone versus effects due to <unk> Ziff deal plus the backbone and number three it gives you time to ensure that you are enrolling the right patients, particularly NPM one sometimes the turnaround time take several days and so you want to make sure that you know.

Troy Wilson: And number three, it gives you time to ensure that you're enrolling the right patients. Particularly with NPM1, sometimes the turnaround time takes several days, and so you want to make sure that, you know, you're not losing slots on patients who aren't, you know, 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, you know, we have a continued good relationship with them.

Youre not youre, not losing slots on patients who arent, who ultimately are not are not eligible those are the three reasons and 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.

I 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 and commercialization in the market I think that was very good advice. It is.

Troy Wilson: They actually encouraged us to do that staggered dosing in all of our combos for exactly the reasons that I enunciated to you. And, you know, these are folks who do research, development, and commercialization in the market. I think that was very good advice.

Troy Wilson: It has served the program well. Thank you. And then just on the expansion coho... And this is really interesting. So patients without NPM1, CAM22A, are there particular mutations you're targeting, or is that correct? The all-comers approach? Just curious, how. Yeah.

Served the program well.

Perfect. Thank you so much thanks for clarifying that and then just on the expansion cohort.

Really interesting so patients without A&P and one came to two way.

Are there particular mutations you're targeting or is that kind of an all comers approach just curious on.

How are you.

Troy Wilson: 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 001 protocol that is looking to dose zyptomenib at its RP2D at 600 mg in patients who are neither KMT2A nor NPM1 mutants. Why are we doing that?

Focus.

Yes. So thanks for the question so so to clarify for everyone.

In the prepared remarks, we announced that we dosed the first patient in.

In addition to 001, it's not part of the Registrational study, but it's part of the yellow one protocol that is looking to dose <unk> added to our <unk> at 600 milligrams in patients who are neither <unk>, nor NPM one mute at why are we doing that well.

Troy Wilson: Well, if you go back to the results from phase 1A and 1B, you'll recall we saw a number of patients, multiple patients, who had evidence of clinical benefit, blast count reduction, and disease stabilization. We even went so far as to a patient with a CETD2 RUNX1 mutant who had a CR at the 100 mg dose. At that time, I don't think we understood, A, how to use Zypto as well as we do today, and, B, really what to look for. And investigators confused differentiation and progression. They're no longer making that mistake.

You go back to the results from the phase one a one b youll 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 set date to run X one double mutants who has.

A CR at the 100 milligram dose.

At that time, I don't think we understood how to use if DAU as well as we do today and be really what to look for and investigators confused in some cases differentiation and and two progression there are no longer making that mistake. So now it's a great time to go back into that population it could.

Troy Wilson: So, now it's a great time to go back into that population, which could be as much as 10 to 15 percent of AML, and ask the question, what do we see as monotherapy? If we see evidence of clinical benefit, we might pursue it as monotherapy. Or 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-comers population.

B 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 mono therapy, 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.

Select it 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 comers population it is enriched and its enriched via an algorithm.

Troy Wilson: It is enriched, and it's enriched via an algorithm. Got it. Perfect. Thank you so much.

Got you perfect. Thanks, so much really appreciate it.

Jason Zemansky: Yep, pleasure. Your next question comes from the line of Justin Zelen with BTIG. 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 another next-gen molecule? And do you have an idea of when we might see some early translational data from this program? Yeah, Justin. A really good question.

Yes pleasure.

Okay.

Your next question comes from the line of Justin Zelman with BT I G.

Please go ahead.

Hi, Thanks for taking the questions and congrats on the progress so you.

You mentioned <unk>.

Interrogating men in in other indications outside of acute leukemia, as you mentioned, some solid tumor and non oncology indications so will that be with the <unk> or next gen molecule and do you have an idea of when we might see some early translational data from those programs.

Yes, Justin really good questions. So, let's tease those two those two parts apart.

Troy Wilson: So let's tease those two parts apart. We really view ZIFTO-MENIB as having ideal properties for oncology applications. And I'll confess to you, it was partly by design and partly by good fortune.

We really view <unk> as having an ideal ideal properties for oncology applications.

And ill confess to you it was partly by design and partly by good fortune.

Troy Wilson: 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 know, 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 the execution of the clinical trial because, you know, look, let's be honest. This is a competitive field, and we view ourselves as scientific innovators.

As you know Zipcode accumulates it has very high tissue penetrates it.

Essentially you are saturating the tissues with high concentrations of Menin inhibitor and there is 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 four non oncology applications. You may actually want to have somewhat of a different pro.

While 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 are waiting to share the translational data until we're further along towards execution of the clinical experiment because like.

Let's be honest this is a competitive field.

We view ourselves as scientific innovators.

Troy Wilson: You know, 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 will share with you some of that 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, you know, multiple options there. Great. I'm looking forward to it.

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 will do the oncology solid tumor experiment, Justin we think with Ziff dough.

The other applications I think we're leaving that open and we will 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 my questions.

Jason Zemansky: Thanks for taking the question. Sure, thank you. The next question comes from the line of Wren Benjamin.

Sure. Thank you.

Okay.

The next question comes from the line of Ren Benjamin.

With citizens JMP.

Please go ahead.

Hey, Thanks for taking the questions guys and congratulations on the progress.

Wren Benjamin: Um, maybe just two questions- in the prior data that you guys talked about, and I don't know if this was asked... This suggests that, of that reg, and others. Thank you. Thank you, and I suggest maybe something else.

Just two questions from me Troy one in the prior data that you guys had had already reported from O. Seven you talked about 10 patients who had already received prior vanadic clocks and and you were still seeing a 40% or are and I don't know if this was asked before or not but does this suggest that then could potentially be.

<unk> taken out of that regimen, and a less toxic call. It ziff DAU as a combination.

Could or should be evaluated.

Or does it suggest maybe something else that you know maybe menin inhibition is re sensitizing patients to bcl two inhibition.

Troy Wilson: That's one question. The other is more from a, You know, it seems, you know, you're evaluating ZYFTA throughout, and it might actually result in something about cannibalization Lateral. How does this work? In the real world, there are all these combinations.

That's one question the other is more from a commercial perspective.

It seems you're evaluating ziff, though throughout the continuum of AML treatment and it might actually result, if I'm thinking about this right and the cannibalization of Ziff dough in later lines of treatment. So.

How does this work in the in the real World you know as you're kind of evaluating this or is this are all of these combination studies really more to to maximize BD discussions and ultimately confirmatory studies will be run in the hands of a partner.

Troy Wilson: Right. Okay, so several questions, several questions packed in there, Ren. Maybe taking your second question, the second set of questions first. So the yes, you will, you know, by design, cannibalize those, cannibalize those later lines if you're successful. Our goal, and 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 to 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?

Right Okay. So.

Several questions.

Several questions packed in there rent.

Maybe taking your second question the second set of questions first so the yes, you will by design.

Cannibalize those.

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 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 well, but ultimately that's that's better for patients offers them a better clinical benefit in and is arguably a more compelling commercial case.

Troy Wilson: It will, but ultimately, you know, 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, you know, there are fewer drugs approved in Europe than in the U.S.

The the the combinations that we're doing.

Yeah.

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 el that combination might be very attractive in in in Europe.

Troy Wilson: The LDAC combination might be very attractive in Europe. You know, Dr. Molly Leone, who's the clinical lead, and our EVP of clinical development for Cura has said it doesn't really matter how you get patients to a response. If you can get them there with a, quote, unquote, softer response, that's better.

Doctor Molly Leoni.

Who's the clinical lead in.

And our EVP of clinical development.

Four four for Kura has said it doesn't really matter how you get patients to a response if you can get them there with a quote unquote softer response, that's better you don't have to use a hard chemo. Your goal is to get them to respond to an L deck might be an attractive way to do that you heard me answer the question on flip three that's another option not so much driven.

Troy Wilson: You don't have to use hard chemo. Your goal is to get them to respond, and LDAC might be an attractive way to do that. You heard me answer the question on FLT3.

Troy Wilson: 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, as 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, you know, multi-billion-dollar sales numbers in a, you know, competitive market. With respect to your specific questions on the 007 study in Veneza, I have a couple of clarifications. So, the significance of seeing responses in patients who are venetoclax failures is, you know, you're in these, these are single-arm dose escalation studies. I mean, you're really kind of squinting at times to say, you know, what the clinical activity is, but it's pretty well established that for patients who failed Ven, they don't respond to Ven retreatment. That's, you know. I think most physicians will agree with that. This is a disease of high unmet need. How is that happening?

By BD considerations, although I will say to you we recognize to fully maximize the value of Menin inhibition in these various indications as 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 general.

Right.

Multibillion dollar sales numbers in a in a in a multiplayer market with respect to your specific questions on the <unk> seven study in Venice.

Yes, a couple of clarifications. So the significance of seeing responses in patients who are venetic lacks failures is.

In these these are single arm dose escalation studies, I mean, you're really kind of squinting at times to say whats clinical activity, but it's pretty well established for patients who failed then they don't respond to then re treatment that I think most physicians will agree with that that is a disease of high unmet need how is that happening is.

Troy Wilson: Is it that we're, you know, blocking a driver mutation like an NPM1 or a KMT2A? Are we blocking MCL1? Are we interacting with BCL2 to resensitize the tumor?

Is it that we're blocking.

A driver mutation like in NPM, one or at KMT <unk> are we blocking mcl. One are we interacting with bcl two to re sensitize the tumor we're still figuring that out what what does appear to be clear is that menin inhibitors plus than or better than then alone that theme.

Troy Wilson: 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 with menin AZA.

It's clear to your question I don't think you would go man in Asia, I think you might go <unk>.

Troy Wilson: I think you might go with venetoclax menin inhibitor and do the doublet. You may not need the AZA, and as we've talked about in the past, you know, 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 will the doublet suffice? And that's something you just have to figure out empirically. But going back to 007, and, you know, again, I'll acknowledge our colleagues at Syndex. We've both seen activity in venetoclax failures, and I think that's highly encouraging about the clinical benefit that these menin inhibitors can provide. Sure. Your next question comes from the line of Brad Canino with Steve... Good afternoon. How important does response durability become in your next combo data? Um, I mean, it's important, Brad.

<unk> Menin inhibitor and do the doublet, you may not need the ASR and as we've talked about in the past we will do that experiment. When the time is right. We'll actually asked the question do we need the triplet than.

And then as a man or can the double the doublet suffice.

That's something you just have to figure out empirically, but but going back to Oh, seven and again I'll acknowledge our colleagues at syntax. We've both seen activity in venetic clacks failures and I think that's highly encouraging of the clinical benefit that these men and inhibitors can provide.

Great. Thanks for taking the questions.

Sure.

Okay.

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

Please go ahead.

Hey, good afternoon.

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.

Brad Canino: It's always important. But I would say, you know, I cautioned people at the time with the 200 milligram dose: we're looking at immature data cut from 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 monotherapy, right? Will the data be mature enough? You know, hard to say.

I caution people at the time with the 200 milligram dose were looking at an immature data cut in a dose escalation study so I'd be careful not to over interpret it.

<unk> you should be seeing a direction of travel that is better than the mono therapy right will the data be mature enough.

Hard to say, we are still I mean, obviously, we havent dose to patients yet at 600 milligrams. So.

Troy Wilson: We're still, I mean, obviously, we haven't dosed a patient yet at 600 milligrams. So, you know, if we were to disclose the results in the next several months, we'll be limited in terms of what we can say about durability. But I do think it's important.

If we were to disclose in the next several months will 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 that theres nothing were seeing theres nothing were seeing from others that would suggest that that wouldn't be the case.

Troy Wilson: 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 it; there's nothing we're seeing. There's nothing, you know, 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 it effectively at 600 milligrams with those standards of care? Because if you go back to monotherapy, that's the optimal dose from a monotherapy perspective. It maximizes exposure.

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 mono therapy, that's the optimal dose from a monotherapy perspective, it maximizes exposure after that at plateau.

Troy Wilson: After that, it plateaus. It should be no different in the combos. That's the critical data point to look for. Durability will come in time.

It should be no different than the combos. That's the critical data point to look for the durability will come in time.

Troy Wilson: And, you know, I think we're cautiously optimistic it will point in the right direction. Okay. And then another question.

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 than is a triplet data from both you and and other met inhibitors that are being developed how do you expect potential differentiation might emerge in those <unk>.

Brad Canino: We talk a lot about potential best-in-class drug properties, you know, in this call and in others. But as we move towards more substantial VenAZA triplet data from both you and other MEN inhibitors that are being developed, how do you expect potential differentiation might emerge in those clinical data reported in Phase I? Yeah, so it's going to take the form in a couple of different ways. So there's a, you know, I would say, does one need to hold the menin inhibitor to allow counts to recover? You know, 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, you know, 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, that is not the mechanism. That's something else. We don't see that.

The nickel data reported in the phase one two studies.

Yeah. So.

It's it's it's going to take the form in a couple of different ways.

So there is a.

I would say does one need to hold the menin inhibitor to allow counts to recover that.

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 <unk> inhibitors were seeing a high rate of thrombocytopenia that is not 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. So I think Brad is 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.

Troy Wilson: 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 in both directions. Number one, can you keep constant pressure and constant exposure?

Troy Wilson: 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 toxicology, that's probably the best thing you can do to delay recurrence. I think that's a good setup for Zyfto because of its physical and chemical properties, because of its tolerability. But 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.

I would argue to you that if you can baize 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 prezista because of its physical chemical properties because of its tolerability, how thats going to manifest itself, that's going to take time.

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 their equivalent on activity. The safest most well tolerated most combinable drug always wins full stop.

Troy Wilson: Something I've said pretty consistently is that if you show me a race between two drugs and their equivalent in activity, the safest, most well-tolerated, most combinable drug always wins, full stop. I think Zyfto's well-positioned there, but for people who are looking for some kind of knockout blow, that's not coming, right? 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 Zyfto, the more excited we become. Very helpful. Thank you. Sure, thanks. Your next question comes from the line of Ava Privetera with TD Cowan. Hi, good afternoon.

And I think ziff does well positioned there but.

Theres not for people, who are looking for some kind of a knockout blow that's not coming right. This is going to be a multi player hopefully multibillion dollar market. That's really good for patients will be competing out there the more data we generate with ziff do the more excited we become.

Very helpful. Thank you.

Sure. Thanks.

Your next question comes from the line of Eva pivot Tera with TD Cowen.

Please go ahead.

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

Ava Privetera: 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 van Asa combos? And what could be a potential design? Do you think MRD negativity could be a registrational impediment? Yeah, Eva, thanks, you're saving the best questions for last.

So with escalation going really well and 007 and the RPT expected midyear when could potentially move into pivotal development with either Ken chemo or Vanessa combos, and what could be a potential design do you think <unk> negativity it could be a registrational endpoint.

Yeah.

Thanks.

Saving the best questions for last so.

Troy Wilson: So in terms of timing for development, you know, it's a little bit early. But we recognize, again, it's a competitive landscape. I think realistically, you probably wouldn't dose a patient in a pivotal trial 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 know, 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?

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 dosing patients 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 Allo seven study I think we're highly encouraged it's a matter of dropping the data into 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 you would it would be very aggressive to dose the patient I dare say it would be impossible to dose patients 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 Mardi probably not.

Troy Wilson: And we do need to do the expansion to make sure that we validate the dose. As for your question about MRD, it's probably not an endpoint at this point. I think, you know, 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 endpoint based on survival. And the agency's been pretty clear that's what they're looking for. Project Frontrunner, you know, they want to see that as a first approval, but the themes of Project Frontrunner carry through to the design. How can we do a seamless design?

And end point 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 end point, but it is likely to be supportive. We do think that theres 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 it's been pretty clear that's what they're looking for project front runner.

To see that as a first approval, but the themes of project front runner carry through to designs. How can we do a seamless design and that's very much what we will be looking at here in the various combinations.

Troy Wilson: 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 HoxNES transcriptional pathway?

Thank you that's helpful and a quick follow up on an earlier question about additional genetic subtypes.

Dork, we're pursuing other activity does this patient selection algorithm enrich for the Hawk Smith transcriptional pathway.

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

So there is an association.

Eva I think we remain unconvinced that if you use <unk> <unk> expression.

As your selection algorithm that that's going to work what we're doing instead is is mutations which are a proxy for that what's clear is.

This is a central node right.

<unk> biology is fundamental to leukemia, it's wired into mcl, one to bcl two to flip three to <unk> I don't think we fully understand all the wiring.

Troy Wilson: It's wired into MCL-1 to BCL-2 to FLT-3 to IDH, but 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 about what might be possible when you then go and layer that on top of, say, example, you know, venetoclax or FLT-3 or something. That might give you an extra oomph. You know, back in the 1A, 1B days, people kind of shrugged. Everybody wants to see a CR, right?

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, venetic lax or flit, three or something that might give you an extra one.

You know back in the <unk> days people kind of shrug, everybody wants to see a CR rate, 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 will see.

Troy Wilson: But actually, blast count reduction, you know, sustained disease stabilization in this setting is really clinically meaningful. And it's telling you to spend more time here. Look here. It's giving you a little neon sign.

Troy Wilson: So that's what we're doing, and we'll see where it goes. But it's associated with Hoppe's-Mies, but it's just an association. It's not going to be a direct correlation.

Where it goes but but it's associated with Hawks meese, but it's it's not it's just an association, it's not going to be a direct correlation I hope that helps.

Ava Privetera: I hope that helps. That helps a lot. Thank you. For more information, visit www. FEMA.gov. I would now like to turn the call back over to Troy Wilson for closing remarks. 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, Tom, or me. Thank you again, and have a good evening, everyone. Ladies and gentlemen, this concludes your conference call for today. We thank you for participating and ask that you please disconnect.

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 will 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.

Okay.

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

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