Q4 2020 Kura Oncology Inc Earnings Call
Ladies and gentlemen, thank you for standing by and welcome to the Kura oncology fourth quarter and full year 2020 earnings conference call.
Operator: Ladies and gentlemen, thank you for standing by, and welcome to the Kura Oncology fourth quarter and full year 2020 earnings conference call. At this time, all participant lines are in a listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you will need to press * 1 on your telephone.
At this time all participant lines are in a listen only mode.
After the speaker's presentation, there will be a question answer session.
Ask a question during the session you will need to press star one on your telephone.
Operator: Please be advised that today's conference is being recorded, and if you require any further assistance, please press star zero. I would like to hand the conference to your speaker today, Pete B. Spain. Please go ahead. Great, thank you, Victor.
Please be advised that today's conference is being recorded and if you kind of any further assistance. Please press star zero and when they like to hand, the conference to your speaker today, Pete de Spain. Please go ahead Sir.
Great. Thank you Victor good morning, and welcome to occur oncology fourth quarter and full year 2020 conference call. Joining me on the call our Doctor Troy Wilson, our President and Chief Executive Officer, and Dr. Marc Grasso, Our Chief Financial Officer, and Chief Business Officer.
Pete De Spain: Good morning, and welcome to Kura Oncology's fourth quarter and full year 2020 conference call. 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. Stephen 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.
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.
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.
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.
Please refer to Curtis filings with the FTC, which are available from the SEC or on the current oncology website for information concerning risk factors that could affect the company.
I'd also like to point your attention to our newly updated corporate presentation, which can be found on the investors section of our website with that I'll now turn the call over to Dr. Troy Wilson, President and CEO of care oncology Troy.
Pete De Spain: I'd also like to point your attention to our newly updated corporate presentation, which can be found in the Investors section of our website. With that, I'll 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 morning.
Troy Edward Wilson: Thank you, Pete, and thank you, everyone, for joining us this morning. We're a precision medicine company with two clinical stage oncology drug candidates for which we own global commercial rights, our menin inhibitor, KO539, and our farnesyl transferase inhibitor, Tipifarnib. Each of our drug candidates targets oncogenic driver mutations in indications of high unmet need, and we're pursuing an accelerated development and fast-to-market strategy. Our pipeline also includes an emerging, next-generation Farnesil transferase inhibitor program that we believe will target innovative biology to address indications of high unmet need through rational combination. We're also in a stronger financial position than ever before, with more than $600 million in cash.
We're a precision medicine company with two clinical stage oncology drug candidates for which we own global commercial rights, our Menin inhibitor, <unk> 539, and our Farnesol transfer Ace inhibitor typify on it.
Each of our drug candidates targeting oncogenic driver mutations in indications of high unmet need and we are pursuing an accelerated development and faster market strategy.
Our pipeline also includes an emerging next generation Farnesol transpiration inhibitor program that we believe will target innovative biology to address indications of high unmet need through rational combinations.
We're also on a stronger financial position than ever before with more than $600 million in cash, which we believe provides us with sufficient resources to advance our programs through multiple value inflection points and.
Troy Edward Wilson: which we believe provides us with sufficient resources to advance our programs through multiple value inflection points, and we have a talented and proven team with the oncology drug development and commercialization expertise required to be successful. Now, I will take you through each of our programs, beginning with our menin inhibitor, KL-539. In December, we reported preliminary clinical data from our Phase I-II Comet-001 clinical trial of KO539 at the American Society of Hematology annual meeting. These data were highlighted by single-agent activity in an all-comer population of patients with relapsed or refractory acute myeloid leukemia, including patients with NPM1 mutations and KMT2A rearrangement.
And we have a talented and proven team with the oncology drug development and commercialization expertise required to be successful now.
Now let me take you through each of our programs beginning with our Menin inhibitor Kale $5 39.
In December we reported preliminary clinical data from our phase one two comment 001 clinical trial of <unk> 39 at the American Society of Hematology annual meeting. These data were highlighted by single agent activity in an all comer population of patients with relapsed or refractory.
<unk> acute myeloid leukemia, including patients with N. P M. One mutations and K M T. Two a rearrangement chaos.
Troy Edward Wilson: KO-539 also demonstrated a favorable safety and tolerability profile with no drug discontinuations due to treatment-related adverse events and no evidence of QTC prolongation. Since the ASH presentation, we've continued to enroll patients in the phase one dose escalation portion of the trial as K0539 continues to demonstrate compelling clinical activity and a wide therapeutic window. We've completed the 600 milligram dose cohort and are currently evaluating an 800 milligram dose cohort. Meanwhile, we recently sought FDA feedback regarding the design of the registration-directed portion of our trial.
K O 539 also demonstrated a favorable safety and tolerability profile with no drug discontinuation due to treatment related adverse events and no evidence of P. T C prolongation.
Since the Ash presentation, we've continued to enroll patients in the phase one dose escalation portion of the trial is K O 539 continues to demonstrate compelling clinical activity and a wide therapeutic window. We've completed the 600 milligram dose cohort and are currently evaluating on 800 milligram dose cohort.
Meanwhile, we recently saw at F. D. A feedback regarding the design of the registration directed portion of our trial in.
Troy Edward Wilson: In the context of those discussions, FDA suggested that we should consider determining a minimum, safe, and biologically effective dose in our ongoing Phase I trial. FDA also agreed that we should modify our primary endpoint from CR-CRI to CR-CRH and incorporate transfusion independence as a secondary endpoint in order to align the endpoints with those that would be meaningful for patients and acceptable for registrational intent.
In the context of those discussions F. D. A guided that we should consider determining a minimum safe and biologically effective dose in our ongoing phase one trial.
D. E. Also agreed we should modify our primary endpoint from CR Cri to see our CRH and incorporate transfusion independence as a secondary endpoint in order to align the endpoints with those that would be meaningful for patients and acceptable for registrational intent.
Troy Edward Wilson: Based on this feedback, we plan to amend our Comet-001 trial protocol to include two Phase I expansion cohorts while we continue to evaluate KO539 in-dose escalation. We expect these Phase I expansion cohorts to include a minimum of 12 patients each at doses that have already met the safety threshold to help us to determine a minimum safe and biologically effective dose. Furthermore, we plan to enrich each of these Phase I expansion cohorts with both NPM1 mutant and KMT2 rearranged relapse or refractory AML patients.
Based on this feedback we plan to amend our common zero-zero one trial protocol to include two phase one expansion cohorts, while we continue to evaluate Kale 539 dose escalation.
We expect these phase one expansion cohorts to include a minimum of 12 patients each at doses that have already met the safety threshold to help us to determine a minimum safe and biologically effective dose.
Furthermore, we plan to enrich each of these phase one expansion cohorts with both N. P. M. One mutant and Kmt two rearranged relapsed or refractory AML patients. This should help us to further characterize the efficacy of <unk> 39 in these target populations and better inform a recommended phase two dose.
Troy Edward Wilson: This should help us to further characterize the efficacy of KL-539 in these target populations and better inform a recommended phase 2 dose. Determination of an optimal phase 2 dose is among the most critical decisions for an early stage clinical program.
Yeah.
Determination of an optimal recommended phase two dose is among the most critical decisions for an early stage clinical program.
Troy Edward Wilson: With these changes to the trial protocol, we have the opportunity to move into genetically defined expansion cohorts prior to reaching a maximum tolerated dose, to obtain a larger data set in an enriched population, and to more confidently determine a recommended phase two dose, thereby increasing the likelihood of success for the program. We believe that the clean safety and tolerability profile, the encouraging signs of clinical activity, and the wide therapeutic window of KO539 support a potential best-in-class profile, both as monotherapy and in combination.
With these changes to the trial protocol, we have the opportunity to move into genetically defined expansion cohorts prior to reaching a maximum tolerated dose to obtain a larger data set in an enriched population and to more confidently determine a recommended phase two dose, thereby increasing the likelihood of success for the program.
We believe that the clean safety and Tolerability profile, the encouraging signs of clinical activity and the wide therapeutic window of K O 539 support a potential best in class profile, both as a monotherapy and in combination.
Troy Edward Wilson: We continue to actively engage with our key opinion leaders and global steering committee to further define a comprehensive clinical development plan for KL-539, including a potential third expansion cohort, combination studies in the front line, and a pediatric development strategy.
We continue to actively engage with our key opinion leaders and global steering committee to further define our comprehensive clinical development plan for <unk> 539, including a potential third expansion cohort combination studies in the frontline and the pediatric development strategy, we intend to move these efforts forward aggressively.
Troy Edward Wilson: We intend to move these efforts forward aggressively, pending the determination of a recommended phase 2 dose, and we look forward to providing updates to you along the way. Now, let's turn our attention to our Farnesyl Transprase inhibitor, Kipifonib. Earlier this morning, we were very pleased to announce that TIPI Farnab has been granted breakthrough therapy designation from FDA for the treatment of patients with recurrent or metastatic HRS mutant head and neck squamous cell carcinoma, or HNSCC, with a variant allele frequency greater than or equal to 20% after disease progression on platinum-based chemotherapy.
Pending determination of a recommended phase two dose and we look forward to providing updates to you along the way.
Now, let's turn our attention to our friends will transfer inhibitor chip on it.
Earlier. This morning, we were very pleased to announce that to be part of its been granted breakthrough therapy designation from FDA for the treatment of patients with recurrent or metastatic HRS meeting head and neck squamous cell carcinoma, or H N. S. C C with a variant allele frequency greater than or equal to 20% after disease progression.
On platinum based chemotherapy.
Troy Edward Wilson: The Breakthrough Therapy designation is based on data from our Phase 2 RUN-HN trial, which was recently accepted for publication in an upcoming issue of the Journal of Clinical Oncology. As a reminder, the RUN-HN trial showed an objective response rate of approximately 50%, a progression-free survival of 6 months, and a median overall survival of 15 months. As a point of reference, the objective response rate for the three FDA-approved therapies for the treatment of HNSCC in the second line ranges from 13 to 16 percent, with a median progression-free survival of two to three months and a median overall survival of five to eight months.
The breakthrough therapy designation is based upon data from our phase II run HN trial, which was recently accepted for publication in an upcoming issue of the journal of clinical oncology as a reminder, the run HN trial showed an objective response rate of approximately 50% of progression free survival of six months.
And a median overall survival of 15 months.
As a point of reference the objective response rate for the three F. D. A approved therapies for the treatment of H N F. C. C. In the second line range from 13% to 16% with a median progression free survival of two to three months and a median overall survival of five to eight months. This breakthrough therapy designation Act.
Troy Edward Wilson: This breakthrough therapy designation acknowledges both the dire unmet need for patients with recurrent or metastatic HRS mutant HNSCC and the promise of tipifarnib to provide clinical benefit to these patients. Benefits of breakthrough therapy designation include more frequent meetings and communications with FDA, intensive guidance on an efficient drug development program, eligibility for rolling review of an NDA submission, and an organizational commitment involving senior managers from FDA.
Knowledge is both the dire unmet need for patients with recurrent or metastatic H Ras mutant nature in S. E T and the promise of typify on them to provide clinical benefit to these patients.
Benefits of breakthrough therapy designation include more frequent meetings and communications with F. D. A intensive guidance on inefficient drug development program eligibility for Rolling review of an NDA submission and an organizational commitment involving senior managers from FDA.
Mark Grasso: We anticipate that breakthrough therapy designation will help to facilitate the development and ultimate approval of tipefarnib for the treatment of HNSCC patients. To that end, we remain focused on conducting our AIM-HN registration-directed trial and bringing tipefarnib to the market as quickly and as efficiently as possible. In addition, we're also leveraging new advances to expand the use of tipifarnib in combination with other oncology therapeutics to address larger patient populations and pursue earlier lines of therapy.
We anticipate the breakthrough therapy designation will help to facilitate the development and ultimate approval of tip, if aren't up for the treatment of H N. S. C. C patients to that end, we remain focused on conducting our aim HN registration directed trial and bringing typify on it to the market as quickly and as efficiently as possible.
In addition, we're also leveraging new advances to expand the use of tip on it in combination with other oncology therapeutics to address larger patient populations and pursue earlier lines of therapy. Among these potential combinations. We've prioritized the combination of typify R&M and an inhibitor of the enzyme <unk>.
Mark Grasso: Among these potential combinations, we've prioritized the combination of tipifarnib and an inhibitor of the enzyme PI3 kinase alpha in patients with HNSCC. Our preclinical data suggest that HRAFs and PI3-kinase alpha are codependent oncogenes in HNSCC and that combining tipifarnib with a PI3-kinase alpha inhibitor has the potential to We believe the total addressable population for TIPI Pharma may be as high as 50% of HNSEC.
Kinase Alpha and patients with H N S T SEC.
Our preclinical data suggest that HRS and <unk> kinase Alpha are codependent, oncogene, and H N NCC and combining typify on them with a path for a tiny self inhibitor has the potential to provide meaningfully better anti tumor activity than inhibiting either target alone.
We believe the total addressable population, particularly foreign it may be as high as 50% of H N S. C C.
Mark Grasso: We continue to prepare for a Phase 1-2 proof-of-concept study of tipifarnab in combination with a PI3 kinase alpha inhibitor in patients who have HRAS overexpressing, PIK3CA mutated, or PIK3CA amplified HNSCC, and we expect to initiate this study in the second half of 2021. Breakthrough therapy designation from FDA is the latest milestone in our effort to pioneer the We view farnesyltransferase inhibition in oncology as a potentially valuable therapeutic and commercial franchise, one that has the potential to deliver multiple opportunities for additional indications.
We continue to prepare for a phase two proof of concept study a particularly fond of in combination with the P. S. Three kinase alpha inhibitor in patients who have a trust over expressing pick three C. A mutated and door pick three C. E amplified H N S. C C and we expect to initiate this study in the second half of two.
<unk> thousand 21.
Breakthrough therapy designation from FDA as the latest milestone in our effort to pioneer the use of Farnesol transfer rates inhibitors to treat patients with cancer, we view farnesol transfer <unk> inhibition in oncology as a potentially valuable therapeutic and commercial franchise, one that has the potential to deliver multiple <unk>.
Opportunities for additional indications.
Mark Grasso: Over the past several years, through our internal efforts and a network of academic collaborations, we've uncovered some compelling opportunities for farnesyl transferase inhibitors in combination with other targeted therapies. These efforts have both revealed some exciting new areas of biology and underscored to us the opportunity for a greater investment in this therapeutic class. Last year, we initiated a discovery stage program to develop a next-generation forensic cell transferase inhibitor. Our goal is to deliver a drug candidate that has comparable potency and selectivity and improved pharmacokinetic and physical chemical properties relative to typefarnin.
Over the past several years through our internal efforts and a network of academic collaborations we've uncovered some compelling opportunities for foreigners feel transfer rates inhibitors in combination with other targeted therapies.
These efforts have both revealed some exciting new areas of biology, and underscored to us the opportunity for greater investment in this therapeutic class.
Last year, we initiated a discovery stage program to develop a next generation foreign sales transfer Ace inhibitor. Our goal is to deliver a drug candidate that has comparable potency and selectivity and improved pharmacokinetics and physical chemical properties relative to typify on it on.
Mark Grasso: I'm pleased to report we've already identified multiple advanced lead compounds and expect to nominate a development candidate for IND-enabling studies in mid-2021. We intend to direct this next-generation FTI at new biology and larger oncology indications, and we look forward to sharing our progress and our plans with you later this year. With that, I'll now turn the call over to Mark Grasso for a discussion of our financial results for the fourth quarter and full year 2020.
I'm pleased to report we've already identified multiple events lead compounds and expect to nominate a development candidate for IND, enabling studies in mid 2021.
We intend to direct this next generation F T I at new biology, and larger oncology indications and we look forward to sharing our progress and our plans with you later this year.
With that I'll now turn the call over to Marc Grasso for a discussion of our financial results for the fourth quarter and full year 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-K filed today for a more detailed discussion.
Mark Grasso: 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-K file today for more detailed discussion. Research and development expenses for the fourth quarter of 2020 were $17.5 million compared to $13.5 million for the fourth quarter of 2019. R&D expenses for the full year 2020 were $60.4 million compared to $47.8 million for the prior year. The increase in R&D expenses was primarily due to an increase in clinical development and manufacturing-related activities related to our K0539 program, personnel costs, and other expenses.
Research and development expenses for the fourth quarter of 2020 were $17 $5 million compared to $13 $5 million for the fourth quarter of 2019 on.
R&D expenses for the full year, 2020 were $64 million compared to $47 $8 million from the prior year.
The increase in R&D expenses was primarily due to an increase in clinical development and manufacturing related activities related to our <unk> hundred 39 program personnel costs and other expenses.
Mark Grasso: General and administrative expenses for the fourth quarter of 2020 were $8.8 million, compared to $5.5 million for the fourth quarter of 2019. G&A expenses for the full year 2020 were $31.5 million, compared to $19.7 million for the prior year. The increase in G&A expenses is primarily due to increases in pre-commercial planning expenses, personnel costs, and on-cash share-based compensation.
<unk> and administrative expenses for the fourth quarter of 2020 for $8 8 million compared to $5 $5 million from the fourth quarter of 2019.
G&A expenses for the full year 2020 were $31 5 million compared to $19 $7 million for the prior year.
The increase in G&A expenses was primarily due to increases in pre commercial planning expenses personnel costs and noncash share based compensation.
Troy Edward Wilson: The net loss for the fourth quarter of 2020 was $26.2 million compared to a net loss of $17.9 million for the fourth quarter of 2019. The net loss for the full year 2020 was $89.6 million compared to a net loss of $63.1 million for the prior year. The net loss for the fourth quarter and full year 2020 included non-cash share base compensation of $3.7 million and $12.8 million, respectively. This compares to $2.4 million and $9.4 million for the same periods in 2019.
Net loss for the fourth quarter of 2020 was $26 $2 million compared to a net loss of $17 9 million for the fourth quarter of 2019.
Net loss for the full year 2020 was $89 $6 million compared to a net loss of $63 1 million for the prior year.
Net loss for the fourth quarter and full year 2020 included noncash share based compensation on $33 7 million and $12 $8 million respectively.
This compares to $2 $4 million and $9 $4 million for the same periods in 2019.
Our cash cash equivalents from short term investments were $633 $3 million as of December 31, 2020, compared with $236 $9 million as of December 31, 2019.
Troy Edward Wilson: Our cash, cash equivalents, and short-term investments were $633.3 million as of December 31st, 2020 compared with $236.9 million as of December 31st, 2019. This includes net proceeds of approximately $324.1 million from our public offering completed in December 2020. Based on our current plans, we believe that our current cash, cash equivalents, and short-term investments will be sufficient to fund current operations into 2024. With that, I will now turn the call back over to Troy.
This includes net proceeds of approximately $324 $1 million from our public offering completed in December 2020.
Based on our current plans, we believe that our current cash cash equivalents from short term investments will be sufficient to fund current operations into 2024.
With that I will now turn the call back over to Troy.
Thank you Mark before.
Before we jump into the question and answer session. Let me lay out our anticipated milestones for the year ahead.
For KL 539 initiation of genetically enriched phase one expansion cohorts in mid 2021, and additional phase one data from Comet 001 in the second half of 2021.
Troy Edward Wilson: Thank you, Mark. Before we jump into the question and answer session, let me lay out our anticipated milestones for the year ahead. For KO539, initiation of genetically enriched Phase I expansion cohorts in mid-2021 and additional Phase I data from Comet-001 in the second half of 2021. For Tippec-Arnab, initiation of a Phase I-II proof-of-concept study in combination with a PI3-kinase-alpha inhibitor in the second half of 2021. And for our Next Generation Pornicotransferase Inhibitor Program, nomination of a development candidate in mid-2021. With that operator, we're now ready for questions.
For <unk> initiation of the phase one two proof of concept study in combination with Patrick on yourself inhibitor in the second half of 2021 and for our next generation for initial transfer Ace inhibitor program nomination of a development candidate in mid 2021.
With that operator, we're now ready for questions.
As a reminder, ladies and gentlemen to ask a question you will need to press star one on your telephone and toy draw. Your question press the pound key.
Our first question on come from the line of Jonathan Chang from Seb Leerink you may begin.
Hi team. This is John Barrett on for Jonathan.
Thanks for taking my questions.
What drove this decision to dose escalate to 800 milligrams and what is your plan moving forward with dose escalation do you still expect to reach our <unk> by the end of the quarter or do you plan to define a dose taken to these expansion cohorts and continue the dose escalation in parallel.
Operator: As a reminder, ladies and gentlemen, to ask a question, you will need to press star 1 on your telephone, and to withdraw your question, press the pound key. Our first question will come from the line of Jonathan Chang from SVB Lyric. You may begin. Hi team, this is John Baradon on behalf of Jonathan.
Yeah. Thanks, John for the question.
And you alluded to the answer at the end of your question. So we're doing two things simultaneously.
Jonathan Chang: Thanks for taking my questions. What drove this decision to dose escalate to 800 mg? And what is your plan moving forward with dose escalation? Do you still expect to reach RPTD by the end of the quarter? Or do you plan to define a dose to take into these expansion cohorts and continue the dose escalation in parallel?
The first is continuing to dose escalate.
We have been very pleasantly surprised at the lack of toxicity that we've seen and the potential for good safety and Tolerability and a wide therapeutic window.
As we indicated in the prepared comments, we're currently evaluating the 800 milligram cohort.
Troy Edward Wilson: Yeah. Thanks, John, for the question. And you alluded to the answer at the end of your question.
Depending on the outcome of that cohort.
On the you know we along with the Safety Review Committee will make the determination of whether to continue the escalation.
Troy Edward Wilson: So we're doing two things simultaneously. The first is continuing to dose escalate. We have been very pleasantly surprised at the lack of toxicity that we've seen and the potential for, you know, good safety and tolerability across a wide therapeutic window. As we indicated in the prepared comments, we're currently evaluating the 800 milligram cohort. Depending on the outcome of that cohort, we, along with the Safety Review Committee, will make the determination of whether to continue the escalation. But as it stands today, we don't see anything that would prevent us from doing that.
But as it stands today, we don't see any you know anything that would prevent us from doing that simultaneously.
We're in the process of amending the protocol to.
To enroll those two phase one expansion cohorts that we mentioned that will comprise N. P. M. One mutant and Kmt to rearrange patients and that's really a john on effort too.
Due to both try to identify a minimum safe and efficacious dose and really titrate for efficacy. What we're seeing is good activity across the dosing cohorts good safety and Tolerability.
Troy Edward Wilson: Simultaneously, we're in the process of amending to enroll those two phase one expansion cohorts that we mentioned that will comprise NPM1 mutant and KMT2 rearranged patients. And that's really, John, an effort to both try to identify a minimum safe and efficacious dose and really titrate for efficacy. What we're seeing is good activity across the dosing cohorts, good safety, and tolerability. We need now really to focus on which of those cohorts is actually optimum from the standpoint of moving forward with a recommended phase 2 dose into the registrational portion of the study.
We need now related to focus down on which of those cohorts is actually optimum from the standpoint of moving forward with our recommended phase two dose into the Registrational portion of the study.
Got it so will you be using the 600 milligram dose in those expansion cohorts.
And just trying to get additional data at that dose.
And then potentially moving up to 800 when you get.
Troy Edward Wilson: Got it. So will you be using the 600 milligram dose in those expansion cohorts and just trying to get additional data at that dose and then potentially moving up to 800 when you get the results?
When you pass through that safety threshold in the dose escalation or are you going to be waiting until.
800.
Passes through the safety and then using the 800 is the.
The dose expansion cohort, though he yes.
Troy Edward Wilson: Yeah, John, it's a good question, and it's one for which I think at this point we don't have a precise answer. You know, the point here is to be able to evaluate at least a couple of different doses. Just to remind everyone, the 200 milligram cohort, we showed data at ASH in December, and in that cohort, we had one NPM1 mutant patient who had a complete remission, and a second NPM1 mutant patient who had morphologic leukemic free state as the best response.
Yeah, John It's a good question and it's one for which I think at this point, we don't have a precise answer.
The point here is to be able to evaluate.
At least a couple of different doses.
To just to remind everyone. The 200 milligram cohort.
We showed data at ash in December and in that cohort, we had one N. P. M. One mutant patient who had a complete remission.
Our second NPM, one patient who had morphologic leukemia free state as best response, so that that appears to be at least on the lower bound.
Troy Edward Wilson: So that appears to be, at least on the lower bound, a good potential going forward dose. To your question on the upper bound, I think that's going to be data-driven by the data that comes out of the 800 milligram cohort, and it'll be a discussion among Stephen, who's on the call with us today, our clinical team, and, of course, the investigators. At this point, I don't have an exact answer for you, but I think you're thinking about it in the right way. A lower dose, a higher dose, and then using these phase one expansion cohorts to titrate for efficacy.
A good potential going forward dose to your question on the upper bound I think that's going to be data driven by the data debt that comes out of the 800 milligram cohort and it'll be a discussion among Stephen who's on the call with us today.
Our clinical team and of course, the investigators at this point don't have an exact answer for you, but I think youre thinking about it in the right way, a lower dose or higher dose and then and then using these phase one expansion cohorts to titrate for efficacy.
Troy Edward Wilson: Got it. And just one more quick one. Given the 539 update is now in the second half, will this still just be focused on the dose escalation data, or might we see some initial expansion cohort data?
Got it and just one more quick one given the 539 update is now in the second half.
Will this still just be focused on the dose escalation data or might we see some initial expansion cohort data.
Yes, that's it's hard to say at this point I think what we'd like to be able to do when we give the next day to update is to provide a fuller picture of the phase one experience for the compound.
Troy Edward Wilson: Yeah, it's hard to say at this point. I think what we'd like to be able to do when we give the next data update is to provide a fuller picture of the phase one experience for the compound, and that would include pharmacokinetic data and exposure, of course, safety and tolerability, and then efficacy.
And that would include a pharmacokinetic data and exposure of course, the safety and Tolerability, yet and then the efficacy.
Troy Edward Wilson: I think it's too early to say. It will take us, John, you know, at least a couple of months. We're guiding toward initiating the phase one expansion cohorts around the middle of the year, and that's just the time that it takes to amend the protocol, FDA review, and then implement the amendment at the sites that are currently enrolling COMET-001. So, you know, we are looking forward to providing a data update.
I think it's too early to say it will take US John you know at least a couple of months, we're guiding toward initiating the phase one expansion cohorts.
Around the middle of the year and that's just the time that it takes to amend the protocol F. D. A review and then implement the the amendment at the sites that we have currently enrolling comment zero-zero. One. So you know we are looking forward to providing a day to update its just a little bit early at this point to say exactly what what data.
Troy Edward Wilson: It's just a little bit early at this point to say exactly what data will be included in that update, but we'll continue to keep you and others on the call informed as we continue to progress.
Be included in that update, but we'll continue to keep you and others on the call you know informed as we as we continue to progress.
Troy Edward Wilson: A lot of thanks and congrats on the continued dose escalation.
Got it thanks, and congrats on the continued dose escalation.
Troy Edward Wilson: Thanks.
Thank you.
Our next question comes Atlanta, Brine I'm Marty Auster.
Operator: Our next question comes from the line of Marty Oster from Credits Police. You may begin. Thanks, operator. Thanks for taking the question. Troy, I think I have a three-parter I just wanted to clarify. In terms of the update on the timing of the next update from Comet, is that just a function of the dose escalation continuing longer than you expected, and you want to have that kind of complete picture at the next update? I know what Ash, you talked about having something early in 2021.
On credit Suisse, you may begin.
Thanks, operator, thanks for taking the question Troy I think that had a.
Three parter just want to clarify a couple of things in terms of the update on the timing of the next update from from comment.
Is that just a function of the dose escalation continuing longer than you expected and you want to have that kind of a complete picture for the next up there on what actually you talked about having something early in 2021 second question was on the change in per protocol.
Marty Oster: The second question was about the change in protocol. I just want to make sure I'm understanding clearly kind of what evolved from your thinking and from your discussions with FDA that kind of deviated from the original plan. And again, it's just getting back to the dose window being a lot wider than expected and needing to kind of clarify that before embarking on the registration path. And then, I guess, getting back to it.
I just want to make sure I'm understanding clearly kind of what evolved and kind of your your for.
Premier thinking and from your discussions with FDA, the kind of deviating from the original plan and again. This is just getting back to the dose window being a lot wider than expected anything to kind of clarify that down before.
Embarking on registration path and then finally, I guess getting back to.
Marty Oster: The Common Feature here, what is your evolving understanding of the kind of wide therapeutic index you're seeing with KO539 and do you think this is a class feature or is there something, Again, unique to the molecule that was kind of triggering efficacy at such a lower level than expected? Thanks. Sure, yeah.
The common feature here what is your evolved understanding of their kind of wide therapeutic index youre seeing with your about three nine and do you think this is a class feature or is there something.
Kind of unique to the molecule that you're there was kind of triggering up clean for true lower level of expected. Thanks.
Sure Yeah. So thanks for the questions and let's take them in turn.
Troy Edward Wilson: Yeah, so thanks for the questions, and let's take them in turn. So, with respect to the timing of the next update, you're exactly right. We have been, I think, pleasantly surprised at the ability to continue to dose escalate. And although we've seen encouraging signals of activity at lower doses, there's definitely a desire among both the investigators and members of our team to push the dose, to understand, you know, is there, are we getting better efficacy, are we getting more efficacy, and also to help define, you know, the properties of the compound.
So with respect to the timing of the next update.
You're exactly right, we have been I think surprised pleasantly.
At the ability to continue to dose escalate.
And although we've seen encouraging signals of activity at lower doses, there's definitely a desire among both the investigators and members of our team to push the dose to understand is there are we getting better efficacy or we are we were getting more efficacy and also to help define.
On the properties of the compound.
Troy Edward Wilson: I'm going to take the third question in turn. We don't know whether you asked whether it is a class effect or whether it is specific to KO539, this wide therapeutic window. As we've said in the past... Preclinically, there really wasn't anything in the GLP toxicology that suggested a dose-limiting toxicity that we might expect. What we did was to evaluate each cohort of patients as we escalated, and we were, again, very surprised at how benign the safety profile is. There were some questions early on, as all of you on the call remember.
And I'm going to take the third question.
And in turn.
We don't know whether it's the U S is it a class a factor or is it specific to <unk> 39, this wide therapeutic window.
As we've said in the past pre clinically there really wasn't anything in the GOP toxicology that suggested a dose limiting tox that we might expect what we've done is to evaluate each cohort of patients as we've escalated and we've been again very surprised that at at how big.
<unk> the safety profile is there were some questions early on as all of you on the call remember there were some aes.
Troy Edward Wilson: There were some AEs in the 200 mg cohort, including pancreatitis and some other AEs, but those we believe were idiosyncratic to that patient. We haven't seen any evidence of any of those AEs in other patients as we've escalated. Now, we can't escalate indefinitely.
In the 200 milligram cohort, including pancreatitis.
And some other aes those those we believe were idiosyncratic to that patient we haven't seen any evidence of of any of those aes in other patients as we've escalated.
Now we can't escalate indefinitely, there will come a point when we've maxed out exposure or the pill burden just becomes too great.
Troy Edward Wilson: There will come a point when we've maxed out exposure, or the pill burden just becomes too great, but we don't think we're there yet. Then the second question that you asked was, what's the rationale for the change in protocol, and what has evolved in our thinking? It really came out of a discussion with FDA. We sought feedback from FDA on the entire registrational design, and we discussed identification of a minimum safe and efficacious dose. The rationale for that is twofold. That's really the essence of all thinking around these targeted therapies. You want to give enough drugs that you're driving maximal efficacy, maximal pharmacologic benefit, and not too much. That's true as monotherapy.
But we.
We don't think we're there yet.
And then the.
The second question that you asked was what's the rationale for the change in protocol and what evolved in our thinking and it was it really came out of a discussion with FDA. So we sought feedback from FDA on the entire Registrational design.
In the context of those conversations F D a.
And we discussed identification of the of a minimum safe and efficacious dose and the rationale for that is twofold.
That's really the agencies evolve thinking around these targeted therapies, you want to give enough drug that youre driving maximal efficacy maximum pharmacologic benefit.
And not too much that's true as a monotherapy, it's even more important in combination and it's our view that you know I don't want to speak for FDA, but certainly everyone anticipates that menin inhibitors will be used in combination with other agents like venetic lax and he's decided dean.
Troy Edward Wilson: It's even more important in combination, and it's our view that, you know, I don't want to speak for FDA, but certainly everyone anticipates that menin inhibitors will be used in combination with other agents like venetoclax and azacitidine. You, you know, one wants to have a minimum safe and efficacious dose to give you the maximum therapeutic window, the greatest chance to combine with those other agents. And the only way to do that is to enroll these phase one expansion cohorts.
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One wants to have a minimum safe and efficacious dose.
To give you the maximum therapeutic window, the greatest chance to combine with those other agents.
And the only way to do that is is to enroll these phase one expansion cohorts.
Troy Edward Wilson: What we've seen as we've continued to enroll is that the phase one dose escalation to this point has been open to all comers, and we literally are getting, you know, an alphabet soup of different genetic backgrounds. We're perhaps getting at most one patient per cohort who's really relevant, an NPM1 mutant or a KMT2A. That's enough to give you some encouraging breadcrumbs.
What we've seen is we've continued to enroll is remember that the phase one dose escalation to this point has been open to all comers and we literally are getting it's an alphabet soup of different genetic backgrounds, where perhaps getting at most one patient per cohort, whose really relevant.
<unk> that's N P M on mutant or a Cam T. Two way that's enough to give you some encouraging bread crumbs, it's not enough.
Troy Edward Wilson: It's not enough to be able to make a determination as to whether one dose is better than another because you just don't have enough data points to relate a dose exposure activity correlation. So the way we're going to get around that is to enroll these two expansion cohorts, one at a lower dose and one at a higher dose. We've, again, with, through a discussion with FDA, modified the endpoints now such that the patients in those phase one expansion cohorts have the potential to be included when the trial rolls over into a trial for registrational intent.
To be able to make a determination as to whether one dose is better than another because you just don't have enough data points to relate a.
Dose exposure activity correlation so the way, we're going to get about get around that is to enroll these two expansion cohorts.
Wanted a lower dose one at a higher dose we are again with with it through a discussion with FDA, we modified the endpoints now such that the patients in those phase one expansion cohorts have the potential to be included.
When the when the trial rolls over into a registrational.
Trial for Registrational intent.
Troy Edward Wilson: So I think it's taking longer because the compound is better tolerated than we expected, and we really want to make sure that we zero in on the right dose to give us the greatest chance of success as a monotherapy and the greatest likelihood of success as a combination therapy. And, and by going into these enriched cohorts, we, you know, we're, we're optimistic that that should give us the data that we need to determine which of these doses that we've evaluated, all of which have cleared the safety hurdle, which of them is optimum on a going forward basis. So that's a long answer to your question.
I think it's taking longer because the compounds better tolerated than we expected and we really want to make sure that we zero and at the right dose two will give us the greatest chance of success as a monotherapy and the greatest likelihood of success as a combination therapy.
And by going into these these enriched cohorts. We you know we're we're optimistic that that should give us the data that we need to determine which of these doses that we evaluated all of which have cleared the safety hurdle, which of them are optimum on a going forward basis. So that's a long answer to your question, but hopefully it.
Marty Oster: Yeah, do you mind, just a quick follow-up, I just wanted to try to restate what you just said and make sure I'm getting the message correctly. On the high end, you feel comfortable that the phase one escalation is establishing safety. And so for monotherapy, you expect that you're going to get better efficacy at higher doses, and that's the upper end of what you want to test. On the lower end, what you want to do then is double check, in an enriched population, whether some of those early CR signals were potentially just fortuitous or lucky; you want to make sure those are real signals.
As you get some additional color.
Do you mind, just a quick follow up I, just wanted to try to restate reverse and make sure I'm getting the message correctly on the high end you feel comfortable that the phase one on escalation is establishing safety. So for monotherapy. There you would expect that youre going to get better efficacy at higher doses for the upper end of what you want to test on the lower end, where you wanted to do was on this double checking and enrich population weather.
Some of those early CR signals, where potentially just fortuitous or lucky you want to make sure. It was a real signals.
For future combination potential use.
I think that's yeah.
Troy Edward Wilson: I think that's yeah, I think that's right. Maybe to restate your restatement, you know, what we're really doing in this phase one expansion is we're now titrating for F. So in a typical phase one escalation, the stopping criteria would be taught. We're not seeing talks, so we've continued to escalate.
That's right maybe to restate your restatements.
What we're really doing in this phase one expansion as we're now tight trading for efficacy. So in a typical phase one escalation the stopping criteria would be talks.
We're not seeing talks so you know we've continued to escalate because were in an all comers population, it's difficult to titrate between different cohorts unless youre in an enriched population. That's what the expansion cohorts will allow us to do if we see equivalent activity at 200 milligrams and a higher dose for example Ah.
Troy Edward Wilson: Because we're in an all-comers population, it's difficult to titrate between different cohorts unless you're in an enriched population. That's what the expansion cohorts will allow us to do. If we see equivalent activity at 200 milligrams and a higher dose, for example, I think the view might be to go with the lower dose, the minimum safe and efficacious dose. But we need the data package to be able to do that. That's a data-driven decision.
The you know the the view might be to go with the lower dose the minimum safe and efficacious dose, but we need the data package to be able to make that that's a data driven decision I think from the standpoint of looking at the program.
Troy Edward Wilson: I think from the standpoint of looking at the program, folks should feel confident that we had, in our view, very encouraging activity at 200 milligrams. And that's continued, and we've only seen now a wider and wider therapeutic window. No evidence of QT prolongation, no cardiac talk, none of the AEs that were observed in the 200 milligram cohort. Everything is lining up nicely. It is taking a little bit longer, but we're doing the drug development that we believe will maximize the value of the program, both as monotherapy and combination.
Folks should feel confident that we had in our view very encouraging activity at 200 milligrams.
And that's continued and we've only seen now you know a wider and wider therapeutic window no evidence of Qt prolongation of cardiac tox, none of the Aes that were observed in the 200 milligram cohort. So it's lining up nicely. It is taking a little bit longer but we're doing the drug development that we believe will Maxim.
Is the value of the program, both as a monotherapy and combination.
Thank you Troy.
Marty Oster: Thank you, Troy.
Sure.
Yes.
Operator: Thank you. Our next question will come from Peter Lawson from Barclays. You may begin.
Thank you and ex <unk>.
<unk>, Pennsylvania, Peter Lawson with Barclays.
May begin.
Peter Richard Lawson: Thanks for taking the questions. Troy, just on the recommended phase two dose, when do you think we'll see that? Will we get that ahead of the second half data, and do you think we will get different recommended phase 2 doses for
Thanks for taking the questions.
Troy just on I guess recommended phase II dose.
When do you think we see that when we get that ahead of the second half day, two and do you think we get different recommended phase two doses for <unk>, one and two other rearrangements yeah.
Troy Edward Wilson: NPM1 and all its rearrangements.
Troy Edward Wilson: Yeah. Yeah, so let's take, Peter, two good questions. Take the second one and then the first.
Yeah. So so let's take Peters two good questions take the second one and then the first there there's nothing debt.
Troy Edward Wilson: There's nothing that suggests to us at this point that different doses are needed for NPM1 mutant patients and KMT2 rearranged patients. Now, admittedly, we have an, you know, an expanding data set. That's an answer that will be forthcoming in these expansion cohorts because we anticipate that we'll enroll both NPM1 and KMT2 rearranged, and so we'll have a better sense of that. But at this point, there isn't anything we've seen preclinically or clinically that suggests we need different doses.
Suggests to us at this point that different doses are needed for N. P. M. One mutant patients and Kmt two rearranged.
Now admittedly, we haven't you know on expanding dataset I think.
That that's an answer that will be forthcoming on these expansion cohorts because we anticipate that will will enroll both N. P. M. One NK and T. Two rearranged and so we'll have a better sense of that but at this point there isn't anything we've seen pre clinically or clinically that suggested we need different doses with respect to your first question.
Troy Edward Wilson: With respect to your first question on timing of RP2D, we've been a little vague about the specific doses, and that's really out of respect for the Safety Review Committee. We don't want to get ahead of the Safety Review Committee and go out and tell you what we think the doses are going to be. It appears, you know, 200 milligrams is probably a good lower bound. The upper bound, I think, has yet to be defined, but that is pending review by the Safety Review Committee.
On timing of the ERP T D.
So we've been a little vague about the specific doses and that's really out of respect for the safety Review Committee. We don't want to get ahead of the of the Safety Review Committee and come out and tell you. What we think the doses are going to be it.
It appears 200 milligrams is probably a good lower bound for the upper bound I think has yet to be defined but that is pending.
Review by the Safety Review Committee, we've tried to provide as much transparency as we can going along.
Troy Edward Wilson: We've tried to provide as much transparency as we can going along. You know, with these Phase I expansion cohorts are intended to enroll a minimum of 12 patients. So, you know, once we're into those cohorts, I think we'll have a better idea. I think it's just a little bit early to say exactly what the timing of nomination of an RP2D is versus, you know, presenting data. We're moving as aggressively as we can.
With these these phase one expansion cohorts are intended to enroll a minimum of 12 patients.
So once we're into those cohorts I think we'll have a better idea I think its just a little bit early to say exactly what the timing of nomination of on RP. Two D is versus presenting data, we're moving as aggressively as we can.
Troy Edward Wilson: You know, it's all hands on deck to get this amendment done. We're adding additional sites to the study to help us drive enrollment. At this point, we have more patients than we have slots, but, you know, but we also recognize we're going to narrow the aperture as we now focus on NPM1 and KMT2A. So there's a, you know, everything's going in the right direction, Peter. It's just a little bit early to be able to say exactly what the timing of the RP2D versus the next data. Thank you.
You know, it's all hands on deck to get this amendment done we're adding additional sites to the to the study to help us drive enrollment.
At this point, we have more patients than we have slots, but but we also.
So recognize we're going to narrow the aperture as we now focus on N. P. M. One Kmt two way. So there's a you know everything is going in the right direction. Peter It's a it's just a little bit early to be able to say exactly what the timing of the <unk> versus the next day to update.
Thank you and just switching gears onto it took a pause on it when do we see I guess the next day tool on when do you think you'll be ready for for filing.
Peter Richard Lawson: and just swishing gears on to Etymophana.
Peter Richard Lawson: When do we see the next data, I guess, or when do you think you'll be ready for filing?
Yeah, It's a great question.
Troy Edward Wilson: Yeah, it's a great question. We're thrilled at the breakthrough therapy designation and really appreciate the agency's acknowledgement of the unmet need. As we've said in the past, the registrational study continues to enroll. The changes that we made to the protocol, we think have really helped both to drive enrollment and to ensure a higher likelihood of success. We're really pleased now that the agency wants to be actively involved with us in the development and, we hope, the ultimate approval of TIPI-Barnab.
We were thrilled that the debt the breakthrough therapy designation.
And really appreciate the agency's acknowledgment of the unmet need as we've said in the past the Registrational study.
Continues to enroll the changes that we made to the protocol. We think it really helps both to drive enrollment into ensure a higher likelihood of success.
We're really pleased now that the agency wants to be actively involved with us in the in the in the development and we hope the ultimate approval of typify on it we're not yet at a point, where we can give guidance on the timing of enrollment or data.
Troy Edward Wilson: We're not yet at a point where we can give guidance on the timing of enrollment or data. We definitely think the study is going in the right direction and the next thing on deck, Peter, as we mentioned, is going to be the combination study, and there's a lot of excitement there within the investigator community. So I would expect that.
But we're.
Definitely we think the studies going in the right direction and the next thing on deck. Peter as we mentioned is going to be the combination study and theres a lot of excitement there within the investigator community. So I would expect that's the next thing you'll see but we will continue to provide updates as much as we can.
Troy Edward Wilson: I would expect that.
Peter Richard Lawson: Thank you.
Troy Edward Wilson: Okay, thanks. Thanks for taking the question.
Operator: Yeah, thank you.
Okay. Thanks, Thanks for taking the questions yes. Thank you.
Tina Afrilek: Yeah, thank you. Our next question comes from Tina Afrilek from Schieffel. You may begin. Hey, thanks for taking my questions. So just looking for further color on the wide therapeutic window for KO539, it seems like the answer is no, but can you say explicitly whether you've seen any DLTs thus far? And I have a quick follow-up.
Our next question comes from the line of Thompson T boots after net from.
From Stifel.
May begin.
Hi, Thanks for taking my questions. So just looking for further color on the wide therapeutic window for <unk> five for non it seems like the answer is no but can you just say explicitly whether you've seen any DLT, thus far and I got a quick follow up.
Yeah. So we.
Troy Edward Wilson: Yeah, so, um... We can't comment specifically, Konstantin, as to whether we've seen any DLTs. We certainly continue to escalate, so, you know, I think that's encouraging. We're now at 4x the dose.
We can't comment specifically Constantine as to whether we've seen any D. L. Ts.
We certainly continue to escalate so I think that's encouraging we're now at a at Forex the dose.
And.
I would say it looks good.
Troy Edward Wilson: I would say it looks good, you never know, as I've joked before, every day is a new day. But we're not seeing, what's important is, typically with toxicities, you'll see them build up over time. You know, you might see grade one, and then as you go higher, you see grade two or grade three. We're not even seeing a regular pattern of grade one across these patients. So we think that that wide therapeutic window will continue.
As I've joked before every day is a new day.
But we're not seeing whats important is typically with toxicities youll see them built in over time.
You might see grade one and then as you go higher you see great true or grade three we're not even seeing a regular pattern of grade one across these patients. So we think that that wide therapeutic window will continue.
Troy Edward Wilson: As I mentioned in the answer to a previous question, at some point, we're going to reach a limit where it's just infeasible to continue dose escalating, but we don't think we're there yet. We're still pushing it as hard as we can, looking at exposure, safety, and tolerability, activity, and at some of the other aspects such as, you know, pill burden. And so far, everything's looking, you know; all the lights are looking green.
As I mentioned in our in the answer to a previous question at some point, we're going to reach a limit where its just in feasible to continue dose escalating, but we don't think we're there yet we're still pushing it as hard as we can looking at it at exposure its safety and tolerability activity and and at some of the other aspects such as you know.
Pill burden.
And so far all everything's looking you know all the lights are looking great.
Tina Afrilek: Thanks for that. And then, do you still plan to open a cohort exploring KO539 in patients with, you know, miscellaneous genetic abnormalities, including CETD2? You know, would that cohort also need to have its own dose titration?
Thanks for that and then do you still plan to open a cohort exploring killed by three nine in patients with other miscellaneous genetic abnormalities, including 72.
Cohort also need to have its own dose titration.
Yeah. So the answer is yes, we do we do anticipate opening that cohort in the Registrational portion of the study we don't want to do that now for the simple reason that we're still defining the selection rules of that third cohort and we're trying to reduce these this this analysis down.
Troy Edward Wilson: Yeah, so the answer is yes, we do anticipate opening that cohort in the registrational portion of the study. But we don't want to do that now for the simple reason that we're still defining the selection rules for that third cohort and we're trying to reduce this, you know, analysis down to single variables. So, as we've said, we've established good safety and tolerability at every cohort.
The single variables. So we as we've said we've established good safety and Tolerability at every cohort.
Troy Edward Wilson: Now we need to titrate for efficacy. So we're gonna try to keep the patient composition relatively fixed with NPM1 and KMT2A and vary the dose. That should give us the data then to be able to make the PK exposure dose decision. At that point, we can fix the recommended phase two dose and then roll into what we would expect to be three cohorts, KMT2A, NPM1, and that third cohort. That will be in the portion of the study that is for registration purposes.
Now we need to titrate for efficacy. So we're going to try to keep the patient composition relatively fixed with N. P. M. One and Kmt two way and very dose that should give us. The data then to be able to make the PK exposure dose decision at that point, we can fix the recommended phase two dose.
And then roll into what we would expect three cohorts Kmt to E. N. P. M. One and that third cohort that will be in the in the portion of the study that is for Registrational intent, we're not going to do it while we're still trying to to fix the <unk> down because it just introduces uncertainty.
Troy Edward Wilson: We're not going to do it while we're still trying to fix the RP2D down because it just introduces uncertainty, and we think it's better to get to that RP2D in the two populations where we have high confidence of recurrent clinical benefit.
And we think it's better to get to that RP to D. In the two populations, where we have high confidence of clinical.
Tina Afrilek: Got it. Thank you. Sure.
Current clinical benefit.
Troy Edward Wilson: Thank you, Konstanthin.
Got it thank you.
Sure. Thank you constantly.
Operator: And our next question will come from the line of Ren Benjamin from J&P Securities. We may begin. Hey, good morning, guys. Excuse me.
And our next question comes from the line of Ren Benjamin from JMP Securities May begin.
Hey, good morning, guys excuse me thanks for taking the questions.
Reni John Benjamin: Thanks for taking the questions. Maybe just a couple. If you, Troy, rerun the analysis, right, on the patients that you've seen, that you've already talked about, with the new modified endpoints that the FDA is, you know, that you've discussed with the FDA, what do you, what do you see? You know, does it change at all?
Maybe just a couple if you Troy if you rerun the analysis right on the patients that you've seen that.
You've already talked about with the new modified endpoints on both the FDA as you know.
I think you've discussed with the FDA, what do you what do you see.
Does it change at all.
Troy Edward Wilson: I guess related to that, how many patients now have been evaluated? So at the 600 milligram dose, was it, I thought in the past we were thinking about six patients were going to be enrolled because we thought that was going to be the final dose, but is that still the case? Or did you only do three, and now we're going to another three at 800? And I guess, finally, just thinking about, you know, exposure. What kind of exposure are you seeing? And you mentioned pill burden could limit it. Are there any thoughts about reformulating the pills so that you might be able to put more per pill?
I guess related to that how many patients now have been evaluated so on the 600 milligram dose was it I thought in the past we were thinking about six patients were going to be enrolled.
Enrolled because we thought that was going to be the final dose, but is that still the case or did you only do three and now we're going to another three at 800.
And I guess finally, just thinking about you know exposure what kind of exposure are you seeing and you mentioned pill burden you know could limit dose are there any thoughts about re formulating the pills. So that you might be able to.
Put put more per pill.
Troy Edward Wilson: Yeah, so let me take the first couple questions, Ren. They're actually going to be the second and third questions, and I'll let Stephen comment on the end point because he's probably better positioned than I am.
Yeah. So let me take the first couple questions rent they are actually going to be the second and third question and I'll, let Stephen comment on the endpoint, because he's probably better better position than I am.
Troy Edward Wilson: In terms of the numbers of patients, the cohorts are designed to enroll a minimum of three patients and up to five patients, and that, you know, nothing has changed there. You're typically getting anywhere between three and five patients in a given cohort. It just depends on whether they all make it through the, you know, cycles.
In terms of the numbers of patients. The cohorts are designed to enroll a minimum of three patients and up to five patients.
And and that nothing nothing has changed there.
You're typically getting anywhere between three and five patients in a given cohort it just depends on whether they all make it through the through the through the cycles.
Troy Edward Wilson: So, you know, I don't think we were enrolling six patients. We're continuing to escalate the number, again, at a minimum of three, and we give the investigators up to five to ensure that, you know, we don't have patients that make it all the way through and then can't get on the study. That same thing will be true at 800 and likely true if we go higher. In terms of exposure, we're continuing to see increases in exposure as we go up.
So.
I don't think we were enrolling six patients.
We're continuing to escalate Adam again at a minimum of three and we give the investigators up to five.
To ensure that we don't have patients that make on all the way through and then can't get on the study that same thing will be true with 800 and likely true if we go higher than 800.
In terms of the exposure, we're continuing to see increases in exposure as we go up we haven't plateaued on exposure yet what we don't know is whether that increased exposure is actually driving better activity and that's really kind of the question that we have to answer in the phase one expansion cohorts.
Troy Edward Wilson: We haven't plateaued on exposure yet. What we don't know is whether that increased exposure is actually driving better activity. And that's really kind of the question that we have to answer in the Phase I expansion cohorts. If we had reached a plateau on exposure, that could be another criterion that would help us to define the RP2D. We're not there yet, although it feels as though we're getting closer.
But we are we have if we had reached a plateau on exposure that could be another criteria that would help us to define the RP Judy we're not there yet although we we.
It feels as though we're getting closer.
On the the final question I think which was the first question. You asked is if we reran the analysis looking at the patients from the standpoint of C. R CRH versus CR Cri.
Troy Edward Wilson: The final question, which was the first question you asked, is if we re-ran the analysis looking at the patients from the standpoint of CR-CRH versus CR-CRI, would anything have changed? And I'll ask Stephen Dale, who's on the line with me. And if you could answer Wren's question on that as to whether we would have gotten a different answer with the revised endpoints we discussed with the agency.
Would anything have changed.
And I'll ask Steven a Dale who's on the line with me Stephen If you could answer rinse question on that as to whether we would have gotten a different answer with the and the revised end points. We've discussed with the agency. Yes. Thank you Troy Hi, Ranga I think Thats a very good question. So the amendments to the to the endpoint the chiefly.
Stephen Dale: Yeah, so thank you, Troy. Hi, Ren.
Stephen Dale: That's a very good question. So the amendments to the end point, chiefly the one where we are changing from a CRI to CRH, where both are actually both composites, and both of these end points are a complete remission, but the only difference between the two is dependent on the absolute neutrophil count and the platelet count. There is a nominal difference between the two. To answer the question of if we were to reanalyze the data, would we see any differences, it's difficult to answer that yet because we haven't run all of the analysis on all these data sets to say the difference. There would be no difference in the criteria for those responses that we've seen and discussed previously regarding complete remission. So those that are CR, those meet the exact same criteria.
The one where we are changing from a cri to see all H well.
Both actually in effect for both composite.
On both of these end point on.
As a complete remission, but the only difference between the two is dependent on the absolute neutrophil count on the platelet count.
There was a there was a nominal difference between the two.
So one for the question of if we were to reanalyze the data would we see any differences.
It's difficult to long for that yet because we haven't run all of the analysis on all these data centers to say the difference there would be no difference in the criteria for those responses that we've seen on already discussed previously regarding complete remission. So those are see all those meet the exact same criteria.
Stephen Dale: We may see a difference between CRI and CRH. We can certainly look at and will be looking at those data further, but to date, we haven't done those analyses, Rang.
For where we may see a difference between <unk> and C. All H, we can certainly look and we will be looking at those data further book to date, we haven't done those analyses rang.
Reni John Benjamin: Got it. Okay. Yep. That makes sense. And Troy, if I could sneak one in, how many sites will you have up and running between, you know, kind of now and by the time you have the expansion course?
Got it okay, yeah that makes sense and then from Troy if I could sneak one in how many sites will you have up and running between kind of now and.
By the time you have the expansion cohorts.
Troy Edward Wilson: Yeah, it's a good question. So, at the moment, I think we have seven or eight sites that are up and running between the U.S. and France. Ren, I would anticipate we'll go to, you know, anywhere between sort of 12 and 20, really with a focus on the U.S. sites initially because those can move a bit quicker with the amendment. But Kathy Ford and our clinical operations colleagues are very focused on this.
Yeah. It's a good question. So at the moment I think we have seven or eight sites that are up and running between the U S and France.
Ran I would anticipate we'll we'll go to you know.
Anywhere between 12 and 20.
Really with a focus on the on the U S sites initially because those those can move a bit quicker with the with the amendment, but Kathy Ford and in our clinical operations colleagues are very focused on this.
Troy Edward Wilson: And, you know, these sites have been waiting for the opportunity to enroll patients. And so, we're anticipating bringing them online with this amendment to help drive enrollment initially in the phase one expansion cohorts, and then they'll just roll into the registrational cohorts if and when we get there.
And these sites have been are just waiting for.
For the opportunity to enroll enroll patients and so.
So we're anticipating bringing them online.
With this amendment to help drive enrollment initially in the expense phase one expansion cohorts and then they'll just rolled into the registrational cohorts, if and when we get there.
Troy Edward Wilson: Terrific. Thanks for taking the question. You're welcome. Our next question will come from Phil Nadeau from Cowan & Company. You may begin. Morning. Thanks for taking my question and congratulations on the progress. Just a couple from us.
Yeah.
Terrific. Thanks for taking the questions.
Youre welcome Thanks, Brent.
Our next question on come from the line, so naidoo from Cowen and company you may begin.
Good morning, Thanks for taking my question on congrats on the progress.
Just a couple from US first on the design.
Operator: First, on the design of the... Expansion cohorts are the phase one cohorts. I guess it's unclear to me what's different between the two cohorts. Are the cohorts divided based on the mutation, or are they different doses?
Ex spectrum cohorts. So the other phase one cohorts I guess, it's unclear to me what's different between the two cohorts are the cohorts divided faced on the mutation or are they different doses.
Philip M. Nadeau: They're, they're, they're filled, they're just...
There was there to fill their gip, yeah, they're different doses. So they will be open to either N. P. M, one or PMT to rearranged patients, we're not going to try to pre specify.
Troy Edward Wilson: Yeah, they're different doses. So, they will be open to either NTM1 or KMT2 rearranged patients. We're not going to try to pre-specify, you know, a blend of those two populations. We'll take the patients as they come. What will separate the two cohorts is that they'll be evaluated at different doses.
A blend of those two populations will will take the patients as they come on.
What will separate the two cohorts is that there'll be evaluated at different doses got it okay and then the doses in the cohorts for himself for those those are fixed so one will be low one will be high.
Troy Edward Wilson: Got it. Okay. And then the doses in the cohorts themselves, are those fixed? So one will be low, and one will be high?
Troy Edward Wilson: That's the intent, correct? That's the intent.
That's the intent to correct that that's the intent you really want to be able to evaluate a.
Troy Edward Wilson: You really want to be able to evaluate, you know, a range to try to draw a conclusion as to whether a higher dose or a lower dose. The agency's feedback to us was, given the profile of the compound, given the activity you've seen and the wide therapeutic window, we would advise you to target a minimum safe and efficacious dose. So, there will be, you know, we think, scrutiny on the lower dose.
On a range to try to to try to draw a conclusion as to whether higher doses for a lower dose the agency's feedback to us was given given the profile of the compound given the activity you've seen in the wide therapeutic window.
We would advise you to target a minimum safe and efficacious dose.
So there will be we think scrutiny on the lower dose. The question is whether you then leave any efficacy on the table at a higher dose and that's what we're going to try to try to tease out as we're tight trading for efficacy in these phase one expansion cohorts.
Troy Edward Wilson: The question is whether you then leave any efficacy on the table at a higher dose, and that's what we're going to try to tease out as we're titrating for efficacy in these phase one expansion cohorts. The, you know, we think the good news and one of the things we're pleased about with the FDA's feedback is we'll come out of these cohorts with a very robust understanding of the recommended phase two dose as we then move into the registration-directed portion.
We think that the good news in that and one thing we're pleased about with the with the Fda's feedback is we'll come out of these cohorts, obviously with a very robust.
Understanding of the recommended phase two dose as we then move into the registration directed portion.
Troy Edward Wilson: And so, that will give us increased confidence in the overall success of the program as we go through this. We had thought we would need to get to an RP2D and then move to the expansion cohort. The FDA has basically done us a great favor by allowing us to evaluate these enriched populations at a couple of different doses to help refine that RP2D.
And so that'll give us increased confidence in the overall success of the program as we're going through this we had thought we would need to get to an RPG to D. And then move to the expansion cohort. The FDA has basically done is a great favor and allowing us to.
Evaluate these enriched populations.
At a couple of different doses to help refine that RPT got.
Troy Edward Wilson: Got it. And you said before you could use some of the data from these as part of the efficacy portion of a filing. Does that assume that, basically, you'd use patients who are at the recommended phase two dose in these cohorts as part of that efficacy filing? Or could you use, is it possible to use different data from a different dose as part of that filing?
Got it and you said before you can do some of the data from these as part of the efficacy portion of a filing.
Does that assume that book.
Could you use for patients who are at the recommended phase two dose in these cohorts as part of that efficacy filing could you use is it possible to use a different data from a different dose as part of their final.
Yeah, I mean for so all of the patients will likely be included for safety of course I think your question is really it at efficacy and sort of two important points I mean, that's the thought would be that debt.
Troy Edward Wilson: Yeah, I mean, all of the patients will likely be included for safety. Of course, I think your question is really about efficacy and sort of two important points. I mean, the thought would be that, you know, the patients going at the RP2D would be the ones that would be included.
For the patients at that going at the <unk> would be the ones that would be included but of course. The FDA is going to look at every patient and you're going to include every patient in an eventual filing. The other thing of course is you know this will ultimately be a review issue as it always is for F. D. A so F. D. A is is guiding us to ensure that those patients have the potential.
Troy Edward Wilson: And of course, the FDA is going to look at every patient, and you're going to include every patient in an eventual filing. The other thing, of course, is this will ultimately be a review issue, as it always is for the FDA. So FDA is guiding us to ensure that those patients have the potential to be counted or being included in the ultimate registrational cohort. But I don't want to misrepresent it; that's ultimately going to be an FDA review issue. It allows us, as we start enrolling these phase one expansion cohorts, to move more quickly and more aggressively against that ultimate endpoint.
Essential of being counted or beat being included in the ultimate Registrational cohort, but that's debt I don't want to misrepresent, that's ultimately going to be an FDA review issue, but it it allows us.
As we're as we start enrolling these phase one expansion cohorts just you know to move more quickly more aggressively against that ultimate endpoint, which where we're very focused on got it. Okay. And this is kind of a follow up on a prior question. So it sounds like you've determined on low dose that's going to go into these expansion cohorts for hydro.
Troy Edward Wilson: you know, which we're very focused on. Okay, and this is kind of a follow-up on a prior question, so it sounds like you've determined the low dose that's going to go into these expansion cohorts. Has that been determined yet, or does that rely upon the continued dose escalation that's ongoing at 800mg?
Ross.
Has that been determined yet.
Is that rely upon the continued dose escalation that's ongoing as credit card members.
Troy Edward Wilson: and Amir Fathi. Yeah, I would say we have ideas on the lower dose. We're very, you know; we have a great partnership with the Safety Review Committee. I wouldn't want the Safety Review Committee to think that we'd already made the decision ahead of having the conversation.
Yeah, I would say we have we have ideas on the lower dose.
We're very you know we have a great partnership with the with the Safety Review Committee I wouldn't want the safety review committee to think that we'd already made the decision ahead of having the conversation.
Troy Edward Wilson: We're, you know, we're going to look at the continued data from phase one escalation and then make a determination. In our view, 200 milligrams is a dose where we're seeing very encouraging signs of clinical activity, but we need to have that discussion with the Safety Review Committee. So, you know, I would say, we're leaning in that direction. We haven't yet finalized it, but what we're trying to communicate to folks is think about a lower dose in the range of 200 and think about a higher dose, you know, 600 to 800, but that's pending. Further data, you know, further data being generated, and then, of course, the appropriate discussions with our Safety Review Committee and our internal colleagues.
We're going to look at at the <unk>. The continued data from the phase one escalation and then make a determination in our view 200 milligrams is it is it is a dose where we're seeing very encouraging signs of clinical activity.
But we need to have that discussion with them with the safety Review Committee.
So I.
I would say you know where we're leaning in that direction, we haven't yet finalized it but what we're trying to communicate to folks is think about a lower dose in the range of 200 think about a higher dose you know six to 800, but that's pending further data for the further.
Data being generated and then of course, the the appropriate discussions with our with our safety Review Committee and are on our internal colleagues.
Troy Edward Wilson: Great. Last question, just kind of a follow-up to Martin's question. As to the rationale why the FDA and you are doing this, we've seen a lot of dose escalation over the years, and usually, in oncology, there isn't a lower effective dose that's identified. And when people want to do that for combination studies, there's a separate phase one that is conducted. So I guess the question is kind of, Why now? Why do you do it as monotherapy?
Last question, just kind of a follow up on Martin's question.
For the rationale for why.
While the FDA can you are doing this we've seen a lot of dose escalations over the years and usually in oncology there isn't.
More effective dose that's that's identified.
And when people want to do that for combination studies.
There's a separate phase one that is conducted so I guess the question is kind of.
Why why now why do it as a monotherapy.
Troy Edward Wilson: Is there something about the profile that makes it particularly important, for example, like the CIP interaction or anything else? Again, it seems a little aggressive to be doing this early in a development program if the real concern is about combination therapies later.
Is there is there something about the profile that makes it particularly important for example, like the Sip interaction on.
Or anything else.
Again, it seems a little aggressive to be doing at this early in the development program. If the real concern is about combination therapies later.
Philip M. Nadeau: Yeah, it's a good question. Let me ask Stephen Dale if he can comment on it. It's certainly not unusual, but let me ask Stephen if he can comment on the rationale and sort of the discussions that we had with the agency on that point.
Yeah. It's a good question, let me ask let.
Let me ask Phil Stephen Dale if he can comment on it it's certainly not unusual.
But let me ask Steven if he can comment on on the rationale on sort of the discussions that we had with the agency on that point.
Stephen Dale: Yeah, no, thank you, Troy. Yeah, so, no, thanks for the question. It's an excellent one.
Yeah no. Thanks.
Thank you Troy.
So thanks for the question.
It's an excellent one.
Stephen Dale: So, in essence, yeah, so, in essence, what we have here is a mount to a Phase I B element of the Phase I study with our Phase I expansions. Indeed, in escalation and in Phase I protocols, it's often the case that this is done to expand out at different doses, especially where you're looking to titrate or look closely for efficacy, so where the Phase Ia in escalation The expansions allow us to be both safety- and efficacy-driven.
So so in essence, yes. So in essence, what we have here is amount to a phase won't be element to the phase one study with all phase one expansions.
Indeed in escalation and even phase one protocol that is often the case with sometimes this is this is done to expand that with different doses, especially where youre looking to titrate on look closely for efficacy.
The phase one a and escalation.
Safety driven.
Expansions allow us to be both safety and efficacy driven so with the expansion we continue to assess the safety and Tolerability book as Troy.
Stephen Dale: So, with the expansions, we continue to assess safety and tolerability, but, as Troy has mentioned, we are really also having the opportunity now to look at and assess efficacy in a target patient population. So, these are enriched patients in the all-comers population during escalation. We're not getting a purist view in terms of those target patients. So, the expansions also give us the opportunity to look at a larger data set. In this case, it occurs in at least 12 patients, which also gives us the opportunity to further characterize PK.
Mentioned, but really also having the opportunity now to look and assess the efficacy and the target patient population. So these are enriched patient.
The old from us population the escalation.
We're not getting pure risk view in terms of those target patients. So the expansion is also gives us the opportunity to look in a larger data set in this case and at least 12 patients, which also gives us the opportunity to further characterize PK, it's certainly nothing around.
Stephen Dale: There's certainly nothing around SIP that's driven any of this. This is to really hone in on trying and to assess more accurately efficacy in a target patient population and then cumulatively work out and look at the benefit-risk ratio, because this will play an important role in determining the recommended Phase II dose.
On the Sip that's driven any of this this is really home down to try and assess more accurately efficacy in the target patient population.
And then cumulatively.
<unk> accounts and look at the benefit risk ratio.
Because this will play an important role in determining the recommended phase II dose.
Philip M. Nadeau: Got it, that's very helpful. Thanks for taking my questions and congrats again on the progress.
Got it that's very helpful. Thanks for Mitek for.
Thanks for taking my questions and congrats again on price.
Operator: Sure. Thank you.
Sure. Thank you.
Tyler Van Buren: Thank you. Our next question will come from Tyler Van Buren, from Piper Sandler. You may begin. Hey guys. Good morning. I have a couple for you. I guess the first one is just a follow-up to Phil's last question. Just to be clear and make sure we're covering all of our bases, the Comet Protocol Amendment recommended by the FDA was not specifically due to a new safety event or DLT like pancreatitis or something that we haven't seen yet.
Thank you our next question will come from.
Tyler Van Buren from Piper Sandler.
You may begin.
Hey, guys. Good morning, a couple for you I guess the first one is just a follow up to Phils last question just to be clear and make sure. We're covering all of our bases. The Comet protocol Amendment recommended by the FDA that was not specifically due to the new safety event or DLT like pancreatitis.
Or something that we haven't seen yet.
Troy Edward Wilson: Correct. In fact, the opposite, Tyler.
Correct. It in fact, the opposite Tyler It was due to the fact that we're.
Troy Edward Wilson: It was due to the fact that we were not seeing any toxicity that allowed us to set the dose. So not only is it not an unexpected toxicity event, but it's in fact the lack of toxicity. You know, we could take the compound forward at any of the doses we've evaluated. Now we need to turn to the question of which of them is best to be able to drive efficacy.
We're not seeing any any toxicity, that's allowing us to set the dose.
So not only is it not an unexpected toxicity event. It's it's in fact, the lack of toxicity.
We could take the compound forward it at at any of the doses. We've evaluated we now need to turn to the question of which of them, it's best to be able to drive efficacy.
Stephen Dale: And Troy, if I can just add to that, you know, and the fact that all the doses that are going to be used in the expansion are all doses that have met the safety threshold in the escalation, again, is testimony to how well they work.
And Troy if I can if I can just sounds as well for that.
And the fact that all the doses are going to be used in the expansion are all doses that have met the safety threshold in the escalation again is testimony to how well tolerated and how wide therapeutic window. It.
Tyler Van Buren: Okay, that's helpful. And then the second one is just, again, related to these expansion cohorts.
Okay. That's helpful. And then the second one is again related to these expansion cohorts I understand based upon the existing expansion that it could make sense to use 200 mix as the lower bound but.
Troy Edward Wilson: I understand, based upon the existing expansion, that it could make sense to use 200 mgs as the lower bound. But how do you accurately pick the upper bound? You know, if the goal is to generate the minimum effective dose with precision, wouldn't a potential dose escalation in genetically defined patients or potentially even intra-patient dose escalation be helpful or informative? Since, as you stated, this initial escalation is generating breadcrumbs on the side of efficacy.
How do you accurately picked the upper bound.
The goal is to generate the minimum effective dose with precision.
Wouldn't a potential dose escalation and genetically defined patients or potentially even intra patient dose escalation b.
Help for or informative.
As you stated this initial escalations generating bread bread crumbs on the side of efficacy.
Stephen Dale: Yeah. That's a great question, Tyler. This question is spot on. Let me ask Stephen if he can comment on that.
Yeah.
That's a great question Tyler its a question is spot on.
Stephen Dale: Yeah, so no, it's another great question. So to do a dose escalation, in essence, it's typically, if it's a 3 plus 3 design, it's safety-driven. And the agency is fairly consistent with dose escalations being done in an Orkham population, which has been done now. The question as to how to select the dose to do the expansions in, which, of course, have the enriched population. It's something which will have to be decided in terms of discussion with the Safety Review Committee.
Me ask Steven if he can comment on that.
Yeah. So no it's a great question so.
They do a dose escalation in essence.
Typically if it's a three plus three design safety driven.
On the agency.
It's fairly consistent with dose escalation is being done on an all comers population, which has been done there the question as to how to select the dose to do the expansions in which of course have the enriched population.
Which will have to be decided in terms of discussion with the safety Review committee, but when we're making those decisions. It's important to note that those all chiefly based on the benefit risk assessment. So we look at clinical activity of that given debt. So we also look at the safety and we also look at one available farmer.
Tyler Van Buren: But when making those decisions, it's important to note that those decisions are chiefly based on a benefit-risk assessment. So we look at clinical activity at that given dose. We also look at safety, and we also look at what available pharmacokinetic data we have. And the decision of which dose to select will then be discussed and agreed with the Safety Review Commission. It's very similar when you're deciding and determining your recommended phase two dose when you have more data, but those decisions will have to be agreed with our SRC Committee. So hopefully, that gives a little more color to what we're trying to do here.
Kinetic data we have on that.
A decision then.
Which dose to select will then be will then be depicted on agreed with the state to review Commission and he's very similar when you deciding in determining your recommended phase II dose as well when you have more day to book, but those decisions will have to be agreed with all SLC committee. So hopefully that puts a little more color on on what.
We're trying to do here.
Tyler Van Buren: Okay, so you guys just have a very high level of confidence that the exposure that you observe in these all-comer patients is going to give you an accurate read on what will be efficacious in genetically defined patients.
Okay. So you guys just have a very high level of confidence that the exposure that you observe in these in these all comer patients or it's going to give you an accurate read on what will be efficacious and genetically defined patients.
Stephen Dale: Yeah, no, absolutely, but it's important to note that whilst we've seen, and we've discussed this previously, we see a dose-related increase in exposure, we see some degree of concentration-related increase in exposure. But what we haven't seen to date, as we've previously said, is a plateau as well. So the data that we're ongoing in monitoring, we're trying to see whether or not we hit that plateau in exposure. So it's a factor in the decision, yes.
Yes.
Pollutant, but it's important to note that whilst we we've seen and we've discussed this previously we see a dose related increase in exposure.
See some degree of concentration.
Related increase in exposure, what we haven't seen today, if we previously said.
Plateau as well so.
The data that were ongoing in monitoring we are trying to see whether or not that we hit that plateau and expose yourself.
Factor in the decision yes.
Okay. Thanks, so much for taking the questions.
Stephen Dale: Okay, thanks so much for taking the question. Thanks, Tom. And as a reminder, that's star one for any questions. Star one.
Thanks Tyler.
And as a reminder, that's a star one for any questions Star one.
Operator: Our next question comes from Joe Panguinis from H.C. Wainwright. You may begin. Hey, good morning, guys. Thank you for taking the question. I have one question at this point, and it's just curious. Troy, if I heard you correctly, did you say the expansion patients, the 12 or the 12, have the opportunity to be included in a potential registration study?
Our next question comes from the line of Joe <unk> from H C. Wainwright.
You may begin.
Morning, guys. Thanks for taking the question I have one question at this point and I was just curious Troy if I heard you correctly did you say the b.
On the expansion patients for 12 of the 12 have the opportunity to be included in a potential registration study and specifically are you ready or to discuss at least from an early standpoint, some broad broad strokes about FDA potential feedback as to the size of that study.
Joe Panguinis: And specifically, are you ready to discuss, at least from an early standpoint, some broad strokes about FDA potential feedback as to the size of that study?
Troy Edward Wilson: Yeah, so Joe... The intent of aligning the endpoints in the phase one expansions with the endpoints in the registrational study is to permit those patients potentially to be included. As I mentioned, that's ultimately up to the FDA, that'll be a review issue, but we're going to do everything we can. We're going to treat those patients as though they were in the registrational phase from the standpoint of the filing, and there's definitely a desire to be able to move quickly here.
Yeah, So Joe.
The intent and aligning the endpoints in the phase one expansions with the endpoints in the Registrational study is is to permit those patients.
Potentially to be included net as I mentioned, that's ultimately.
You know up to the FDA that it'll be a review issue, but we're going to do everything we can't we're going to treat those patients as though they were in the Registrational portion.
From the standpoint of the filing in and.
There's definitely a desire to be able to move quickly here in terms of the size of the trial.
Troy Edward Wilson: In terms of the size of the trial, I think what we've guided to is potentially three different registrational cohorts, one in NPM1, one in KMT2A, and one in a third cohort. And the number of patients is anywhere from sort of 40 to up to 100, depending on the level of activity that we see, so the trial will have sizing to allow you to basically expand the population, you know, given a given level of clinical activity in those populations.
You know I think what we've guided to is you know three potentially three different registrational cohorts, one and N. P. M. One one Kmt two way and one in a in a third cohort.
And the number of patients is anywhere from sort of 40 to up to 100, depending on the level of activity that we see so that the trial will be will have sizing.
To allow you to basically expand the population you know.
Given our given a given level of clinical activity on those populations.
Troy Edward Wilson: We still have some work to do to finalize the details on the portion of the study that's for registrational intent. I think we'll be in a position to talk about that later in the year, but, you know, it's consistent with what's been done with other targeted therapies. Here you just have, you know, multiple genetically defined subsets.
We still have some some work to do to finalize the details on the portion of the study that's for Registrational intent I think it will be it on a position to talk about that later in the year, but it's consistent with what's been done with other targeted therapies.
Here you just have multiple genetically defined subsets got.
Troy Edward Wilson: Got it. Thanks. Thank you. And I'm not showing any further questions at this time. I'd like to turn the call over to Troy Wilson for any closing remarks. Great.
Got it thanks Troy.
Sure.
Yeah, and I'm not showing any further questions at this time I'd like to turn the call over to us the Troy Wilson for any closing remarks.
Great. Thank you operator, and thank you all once again for participating on the call we're going to be at a number of virtual investor conferences over the next couple of weeks beginning.
Troy Edward Wilson: Thank you, Operator, and thank you all once again for participating in the call. We're going to be at a number of virtual investor conferences over the next couple of weeks, beginning with the SBB Lyrinc Global Healthcare Conference tomorrow, and we'll look forward to speaking with many of you then. In the meantime, if you have any additional questions, of course, you can always reach out to Pete, Mark, or me, and we're happy to connect with you. Thanks again, and have a good day, everyone.
Beginning with the SBB Leerink Global Healthcare Conference Tomorrow, and we'll look forward to speaking with many of you then in the meantime, if you have any additional questions of course, you can always reach out to to Pete to mark or to me on.
We're happy to connect with you. Thanks, again and have a good day everyone.
Operator: Ladies and gentlemen, this concludes today's call. Thank you for participating. You may now disconnect.
Ladies and gentlemen, this concludes today's call. Thank you for participating you may now disconnect.
Yeah.
Yeah.
Yes.
Yeah.
Yeah.
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