Q3 2020 Kura Oncology Inc Earnings Call

And welcome to the Q3 2020, Cara Oncology conference call.

Operator: And welcome to the Q3 2020 Kura Oncology Conference Call. At this time, all lines are placed in a listed-only mode.

At this time all lines are placed in a listen only mode.

Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you will need to press star 1 on your telephone. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today. Pete, this is Spain. Thank you, and please go ahead, sir.

After the speaker presentation, there will be a question and answer session to ask a question. During the session you will need to press star one on your telephone if you require any further assistance. Please press star zero.

I would now like to hand, the conference over to your Speaker today Pete This Spain. Thank you. Please go ahead Sir.

Pete De Spain: Thank you, operator. Good morning and welcome to Kura Oncology's third quarter 2020 conference call. Joining me on the call from Kura are Dr. Troy Wilson, our President and Chief Executive Officer, and Dr. Mark Grasso, our Chief Financial Officer and Chief Business Officer.

Thank you operator, good morning, and welcome to occur Oncologys third quarter 2020 conference call joining me on the call concur or Dr. Troy Wilson, our President and Chief Executive Officer, and Dr., Mark Russell, Our Chief Financial Officer, and Chief Business Officer.

Pete De Spain: Jim Basta, our Chief Legal Officer, Dr. Stephen Dale, our Chief Medical Officer, Kirsten Flowers, our Chief Commercial Officer, and Kathy Ford, our Chief Operating Officer, are also with me. 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, As of today, it 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 Dr. Troy Wilson, President and CEO of Kura. Thank you, Pete, and thank you all for joining us bright and early this morning.

Jim Boss to our Chief legal Officer, Dr., Stephen Dale, Our Chief Medical Officer, Kierston flowers, our Chief commercial officer, and Kathy Ford Our Chief operating Officer are also with us and available to answer questions before.

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 others.

Excuse me as of today and May involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Chris filings with the FCC, which are available from the FCC or on the current called your website for information concerning risk factors that could affect the company with that I'll now turn the call over to Dr. Troy Wilson President.

CEO occur oncology.

Thank you Pete and thank you all for joining us bright and early this morning.

Troy Edward Wilson: Kura was founded six years ago with a fundamental mission to realize the promise of precision medicines to help patients with cancer lead better, longer lives. We've made tremendous progress over that time, with much of our effort centered around our lead drug candidate, Tipifarnib. Harnessing the power of precision medicine, we've demonstrated a compelling level of clinical activity in HRS mutant head and neck squamous cell carcinoma, a particularly difficult to treat patient population.

Kurt was founded six years ago with a fundamental mission to realize the promise of precision medicines to help patients with cancer lead better longer lives Weve made tremendous progress over that time with much of our efforts centered around our lead drug candidate Tipifarnib harnessing the power of precision medicine, we've demonstrated a compelling love.

Full of clinical activity and attracts mute and head and neck squamous cell carcinoma, a particularly difficult to treat patient population, culminating in the in our ongoing aim matron registration directed trial.

Troy Edward Wilson: Culminating in our ongoing AMHN registration directed trial. We're also pioneering new approaches to expand the use of tipifarnib into larger patient populations with preclinical data that support the potential to expand the therapeutic utility of tipifarnib to HRAFs and PI3 kinase-dependent tumors that may represent up to half of HNSCC. All the while, we've been optimizing, testing, and advancing our menin inhibitor, K0539, an exciting new class of drugs for patients with acute leukemias, and we look forward to presenting preliminary clinical data for this program at the American Society of Hematology annual meeting next month. And we do all of this from a position of strength in terms of our proprietary assets, our financial resources, and our talent, the latter of which I'm pleased to say has been further enhanced with the recent addition of Dr. Stephen Dale as our Chief Medical Officer.

We're also pioneering new approaches to expand the use of tipifarnib into larger patient populations with preclinical data that supports the potential to expand the therapeutic utility of Tipifarnib, two h. Ross and Pi three kinase dependent tumors that may represent up to half of each NFC.

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All the while weve been optimizing testing and advancing our men an inhibitor Kale 539, an exciting new class of drugs for patients with acute leukemias and we look forward to presenting preliminary clinical data for this program at the American Society of Hematology annual meeting next month.

And we do all this from a position of strength in terms of our proprietary assets, our financial resources and our talent the latter of which I'm pleased to say has been further enhanced with the recent addition of Dr. Stephen Dale as our Chief Medical Officer.

Troy Edward Wilson: Stephen joined us in August, most recently from Kyokuren, where he served as Senior Vice President, Global Head of Medical Science, with responsibility for oncology, neuroscience, immunology, and rare diseases. Previously, he was global clinical vice president and clinical head of oncology at AstraZeneca, where he oversaw the development of Tegresso for metastatic EGFR-T790M mutation-positive non-small cell lung cancer Stephen also worked with the ARESA team on the IPATH study in patients with EGFR-activating mutations, which caused a paradigm shift in the way non-small-cell lung cancers are treated. His experience leading late-stage drug development teams, including the successful development and approval of multiple targeted therapies, is already having a profound impact on our organization as we continue to focus on our two major clinical development programs, tipifarnib and HRAF-dependent H Now let's dig into both programs a little deeper, beginning with our menin inhibitor, KL539. KO539 is a potent, selective, oral, small-molecule inhibitor of the Menin-KMT2A or MLL interaction with downstream effects on HoxA9 and MIS1 gene expression.

Stephen joined US in August most recently from killing Karen where he served as senior Vice President Global head of medical science with responsibility for oncology neuroscience immunology and rare diseases.

Previously he was global clinical Vice President and President called head of oncology at Astra Zeneca, where he oversaw the development of Tagrisso for metastatic EG, a far T 790, m. mutation positive non small cell lung cancer.

Stephen also worked with the arrest the team on the I. pet study in patients with easier for activating mutations which are both the paradigm shift in the way non small cell lung cancer is treated.

His experience at leading late stage drug development teams, including the successful development and approval of multiple targeted therapies is already having a profound impact on our organization as we continue to focus on our two major clinical development programs Tipifarnib in a trust dependent h. in FCC and Kale five.

39 in nano now, let's dig into both programs a little deeper beginning with amending inhibitor Kale 539.

Tailpipe 39 is a potent selective oral small molecule inhibitor of the men Kmt to a or MLL interaction with downstream effects on Hawk say nine and missed one gene expression.

We generated preclinical data that supports the potential anti tumor activity of tail fivethirty nine and genetically defined subsets of acute leukemia, including but not limited to those with rearrangements into Kmt two way gene as well as those with oncogenic driver mutations in genes such as MTN one.

Troy Edward Wilson: We've generated preclinical data that support the potential anti-tumor activity of KO539 in genetically defined subsets of acute leukemia, including, but not limited to, those with rearrangements in the KMT2A gene, as well as those with oncogenic driver mutations in genes such as NPM1. We believe KL539 represents a differentiated approach to target genetic subsets representing potentially 35% or more of the total adult population. We dosed our first patients in our Phase 1, 2A clinical trial of KL539 in relapsed refractory AML late last year. The trial, which we've named COMET001, is using an accelerated adaptive design with dose selection based on a modified toxicity probability interval, a trial design that enables treatment of a single patient at each dose level early on, exposing fewer patients to dose levels that are believed to be subtherapeutic.

We believe Kale Fivethirty nine represents a differentiated approach to target genetic subsets, representing potentially 35% or more of the total adult population.

We dosed our first patient in our phase one to a clinical trial of keel 539 in relapsed refractory AML late last year, the trial, which we've named common 001 is using an accelerated adaptive design with dose selection based on a modified toxicity probability interval a trial design that enable.

For the treatment of a single patient per dose level early on exposing fewer patients to dose levels that are believed to be sub therapeutic.

Although the first several escalations were conducted with single patient cohorts, we advance to a more traditional three plus three design for dose escalation concurrent with the submission of our ash abstract in early August to gather more data in a larger number of patients last month, we were pleased to learn our abstract.

Reporting preliminary data from Comet 001 was accepted for oral presentation at ash, the abstract which was posted on the ash website yesterday morning.

Highlighted encouraging safety and Tolerability as well as evidence of anti leukemic activity as of the data cut off of August 10th.

We look forward to sharing more mature dataset, including preliminary data from approximately 10 patients with relapsed refractory AML in the oral presentation at Ash on December 5th. It's also worth, noting we will be hosting a virtual investor event, featuring two of the trials investigators immediately following.

Troy Edward Wilson: Although the first several escalations were conducted with single-patient cohorts, we advanced to a more traditional 3-plus-3 design for dose escalation concurrent with the submission of our ASH abstract in early August to gather more data in a larger number of patients. Last month, we were pleased to learn that our abstract reporting preliminary data from Comet 001 was accepted for oral presentation at ASH.

Oral session on December 5th.

Please stay tuned for more details.

In the meantime, we're very encouraged with the progress we have made with the study as common 001 continues in dose escalation given the favorable safety and Tolerability. We've seen thus far we now expect to determine a recommended phase two dose for Kale 539 in the first quarter of Twentytwenty one.

We continue to add clinical sites in anticipation of moving into the expansion cohorts pending additional clinical data.

Troy Edward Wilson: The abstract, which was posted on the ASH website yesterday morning, highlighted encouraging safety and tolerability, as well as evidence of anti-leukemic activity as of the data cutoff of August 10th. We look forward to sharing a more mature data set, including preliminary data from approximately 10 patients with relapsed refractory AML in the oral presentation at ASH on December 5th. It's also worth noting that we will be hosting a virtual investor event featuring two of the trial's investigators immediately following the oral session on December 5th. Please stay tuned for more details.

The planned expansion cohorts include NPM, one mutant AML and Kmt two way or MLL rearranged am out.

Selected patient populations, where we believe Kale 539 has the potential to demonstrate increased clinical benefit. In addition, we're exploring options to potentially broaden the opportunity in the treatment of acute leukemias in adults as well as the combination of scale fivethirty nine with chemotherapy and targeted therapies in the front line.

Now, let's move to our most advanced program Tipifarnib for the treatment of patients with head and neck squamous cell carcinoma, a population in dire need of effective new treatments. In addition to conducting our ongoing registration directed trial of Tipifarnib in recurrent or metastatic HRS meet nature and FCC a try.

Well that we call Amy Chen we're also leveraging new advances to expand the use of tipifarnib into larger patient populations.

Troy Edward Wilson: In the meantime, we're very encouraged with the progress we have made with the study as COMET-001 continues its dose escalation. Given the favorable safety and tolerability we've seen thus far, we now expect to determine a recommended Phase II dose for KO539 in the first quarter of 2021. We continue to add clinical sites in anticipation of moving into the expansion cohorts pending additional clinical data. The planned expansion cohorts include NPM1 mutant AML and KMT2A or MLL rearranged AML. Selected patient populations where we believe KO539 has the potential to demonstrate increased clinical benefit

Over the past several years, our internal translational research team led by Dr. Francis Burrows has identified what we believe to be a compelling opportunity.

You combine tipifarnib with inhibitors of the enzyme pithree kinase alpha to treat h. and FCC patients, whose tumors are dependent on HRS and or Pithree kinase Alpha. This work, which has been multiple years in the making was the subject of our poster presentation at the RTC and see.

Hi, HCR molecular targets and cancer Therapeutics Symposium also called the Triple meeting a couple of weeks ago, our preclinical data support the observation that H. Ross and Pithree kinase, our co dependent on can genes in H. and S.C.C.

And suggest that a combination approach has the potential to provide meaningfully better anti tumor activity than inhabit inhibiting either target alone.

The compelling preclinical data presented at the Triple meeting underscore the potential to combine tipifarnib with Apache kinase alpha inhibitor to treat patients with head and neck squamous cell carcinoma.

Troy Edward Wilson: In addition, we're exploring options to potentially broaden the opportunity for the treatment of acute leukemias in adults, as well as the combination of KO539 with chemotherapy and targeted therapies in the front line. Now we move to our most advanced program, TIPIFARNIV, for the treatment of patients with head and neck squamous cell carcinoma, a population in dire need of effective new treatment. In addition to conducting our ongoing registration-directed trial of tipifarnib in recurrent or metastatic HRAS mutant HNSCC, a trial that we call AIMHN, we're also leveraging new advances to expand the use of tipifarnib into larger patient populations. Over the past several years, our internal translational research team, led by Dr. Francis Burroughs, has identified what we believe to be a compelling opportunity to combine tipifarnib with inhibitors of the enzyme PI3 kinase alpha to treat HNSCC patients whose tumors are dependent on HRAS and or PI3 kinase alpha.

As such we're prioritizing the conduct of the phase one two proof of concept study of Tipifarnib in combination with the pediatric kind itself inhibitor and advanced or Unresectable relapsed refractory h. in FCC, harboring, pikthreeca mutations or amplifications and or a trend over expression.

We look forward to sharing more details with you about the trial in the months ahead with that ill now turn the call over to Dr., Mark Grasso for a discussion of our financial results for the third quarter Twentytwenty.

Thank you Troy and good morning, 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 more detailed discussion.

Research and development expenses for the third quarter of 2020.

Were $16.6 million compared to $12.5 million for the third quarter of 2019.

The increase in R&D expenses was primarily due to an increase in clinical development activities related to our ongoing trials and personnel costs and other expenses.

General and administrative expenses for the third quarter of 2000 $27.6 million compared to $5.1 million for the third quarter of 2019.

The increase in DNA expenses was primarily due to increases in pre commercial planning expenses personnel costs and noncash share based compensation.

Net loss for the third quarter, 2020 was $23.8 million or 42 cents per share compared to a net loss of $16.4 million or 36 cents per share for the third quarter of 2019.

As of September 32020, we had cash cash equivalents and short term investments of $325.4 million compared with $236.9 million as of December 30, Onest 2019.

Troy Edward Wilson: This work, which has been multiple years in the making, was the subject of our poster presentation at the EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium, also called the TRIPLE meeting, a couple of weeks ago. Our preclinical data support the observation that HRAS and PI3 kinase are codependent oncogenes in HNSCC and suggest that a combination approach has the potential to meaningfully improve outcomes. The compelling preclinical data presented at the triple meeting underscore the potential to combine tipifarnib with a piatre kinase alpha inhibitor to treat patients with head and neck squamous cell carcinoma.

Based on our current plans, we continue to believe that our current cash cash equivalents and short term investments will be sufficient to fund current operations into 2023.

Ill now turn the call back over to Troy.

Thank you Mark.

Despite the ongoing challenges of a global pandemic, we continue to execute on our two major clinical development programs I'm proud of the team Im pleased by the terrific progress, we're making we remain in a strong cash position as we approach important catalyst beginning with the first presentation of clinical data from our common zero zero.

One study at Ash with that operator, we're now ready to take questions.

Mark Grasso: As such, we're prioritizing the conduct of a Phase I-II proof-of-concept study of tipifarnib in combination with a PI3-kinase alpha inhibitor in advanced or unresectable relapsed refractory HNSEC harboring PIK3CA mutations or amplifications and or HRAS overexpression. We look forward to sharing more details with you about the trial in the With that, I'll now turn the call over to Dr. Mark Grasso for a discussion of our financial results for the third quarter of 2020. Thank you, Troy, and good morning, everyone. I'll provide a brief overview of our financial results here on the call and invite you to review our 10-Q file today for more detailed discussion. Research and Development Expenses for the Third Quarter of 2020 were $16.6 million compared to $12.5 million for the third quarter of 2019. The increase in R&D expenses was primarily due to an increase in clinical development activities related to our ongoing trials, personnel costs, and other expenses. General and administrative expenses for the third quarter of 2020 were $7.6 million, compared to $5.1 million for the third quarter of 2019.

If you would like to ask a question at this time. Please press Star then the number one on your telephone keypad.

If you like to withdraw your question press the pound key we will pause for just a moment to compile the Q1 day roster.

And your first question comes from the line of Jonathan Chang.

Good morning, and thanks for taking my questions.

First question can you talk about the potential opportunities for Q3, nine beyond and handling Ellington that not all of your range stand now.

Sure Jonathan Thanks, Thanks for the question and good morning. So.

That's it's a timely question as you saw in the abstract we were quite excited too.

To be able to enroll a patient who had.

As set the two wrongs one you amie.

And now.

And I think that that's an example that speaks to a potentially broader application of amending inhibitors and.

The way to think about it is.

MLL controls the expression of two critical transcription factors meets one and Hawk say nine those two transcription factors in turn control a set of genes that determine whether leukemic blasts remain in an undifferentiated state sort of an angry.

He adolescence, if you will or if that the sell much differentiates and matures into a granular side or monocyte more mature sell out.

What it meant an inhibitor does is it blocks the action of MLL and it down regulates the expression of of Hawk say nine at least one and switches the sell from one state to the other.

Mark Grasso: The increase in G&A expenses was primarily due to increases in pre-commercial planning expenses, personnel costs, and non-cash share-based compensation. The net loss for the third quarter of 2020 was $23.8 million, or $0.42 per share, compared to a net loss of $16.4 million, or $0.36 per share, for the third quarter of 2019. As of September 30, 2020, we had cash, cash equivalents, and short-term investments of $325.4 million, compared with $236.9 million as of December 31, 2019. Based on our current plans, we continue to believe that our current cash, cash equivalents, and short-term investments will be sufficient to fund current operations into 2023. With that, I will now turn the call back over to Troy. Thank you, Mark. Despite the ongoing challenges of a global pandemic, we continue to execute on our two major clinical development programs. I'm proud of the team and pleased by the terrific progress we're making.

Increasingly what we're learning is that a number of mutations in AML can contribute to the tumors dependence on the MLL pathway.

And 72 is a good example, it actually appears to to modulate particular methyl mark on his stones.

And and the challenge of course is given that the genetic complexity of them now it's difficult to have preclinical models to represent all the various combinations, but we're optimistic that there is a god.

Set of of acute leukemia as that may be as large as an additional 15% of they have now above and beyond NPM, one and MLL R where the tumor is dependent on the MLL pathway and has.

Two were more mutations that are driving that MLL dependence set the two rungs that one mutant is such an example, we're very actively investigating whether there are other instances, both pre clinically and clinically.

Got it. Thank you and one other question for me can you provide any color around how we should be thinking about the dose level, you're currently treating patients.

Hi, Threenine versus the dose level, where you see are disclosed in the abstract.

Yeah, Yeah happy happy to take that so.

When before we dose the patient based on Allometric scaling calculations and.

And a lot of sort of preclinical work that we had done we estimated that the recommended phase two dose for cable side 39 would be approximately 600 milligrams.

Troy Edward Wilson: We remain in a strong cash position as we approach important catalysts, beginning with the first presentation of clinical data from our Comet 001 study at Ash. With that operator, we're now ready to take questions. If you would like to ask a question at this time, simply press star, then the number 1 on your telephone keypad.

Per kilogram QD the.

The.

We were very surprised when we saw evidence of biological activity in the first three dosing cohorts, which were 50 102 hundred.

And in particular, what we observe the patient with a complete response at the 100 milligram dosing cohort what that suggested to US was that the compound was active at lower doses than we expected. We think we now have an explanation for that and that's some intrinsic proper.

Operator: If you would like to withdraw your question, press the pound key. We will pause for just a moment to compile the Q&A roster. And your first question comes from Jonathan Chang. Good morning, and thanks for taking my question. First question: can you talk about the potential opportunities for KO-539 beyond NPM-1 mutant and MLL rearranged AMs? Sure, Jonathan.

Properties of Kale 539.

But it motivated us to to expand the cohort and then continue escalation. We are currently evaluating patients in a 400 milligram cohort.

Troy Edward Wilson: Thanks for the question and good morning. So... It's a timely question, As you saw in the abstract... We were quite excited to be able to enroll a patient who had a set D2 RUNX1 mutant AML. And I think that that's an example that speaks to a potentially broader application of menin inhibitors. And the way to think about it is that MLL controls the expression of two critical transcription factors, MIS-1 and HoxA9. Those two transcription factors, in turn, control a set of genes that determine whether leukemic blasts remain in an undifferentiated state, sort of an angry adolescence, if you will, or if the cell differentiates and matures into a granulocyte or a monocyte, you know, a more mature cell. What a menin inhibitor does is it blocks the action of MLL, and it downregulates the expression of HoxA9 and MIS-1 and switches the cell from one state to the other.

So weve now dose.

Multiple patients 200 multiple patients at 400, if we're successful in clearing the 400 milligram cohort, we likely will then go to 600 milligrams.

As you I think your question correctly points out we may not that may not be the recommended phase two dose.

Given that were multiple times higher than where we observed.

The CR, but we think it gives us the flexibility to be able to determine a recommended phase two dose and potentially a large therapeutic window, which is really the ideal combination for our compounds such as cable side 39, so the ash data that you'll see will likely be.

The 204 hundred milligram cohorts. In addition to what's been disclosed in the abstract we're continuing in dose escalation and from our perspective, although we push the timeline out by.

By one additional quarter, we view that as a good thing because it gives us the potential to push the dose and really explore you know do we have a wide therapeutic window and flexibility in the dosing range hopefully that helps address your question.

It does thank you very much.

Thank you Jonathan.

And your next question comes from the line of Peter Lawson.

Barclays.

Thanks, Troy, Thanks for taking the questions and congratulations on the on the initial data the Q 539.

Troy Edward Wilson: Increasingly, what we're learning is that a number of mutations in AML can contribute to the tumor's dependence on the MLL pathway, and SetD2 is a good example. It actually appears to modulate a particular methyl mark on histones. And the challenge, of course, is given the genetic complexity of AML; it's difficult to have preclinical models to represent all the various combinations. But we're optimistic that there is a set of leukemias that may be as large as an additional 15% of AML above and beyond NPM1 and MLLR, where the tumor is dependent on the MLL pathway and has two or more mutations that are driving that MLL dependence. The SETI 2 rung SETI 1 mutant is such an example.

Seeing Qt prolongation.

And then for the tablet as some of the drug is exclusively going through three four.

Through that please.

Yeah, Peter how happy to answer both of those so with respect to the Herg inhibition in Qt prolongation.

Let me be clear because I know there were some questions after the abstract draw.

Dropped rather unexpectedly yesterday.

We have not seen any evidence of Qt prolongation.

As I've said in previous calls we.

We did extensive testing pre clinically the compound shows a low propensity for.

Any kind of Qt interval prolongation or cardiac signal. We are of course monitoring every patient on the study closely we've not seen any evidence of Qt prolongation and Weve looked very carefully so to the point that I was I was making Jonathan in the preceding question I think we feel like we have a very.

Troy Edward Wilson: We're very actively investigating whether there are other instances, both preclinically and clinically. Got it. Thank you, and one other question for me: can you provide any color around how we should be thinking about the dose level you're currently taking? Yeah. Happy, happy to take that. So, before we dosed the patient, based on allometric scaling calculations and a lot of sort of preclinical work that we had done, we estimated that the recommended phase 2 dose for KO539 would be approximately 600 milligrams per kilogram QD. We were very surprised when we saw evidence of biological activity in the first three dosing cohorts, which were 50, 100, and 200. And in particular, we observed a patient with a complete response in the 100 milligram dosing cohort.

We're very encouraged by the safety and Tolerability, not just with respect to Q T, but overall and.

And we think potentially we have a broad therapeutic window in terms of your second question Peter on the pharmacokinetics. So as I mentioned, we were surprised pleasantly surprised to see evidence of biologic activity in the early cohorts.

It's clear that the drug was after the doses below what we were expecting.

We added the abstract really remember is that is that is a snapshot in time.

We evaluated whether it was the contribution of.

Of concomitant medications, such as Angels and their effects on sixthree for inhibition that might be driving the the activity of 539, we've ruled that out at least for now.

Troy Edward Wilson: What that suggested to us was that the compound was active at lower doses than we expected. We think we now have an explanation for that, and that is some intrinsic property of KO539. But it motivated us to expand the cohort and then continue escalation. We are currently evaluating patients in a 400 milligram cohort, so we've now dosed multiple patients at 200 and multiple patients at 400. If we're successful in clearing the 400 milligram cohort, we likely will then go to 600 milligrams. However, as you, I think your question correctly points out, that may not be the recommended phase 2 dose, given that we're multiple times higher than where we observed the CR. But we think it gives us the flexibility to be able to determine a recommended phase 2 dose and potentially a large therapeutic window, which is really the ideal combination for a compound such as KO539. So the ASH data that you'll see will likely be from the 200 and 400 milligram cohorts, in addition to what's been disclosed in the abstract.

Assistant to that because it didn't hibbitts its own metabolism to your final question. Peter there are likely other metabolic enzymes also at work you know and that's part of the overall package that we're characterizing them as we are as we are conducting the phase one dose escalation study really trying to understand P. K.

Troy Edward Wilson: We're continuing with dose escalation. And from our perspective, although we pushed the timeline out by one additional quarter, we view that as a good thing because it gives us the potential to push the dose and really explore whether we have a wide therapeutic window and flexibility in the dosing range. Hopefully, that helps address your question.

Hey exposure key metabolites and all of the questions and that's the basic bread and butter of early stage drug drug development, nothing really unusual to report their.

Great. Thank you and then the initial side effect profile you see in a couple of great. Three's. Just do you think that in any way can preclude you from going higher and dosing.

Troy Edward Wilson: Thank you very much. Thank you, Jonathan. And your next question comes from the line of Peter Lawson from Barclays. True, things, and congratulations on the initial, Q539, are you seeing... Prolongation. And then for the metabolism of the drug, is that exclusively going through CYP3A4, could you walk through that? Yeah, Peter.

No it doesn't not at all and actually Peter Let me use that as an opportunity to invite Steven Dale to comments on those two grade three a he's what what we saw on what they might mean in terms of our ability to both does higher and potentially expand into.

Other indications such as pediatric.

Steven are you are you able to take Peter's question.

Troy Edward Wilson: I'd be happy to answer both of those. So, with respect to HERG inhibition and QT prolongation, let me be clear, because I know there were some questions after the abstract dropped rather unexpectedly yesterday. We have not seen any evidence of QT prolongation. As I've said in previous calls, we did extensive testing preclinically. The compound shows a low propensity for any kind of QT interval prolongation or cardiac signal. We are, of course, monitoring every patient on the study closely. We've not seen any evidence of QT prolongation, and we've looked very carefully.

<unk>. Thank you Troy Hi, Pizza nurse is a great question. So as you say from abstract we saw to grade threes in the early single patient cohort escalation when was thromboembolic events, great three and that was a patient of 100 milligrams and one was chairman license syndrome 50 milligrams.

So if we look at the thromboembolic events first uhm.

And we should say that the association or the known association of V. Ts with a amount in the acute leukemias is actually pretty well understood. It has it background incidence of around about 5%. So the event itself isn't a typical.

The reason.

Why the causality was assigned was a conservative approach and the SLC meetings between investigators on ourselves.

We agreed that given the size of the clock rather than the event itself than we would on this occasion look to assign it to causality. However in terms of your question does it affects escalation amounts was no.

Troy Edward Wilson: So, to the point that I was making with Jonathan in the preceding question, I think we feel like we have a very – we're very encouraged by the safety and tolerability, not just with respect to QT, but overall, and we think potentially we have a broad therapeutic window. In terms of your second question, Peter, on the pharmacokinetics, As I mentioned, we were pleasantly surprised to see evidence of biological activity in the early cohorts. It was clear that the drug was active at doses below what we were expecting. And the abstract, really, remember, is a snapshot in time.

It wasn't deemed to be D O T.

The event is an isolated event.

There was no dose interruption and there was no discontinuation of the of the compound kowhai three nine because of the event and I think it's important to know as well. This is the patient at 100 milligrams, you'll actually went on to have the complete remission, which was late and then found to be M. O D.

Negative through flow cytometry, so and we've not seen anything else. Since this particular episode than looking at the the cumulative syndrome. The patient 50 milligrams once again.

Ross.

As a manifestation.

Not uncommon certainly in hematology and actually can be seen as a surrogate pharmacodynamic marca biological effect.

Troy Edward Wilson: We evaluated whether it was the contribution of concomitant medications, such as azoles, and their effects on STIP3A4 inhibition that might be driving the activity of 539. We've ruled that out, at least for now. There doesn't seem to be any dependence of KO539 on whether patients are on moderate or strong azoles, for example. However, what we do observe, both preclinically and clinically, is that KO539 and at least one of its metabolites appear to inhibit the action of STIP3A4. And by doing that, essentially, they are inhibiting their own metabolism. And they do it in a time-dependent manner. And so you can imagine the compound accumulates over time. We're still characterizing its pharmacokinetics and exposure. I want to stress that we've continued dosing on a once-daily schedule throughout each cohort, and as I've commented, we see very encouraging safety and tolerability. The significance of that auto-inhibitory activity on STIP3A4 is important because STIP3A4 is an enzyme that's present not only in the liver but in bone marrow. It's one of the ways that bone marrow actually protects itself from xenobiotics.

The reason for this is that the rapid breakdown of malignant cells and the leakage of new nuclear cast it into the bloodstream causes various different issues such as hypocalcemia, He already Cassie crystallize Asian, and all of these elements well managed.

But it shows that the drug is having an effect and I think once again.

Didn't lead to any discontinuation that was drug related in this particular case and we haven't seen anything like this again, so hopefully that helps to put those two events into context and once again just to echo Troy very.

Very encouraged by the safety until the ability of the compound and we continue to escalate as part of our phase one dose escalation study.

Great. Thank you so much things really helped put into perspective. Thank you. Thank you.

Thank you Peter.

And your next question comes from the lineup Marty.

Marty.

Since we're taking the question I think I want to follow up on something Jonathan <unk>.

You're looking at the potential for K O 539, and the other two rooms that may be utilized a minute pathway, let me see.

And oxendine overexpression situations I was curious if you could comment on what the gating steps in timeframe might look like for you to kind of make decisions about potentially including those sorts of the patient neither future does too cohort expansion or some other study.

[noise], Yeah, Mardi <unk>, it's a great question. Thank you.

So as I indicated in my answered to Jonathan's question were quite keen to evaluate the potential clinical.

Clinical activity at 539, and tumors that are not M. P. M O N P M, one or Newton tour M. L. L. Rearranged what we require is a way of trying to enrich for those patients <unk>.

Troy Edward Wilson: And there are reports in the literature that a number of compounds, such as split-3 inhibitors, are deactivated in bone marrow because they're metabolized by STIP3A4. This compound appears to be resistant to that because it inhibits its own metabolism. To your final question, Peter, there are likely other metabolic enzymes also at work.

One potential way to do it is amiss one assay at least one expression assay are hawk say nine expression assay that could be used in the clinic.

That is something that we're working on it's not quite ready for implementation in the clinic, but it is an inactive development. There are other approaches that one can also use potentially to enrich for that patient population and we're actively evaluating them internally and also talking.

Troy Edward Wilson: And that's part of the overall package that we're characterizing as we are conducting the Phase I Dose Escalation Study, really trying to understand PK, exposure, key metabolites, and all of the questions. And that's the basic bread and butter of early-stage drug development. There's nothing really unusual to report there.

With our investigators in Kols I I am optimistic that will be in a position to to have potentially a third cohort it will probably lagged behind the other two.

As we're working through some of these these technical challenges the advantage of course of M. P. M. One and M. L or is that you can use next year generation sequencing to identify the patients that is standard of care. It's available at all sites. So there really aren't operational hurdles to.

Troy Edward Wilson: And then the initial side effect profile, you've seen a couple of grade threes. Does that in any way kind of preclude you from going higher in dose? No, it doesn't. Not at all.

Implementing it in a clinical trial.

Stephen Dale: And actually, Peter, let me use that as an opportunity to invite Stephen Dale to comment on those two grade 3 AEs, you know, what we saw and what they might mean in terms of our ability to both dose higher and potentially expand into other indications such as pediatric. Stephen, are you able to take Peter's question? Yeah, of course. Thank you, Troy.

When you're expanding the patient population unless you want to go with them all comers population.

You have to do a bit more assay development and that's where we are currently and I I imagine Marty that will have will be able to give you more guidance in the in the coming months as to exactly how to think about that and specific timing.

Super look forward to be updates and thanks for your post Street.

Yeah happy too.

And your next question.

Come from the line.

Benjamin.

Security.

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

Stephen Dale: Hi Peter. No, it's a great question. So as you can see from the abstract, we saw two grade 3s in the early single patient cohort escalation. One was a thromboembolic event, grade 3, and that was a patient at 100 milligrams, and one was tumor lysis syndrome at 50 milligrams. So, if we look at the thromboembolic event first, and we should say that the association or the known association of VTEs with AML and acute leukemias is actually pretty well understood. It has a background incidence of around 5%. So, the event itself isn't atypical. The reason why the causality was assigned was a conservative approach. And at the SRC meeting, between the investigator and ourselves, we agreed that given the size of the clot rather than the event itself, then we would, on this occasion, look to assign it to causality. However, in terms of your question, does it affect escalation, the answer is no. It wasn't deemed to be a DLT

And the temptation. So so that we're gonna see it as are are you know how many of them will be other M. L. L.

That's R M T. One.

Yeah. Thanks round now we get this question a lot.

And the.

The trial is is a dynamic.

A dynamic process.

So I don't want to.

Pin down specific numbers, what we can tell you is we're pretty consistently guide that.

And P M. One mutant AML.

Represents about 30% of the population in the relapsed refractory setting the MLR represents 5% to 10%.

When you get the small numbers, it's a bitch to Castex, we ask you shouldnt over interpret it but.

Based on what we're seeing in the patient flow.

Those numbers are not unreasonable, we're not we're not pushing people off of those numbers. If that helps give you some guidance I want to reiterate to everyone. This isn't all comers trial.

You should expect most of the patients not to fall into those categories.

And that's that's both by request of FDA and by design to ensure that we get an adequate picture of safety and Tolerability and we also get to potentially uncover the clinical activity of the compound as we have with the the set the two runs one mutant patient.

Stephen Dale: The event is an isolated event. There was no dose interruption, and there was no discontinuation of the compound, KO539, because of the event. And I think it's important to know as well, this is the patient at 100 milligrams who actually went on to have complete remission, which was later found to be MRD negative through flow cytometry. So, and we've not seen anything else since this particular episode.

But we do think that the ash update red will be a meaningful updates beyond what you've seen in the abstract both in terms of number of patients.

Follow up and and potentially new patients as well.

Got it and and I know that you were talking about biomarkers environment for signatures, maybe I'll upside of them I will if I remember your comments correctly, especially when looking at other indications.

Stephen Dale: Then looking at the tumor lysis syndrome, the patient at 50 milligrams, once again, you know, TLS is a manifestation that is not uncommon, certainly in hematology, and actually can be seen as a surrogate pharmacodynamic marker of biological effect. The reason for this is that the rapid breakdown of malignant cells and the leakage of nucleic acid into the bloodstream causes various different issues such as hypocalcemia, and uric acid crystallization, and all of these elements were well managed. But it shows that the drug is having an effect, and I think once again, you know, this didn't lead to any discontinuation that was drug-related in this particular case, and we haven't seen anything like this again, so hopefully that helps to put those two events into context. And once again, just to echo Troy, we're very encouraged by the safety and tolerability of the compound, and we continue to escalate it as part of our phase 1A dose escalation study. Great, thank you so much; it really helps.

Go after but within ml in this study for example, you sound to 72 and we're on this one.

Can you talk about other signatures that might be that might be popping up. That's that's interesting you know that you think you might pursue going further and then also as we look towards 2021 and and <unk> getting established.

What is now the the I guess the the pet.

Forward is it monotherapy studies, you know focused on kind of like last line is it more combination studies and do you think you could go straight to a registrational study given the.

Begin with a biomarker define indications has have been have been able to do that.

Sure rent so that's great. So so there's three parts to your question.

On the first part I wanted to be a little bit cautious in terms of describing how.

How we might think about potential other mutations are biomarkers and that's both because it's an area of active investigation and as some of you may know this is a competitive this is a competitive field.

Peter Richard Lawson: Thank you, Peter. And your next question comes from the line of Marti Osler of British Leeds. Hey guys, thanks for taking my question. I think I wanted to follow up on something Jonathan said. As you're looking at the potential for KO539 and other tumors that may be utilized in the Mennon Pathway, the MIS form, and HoxA9 overexpression situations, I was curious if you could comment on what the gating steps and timeframe might look like for you to kind of make decisions about potentially including those sorts of patients in either a future dose 2 cohort expansion or some other study. Yeah, Marty, it's a great question.

And so we're doing a lot of innovation there Dr. Francis boroughs to a number of you have engaged with is really leading that effort on the translational side. So we will have more to say about that but I don't think there's much more we can say today in terms of the the study.

Red and we are expecting to continue as a monotherapy in the relapse and refractory setting.

It is our view that there is an opportunity if we if we're seeing good safety and tolerability and and encouraging level of clinical activity that one could run a a single arm steady at least in the U S. Using response rate is the primary endpoint very much in.

The manner that the I D. H inhibitors have done and flipped three inhibitors have done.

Troy Edward Wilson: Thank you. So, as I indicated in my answer to Jonathan's question, we're quite keen to evaluate the potential clinical activity of 539 in tumors that are not NPM1 or mutant or MLL rearranged. What we require is a way of trying to enrich for those patients. One potential way to do that is by using an MIS-1 expression assay or HoxA9 expression assay that could be used in the clinic.

In there the hurdle rate for us is approximately 25% to 30% again, either in the <unk> or the MLR population those or both populations of high unmet need for those wondering NPM one mutations in the relapsed refractory setting are typically accompanied by other mutations.

Such as Dnm T. Three a slipped three or Ivy age that makes them a very negative prognosis. So there's a high unmet need in both populations. The feedback that we've received from investigators in Kols suggest there may be a path forward as a monotherapy in the relapsed refractory setting.

Troy Edward Wilson: That is something that we're working on. It's not quite ready for implementation in the clinic, but it is in active development. There are other approaches that one can also use potentially to enrich that patient population, and we're actively evaluating them internally and also talking, you know, with our investigators and KOLs. I am optimistic that we'll be in a position to have potentially a third cohort. It will probably lag behind the other two as we're working through some of these technical challenges. The advantage, of course, of NPM1 and MLLR is that you can use next-generation sequencing to identify the patients. That is the standard of care.

Troy Edward Wilson: It's available at all of the sites, so there really aren't any operational hurdles to implementing it in a clinical trial. However, when you're expanding the patient population, unless you want to go with an all-comers population, you have to do a bit more assay development, and that's where we are currently. I imagine, Marty, that we'll be able to give you more guidance in the coming months as to exactly how to think about that and specific times.

Troy Edward Wilson: I look forward to the updates and thanks for the insights, Troy. Yeah, happy to. Time for your next question comes from the line of Ren Benjamin from J.M. Hey, good morning, guys.

Troy Edward Wilson: Thanks for taking the call. Troy, in the ten patients or so that we're going to see at ASH, how many of them will be either MLL rearrangements or an MT1? Yeah, thanks, Ren. We get this question a lot.

This is.

Troy Edward Wilson: And, you know, the trial is a dynamic process, so I don't want to pin down specific numbers. But what we can tell you is that we pretty consistently guide that NPM1 mutant AML represents about 30% of the population in the relapsed refractory setting, and the MLLR represents 5 to 10%.

Not reinventing the wheel here. This is something that has been done successfully with a number of targeted therapies in oncology. So we feel like there's good strong precedent, both and targeted oncology and specifically an email.

Got it thanks, very much Troy and you'll get the award for remembering all my questions, even I didn't remember [laughter]. Thanks Red.

And your next question comes on the line of Alexander Duncan of Piper Sandler.

Troy Edward Wilson: But we do think that the ASH update RUN will be a meaningful update beyond what you've seen in the abstract, both in terms of number of patients, follow-up, and potentially new patients as well. And I know that you were talking about, you know, biomarkers and biomarker signatures. Maybe outside of AML, if I was remembering your comments correctly, especially when looking at other indications, go after, but within AML, in this study, for example, you found the CETD2 and RUNX1, can you talk about other signatures that might be popping up that are interesting, you know, that you think you might pursue going further? And then also, as we look towards 2021 and an RP2D getting established, what is now Last line, are they more combination studies, and do you think you could go straight to a registrational study given that biomarker-defined indications have been able to do that? Sure, Ren, so that's great.

Hi, good morning, and thanks for the questions Ah Multipart question on K O 539 of course, so please bear with me the P. K you've discussed and as was highlighted in the abstract is pretty interesting. So one Bradley are you aware of any other drugs that have a similar inhibition effect that was beneficial for exposure.

As your inefficacy.

Secondly, do you believe the anti tumor activity. Your scene is driven by C Max or a U C and based on that unique PK profile do you still think daily dosing is required if it seem X driven and lastly.

Related to the last question and the team is already touched on this but are you concerned for the potential of K O 539, accumulation and patients over time and the potential precipitation I'm in queue. Okay. I went ahead and put you.

And and.

And maybe some color on the timing of the thromboembolic of that with respect to initiation of dosing would be helpful. There. Thanks.

Sure Alex.

So in terms of.

Troy Edward Wilson: So there are three parts to your question. On the first part, I want to be a little bit cautious in terms of describing how we might think about potential other mutations or biomarkers. And that's both because it's an area of active investigation and, as some of you may know, this is a competitive field.

The first part of your question, we don't have an immediate other example to give you at least I don't and and I didn't bite Steven Uhm. If he does to to comment I don't I don't have a another example of a compound we can give you that Phoenix copies, what we're saying with K O 539.

It is and that's just off the top of my head certainly something that we can you know we can look into and get back to you on Steven I don't know if you have any if if if it's come up in the discussion in the development group of any other compound. It exhibits this kind of auto inhibitory activity.

Troy Edward Wilson: And, and, and so we're doing a lot of innovation there. Dr. Francis Burroughs, who a number of you have engaged with, is really leading that effort on the translational side. So we'll have more to say about that, but I don't think there's much more we can say today. In terms of the study, Ren, we are expecting it to continue as monotherapy in the relapse and refractory setting. It's our view that if we, if we're seeing good safety and tolerability and an encouraging level of clinical activity, one could run a single-arm study, at least in the U.S., using a response rate as the primary endpoint, very much in the manner that the IDH inhibitors have done and the FLT3 inhibitors have done. And there, the hurdle rate for us is approximately 25 to 30%, again, either Those are both populations of high unmet need.

Of.

Three or four yeah, that's right I'm, sorry, [laughter] no. It's a great question, but he's not actually come up so so on the semi <unk>, giving it. Another example, just at the moment sorry.

Yeah, No worries uhm, so Alex said that the let us let us let us go back to the team and and see if we can give you. Another example to to take a look at in terms of the antitumor activity.

I I I don't know that we're really thinking about at this point in terms of see Max or a you see we you know this this biology is a little bit unusual.

And it's not as though we're inhibiting we're inhibiting enzymatic activity. What we're doing is blocking of protein protein interaction, which then induces an irreversible you know step and differentiation. So essentially you have to inhibit that that interaction.

Sufficiently enough that you can dissociate men in from chromatin and start the tumor rolling down the hill, but it wants to go down right. It it it desperately wants to differentiate and it's prohibited from doing this <unk> from differentiating. So I think there are multiple ways you can get there in fact, we see.

Troy Edward Wilson: For those wondering, NPM1 mutations in the relapse and refractory setting are typically accompanied by other mutations, such as DNMT3A, FLT3, or IDH. That makes them have a very bad prognosis. So there is a high unmet need in both populations. The feedback that we've received from investigators and KOLs suggests there may be a path forward as a monotherapy in the relapse and refractory setting. We are, Ren, as the third part of your three-part question, actively doing preclinical work to support studies that would evaluate KO539 in combination with both chemotherapy and targeted therapies.

The the biology is pretty permissive in terms of Ah Ah Ah schedule, we're able to drive differentiation with schedules ranging from continuous too you know three weeks on one week off two weeks on two weeks off and so forth. We are continuing to do day.

Troy Edward Wilson: And that would be earlier lines of therapy, potentially frontline. We have to do the critical preclinical work to set the stage and understand the safety and tolerability and how to think about the combinations. But that's very much an area of active interest and active investigation. It will probably come behind the monotherapy studies. And I realized, Ren, I skipped over sort of Part 2B of your question.

Troy Edward Wilson: We are conducting trials as a monotherapy right now. Sorry, but we anticipate evaluating the expansion cohorts in MLLR and NPM1 mutant AML. Initially, those cohorts will be designed to evaluate for clinical proof of concept. Do we see a threshold level of activity? If that is successful, if we do see it, our intent is that those cohorts will be designed to become registration-enabling cohorts. And again, we're not reinventing the wheel here.

Events occurred in cycle warm in that particular case, but again it wasnt deem to be a deal to buy our protocol and once again invest.

Investigators well prime from the protocol to monitor for Tls for tumor lysis syndrome.

And again, we've not had any issues with that moving forward. So nothing to stop the escalation to date.

Troy Edward Wilson: This is something that has been done successfully with a number of targeted therapies in oncology. So we feel like there's good, strong precedent both in targeted oncology and specifically in AML.

Which we carry on escalating as part of Phase one night, So I hope that gives a little more context.

Yes very helpful. Thank you.

Great. Thanks, Alex.

Troy Edward Wilson: Thanks very much, Troy, and you get the award for remembering all my questions, even if I didn't ask them. Thanks, Ren. And your next question comes from the line of Alexander Duncan of Piper Samuels: Hi, good morning. And thanks for the questions. A multi-part question on chaos 539.

Operator: Of course, so please bear with me. The PK you've discussed, and as was highlighted in the abstract, is pretty interesting. So one, broadly, are you aware of any other drugs that have a similar inhibition effect that was beneficial for exposure and efficacy? Secondly, do you believe the anti-tumor activity you're seeing is driven by C-Max or AUC? And based on that unique PK profile, do you still think daily dosing is required if it's CMAX driven? And lastly, related to the last question, and the team has already touched on this, but are you concerned about the potential for KO-539 accumulation in patients over time and the potential precipitation of A I'm in Q and A. Do I have to put you on hold?

Troy Edward Wilson: and maybe some color on the timing of the thromboembolic event with respect to initiation of dosing would be helpful there. Thanks. You're Alex, um...

Stephen Dale: So, in terms of..., the first part of your question, we don't have an immediate other example to give you, at least I don't, and I'd invite Stephen, if he does, to comment. I don't have another example of a compound we can give you that phenocopies what we're seeing with KL-539, and that's just off the top of my head. Maybe something that we can look into and get back to you on. Stephen, I don't know if you have any, or if it's come up in the discussion in the development group of any other compound that exhibits this kind of auto-inhibitory activity.

And by design, So I think you're characterizing it correctly, which is.

Youre, you're going to get an all comers population I think I think the way you're thinking you're positioning it and thinking about it those is exactly right.

From our standpoint.

If one sees evidence of clinical activity.

Clinical benefit in NTM, one inpatient obviously I think we'll all we'll all feel much better.

Stephen Dale: It's a great question, but it hasn't actually come up, so I'm going to give another example just at the moment. Yeah, no worries. So, Alex, let us go back to the team and see if we can give you another example to take a look at. In terms of the anti-tumor activity, I don't know that we're really thinking about it at this point in terms of CMAX or AUC. This biology is a little bit unusual, and it's not as though we're inhibiting enzymatic activity. What we're doing is blocking a protein-protein interaction, which then induces an irreversible step in differentiation. So essentially, you have to inhibit that interaction sufficiently enough that you can dissociate menin from chromatin and start the tumor rolling down the hill that it wants to go down. It desperately wants to differentiate, and it's prohibited from doing this. from differentiating

Troy Edward Wilson: So I think there are multiple ways you can get there. In fact, we see the biology is pretty permissive in terms of schedule. We're able to drive differentiation with schedules ranging from continuous to three weeks on, one week off, two weeks on, two weeks off, and so forth. We are continuing to do daily dosing, which is, of course, optimal from the standpoint of compliance and patient convenience. But is it necessary?

You can get very clear instruction to the investigators in the expansion phase and beyond as to what to expect and how to use K O 539, as a as a therapeutic and patience and then we'll transition to the expansion cohorts and we can start to talk about response rates and.

Troy Edward Wilson: Again, that's something that I think we'll continue to give attention to. At this point, as Stephen mentioned in his comments to an earlier question, you typically do intermittent dosing because you're trying to dose around a toxicity, and we don't see any toxicity here. It is important that you characterize the PK and the exposure of your compound, but the advantage that one has with a menin inhibitor is that because this is such a unique event and you have only eight or nine genes that are under the control of MLL, you have the potential for a broad therapeutic window, and that seems to be consistent with what we're seeing.

Unless and until you are in a genetically enriched population, it's really premature to think about a response rate if you're if you're seeing anecdotal evidence of of.

Of of clinical activity, you're seeing a responder here or there that's great. I mean, that's certainly tells you you're on the right path, but I think our our view is and I. This is not just for 539 I think this is across oncology in phase one it's just premature to be thinking about response rate the trials not designed for that.

Troy Edward Wilson: So at the moment, we're not seeing a reason to deviate from daily dosing, but it is certainly something that we will continue to evaluate. And then on your final question, which is what was the timing of the embolic event relative to dosing, let me turn that over to Stephen. Stephen, I don't know if you have anything more to share with Alex on the specific timing of the AE versus the start of dosing, if there's anything to learn there. Yeah, no.

Not designed to test that and we will absolutely get there as quickly as we can we're anticipating as I said the.

Finishing up the dose escalation in the first quarter of next year, and where we've already gotten alignment from F. D. A to be able to move into the expansion cohorts as quickly as possible Uhm and we're at a point, where you know there's good excitement for this and the mechanism of action, we have more patience than we have slots. So I think we're I think we're in a very very strong position.

Stephen Dale: It's a great follow-up question. So, you know, neither were determined to be dose-limiting toxicities. I think just going back to the thromboembolic event, that patient continued dosing, and actually, there was an intrapatient escalation in this particular subject from 100 milligrams to 200 milligrams, and again, the 100 milligram dose, we saw this complete remission. Putting a bit more context around this particular case, the patient, as all these patients are there anyway for an increased risk of DVT, We've not seen any duplication of this.

<unk> to maintain the momentum and and and to be able to answer your question with actual data Phil Hope hope that helps us a lot of a lot of explanation, but I hope that gives you some color, but does that that helps a lot and then second on the the ever since they were noted in the abstract tuberculosis and thromboembolic.

Have you put in there was any prophylaxis as part of the protocol come out of those events or cause you mentioned it sounds like they were one off events with or was that just actually went off and you haven't changed the prophylaxis switching that was the first time.

Stephen Dale: In terms of the tumor lysis syndrome, a very similar pattern not seen before. It's a recognized event in terms of drugs in hematology with rapid breakdown of malignant cells. The actual event occurred in cycle one in that particular case, but again, it wasn't deemed to be a DLT by our protocol.

There isn't there haven't been any steps implemented fill in either case to to to prophylactic <unk> patients to protect against those as Steven mentioned in his comments both of those events are not uncommon in a M. L. S.

Stephen Dale: And once again, investigators are well primed from the protocol to monitor for TLS, for tumor lysis syndrome, and again we've not had any issues with that moving forward. So nothing has stopped the escalation to date, which we carry on escalating as part of phase 1A. So I hope that gives a little more context. Yep, very helpful. Great. Thanks, Alex. Good morning, congratulations on the progress, and thanks for taking my question. As we look forward to ASH, I'm kind of curious to hear your thoughts on how we should set our expectations.

And people shouldn't read too much into them there, there's certainly something to be aware of but as we've dose escalated. We're now at 400 milligrams. We haven't seen any any other evidence to date is obviously study is still ongoing but we haven't seen any other evidence of either of those two events. So they're really at this point is.

A need for for prophylaxis.

Perfect. That's very helpful. Thanks for taking my questions. Thank.

Thank you.

Troy Edward Wilson: So you've suggested that there are going to be maybe 10 patients at the meeting. Are all 10 of those patients going to be available for response? And given the percentages that you've suggested in the population of MLLR and NPM1, if there are approximately 10 patients, then we expect to see maybe three NPM1 patients, maybe one MLLR patient, although we've already seen one. It doesn't seem like we're going to have enough patient numbers to evaluate, really, response rates. How should we be thinking about what is intriguing efficacy, what's good, what's bad. Is it ACR, is it some reduction in hydroxyurea? Just curious to hear your thoughts.

Troy Edward Wilson: Yeah, Phil, it's a great question. And it's another question that we get often, so I'm glad you raised it. This is, I absolutely, we absolutely understand, you know, everyone's impatience to get to a response rate. And that's kind of the natural human condition.

Troy Edward Wilson: That being said, this is a phase one dose escalation study in an all-comers population, and it is that again by request of FDA and by design. So I think you're characterizing it correctly, which is, you know, you're going to get an all-comers population. I think the way you're positioning it and thinking about it, Phil, is exactly right. From our standpoint, if one sees evidence of clinical activity, clinical benefit in an NPM1 mutant patient, obviously, I think we'll all feel much better. If you see a couple of examples, you'll feel even better. I will stress, I will point out to you that there's really nothing magical about NPM1. And that's really the significance of this set D2 RUNX1 mutant.

Troy Edward Wilson: So, again, the biology here is you have mutations in AML that are driving dependence of the tumor on the MLL pathway. The reason everyone's focused on NPM1 is it's a large population and it's very well validated preclinically. But the significance of the set D2 RUNX1 mutant patient is that you're actually seeing an example of the drug doing exactly what we hoped it would do. Namely, it's inhibiting the MNN-MLL interaction. It's down regulating gene expression and driving a CR. NPM1 is one special example.

Troy Edward Wilson: Set D2 RUNX1 is another. And then we'll transition to the expansion cohorts, and we can start to talk about response rates. Unless and until you are in a genetically enriched, you know, population, it's really premature to think about a response rate. If you're seeing anecdotal evidence of clinical activity, you're seeing a responder here or there, that's great. I mean, that certainly tells you you're on the right path.

Additional questions. Please feel free to contact Pete Mark or or me of course.

Thanks, again and have a great rest of the day everyone.

Ladies and gentlemen, this does conclude today's conference call. You may now disconnect. Thank you for participating.

Troy Edward Wilson: But I think our view is, and this is not just for 539, I think this is across oncology, in phase one, it's just premature to be thinking about response rates. We're finishing up the dose escalation in the first quarter of next year, and we've already gotten alignment from FDA to be able to move into the expansion cohorts as quickly as possible. And we're at a point where, you know, there's good excitement for this mechanism of action. We have more patients than we have slots.

[music].

Troy Edward Wilson: So I think we're in a very, very strong position to maintain the momentum and to be able to answer your question, you know, with actual data flow. Hope that helps. A lot of explanation, but I hope that gives you some color.

Troy Edward Wilson: That helps a lot. And second, on the adverse events that were noted in the abstract tumor lysis and the thromboembolic event, have you put in place any prophylaxis as part of the protocol in either of those events? Or, as you mentioned, it sounds like there were one-off events. Was that just naturally one-off, and you haven't changed the prophylaxis since seeing them? There haven't been any steps implemented, Phil, in either case to prophylaxis patients to protect against those.

Troy Edward Wilson: As Stephen mentioned in his comments, both of those events are not uncommon in AML, and people shouldn't read too much into them. There's certainly something to be aware of, but as we've dose escalated, we're now at 400 milligrams, and we haven't seen any other evidence to date.

Troy Edward Wilson: Obviously, the study is still ongoing, but we haven't seen any other evidence of either of those two events, so there really is not a need for prophylaxis at this point. Perfect. That's very helpful. Thanks for taking the time to answer my question. Thank you. Hey guys, good morning. Thanks for all the details you provided thus far. Guys, to the extent that you can, I want to switch gears for a second and go to AMHN. And I guess my question really would be based on the current conduct of the study with regard to sites coming on and off. Are you seeing a lot of variability? Any sites shutting down again, or how?

Troy Edward Wilson: Yeah, Joe, it's a great question. We all, for a lot of reasons, I think we all wish we could shake this pandemic. We continue, Joe. We put in place a cross-functional team to, you know, comprised of clinical operations and regulatory and quality and all the key functions to monitor the sites, the patients. That team remains intact. We haven't, as of yet, seen an impact.

Troy Edward Wilson: You know, a lot of European countries are beginning to go back into lockdown. It is certainly something that I think we all have to be mindful of. But I can tell you that to this point, we have not seen any sort of another dip. It is something that we're monitoring quite closely. So I'm optimistic that that amendment will help, you know, help even in the face of maybe a renewed wave of COVID that we seem to be looking into.

Operator: Sure. Thank you, Jim. And at this time, there are no further questions. I would now like to turn the conference back to Troy Wilson for any closing remarks. Thank you, Operator, and thank you all for participating in our call today. We'll be participating in several virtual investor conferences in the weeks ahead, and we look forward to speaking with many of you then. In the meantime, if you have any additional questions, please feel free to contact Pete, Mark, or myself. Thanks again, and have a great rest of the day, everyone. Ladies and gentlemen, this does conclude today's conference call. You may now disconnect. Thank you for participating.