Q1 2021 Kura Oncology Inc Earnings Call

[music].

Welcome to the quarter, one 2021 care Oncology, Inc. Earnings Conference call. My name is Jenny I'll be your operator for today's call. At this time all participants are in a listen only mode. Later, we will conduct a question and answer session. During the question and answer session. If you have a question. Please press Star then one on your touch.

At home phone.

Now I'll turn the call over to Peter to Spain, you may begin.

Operator: Order 1, 2021 Kara Oncology Inc. earnings conference call. My name is Jenny.

Operator: I'll be your operator for today's call. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session. During the question and answer session, if you have a question, please press star than one on your touch-tone phone. I'm going to turn the call over to Peter in Spain. You may begin.

Thank you Jenny good afternoon, and welcome to occur oncology first quarter 2021 conference call joining.

Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer, and Dr. Marc Grasso, Our Chief Financial Officer, and Chief Business Officer.

Jim Foster our Chief legal officer, Dr. Steven <unk>, our Chief Medical Officer, Kirsten flowers, our Chief commercial officer, and Kathy Ford Our Chief operating officer are also with us and available to answer questions.

Pete De Spain: Thank you, Jenny. Good afternoon, and welcome to Curral Oncology's first quarter 2021 conference. Joining me on the call are Dr. Troy Wilson, our president and chief executive officer, and Dr. Mark Grasso, our chief financial officer and chief business officer. Jim Basta, our chief legal officer, Dr. Steven Dale, our chief medical officer, Kirsten Flowers, our chief commercial officer, and Kathy Ford, our chief operating officer, are also with us and available to answer questions.

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.

Pete De Spain: 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 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 will now turn the call over to Dr. Troy Wilson, President and CEO of Koura.

On the Kura oncology website for information concerning risk factors that could affect the company with that I will now turn the call over to Dr. Troy Wilson, President and CEO of Kura oncology.

Thank you Pete and thank you everyone for joining us this afternoon over the past quarter. We've continued to make significant progress as a company and we believe the relative positioning of our Menin inhibitor program <unk> 539 has improved meaningfully.

We've also witnessed a number of new developments in the space, including updated clinical data from a competitor program that further validated men and MLS therapeutic target in AML as well as the emergence of two additional clinical stage programs.

Troy Edward Wilson: Thank you, Pete, and thank you, everyone, for joining us this afternoon. Over the past quarter, we've continued to make significant progress as a company, and we believe the relative positioning of our Menin inhibitor program, K0539, has improved meaningfully. We've also witnessed a number of new developments in the space, including updated clinical data from a competitor program that further validated men in MLL as a therapeutic target in AML, as well as the emergence of two additional clinical stage programs.

This heightened activity speaks to the mounting excitement surrounding the menin inhibitor space and the significance of driving meaningful clinical activity in genetically defined subsets of AML. It's also served to highlight our leadership position, while underscoring the value of an aggressive clinical development strategy and the importance of operational execution.

Troy Edward Wilson: This heightened activity speaks to the mounting excitement surrounding the men in the inhibitor space and the significance of driving meaningful clinical activity in genetically defined subsets of AML. It's also served to highlight our leadership position while underscoring the value of an aggressive clinical development strategy and the importance of operational execution.

We believe <unk> 39 is well positioned as a potentially best in class and first in class Menin inhibitor.

This confidence is supported by a growing body of clinical data, including compelling activity, a favorable safety and tolerability profile and a wide therapeutic window as such we intend to conduct a comprehensive clinical development plan for <unk> 539, both as a monotherapy and in combination aimed at providing the greatest benefit to patients.

Troy Edward Wilson: We believe KO539 is well positioned as a potentially best-in-class and first-in-class male inhibitor. This confidence is supported by a growing body of clinical data, including compelling activity, a favorable safety and tolerability profile, and a wide therapeutic window. As such, we intend to conduct a comprehensive clinical development plan for KO539, both as monotherapy and in combination, aimed at providing the greatest benefit to patients with acute leukemia. A critical component of our development plan is the determination of an optimal phase two dose.

With acute leukemia.

A critical component of our development plan is the determination of an optimal phase two dose in.

In order to better inform our recommended phase two dose and beyond we've amended our comment 001 trial of $5 39 to include two phase <unk> expansion cohorts, one at a higher dose and one of the lower dose each enriched with N. P. M. One mutant and Kmt <unk> rearranged relapsed <unk> refractory AML.

Troy Edward Wilson: In order to better inform a recommended phase two dose and beyond, we've amended our Comet-001 trial of KO539 to include two Phase 1B expansion cohorts, one at a higher dose and one at a lower dose, each enriched with NPM1 mutant and KMT2A rearranged, relapsed, and or refractory AML patients. These expansion cohorts should enable us to maximize the benefit risk for KO539 in our target patient populations, similar to what has been done previously with other targeted therapies in AML.

Patients these expansion.

<unk> cohorts should enable us to maximize the benefit risk for K O $5 39 in our target patient populations similar to what has been done previously with other targeted therapies in AML.

We expect to enroll at least 12 patients in each of our two phase one expansion cohorts and assess those patients for safety and Tolerability, PK and PD and efficacy in order to determine the recommended phase two dose. In addition, the amended phase <unk> protocol gives us flexibility to enroll.

Troy Edward Wilson: We expect to enroll at least 12 patients in each of our two Phase 1B expansion cohorts and assess those patients for safety and tolerability, PK, and PD, and efficacy in order to determine the recommended Phase 2 dose. In addition, the amended Phase 1b protocol gives us the flexibility to enroll up to an additional 18 patients per cohort as appropriate.

Up to an additional 18 patients per cohort as appropriate.

Importantly, we believe patients enrolled in the cohort selected as the recommended phase two dose has the potential to be included in the subsequent registration directed portion of the comment 001 trial.

The amended protocol has been submitted to cites for IRB approval and we will begin we will shortly begin enrolling patients in the phase one expansion cohorts at both existing and new clinical sites.

Troy Edward Wilson: Importantly, we believe patients enrolled in the cohort selected as the recommended phase two dose have the potential to be included in the subsequent registration-directed portion of the Comet-001 trial. The amended protocol has been submitted to sites for IRB approval, and we will shortly begin enrolling patients in the Phase 1B expansion cohorts at both existing and new clinical sites. Meanwhile, we continue to engage with our key opinion leaders and global steering committee to further define a comprehensive clinical development plan for KL539.

And while we continue to engage with our key opinion leaders and global steering Committee to further define our comprehensive clinical development plan for <unk> 539 additional opportunities include frontline combination studies additional genetic subtypes of pediatric development strategy in other indications such as acute lymphocytic leukemia and myelodysplastic.

From.

We intend to move these efforts forward aggressively pending determination of an optimal dose we look forward to providing an update including additional phase one data from comet 001 later in the year.

Troy Edward Wilson: Additional opportunities include frontline combination studies, additional genetic subtypes, a pediatric development strategy, and other indications such as acute lymphocytic leukemia and myeloplastic syndrome. We intend to move these efforts forward aggressively pending determination of an optimal dose. We look forward to providing an update, including additional Phase 1 data from Comet-001 later in the year. Given the excitement around our men in space program, it's easy to understand why it's captured Wall Street's attention over the past year.

Given the excitement around our Menin program, it's easy to understand why it's captured wall street's attention over the past year. However, we remain just as excited about the opportunity for foreign cell transfer <unk> inhibition in oncology and evolving story that is told in three chapters for those newer to our story as a prelude we in licensed <unk>, our first generation <unk>.

Initial transfer Ace inhibitor from Janssen in December 2014, previously it had been studied in more than 5000 patients and demonstrated compelling and durable anticancer activity in certain non selected popular unselected patients.

Troy Edward Wilson: However, we remain just as excited about the opportunity for Farnesil Transferi's inhibition in oncology, an evolving story best told in three chapters. For those new to our story, as a prelude, we enlicensed Tippy Farnip, our first-generation Farnesil Transverse Inhibitor from Yansen in December 2014. Previously, it had been studied in more than 5,000 patients and demonstrated compelling and durable anti-cancer activity in certain unselected patients. Using advancements in cancer genetics and tools such as next-generation sequencing, we identified multiple genetically defined subsets of patients most likely to respond to Tipi Farnet.

Using advancements in cancer genetics and tools such as next generation sequencing, we identified multiple genetically defined subsets of patients most likely to respond to tip. The foreign at the most advanced of these initiatives is focused on patients with head and neck squamous cell carcinoma, or H N FCC that carry mutations in the HRS gene.

We estimate 4% to 8% of H N S. C patients have a trust mutations this is chapter one earlier.

Troy Edward Wilson: The most advanced of these initiatives is focused on patients with head and neck squamous cell carcinoma or HNSCC that carry mutations in the HRS gene. We estimate 4 to 8% of HNSCC patients have H-RS mutations. This is Chapter 1.

Earlier this year <unk> was granted breakthrough therapy designation from FDA for the treatment of patients with recurrent or metastatic HRS mute nature in FCC.

The breakthrough therapy designation was based on data from our phase II run HN trial, which was recently published in the journal of clinical oncology.

Troy Edward Wilson: Earlier this year, Tippy Farnin was granted a breakthrough therapy designation from FDA for the treatment of patients with recurrent or metastatic H-Rest mutin HNSCC. The breakthrough therapy designation was based on data from our Phase 2 run HN trial, which was recently published in the Journal of Clinical Oncology. Development of targeted therapies in HNSCC has lagged behind other cancer indications. Thus, we were very gratified by the FDA's award of breakthrough therapy designation, which acknowledges both the dire unmet need for patients with recurrent or metastatic H.R.S.M.S.C.

Development of targeted therapies in H N FCC has lagged behind other cancer indications. Thus we were very gratified by the Fda's awarded breakthrough therapy designation, which acknowledges both the dire unmet need for patients with recurrent or metastatic <unk> mutant nature, and ACC and the promise it could be far enough to provide clinical.

Benefit to patients.

We're motivated by our data and the potential that <unk> could represent the first approved small molecule targeted therapy in H N. S. C. C. We remain focused on conducting our aim HN registration directed trial and bringing <unk> to market as quickly and as efficiently as possible, providing a beachhead to the development of rational combinations.

Troy Edward Wilson: And the promise of Tippy Farnib to provide clinical benefit to patients. We're motivated by our data and the potential that TIPIFarnib could represent the first approved small molecule targeted therapy in HNSCC. We remain focused on conducting our AIMHN registration-directed trial and bringing TIPAFarnib to market as quickly and as efficiently as possible, providing a beachhead for the development of rational combinations and expansion to larger genetic subtypes. Among these potential combinations, we've prioritized the combination of TIPIFARNib and a PI3 kinase alpha inhibitor. Our preclinical data suggests that Atras and PTI-Kinae alpha are codependent onch genes in HNSCC, and that combining TIPIPA with a PI-3-Kinae alpha inhibitor has the potential to provide meaningfully better antitumor activity than inhibiting either target alone.

And expense expansion to larger genetic subtypes among.

Among these potential combinations, we've prioritized the combination of TP foreign had been a patchwork kind of alpha inhibitor.

Our preclinical data suggest that HRS and <unk> kinase Alpha are codependent, oncogene, and H N FCC and combining <unk> with a <unk> kinase Delta inhibitor has potential to provide meaningfully better antitumor activity, then inhibiting either target alone.

We believe this has the potential to increase the total addressable population for tip aren't up to as high as 50% of HSBC building on the promise of tip you found him as a mono therapy. This combination represents chapter two of our story.

We're currently preparing a phase two proof of concept study of <unk> in combination with a <unk> kinase delta inhibitor in patients who have HRS over expressing and or pick three CA dependent H N. FCC, we expected to initiate this study in the second half of 2021.

Mark Grasso: We believe this has the potential to increase the total addressable population for TIPI Farnib to as high as 50% of HNSCC. Building on the promise of Tippy Farnum as a monotherapy, this combination represents Chapter 2 of our story. We're currently preparing a Phase 1-2 proof-of-concept study of Tippipif in combination with a Piaginibator in patients who have HRAS overexpressing and or PIC-3CA-dependent HNSCC. We expect to initiate this study in the second half of 2021.

Meanwhile, through internal efforts and our network of academic collaborations we've uncovered some compelling opportunities for Farnesol transfer Ace inhibitors in combination with other targeted therapies. This biology is totally novel and we believe it warrants a greater investment in the therapeutic class.

Mark Grasso: Meanwhile, through internal efforts and our network of academic collaborations, we've uncovered some compelling opportunities for Farnesil Transprice inhibitors in combination with other targeted therapies. This biology is totally novel, and we believe it warrants a greater investment in the therapeutic class. From this investment, we're advancing a discovery stage program to develop a next generation Farnesil Transphase Inhibitor designed to target innovative biology and address large oncology indications of high unmet need through rational combinations.

From this investment we're advancing a discovery stage program to develop a next generation foreign cell transfer Ace inhibitor designed to target innovative biology, and address large oncology indications of high unmet need through rational combinations. This represents chapter three of our story and potentially the largest opportunity.

Our goal for this program is to deliver a drug candidate that has comparable potency and selectivity and improved pharmacokinetic and physical chemical properties relative to typify. It we've already identified a number of advanced lead compounds and we anticipate nomination of a development candidate for IND, enabling studies later this year.

Mark Grasso: This represents chapter three of our story and potentially the largest opportunity. Our goal for this program is to deliver a drug candidate that has comparable potency and selectivity and improved pharmacokinetic and physical chemical properties relative to TIPA Farnet. We've already identified a number of advanced lead compounds, and we anticipate nomination of a development candidate for I&D enabling studies later this year. None of this would have been possible without the pioneering work our team has done over the last five years.

None of this would have been possible without the pioneering work our team has done over the last five years.

While we continue to focus on the opportunity with a trust mutant H N. S. C. C. We view Farnesol transport <unk> inhibition in oncology as a potentially broader and more valuable therapeutic and commercial franchise and one that has potential to deliver multiple opportunities for additional indications. We look forward to sharing an update with you as the story.

Mark Grasso: While we continue to focus on the opportunity with ATRs mutant HNSCCC, we view Farnesol Transpricin inhibition in oncology as a potentially broader and more valuable therapeutic and commercial franchise, and one that has the potential to deliver multiple opportunities for additional indications. We look forward to sharing an update with you as the story continues to evolve. With that, I'll now turn the call over to Mark Grasso for a discussion of our financial results for the first quarter of 2021.

To evolve with that I'll now turn the call over to Marc Grasso for a discussion of our financial results for the first quarter 2021.

Thank you Troy and good afternoon, everyone I'll provide a brief overview of our financial results here on the call and invite you to review our 10-Q filed today for a more detailed discussion.

Research and development expenses for the first quarter of 2021, or $20 3 million compared to $12 $6 million from the first quarter of 2020.

Mark Grasso: Thank you, Troy, and good afternoon, everyone. I'll provide a brief explanation.

Mark Grasso: of our financial results here on the call and invite you to review our 10Q file today for more detailed discussion. Research and Development expenses for the first quarter of 2021 were $20.3 million compared to $12.6 million for the first quarter of 2020. The increase in R&D expenses was primarily due to an increase in companion diagnostic development activities and clinical trial costs related to a registration directed to the form of trial, clinical development, and manufacturing activities related to our K0539 program.

The increase in R&D expenses was primarily due to increases in companion diagnostic development activities and clinical trial costs related to our registration directed to be part of trial.

The nickel development.

And manufacturing activities related to our <unk> 539 program.

Personnel costs and other expenses.

General and administrative expenses for the first quarter of 2021 were $10 6 million compared to $7 $6 million from the first quarter of 2020 the.

The increase in G&A expenses was primarily due to increases in personnel costs and noncash share based compensation.

Mark Grasso: Program, Personnel Cost, and Other

Mark Grasso: General and administrative expenses for the first quarter of 2021 were $10.6 million compared to $7.6 million for the first quarter of 2020. The increase in GNA expenses was primarily due to increases in personnel costs and non-cash share-based compensation. The net loss for the first quarter of 2021 was $30.7 million, or 46 cents per share.

Net loss from the first quarter of 2021 was $30 7 million or <unk> 46 per share compared to a net loss from $19 $2 million or reported <unk> per share from the first quarter of 2020.

As of March 31, 2021, we had cash cash equivalents and short term investments of $603 $9 million compared with $633 3 million as of December 31st 2020.

Mark Grasso: compared to a net loss of $19.2 million or 42 cents per share for the first quarter of 2000. As of March 31, 2021, we had cash, cash equivalents, and short-term investments of $603.9 million compared with $633.3 million as of December 31st, 2020. Pits in our current plans, we continue to believe that our cash equivalence and short-term investments will be

It's in our current plans, we continue to believe that our cash cash equivalents and short term investments will be sufficient to fund our operations into 2024.

With that I will now turn the call back over to Troy.

Thank you Mark before we jump into the question and answer session. Let me lay out our anticipated milestones for the remainder of this year for <unk> 539 initiation of genetically enriched phase one expansion cohorts in mid 2021.

Mark Grasso: will be sufficient to fund our operations into 2024. With that, I will conclude.

Mark Grasso: With that, I will now turn the call back over to Troy.

And additional phase one data from comments there was one in the second half of 2021 for.

Troy Edward Wilson: Mark. Before we jump into the question and answer session, let me lay out our anticipated milestones for the remainder of this year. For KO539, initiation of genetically enriched Phase 1B expansion cohorts in mid-2020, and additional Phase 1 data from Comet,001 and the second half of 2021. For Kipiparnav, initiation of a Phase 1-2 proof-of-concept study in combination with a PS3-Kinthalpha inhibitor in the second half of 2021, and for our next-generation Farnesil Transverse Inhibitor With that, operator, we're now ready for questions. Thank you.

<unk> initiation of a phase two proof of concept study in combination with the payer three kinase Delta inhibitor in the second half of 2021 and for our next generation financial transports inhibitor program nomination of a development candidate in mid 2021.

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

Thank you if you have a question. Please press Star then one on your Touchtone phone.

Wish to be removed from the queue. Please press the pound sign or the hash key if you're using a speakerphone you may need to pick up the handset first before pressing the numbers. Once again if you have a question. Please press Star then one on your Touchtone phone.

Operator: Thank you. If you have a question, please press star and then one on your touchtone phone. If you wish to be removed from the queue, please press the pound sign or the hash key. If you're using a speaker phone, you may need to pick up the handset first before pressing the numbers. Once again, if you have a question, please press star than one on your touchtone phone. And our first question comes from Jonathan Chang from SVV Learning. Please go ahead.

And our first question comes from Jonathan Chang from SBB Leerink. Please go ahead.

Hi, guys. Thanks for taking my questions first question I'd Love to get your thoughts on the recent Amgen disclosures on their K recipe 12 C inhibitor and their efforts to evaluate whether a lower dose is also safe and efficacious and that seems to have parallels to your own efforts determine minimums.

Jonathan Chang: Hi Guys, thanks for taking my questions. First question, I'd love to get your thoughts on the recent Amgen disclosures about their KRS G12C inhibitor and their efforts to evaluate whether a lower dose is also safe and efficacious. That seems to have parallels to your own efforts to determine a minimum safe and biologically effective dose.

And biologically effective dose how should investors be thinking about this.

Hi, Jonathan Thanks for the question.

When we communicated the feedback that we received from FDA.

About eight weeks ago at our at our last quarterly call.

We put that feedback in the context that it was our understanding. This is an initiative at F. D. A to ask sponsors to really do the work to define the optimum phase two dose and that optimum and there was a there is a fair amount of of.

Troy Edward Wilson: Hi Jonathan. Thanks for the question. When we communicated the feedback that we received from FDA just about eight weeks ago at our last quarterly call, we put that feedback in the context that, you know, it was our understanding, this is an initiative at FDA, to ask sponsors to really do the work to define the optimum phase two dose and that optimum, and there was a fair amount of discussion around that. What we've seen, and let's take the Flit3 inhibitor, Gilterritinib, as an example, is that with these targeted therapies, one has the potential, because of the wide therapeutic window, to saturate the target and then continue dose escalating.

A discussion around that.

What we've seen.

And let's take let's take the flit three inhibitor Delta written up as an example is with these targeted therapies.

One has the potential because of the wide therapeutic window to saturate the target and then continue dose escalating.

So F D a.

Our understanding and it was part of the discussion we had around our trial.

FDA is really asking sponsors to define the lowest dose with maximum pharmacologic and clinical activity.

You know in the Amgen case.

Troy Edward Wilson: So FDA, it's our understanding, and it was part of the discussion we had around our trial. FDA is really asking sponsors to define the lowest dose with maximum pharmacologic and clinical activity. Now, in the Amgen case, you know, they have essentially a completed registrational study. They're going to go back and do some work, you know, to bridge potentially to a lower dose. In our situation, it was actually not a request from FDA.

They're they have essentially a completed registrational study, they're going to go back and do some some work.

Bridge potentially to a lower dose.

In our situation it was actually not a request from FDA. It was a recommendation that we made to FDA that given we have.

Multiple doses potentially at which we could move forward.

We made a proposal to FDA that we we do the gold standard and do a phase one b expansion with a lower dose and a higher dose and ask the question.

Troy Edward Wilson: It was a recommendation that we made to FDA that given we have, you know, multiple doses at which we could move forward, we made a proposal to FDA that we do the gold standard and do a phase 1B expansion with a lower dose than a higher dose and ask the question, between those two doses, is there a difference in PK and exposure. Is there a difference in PD, safety, and tolerability, and, of course, F2?

Between those two doses is there a difference in PK and exposure is there a difference in P. D safety and Tolerability and of course efficacy and FDA I think I think it was a little bit coincidental F.

<unk> was very much in agreement with that approach. So we're earlier in the development paradigm, Jonathan if you want to sort of make a direct comparison between between our efforts and those of Amgen, but at the end of.

Troy Edward Wilson: And FDA, you know, I think it was a little bit coincidental. You know, FDA was very much in agreement with that approach. So we're earlier in the development paradigm, Jonathan, if you want to sort of make a direct comparison between our efforts and those of Amgen. But the rationale is the same, and that is, with these targeted therapies, particularly as one is thinking about polypharmacy and combinations, you really want to do the work needed.

The rationale is the same and that is with these targeted therapies.

Particularly as one is thinking about polypharmacy in combinations, you really want to do the work needed to zero in on the lowest dose with maximum pharmacologic and clinical activity and that's particularly important in AML because as you go to earlier lines you have patients on seven plus three azole.

<unk> been out of class as well as potentially P. P is antidepressants.

Troy Edward Wilson: to zero in on the lowest dose with maximum pharmacologic and clinical activity. And that's particularly important in AML because as you go to earlier lines, you have patients on 7 plus 3, azales, you know, benedoclacs, as well as potentially PPIs, antidepressants. So I think we'll, you know, it's our view that this is going to be an increasing trend for companies doing work early on to really zero in on the right dose.

So so I think we will argue that this is going to be an increasing trend.

Companies doing doing work early on to really zero in on the right dose in our case, it's exactly the right thing to do we've got two good doses, we think will come out of the come out of this phase one b expansion with really the best answer moving forward into the Registrational study and beyond sorry for the long answer, but I think it's important to provide that context.

Troy Edward Wilson: In our case, it's exactly the right thing to do. We've got two good doses. We think we'll come out of this phase 1B expansion with really the best answer moving forward into registration and beyond. Sorry for the long answer, but I think it's important to provide that context.

Great. That's helpful and second question with the recent data disclosure from the competitors men and MLR and have their program.

The reasons for confidence that came from.

<unk> nine could do better.

Troy Edward Wilson: Great, that's helpful. And second question: with the recent data disclosure from the competitor's men in the MLL Inhibitor program, what are the reasons for confidence that KL39 could do better?

Yeah, Yeah, that's a really good question.

So.

Break it down because there's sort of several elements there I think first and foremost the competitor data underscores the importance of the men and MLR pathway is a therapeutic target where a competing program. We play to win but you have to be impressed by the level of clinical benefit in terms of both rich.

Troy Edward Wilson: Yeah, yeah, that's a really good question. So. Let's break it down because there are sort of several elements there. I think, first and foremost, the competitor data underscores the importance of the male and MLL pathway as a therapeutic target. You know, we're a competing program; we play to win, but you have to be impressed by the level of clinical benefit in terms of both response rate and the number of patients that were converted to MRD negative, right? Zero measurable residual disease. The challenge that that competing program has is that they're trying to navigate the straits between two cliffs.

Sponsoring and and the ability of the number of patients that were converted to MRV negative right zero measurable residual disease. The challenge that that competing program has is they're trying to navigate the straits between two to cliffs on the one hand, they have a their comps.

<unk> is a very sensitive sip three four substrate.

Which makes it difficult potentially if theyre in a in an environment, where they have inhibitors of Sip three or four they also have Ah.

Dose limiting toxicity in the form of Qt prolongation.

Troy Edward Wilson: On the one hand, their compound is a very sensitive SIP-3A-4 substrate, which makes it difficult, potentially, if they're in an environment where they have inhibitors of SIP-3-A-4. They also have dose-limiting toxicity in the form of QTC prolongation. The SIP, the SIP sensitivity, is an issue in that the exposure of their compound can vary depending on the other agents that the patient is taking. Those can be, you know, things like antifungals, asles, asles, as well as grapefruit juice, St. John's War, right?

The Sip.

ZIP sensitivity is an issue in debt the exposure of their compound can vary depending on the other agents that the patient is taking those can be things like <unk>.

And he antifungals azole as well as great grew two St. John's work right. All of these are known well known to be inhibitors of three and four.

It doesn't mean, there isn't a path forward. It just means it's more complicated both as a monotherapy and in combination.

In contrast, the current program.

We show no dependence on nasals, we've said that repeatedly.

Troy Edward Wilson: All of these are well known to be inhibitors of 3A4, but that doesn't mean there isn't a path forward, it just means it's more complicated, both as a monotherapy and as a combination. In contrast, the Curra program, we show no dependence on Azles. We've said that repeatedly. Our compound has a very wide therapeutic window, good safety, and tolerability. There is, you know, an

Our compound has a very wide therapeutic window, good safety and Tolerability.

There is there is a.

Increases in exposure with increasing dose we need to do the rest of the work to decide which dose is the right one to move forward as a recommended phase two dose, but we don't we don't require the addition of exogenous agents to address that Sip three for liability as you see with the competing program.

Troy Edward Wilson: We need to do the rest of the work to decide which dose is the right one to move forward as a recommended phase two dose, but we don't require the addition of exogenous agents to address that CIP-3A4 liability, as you see with the competing program. And I think, you know, we don't have the... QTC prolongation. We've seen no evidence of cardiac talk.

And I think we don't have the Q T. C. Prolongation, we've seen no evidence of cardiac tox. It. It's early days for both programs I think.

We believe that $5 39 has the potential to be both best in class and given that we're now just about ready to transition into the phase. One portion. We think we can also be first in class.

And we're really going to work hard towards achieving both of those goals.

Troy Edward Wilson: It's early days for both programs, but I think, you know, we believe that 539 has the potential to be both best in class and first in class. And given that we're now, you know, just about ready to transition into the phase 1B portion, we think we can also be first in class. And we're really, you know, going to work hard toward achieving both of those goals.

Got it thanks for taking the questions.

Thank you.

And our next question comes from Peter Lawson from Barclays. Please go ahead.

Hey, Troy. Thanks, so much for taking my questions just on the data Readouts. This year. So just wonder if you could talk to the extent that day to that we could see in the second half minutes. If it's around a few of us mostly.

Jonathan Chang: Got it. Thanks for taking the question.

Peter Richard Lawson: And our next question comes from Peter Lawson from Berkeley. Please go ahead.

Free escalation Bacon.

Peter Richard Lawson: Hey, Troy, thanks so much for taking our questions. Just on the data readouts this year, so just, I wonder if you could talk about the extent of the data.

Yes, Peter so so it's a good question, we've guided toward providing a data update in the second half of the year.

Peter Richard Lawson: That they

Our focus shifts.

Just so we're clear for you and everyone else on the call. Our focus is to get into and then through those phase one be expansions as quickly as possible because we know we have good safety and tolerability.

Troy Edward Wilson: Yeah, Peter, so it's a good question. We're aiming toward providing a data update in the second half of the year. Our focus, just so we're clear for you and everyone else on the call, our focus is to get into and then through those Phase 1B expansions as quickly as possible because we know we have good safety and tolerability, you know, we have compelling evidence of activity. We need a dose, a recommended Phase 2 dose. And that's really what we have and are looking to achieve and then looking to share as quickly as we can.

We have compelling.

Compelling evidence of activity, we need to dose a recommended phase two dose and that's really what we're looking to achieve and then looking to share as quickly as we can.

We'd like to provide an update later in the year I I'm.

I don't know yet.

Exactly what that's going to look like.

But in terms of will it include any of the phase one data I think we'll continue to give kind of qualitative updates on how the programs going on in terms of what we're seeing but we are looking toward an update later this year and then of course you know.

Troy Edward Wilson: We'd like to provide an update later in the year. I don't know yet exactly what that's going to look like, but, you know, in terms of whether it will include any of the Phase 1B data. I think we'll continue to give kind of qualitative updates on how the program is going in terms of what we're seeing, but we are looking toward an update later this year. And then, of course, you know, we haven't even dosed the first patient yet in phase 1B.

We haven't even dose the first patient yet in the phase one b I would expect that when that data is ready.

And we have determined the recommended phase two dose and are then moving into the registration enabling portion will then provide another update to you. The other analysts and of course to the street to help understand what was the output of the phase One day. We just at this point, we don't have any clarity yet on the timing of that we have goes.

Troy Edward Wilson: I would expect that when that data is ready, and we've determined the recommended phase two dose and are then moving into the registration enabling portion, we'll then provide another update to you, the other analysts, and, of course, to the street to help understand what was the output of phase 1B. We just, at this point, we don't have any clarity yet on the timing of that. We have goals, but until we're really, really in rolling steady state in those phase 1B cohorts, it's a little bit hard to be more.

<unk>, but.

But until we're really enrolling steady state in those phase one day cohort, it's a little bit hard to be more concrete.

Thank you and then just.

From the press release, you talked about expansion opportunities for the Menin inhibitor into.

Other genetic subtypes and.

So what are those and you also mentioned Mds patients. So I'm, just curious what percentage of Mds patients could benefit from it.

Troy Edward Wilson: Just from the press release, you talk about expansion opportunities for the many inhibitors into other genetic subtypes and what they are, and you also mentioned MDS patients, so I'm just curious what percentage of MDS patients could benefit from it. Yeah. So this is

Yeah. So so this is the so let's take those two those two separately so as far as the other genetic subtype.

People on the call will recall that at Ash in December we showed that $5 39 was able to drive complete remission in a patient with.

Troy Edward Wilson: Yeah, so this is the, so let's take those two those two separately. As far as the other genetic subtype, people on the call will recall that at Ash in December, we showed that 539 was able to drive complete remission in a patient with set T2 run X1, co-mutin AML. And we were pleasantly surprised by that. We weren't completely thunderstruck, but we were surprised.

72 run ex one co mutant AML.

And we were pleasantly surprised by that we weren't completely thunderstruck, but we were surprised.

We've continued to see evidence of biologic and clinical activity outside of the genetic subtypes of NPM one an MLR. The challenge we have Peter just to be candid is I don't think we fully understand the selection rules. We know that they are men and MLR pathway is important we know that day to interact with other.

Troy Edward Wilson: We've continued to see evidence of biologic and clinical activity outside of the genetic subtypes of NPM 1 and MLLR. So the challenge we have, Peter, just to be candid, is I don't think we fully understand the selection rules. We know that the MLL pathway is important. We know that it interacts with other targets.

Targets were still trying to define those selection rules that would help us to enroll a third potential cohort.

The phase one b really the goal there is to select a going forward a recommended phase two dose and in doing that we're going to enrich in PMT to a N N P M. One.

Troy Edward Wilson: We're still trying to define those selection rules that would help us to enroll a third potential The phase 1B, really the goal there is to select a going forward, a recommended phase two dose. And in doing that, we're going to enrich for KMT2A and NPM1. And by doing that, we're trying to enroll a population where we have the highest likelihood of seeing clinical benefit and, you know, as few variables as possible.

And we're trying with by doing that we're trying to enroll in a population where we have the highest likelihood of seeing clinical benefit and you know as few variables as possible. So that we can really say between these two dose cohorts are.

Are we seeing a meaningful difference in one versus the other when we're on the other side of that.

We are determined to recommended phase two dose using that recommended phase two dose than we can.

Troy Edward Wilson: So that we can really say between these two dose cohorts, you know, are we seeing a meaningful difference between them? When we're on the other side of that, and we've determined a recommended phase two dose, using that recommended phase two dose, then we can look toward expanding the application of KO539 to other genetic subtypes. When you're trying to both understand the biology and the dose at the same time, it's complicated, but if you do them serially, you know, it makes much more sense.

We can look toward expanding the application of <unk> $5 39 to other genetic subtypes, when you're trying to both understand the biology and the dose at the same time, it's complicated, but if you do them serially. It makes much more sense and this is consistent with what's been done with other targeted therapies as for your question.

Around Mds, yes, there is a percentage of patients with Mds, they're pre AML, who have NPM one mutations there's some very interesting work going on in.

Troy Edward Wilson: And this is consistent with what's been done with other targeted therapies. As for your question around MDS, yes, there is a percentage of patients with MDS, their pre-AML, who have NPM1 mutations. There's some very interesting work going on in academic labs looking at the sequencing of mutations in these myeloprolifurative and myelisplastic diseases. We're intrigued that there might be a possibility there to intervene before a patient ever develops full-blown AML. And, you know, there's both pre-clinical work going on and, of course, then you look at the work we're doing in AML.

And academic labs looking at the sequencing of mutations in these these myeloid proliferative and Myelodysplastic diseases.

We're intrigued that there might be a possibility there to intervene before a per patient ever developed full blown AML.

And.

There's both preclinical work going on in and of course, then looking at the work we're doing in AML, but that's it if one could prevent the onset of AML that would of course be the ideal situation.

Don't know whether that's possible.

But certainly something that when the time is right and we have a recommended phase II dose it will be an opportunity to explore.

Troy Edward Wilson: But that's a, you know, if one could prevent the onset of AML, that would, of course, be the ideal situation. Don't know whether that's possible, but certainly something that when the time is right and we have a recommended phase two dose, it will be an opportunity to explore.

And our next question comes from Reni Benjamin from JMP security.

Hey, good afternoon, guys. Thanks for taking the questions.

Alright.

Just.

Maybe just expand a little bit more on these on the phase one B you mentioned the lower dose cohort at a higher dose cohort have you have you guys pick.

Reni John Benjamin: And our next question comes from Rennie Benjamin from JMP Security.

<unk>.

What those doses will be and why why pick between one and the other why not explore some granular.

Reni John Benjamin: Good afternoon, guys. Thanks for taking the questions.

Reni John Benjamin: Troy, I'd

Troy Edward Wilson: Um, maybe just expand a little bit more on phase 1b. You mentioned a lower dose cohort and a higher dose cord. Have you, have you guys picked out what those doses will be? And why pick, you know, between one and the other?

Doses as well, maybe something between the 50 and 100 right or wrong.

Maybe even change the dosing schedule.

Yeah. So.

It's a good question Ren so really good question.

Troy Edward Wilson: Why not explore some granular doses as well? Maybe something between 50 and 100, right? Or maybe even change the dose and schedule a little. Yeah, so it's a good question, Ren. It's a really good question.

So again youre looking at Youre looking at a number of variables right.

Number one is safety and Tolerability.

Yeah.

It's our belief that both doses.

We'll have passed the safety.

Threshold for the escalation.

Troy Edward Wilson: So again, you're looking at a number of variables, right? Number one is safety intolerability. It's our belief that both doses will have passed the safety threshold for the escalation, but that's the first thing you need to look at.

But that's the first thing you need to look at then the question is exposure and we've said, although we are seeing increases in exposure at increasing doses eventually you'll reach a plateau and that's part of it.

And the answer to.

To the earlier question from Jonathan.

FDA is saying why beyond that if you think of the dose exposure curve is looking like a like a knee right you.

Troy Edward Wilson: Then the question is exposure. And we've said, you know, although we are seeing increases in exposure at increasing doses, eventually you'll reach a plateau. And that's part of, you know, in the answer to the earlier question from Jonathan, FDA is saying, you know, why be on the... If you think of the dose exposure curve as looking like a knee, right? You want to be up on top of it, but you don't want to be all the way up on the side.

<unk> you want to be up on top of it but you don't want to be up all the way up on the site you want to give as much drug as you need to give and not a lot more.

Then the final and probably most important as clinical efficacy and we just to date, we haven't had enough enrichment to be able to say, whether one is different than another.

Our belief that with two doses, we can define whether there is an advantage of the higher dose.

Troy Edward Wilson: You want to give as much of the drug as you need to give, and not a lot more. Then, the final and probably most important is clinical efficacy. And we just, to date, we haven't had enough enrichment to be able to say whether one is different than another. It's our belief that with two doses, we can define whether there's an advantage of the higher dose. You know, the lower dose, the dose of 200 milligrams, you'll recall we saw two responses, or I should say, you know, an MRD negative CR in one NPM, one mutant patient, and a morphologic leukemic-free state in the other. The question is, are you getting any incremental benefit as you go higher?

The lower dose the dose 200 milligrams youll recall, we saw two responses or I should say.

And <unk> negative CR in one N P M. One patient and then in <unk>.

Morphologic leukemia free state and the other the question is are you getting any incremental benefit as you go higher.

One can be as granular as you want to your question. There's nothing that says you couldn't explore.

More doses, but we're trying to balance.

We're trying to say, let's get to the to the to the right answer without necessarily the perfect answer.

Troy Edward Wilson: One can be as granular as you want with your question. There's nothing that says you couldn't explore, you know, more doses, but we're trying to balance, you know, we're trying to say, let's get to the right answer without necessarily the perfect test. And we do recognize, you know, this is a competitive space, both with the existing competition and new entrants in the field. So we're trying to really strike that balance between getting the right recommended phase two dose and moving as quickly as we can to registration.

And we do recognize this is a competitive space.

Both with the existing competition and new entrants in the field.

So we're trying to really rent strike that balance between getting the right recommended phase two dose and moving as quickly as we can to registration.

And I think the phase one b is nicely set up for that.

As with every studying from data driven if there is a reason to do two to explore something a little different we will do that but we're trying to keep it keep it fairly simple.

Okay, and then just as a follow up you mentioned the Registrational study. The fact that you might be able to utilize patients from either dose you know that yet, but you wanted to choosing for the Registrational study can you talk a little bit about you know what you think a registrational study could look like and then also.

Troy Edward Wilson: And I think phase 1B is nicely set up for that. As with every study, we're data-driven. If there's a reason to explore something a little different, we'll do that, but we're trying to keep it fairly simple. Okay. And then just as a follow-up, you know, you're mentioning the registrational

You know just just in terms of timing and I'm not trying to pin you guys do anything but that.

Troy Edward Wilson: study, the fact that you might be able to utilize patients from.

Troy Edward Wilson: whichever dose you wind up choosing for the registrational study. Can you talk a little bit about what you think a registrational study could look like? And then also, you know, just in terms of timing, and I'm not trying to pin you guys to anything, but I would think that maybe those 12 patients could get enrolled, you know, even if you start the study by the middle of this year, that it could be done this year, just given the fact that I think you've mentioned in the past that you hope to be at about 20, sites or so, you know, total once this is up and Sure, so there are a few things packed into that question.

I would think that maybe those 12 patients could get enrolled even if you start the study by the middle of this year that it could be done. This year just given the fact that I think you've mentioned in the past that you hope to be at about 20 sites or so.

Total loans to loosen up and running can you maybe help fine tune those assumptions.

Sure. So there's a few things packed into that question.

We are let let's start with number of sites because that's our current focus right. It's getting the protocol through IRB getting new sites booted up and getting the existing sites able to enroll under the phase <unk> portion of the protocol.

Troy Edward Wilson: Let's start with the number of sites, because that's our current focus, right? It's getting the protocol through IRBs, getting new sites booted up, and getting the existing sites able to enroll under the Phase 1B portion of the protocol. We're at seven or eight sites now, and I want to say we're anticipating tripling that, you know, over the next several months as we bring new sites online to the sites currently enrolling. We don't, we have projections based on, you know, different data sources.

Troy Edward Wilson: Until you're really in there, actually, at sort of a steady state, no one really knows what the rate of bringing patients on study is. We're, if anything, trying to power it appropriately with enough sites to help drive enrollment, both in phase 1B and ultimately in phase 2. But we just, you know, right now. Wren, our goal is to determine a recommended phase two dose this year. It's hard to be a lot more granular than that until you both get the sites open and you get some experience with how many patients they're seeing. Not every patient that we see.

One of the advantages of doing it. This way is we've now aligned the endpoints of the phase one b with those that will be used in the registrational portion. So we're looking at CRM CRH with transfusion independence is a key secondary endpoint.

That will be important that was actually a recommendation from FCA too.

To allow us to count patients toward it towards the total.

In terms of what we think is needed so theres a little bit of background noise.

Troy Edward Wilson: Once the recommended phase two dose is selected, it's our belief we can take the patients from the selected cohort, the Phase 1B selected cohort, and then we will separate the patients by genetic subtype. So we'll have a KMT2A arm, we'll have an NPM one arm, and we're anticipating having a third arm, which was the question I was answering from Peter earlier in the call. And those will look fairly typical with what you've seen with others.

We're anticipating having a third arm, which was the question I was addressing from Peter.

Earlier in the call.

And those will look fairly typical with what you've seen with other small molecule small molecule targeted therapy given that the.

You want to meet or exceed that 20% to 30% response rate I hope does that give you sufficient sufficient color on your question.

Yes, yes. It does thank you very much for taking the questions.

Troy Edward Wilson: you know, small molecule targeted therapies given that the, you know, you want to meet or exceed that 20% to 30% response rate. I hope that gives you sufficient, sufficient color on your question. Yes, yes, it does.

Our pleasure thank you.

And our next question comes from Joel Thank goodness from H C. Wainwright. Please go ahead.

Hey, guys good afternoon.

My first question might be from Marc I know you guys don't usually give granular financial guidance, but when you look at our Opex.

Reni John Benjamin: Yes, yes, it does. Thank you very much for creating the questions.

Opex for the rest of the year I guess from an R&D standpoint, you know I'll ask specifically, though can we look at this as a bit of a base line or are there sort of one off with regard with regard to say you know manufacturing that took place to have drug supply for clinical studies and just wanted to get some sort of read thanks.

Joe Pank Guinness: And our next question comes from Joe Pank Guinness from H.C. Wayne Wright. Please go ahead.

Joe Pank Guinness: Hey guys, good afternoon. My first question might be for Mark. I know you guys don't usually give granular financial guidance, but when you look at, you know, OPEX for the rest of the year, I guess from an R&D standpoint, you know. I'll ask specifically, though, can we look at this as a bit of a baseline, or are there sort of one-offs with regard to, say, manufacturing that took place to have drugs applied for clinical studies? I just wanted to get some sort of read.

Yeah. Thanks, Joe.

So to answer the question.

There are some one offs from the first quarter debt.

Would potentially make the first quarter.

More outsized in particular, there was some spend on the companion diagnostic from.

Mark Grasso: Yeah, thanks, Joe. So to answer your question, there are some.

That said, we do anticipate the spend to be.

Mark Grasso: There are some one-offs in the first quarter that could potentially make the first quarter more outsized. In particular, there is some spend on the companion diagnostic front. That said, we do anticipate the spend to be continuing to increase over the course of the year. And while we haven't given specific OPEX guidance for the year, you know, that may be something that we're going to do in the short term. And I think you should continue to see an increase in R&D spend over the course of the year.

<unk> to increase over the over the course of the year and while we haven't given specific opex guidance for the year.

That may be something that we're going to do in the short term and I think you should continue to see an increase in R&D spend.

Over the course of the year.

That's helpful. Thanks, and then.

When you just switching to sort of some of the backend prepared comments and Troy you gave a lot of <unk>.

Different kinds of properties with regard to the next generation Farnesol transfer Ace inhibitor.

Joe Pank Guinness: No, that's helpful, thanks. And then when you switched to sort of some of the back-end prepared comments, and Troy, you gave a lot of different kinds of properties with regard to the next generation Farnesil Transfer.

Just curious with some of your lead candidates any of those properties that are sort of rising to the top that you really wanted to see as part of your rational design.

Yeah, Joe Thanks, It's a good question.

Tip is a real it's a very good drug however, you know as with as we've seen with <unk>.

Troy Edward Wilson: Trans Race Inhibitor, I was just curious about some of your lead candidates, any of those properties that are sort of rising to the top that you really wanted to see as part of your rational design. Yeah, Joe, thanks. It's a good question.

A number of other drugs Egfr inhibitors.

As kind of the most notable.

You can generally improve kind of upon first generation technology, one of the things we'd love to be able to do a very simple is to lower the dose and to be able to have the drug given once a day as opposed to twice a day for.

Joe Pank Guinness: TIPB is a very good drug. However, as we've seen with a number of other drugs, EGFR inhibitors, and, you know, as kind of the most notable, you can generally improve upon first generation technology. One of the things we'd love to be able to do that's very simple is to lower the dose and to be able to have the drug given once a day as opposed to twice.

For the head and neck patients, we're dosing patients at 600 milligrams twice daily that's a lot of drugs for head and neck patient.

And you know based on what we know we think theres the potential to come in with a candidate development candidate that's more potent potentially has less inter patient variability and and better bioavailability search you can basically have a smaller pill.

Joe Pank Guinness: You know, for the head and neck patients, we're dosing patients at 600 milligrams twice daily. That's a lot of medicine for a head and neck patient. And, based on what we know, we think there's the potential to come up with a development candidate that's more potent, potentially has less interpatient variability, and better bioavailability, such that you could basically have a smaller pill but give all the therapeutic punch that you see with tippifarnum.

But give all the all the therapeutic punch that you see with typical R&M. So those are.

We want to make sure we maintain the good safety profile.

Tippy, but we do think both in terms of the physicochemical and pharmacokinetic properties, we might be able to improve on it. The early compounds suggests that's possible.

Joe Pank Guinness: So those are, we want to make sure we maintain, you know, the good safety profile of TIPI, but we do think, both in terms of the physical chemical and the pharmacokinetic properties, that we might be able to improve on it. The early compound suggests that's possible.

Got it and then my last question I guess, it's sort of might mandatory you have to ask.

Regarding the status of the Ames study and it's more of like you know not like do you have any timelines to provide but maybe some sort of anecdotes as to.

Troy Edward Wilson: Got it. And then my last question.

You know are you seeing some sites getting ready to open again post COVID-19.

Joe Pank Guinness: and I guess it is sort of my mandatory question, you know, I have to ask regarding the status of the AIM study. And it's more of like, you know, not like, do you have any timelines to provide, but maybe some sort of anecdotes as to, you know, are you seeing some sites getting ready to open again post-COVID, you know, where you're seeing some activities in particular regions, you know, something maybe more benign than along those. Yeah, it's a good question, Joe.

Where you're seeing some activities or particular regions something maybe more benign along those lines.

Yeah. It is.

It's a good question, Joe and and and it's an important study it's potentially the first targeted approved first approval of a targeted therapy in head and neck.

You do see country specific effects.

And it's not entirely clear whether they're due to COVID-19.

Troy Edward Wilson: And it's an important study. You know, it's potentially the first targeted, first approval of a targeted therapy in head and neck. You do see country-specific effects, and it's not entirely clear whether they're due to COVID, to be honest. It's, you know, the country sort of waxes and wanes.

To be honest, it's you know they the country sort of wax and wane.

Europe has largely been locked down and what we have found with head and neck patients generally is they're reluctant to travel if you don't get very close to them in terms of their ability to get therapy they're.

They're just they're they're going to try to you know.

Troy Edward Wilson: Europe has largely been locked down, and what we have found with head and neck patients generally is that they're reluctant to travel. If you don't get very close to them in terms of their ability to get therapy, they're just, you know, they're going to try to, you know, pursue other options. And that's partly because by the time we get them, they're so far down the disease path that, you know, it's tough for them, right? It's usually either a trial like this or hospice. So COVID definitely makes that worse.

Pursue other options.

That's that's partly because by the time, we're getting them there so far down the disease path that its a tough its tough for them right there.

It's it's usually either a trial like this or hospice.

So COVID-19 definitely makes that worse, but but I think the other thing is.

We're seeing where we seem to get the best traction is where patients are newly identified.

If you go into databases for example.

Youll find a trust mutant patients, but often those patients have passed on so that's why we have such an active screening campaign to find these patients as we've indicated in the past we've made changes to the protocol to allow make it easier for patients to come on study those changes do appear to be.

Troy Edward Wilson: But I think the other thing is, you know, we're seeing where we seem to get the best traction is where patients are newly identified. If you go into databases, for example, you'll find atrial mutant patients, but often those patients, you know, have passed on. So that's why we have such an active screening campaign to find these patients. As we've indicated in the past, we've made changes.

To be yielding some benefit. We're also looking we can't move fast enough to comp to have our next study to pantry kinase Alpha combo study online because you really need physicians study teams sites patients thinking about genetic screening genetic screening is key to this puzzle.

Troy Edward Wilson: to the protocol to allow, make it easier for patients to come on study, those changes do appear to be, you know, yielding some benefit. We're also looking, we can't move fast enough to have our next study, the Piatri Kinase Alpha-Combos study online, because you really need physicians, study teams, sites, and patients thinking about genetic screening. Genetic screening is key to this puzzle. And so if they're screening for Pi-chre-Kinase mutations or amplification, in addition to ATRS, we think that they will ultimately be better off.

So if their screening for PRT kinase mutations or amplifications. In addition to a trash we think that ultimately will be better off were really sort of looking at <unk> mutant head and neck as a beachhead to potentially a much larger opportunity with the combo and that's borne out by the preclinical data Joe as well as just the what we're hearing from the <unk>.

The Gators in the study teams as we're preparing for the current study, which will be the combo study of typify net plus up yet three kinase inhibitor due to start here in the second half of the year.

Troy Edward Wilson: We're really sort of looking at the ATRS mutant head and neck as a beachhead to potentially a much larger opportunity with the combo. And that's borne out by the preclinical data, Joe, as well as just what we're hearing from the investigators and the study teams as we're preparing for the current study, which will be the combo study of Tipipharinib and plus a pitri kinase alfinibator due to start, you know, here in the second half of the year.

Joe Pank Guinness: Got it. Thank you very much.

Got it thank you very much.

Thank you.

As a reminder, if you have a question. Please press Star then one on your Touchtone phone. Our next question comes from Phil Nadeau from Cowen and company. Please go ahead.

Good afternoon, Thanks for taking my questions.

Operator: Our pleasure. Thank you.

A couple on the phase one expansion cohorts. He mentioned in particular that one of the goals is PK PD.

Philip M. Nadeau: As a reminder, if you have a question, please press star than one on your touchtone phone. Our next question comes from Phil Nudu from Cohen and Company. Please go ahead.

Those cohorts I'm sure sure if you'd be willing to share with us what maybe some of the pharmacokinetic pharmacodynamic coals are.

In particular is there like I mean, you see that you're going for a time above IC 90.

Or other.

There are markers.

Okay.

Thanks, Phil for the question no not really no and that's in contrast to our competitors program.

It's not that we're looking for for a particular plasma concentration or time above IC 90 day.

Rather and this was this was suggested we showed kind of an early cut of the cycle. One day, one data at Ash, you do see inter patient variability and exposure.

Philip M. Nadeau: Thanks, Phil, for the question. No, not really. No.

And now that that variability and exposure doesn't appear to be associated with with toxicity. It's.

It's not clear that it's associated with efficacy it's not like the outliers are the are the patients that are seeing the responses, but we'd like to understand that better and.

And it's easier when you are in an enriched population of being able to say okay.

What's the basis for the inter patient variability is it for example.

The PK of the compound is there a food effect you know the sort of standard stuff you do in drug development and then how do you optimize that in terms of driving the greatest efficacy. So it'll it'll be an element of of the dataset that we look at it from the phase one b, but ultimately what we think will be the greatest deter.

Imminent between the two doses is gonna be pharmacologic and clinical activity the biomarkers fill our and again our competitors showed I think some nice data in this genetically selected populations you would expect to see knockdown of target genes from each one and <unk> nine.

Are you seeing that consistently is that our the arrows lining up with the clinical activity and exposure. It. It's part of the overall package, but we firmly believe we've got two good doses, both the higher and the lower.

We want to we want to do what I think is increasingly going to be the gold standard and that is which of those two is the is the optimal phase two dose going forward and we will go as fast as we can to get that answer.

And I think that will put us in a very good position as we are then segway into the Registrational portion.

One question on the Biomarkers your competitors showed really good knockdown from each one akshay <unk> was.

Lockdown, although not completely suppressed in I guess investors have been debating whether that's a function of approximately nine or that specific compound do you have an opinion on whether its possible, but total we suppress oksana.

Philip M. Nadeau: One question on the biomarkers. Your competitors showed really good knockdown of MIS I. Huxi 9 was knocked down, although not completely suppressed. And I guess investors have been debating whether that's a function of Hoxi 9 or that specific compound. Do you have an opinion on whether it's possible to totally suppress Hox A9?

It's so so miss one our preclinical data.

Suggests a.

Troy Edward Wilson: So MIS 1, our pre-clinical data suggests that MIS 1 is the better biomarker from a PD perspective relative to Hox 9. Sorry, Hux A-9. You can knock down MIS 1 nearly completely and consistently, but Hux A-9 appears to be more variable. We would prefer to use MIS 1 as a marker of activity because you just get a better signal to noise ratio, in our view. So for the investors that are one wondering, I think we think it's probably more the biology of Hocanine relative to MIS1, and they should really focus on MIS1.

Troy Edward Wilson: Past, when we were developing K-0-539 as part of the collaboration with the University of Michigan, business back in the early days before there was much interest, we actually pursued both covalent and non-covalent approaches. We had, you know, we had hits that we were evaluating using both approaches.

Troy Edward Wilson: Men and turnover in cells is about six hours, and we made a very data-driven decision. If we could knock down, we could, we could disassociate testosterone from MLL and chromatin completely. We could induce differentiation with a reversible inhibitor, but an irreversible or a covalid inhibitor didn't really seem to get us anything. As far as being able to drive dissociation of Mennon from MLLL, the flip side, of course, is that covalent inhibitors are not without cost. And just to remind everyone, for those who are

Completely we could induce differentiation with a reversible inhibitor uhm and irreversible or a call them a inhibitor. It didn't really seem to get us anything as far as being able to drive dissociation of men in from M. L. L. The the flipside of course is covalent inhibitors are not without cost.

And just to remind everyone for those who are newer to the current story the chemistry team that developed our minute inhibitor get all of the pioneering work on the cable box to 12 feet inhibitors. You can follow the publications in a pattern. So they they come from great knowledge of covalent inhibitors.

We've even seen not only with K rash, but with other targets as well you can get idiosyncratic off target toxicity due to the fact that the Electra file into covalent inhibitor is binding sustains other than your target system and your target protein and that that toxicity often doesn't manifest so.

<unk> until your impatience because animals preclinical models are not predictive of it so filled both from and not really needing it to drive activity I mean, you've you've got current and syntax bills showing see ours at you know the first or second dose, it's not clear what a covalent inhibitors gonna do better than that <unk>.

And you want to avoid any you Wanna have is squeaky clean a compound as you can so we made a day to driven decision to go with the with the reversible inhibitor with 539 and ultimately I think that was the right decision.

That's very helpful. Thanks, so much for taking our questions.

My pleasure. Thank you.

And our next question comes from Tiago thoughts from Paradise. Please go ahead.

Thanks for your question. So just a quick one on M. T M. One <unk> the questions on the relative merits targeting.

Philip M. Nadeau: That's very helpful. Thanks so much for taking the time to answer our question.

Troy Edward Wilson: Our pleasure. Thank you.

Either email off the <unk> and then one population given the day pump line I'll look it's fairly difficult process do superglacial from the the extent that you've seen some data, but not as much as I made a lot of it cause me some day at any nine P. M. One.

Tiago Fauch: And our next question comes from Tiago Fauch from Proditus. Please go ahead.

Tiago Fauch: Thanks for the question. So just a quick one on NPM 1, so we

Tiago Fauch: specific questions on the relative merits of targeting either the MLR versus M-TEM1 population given that the front-line outlook is fairly different across the super

From you guys and from competitors, how how consistently the day that would seem to date with perhaps a worse prognosis. Once you restart the lesser February stage and what's the actual attractiveness of the class within that patient population, what what what part of the bar for that and again back 20 to 30 seems about right but.

Tiago Fauch: Regulations, so to the extent that you've seen some data, but not as much as an NLR, but

Tiago Fauch: LARP, but there's some data in NPM 1, from you guys and from competitors, how consistent is the data would seem to date with perhaps the worst prognosis once you reach that replicating factory stage? And what's the actual attractiveness of the class within that patient population? What sort of bar for that? And again, that 20 to 30 seems about right, but I'm serious; if you should break down for subsets, you may have a different answer necessarily. Thanks.

Troy Edward Wilson: Sure, Tiago. So it's a good question. So in the relapse-refractory setting, NPM one commonly appears with other mutations, DNMT3A, IDH, Flit 3, and has a very negative prognosis. Those patients do not do well on existing therapies. And, you know, I think both we and Syndex have shown encouraging early signals of activity in that population. And what is meaningful there is the ability to... drive MRD positivity, right? That will increasingly be the gold standard in AML.

Troy Edward Wilson: And I think, you know, we've shown one anecdotal example, as of the Ash update. Syndex had, I think, a second one in NPM one, and then some MRD negative patients in the MLLR patient population. That's all encouraging.

Troy Edward Wilson: As you transition to frontline, particularly in patients who cannot tolerate intensive chemo, If you look at the response rate and the rate of MRD negativity with Venetoclaxenaseocytidine, there's a landmark phase three study. The response rate is about, I think, 60%, about a 20% MRD negativity rate, 2025, and 15 months of overall survival. You'd really like it, there's clear literature, and it's available if people want it; they can ask Pete; we can give you the citations.

Patients Theres clear literature that says if patients with <unk> negative.

Responses have better survival.

And that's why FDA gave the green light to Kronos for their for their trial with a second EBITDA.

Potential Thiago of an M of the Menin inhibitor to drive on MLD negative response in that frontline a durable response, that's really what you're going for and this mechanism of action is like it's the perfect tool for that problem because the N. P. M. One is is directly related to the man.

Troy Edward Wilson: There's clear literature that says patients with MRD negative responses have better survival, and that's why FDA gave the green light to Kronos for their trial with the sick inhibitor. The potential Tiago of a MNNNNin inhibitor to drive an MRD negative response in that front line, a durable response, that's really what you're going for. And this mechanism of action is like it's the perfect tool for that problem.

In MLR pathway and by virtue of the mechanism that you're reducing differentiation and driving these mrna negative responses.

We're keen to get to that frontline setting because.

Troy Edward Wilson: because NPM 1 is directly related to the MNML pathway. And by virtue of the mechanism that you're inducing differentiation and driving these MRD negative responses, we're keen to get to that front line setting. Because although you may increase the response rate, the hope is that you will make those responses deeper and more durable, and that will be a benefit to patients, both in the non-intense chemo populations as well as in the intense chemo populations. understood.

You may increase the response rate. The hope is that you will make those responses deeper more durable and that will you know that'll be a benefit to patients both in the in the non intense chemo as well as in the intense chemo populations.

Tiago Fauch: Understood. I appreciate the answer. All right. Thanks.

Yeah understood understood.

Thanks.

Thanks Thiago.

As a reminder, if you have a question. Please press Star then one on your Touchtone phone. Our next question comes from Jonathan Chang from SBB Leerink. Please go ahead.

Yeah.

Hi, guys. Thanks for taking the follow up.

What is co business stat, and what impact could this have in combination with a minimum MLR inhibitor and future development strategy.

Operator: As a reminder, if you have a question, please press star than one on your touchtone phone. Our next question comes from Jonathan Chang from SVV Lerink. Please go ahead.

Jonathan Kudos for you for getting back in the queue I'm.

Jonathan Chang: Hi guys, thanks for taking the follow-up. What is Kobysistat, and what impact could this have in combination with MLL-Ninthin and future development strategies?

Sure. So could this stat is a strong three four inhibitor.

As you know and and for those who may not be aware I think jonathan's referring to up.

Troy Edward Wilson: Jonathan, kudos for you for getting back in the queue. Sure. So, Kibisostat is a strong Sip3A4 inhibitor. And for those who may not be aware, I think Jonathan's referring to, you know, an update on ClinicalTrials.gov from one of our competitors. As far as we know, Kibisostat is used to increase the drug levels of sensitive SIP 3A4 substrates, and the thought is that our competitor is dosing their compound with kibisostat as a way of trying to increase the exposure of their menin inhibitor and reduce the sensitivity to azals.

An update on clinical trials dot Gov from from one of our competitors as far as we know the business that is used to increase the drug levels of sensitive Sip three or four substrates.

And the thought is that our competitor is dosing their compound with COVID-19 stat as a way of trying to increase the exposure of their menin inhibitor.

And and make.

Reduce the sensitivity to <unk>.

They're trying to increase the exposure at lower doses by effectively giving all of the patients co business debt.

Now if you can do that then potentially you could remove the requirement of having two doses one for diesel and one for the non azole. The liabilities. The complication of course is it makes it much more difficult to then.

Troy Edward Wilson: So they're trying to increase the exposure at lower doses by effectively giving all of the patients kubisostat. Now, if you can do that, then potentially, you could remove the requirement of having two doses, one for the asol and one for the non-asol. The liability, the complication, of course, is that it makes it much more difficult to then use that in combination with other drugs. And you can just go into the package insert for Kibisostat and look at the drugs that are contraindicated, and you'll see it includes azals, right?

Use that in combination with other drugs.

And you can just go into the package insert for a business that and look at the Contra the drugs that are contra indicated and youll see it includes as holes.

Right because of the the the the Sip terrain four interactions. So it may ultimately help in the near term with increasing plasma exposures at lower doses in the long term, it's going to make combinations. We think much more complicated and in contrast, you of course 539 weeks.

Troy Edward Wilson: because of the SIP-3-4 interactions. So it may ultimately help in the near term with increasing plasma exposures at lower doses. In the long term, it's going to make combinations, you know, we think, much more complicated. And in contrast, of course, 539 needs none of that, right? We're into, our exposures are independent of whether patients are on no azal, modern asal, or strong azal. You know, we don't, we don't have to, we don't have to dose with kibisostat or another compound that's commonly used is rittonavir. So it's just a much better setup both for monotherapy and in common.

Right we were in debt.

Our exposures are independent of whether patients are on no wasteful moderate names or strong as Ole.

You know we don't we don't have to we don't have to dose with Quebec stat or another compound commonly used just photonics here.

So it's just a much better set up both for the monotherapy and in combination.

Got it thanks for taking the follow up.

Sure I appreciate the question.

We have no further questions at this time.

Great. Thank you operator, and thank you all once again for participating in the call today, we will be at the JMP Securities Life Science Conference next month look forward to speaking with many of you then in the meantime, if you have any questions. Please feel free to contact Pete Marc or myself. Thank you again and have a good evening everyone.

Jonathan Chang: Got it. Thanks for taking the follow-up.

Operator: We have no further questions at this time.

Troy Edward Wilson: Great. Thank you, operator. And thank you all once again for participating in the call today. We'll be at the JMP Securities Life Science Conference next month. Look forward to speaking with many of you then. In the meantime, if you have any questions, please feel free to contact Pete, Mark, or myself. Thank you again, and have a good evening.

Thank you ladies and gentlemen. This concludes today's conference. Thank you for participating you may now disconnect.

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Operator: Thank you, ladies and gentlemen. This concludes today's conference. Thank you for participating. You may now disconnect.

Operator: and and and and and and and and and You know? Thank you. Thank you. Thank you. Thank you. Thank you. Thank you, and and Thank you, Thank you.

Operator: Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you, and and and The

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