Q2 2021 Kura Oncology Inc Earnings Call
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Good day, and thank you for standing by and welcome to the second quarter 2021 Kura Oncology, Inc earnings Conference call.
Operator: Good day and thank you for standing by, and welcome to the second quarter 2021 Kura Oncology Inc. Earnings Conference. At this time, all participants were in a listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press par 1 on your telephone or touch tone. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Vice President of Investor Relations, Mr. Pete DeStain. Thank you. Please go ahead.
At this time all participants are in a listen only mode. After the speaker's presentation. There will be a question and answer session to ask a question. During the session you will need to press star 1 on your telephone are attached to them.
If you require any further assistance. Please press star zero I would now like to hand, the conference over to your Speaker today, Vice President of Investor Relations. Mr. Pete. This thing. Thank you. Please go ahead Sir.
Thank you operator, good afternoon, and welcome to occur oncology second quarter 2021 conference call joining.
Pete De Spain: Thank you, operator. Good afternoon, and welcome to Curra Oncology's second quarter 2021 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. 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.
Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer, and Dr. Marc Grasso, Our Chief Financial Officer, and Chief Business Officer.
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: Please refer to Curas filings with the SEC, which are available from the SEC or on the Curra Oncology website for information concerning risk factors that could affect the country. With that, I'll now turn the call over to Dr. Troy Wilson, President and CEO of Curra Oncology.
Please refer to <unk> filings with the SEC, which are available from the FCC or on the current oncology website for information concerning risk factors that could affect the company with that I'll now turn the call over to Dr. Troy Wilson, President and CEO of <unk> oncology.
Thank you Pete and thank you all for joining US. This afternoon I'm extremely proud of the progress our team has made across the pipeline over the past several months underscoring our focus on operational execution. This progress is highlighted by the first patients dosed in the phase <unk> expansion cohorts with our Menin inhibitor <unk> $5.30.
Troy Edward Wilson: Thank you, Pete, and thank you all for joining us this afternoon. I'm extremely proud of the progress our team has made across the pipeline over the past several months, underscoring our focus on operational execution. This progress is highlighted by the first patients dosed in the Phase 1B expansion cohorts with our Mennon inhibitor, K.O539; a clinical collaboration with Novartis to evaluate Kipharnib, in combination with the PI3-Kinae alpha inhibitor, alpelisib, in head-and-neck cancer. squamous cell carcinoma and the nomination of K0-2806 as the lead development candidate in our next generation Farnesil Transphrase Inhibitor Program.
9 a clinical collaboration with Novartis to evaluate <unk> in combination with the <unk> kinase Alpha inhibitor are palliative in head and neck squamous cell carcinoma and nomination of K O 28 O 6 as the lead development candidate in our next generation Farnesol transfer Ace inhibitor program.
Now, let's take a closer look at the progress within each of our programs beginning with our Menin inhibitor Ko 539.
Troy Edward Wilson: Now let's take a closer look at the progress within each of our programs, beginning with our Mennin inhibitor, K-0539. We continue to have strong conviction in K0539 and its potential to be both a first in class and a best in class Mennin inhibitor. This confidence is supported by the results from the Phase 1A dose escalation portion of Comet 001, our Phase 12 clinical trial of K0539. These data showed promising single agent activity in an all-comer population of patients with relapsed or refractory AML, including patients with NPM1 mutations and KMT 2A rearrangements.
We continue.
To have strong conviction in <unk> $5.39, and its potential to be both a first in class and the best in class Menin inhibitor. This confidence is supported by the results from the phase <unk> dose escalation portion of comment 001, our phase 1.2 clinical trial of K O $5.39.
These data showed promising single agent activity in an all comer population of patients with relapsed or refractory AML, including patients with MTM, 1 mutation and Kmt <unk> rearrangements. We're also encouraged by the clinical activity observed in patients with other co mutations, including a complete remission in <unk>.
Troy Edward Wilson: We're also encouraged by the clinical activity observed in patients with other co-mutations, including a complete remission in a patient with a set D2 run X1 mutation. We believe these patients may represent a potential third expansion cohort, a differentiating feature of our program. KO539 also demonstrated a favorable safety and tolerability profile with no evidence of QTC prolongation, another important differentiating feature of the program.
With a 32 run ex 1 mutation.
We believe these patients may represent a potential third expansion cohort a differentiating feature of our program.
<unk> 39 also demonstrated a favorable safety and Tolerability profile with no evidence of Qt prolongation. Another important differentiating feature of the program.
Given the wide therapeutic window <unk> $5.39 demonstrated in the phase <unk> dose escalation portion of the study we have now advanced to phase <unk> expansion cohorts, a lower dose of 200 milligrams and a higher dose of 600 milligrams, each comprising NPM, 1 mutant and Kmt to rearrange.
Troy Edward Wilson: Given the wide therapeutic window, K0539, demonstrated in the Phase 1A dose escalation portion of the study, we've now advanced two Phase 1B expansion cohorts, a lower dose of 200 milligrams and a higher dose of 600 milligrams, each comprising NPM1 mutant and KMT2 rearranged relapsed and refractory AML patients. These two doses demonstrated preliminary evidence of activity and were determined to be safe and well tolerated in the dose escalation portion of the study.
Relapsed and refractory AML patients. These 2 doses demonstrated preliminary evidence of activity and we're determined to be safe and well tolerated in the dose escalation portion of the study.
The phase <unk> is designed to determine the lowest dose of <unk> $5.39 that provides maximum biologic and clinical effect in keeping with guidance from FDA relating to targeted therapies in oncology now known as project Optimists.
Troy Edward Wilson: The Phase 1B is designed to determine the lowest dose of KO539 that provides maximum biological and clinical effect in keeping with guidance from FDA relating to targeted therapies in oncology, now known as Project Optimus. The first patient was dosed in the 600 milligram cohort of the Phase 1B study in late June. We've now enrolled patients in each expansion cohort and have a queue of patients in screening. Approximately half of an estimated 20 U.S. sites are actively screening patients in Phase 1B, with sites pending across five European countries, a demonstration of the strong execution of our clinical operations team. Our base case is that we should complete enrollment of the 12 evaluable patients in each cohort by the first quarter of 2022.
The first patient was dosed in the 600 milligram cohort of the phase <unk> in late June we've now enrolled patients in each expansion cohort and have a queue of patients and screening approximately half of an estimated 20 U S sites are actively screening patients from the phase 1 b with sites pending across 5 European.
Countries, a demonstration of the strong execution of our clinical operations team.
Our base case is that we should complete enrollment of the 12 evaluable patients in each cohort by the first quarter of 2022. We will then assess these patients for safety and Tolerability pharmacokinetics and efficacy in order to determine the recommended phase II dose. This.
Troy Edward Wilson: We will then assess these patients for safety and tolerability, pharmacokinetics, and efficacy in order to determine the recommended phase two dose. The study protocol gives us the flexibility to enroll up to 30 patients in the selected cohort. This enables us to continue enrolling patients in the Phase 1B at the recommended Phase 2 dose while we transition into the subsequent registration-directed portion of Comet-Z01. Importantly, we believe data from all patients treated at the recommended phase 2 dose will contribute to the registrational patient population.
The study protocol gives us the flexibility to enroll up to 30 patients in the selected cohort. This enables us to continue enrolling patients in the phase 1 b at the recommended phase II dose, while we transition into the subsequent registration directed portion of comment 001 <unk>.
Importantly, we believe data from all patients treated at the recommended phase II dose, we will contribute to the registrational patient population.
Troy Edward Wilson: Thus, our phase 1B not only helps us to gather a more robust data set in our target populations and to refine the selection of a recommended phase two dose, but it enables us to start our path toward registration and maintain an aggressive development timeline for the program. Although it's early, and results are still preliminary, we're encouraged by observations of early signs of clinical activity in phase 1B. We intend to provide an update on both the Phase 1A and the Phase 1B at a future medical meeting pending the determination of the recommended Phase 2 dose. In addition, we'll seek to provide qualitative updates on the progress of the Phase 1B study in the months ahead, as appropriate.
Thus, our phase <unk>, not only helps us to gather a more robust dataset and our target populations and to refine the selection of a recommended phase 2 dose, but it enables us to start our path towards registration and maintained an aggressive development timeline for the program.
Although it is early and results are still preliminary we're encouraged by observations of early signs of clinical activity in the phase 1 b, we intend to provide an update on both the phase <unk> and phase 1 b at a future medical meeting pending determination of the recommended phase II dose. In addition, we will seek to provide qualitative.
Updates on the progress of the phase <unk> in the months ahead as appropriate.
In the meantime, we're preparing to conduct a comprehensive clinical development plan for <unk> 539, pending determination of a recommended phase II dose additional development opportunities include combination studies other genetic subtypes pediatric development strategy in other indications such as acute lymphocytic leukemia and myelodysplastic.
Plastic syndrome.
Troy Edward Wilson: In the meantime, we're preparing to conduct a comprehensive clinical development plan for KL539 pending determination of a recommended phase two dose. Additional development opportunities include combination studies, other genetic subtypes, pediatric development strategy, and other indications, such as acute lymphocytic leukemia and myeloplastic syndrome. Efforts are already underway to support some of these larger opportunities. For example, encouraging preclinical data has been generated through one of our research collaborations showing evidence of synergistic activity of K0539 in combination with Venetac in KM2 rearranged and NPM1 mutant AML models. We expect to have more to say regarding these data later this year.
Efforts are already underway to support some of these larger opportunities for example, encouraging preclinical data has been generated through 1 of our research collaborations showing evidence of synergistic activity of <unk> $5.39 in combination with <unk> in Kmt, 2 rearranged and <unk> mutant AML.
Models, we expect to have more to say regarding these data potentially later this year.
Although our Menin program continues to capture much of the attention. We remain just as excited about the opportunities per farnesol transfer <unk> inhibition in oncology. The most advanced of these opportunities is focused on patients with head and neck squamous cell carcinoma, or <unk> FCC that carry mutations in the HRS gene.
Earlier this year typify net was granted breakthrough therapy designation from FDA for the treatment of patients with recurrent or metastatic <unk> mutant <unk> SEC. The breakthrough therapy designation was based upon data from our phase II run HN trial, which was published 2 months later in the journal of clinical oncology, we continue to be motivated.
Troy Edward Wilson: Although our Mennon program continues to capture much of the attention, we remain just as excited about the opportunities for Farnasil Transprase inhibition in oncology. The most advanced of these opportunities is focused on patients with head and neck squamous cell carcinomas or HNSC that carry mutations in the HRS-Gene. Earlier this year, Tippafarnin was granted breakthrough therapy designation from FDA for the treatment of patients with recurrent or metastatic, H-R-S mutant HNSCC. The breakthrough therapy designation was based on data from our Phase 2-Run HN trial, which was published a month later in the Journal of Clinical Oncology.
These data by the BTT award from FDA, and the potential, particularly foreign it to represent the first approved small molecule targeted therapy and <unk> FCC as such we remain focused on our aim HN registration directed trial and bringing <unk> to market as quickly and as efficiently as possible.
In addition to addressing an unmet need for patients we believe the opportunity for <unk> mutant <unk> FCC provides a beachhead to the development of rational combinations and expansion to larger genetic subsets. Among these potential combinations, we've identified as a priority the combination of <unk>.
<unk> been a pediatric kinase delta inhibitor, our preclinical data suggests that HRS and <unk> kinase Alpha are codependent, oncogene, and <unk> FCC and that combining <unk> with a <unk> alpha inhibitor has the potential to meaningfully to provide meaningfully better antitumor activity relative to inhibiting either target alone.
Troy Edward Wilson: We continue to be motivated by these data, by the BTD award from FDA, and the potential for TIPPFARNIP to represent the first approved small molecule targeted therapy in HNSCC. As such, we remain focused on our AMHN registration-directed trial and bringing TIPIFarnib to market as quickly and as efficiently as possible. In addition to addressing an unmet need for patients, we believe the opportunity for TIPIFarniv and H-Rs mutant HNSCC provides a beachhead for the development of rational combinations and expansion to larger genetic subsets.
We believe this combination has the potential to increase the total addressable population for <unk> to as much as 50% of patients with HCC.
Last month, we announced a clinical collaboration with Novartis to evaluate the combination of <unk> and the <unk> kinase inhibitor <unk> in patients with HSBC.
<unk> is approved to treat patients with <unk> mutant breast cancer and it has demonstrated encouraging evidence of clinical activity in patients with HSBC.
Given the strong preclinical rationale and data we look forward to evaluating the 2 drugs in combination.
Now actively preparing for a phase 1.2 study of <unk> in combination with our <unk> and <unk>, which we call. The current trial. This the initial cohort will include patients who have pick 3 CA dependent <unk> FCC. These patients can be identified using next generation sequencing, which will allow.
Troy Edward Wilson: Among these potential combinations, we've identified the combination of TIPIFARNiv and a Piatri-Kinase alpha inhibitor as a priority. Our pre-clinical data suggests that H-RAS and Piacircinae's alpha are codependent oncogenes in HNSCC and that combining TIPIPFARNED with a PS3-Kina alpha inhibitor has the potential to meaningfully provide meaningfully better antitumor activity relative to inhibiting either target alone.
Low us to identify a recommended phase II dosing schedule for the combination.
Under the terms of the collaboration agreement, we will sponsor the current trial and supply <unk> and Novartis will supply <unk>, we expect to initiate this study in the fourth quarter of 2021, and we look forward to sharing our progress with you.
Meanwhile, through our own internal efforts and our network of academic collaborations we've uncovered some exciting opportunities for foreign sales transfer ace inhibitors in combination with other targeted therapies last year, we initiated a discovery stage program to develop a next generation Farnesol transfer Ace inhibitor designed to talk.
Troy Edward Wilson: We believe this combination has the potential to increase the total addressable population for tippiforneb to as much as 50% of patients with HNSCC. Last month, we announced a clinical collaboration with Novartis to evaluate the combination of tippy fornib and the PS3-Kinhibitor, Alpelisib, in patients with HNSCC. Alpelisib is approved to treat patients with PIC3CA mutant breast cancer, and it has demonstrated encouraging evidence of clinical activity in patients with HNSCC.
<unk> innovative biology, and address large oncology indications of high unmet need through rational combinations. Our goal for this program was to deliver a drug candidate that has improved potency pharmacokinetic and physical chemical properties relative to <unk>.
Our team identified multiple advanced lead compounds and I'm pleased to report we've nominated 1 in particular, a compound we call Kao 28, 6 as our lead development candidate. We're now conducting IND, enabling studies and expect to submit an IND application for <unk> thousand 806 by the end of 2022, we believe.
Farnesol transfer <unk> inhibition in oncology has the potential to deliver multiple opportunities for large indications and we look forward to sharing an update with you. As this story continues to evolve with that I'll now turn the call over to Marc Grasso for a discussion of our financial results. Thank you Troy and good afternoon, everyone I'll provide a brief overview of our financial.
Troy Edward Wilson: Given the strong preclinical rationale and data, we look forward to evaluating the two drugs in combination. We're now actively preparing for a phase 1-2 study of Tipifarnib in combination with Alpalib and HNSCC, which we call the current trial. The initial cohort will include patients who have Pick 3 CA-dependent HNSCC.
Results from the second quarter 2021, along with guidance from the full year 2021.
And by you to review, our 10-Q filed today for a more detailed discussion.
Research and development expenses for the second quarter of 2021, or $21.1 million compared to $13.7 million for the second quarter of 2020 the.
Troy Edward Wilson: These patients can be identified using next-generation sequencing, which will allow us to identify a recommended phase two dose and schedule for the combination. Under the terms of the collaboration agreement, we will sponsor the current trial and supply tippifarnib, and Novartis will supply alpelsim. We expect to initiate this study in the fourth quarter of 2021, and we look forward to sharing our progress with you. Meanwhile, through our own internal efforts and our network of academic collaborations, we've uncovered some exciting opportunities for Farnesil Transphrase inhibitors in combination with other targeted therapy.
The increase in R&D expenses was primarily due to increases from clinical trial cost development and manufacturing activities related to our <unk> hundred 39 program.
Clinical trial costs related to our registration directed to be funded trial noncash share based compensation personnel costs and other expenses.
General and administrative expenses from the second quarter of 2021 were $12.6 million compared to $7.5 million for the second quarter of 2022.
The increase in G&A expenses was primarily due to increases in personnel costs and noncash share based compensation.
Net loss from the second quarter of 2021 was $33.7 million.
Or <unk> 51 per share compared to a net loss of $25 million per <unk> 40 per share for the second quarter dose 20.
As of June 32021, we had cash cash equivalents and short term investments of $567.5 million.
Compared with $633.3 million as of December 31, 2020.
The cash balance as of June 30 reflects the spend of $6.6 million to repay in full our existing debt facilities at a reduced prepayment fee leveraging our strong cash position.
Looking ahead, we anticipate our operating expenses for the full year 2021 to be in the range of $130 million to $140 million as we continue to invest from the clinical and preclinical development of our pipeline important drivers of our future growth.
Troy Edward Wilson: Last year, we initiated a discovery stage program to develop a next-generation Farnesil Transphrates Inhibitor designed to target innovative biology and address large oncology indications of high-unmet need through rational combinations. Our goal for this program was to deliver a drug candidate that has improved potency, pharmacokinetic, and physical chemical properties relative to TIPI-Farnib. Our team identified multiple advanced lead compounds, and I'm pleased to report we've nominated one in particular, a compound we call K0-2806, as our lead development candidate.
Our net cash used in operating activities for the full year 2021 to be in the range of $105 million to $115 million based on our current plans. We continue to believe that our 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.
Thank you Mark.
Before closing I'd like to take this opportunity to welcome Carol Schafer and Dr. Helen Collins to our board of Directors Carol brings more than 25 years of experience as a trusted strategic and financial adviser to the leadership teams of growing biopharmaceutical companies. Most recently as vice chair of equity capital markets at Wells Fargo Securities.
Alan joins with more than 25 years of medical experience. Most recently as Chief Medical Officer at 5 Prime Therapeutics, where she oversaw the development of.
Troy Edward Wilson: We're now conducting I&D enabling studies and expect to submit an I&D application for KO-2806 by the end of 2022. We believe varnesal transprase inhibition and oncology have the potential to deliver multiple opportunities for large indications, and we look forward to sharing an update with you as this story continues to evolve.
<unk> a first in class anti <unk> antibody for the treatment of patients with gastric cancer Carolyn Helen each bring a unique perspective to the board and we look forward to their contributions as we work as we work to bring our oncology drug candidates to market expand their use to larger patient.
<unk> and create value for patients and our shareholders. I also want to take this opportunity to express my sincere appreciation to Robert Hoffman for his many contributions throughout his 6 years on the current board of directors.
Mark Brasso: With that, I'll now turn the call over to Mark Brasso for a discussion of our financial results. Thank you, Troy. Good afternoon, everyone.
Deeply grateful for his service as a board member and as chair of our audit Committee on behalf of everyone at <unk>, we wish Robert well in his future endeavors now before we jump into the question and answer session. Let me lay out our anticipated milestones for the remainder of the year.
Mark Brasso: I'll provide a brief overview of our financial results for the second quarter of 2021, along with guidance for the full year 2021.
Initiate the current phase 1.2 study of <unk> in combination with <unk> in the fourth quarter of 2021.
Mark Brasso: I invite you to review our 10Q file today for more detailed discussion.
Complete enrollment of 24 evaluable patients in the comment 001 phase <unk> expansion cohorts by the first quarter of 2022.
Mark Brasso: Research and development expenses for the second quarter of 2021 were $21.1 million compared to $13.7 million for the second quarter of 2020. The increase in R&D expenses was primarily due to increases in clinical trial costs, development, and manufacturing activities related to our K0539 program, clinical trial costs related to a registration directed to be farnded trial, non-cashar base compensation, personnel costs, and other expenses. General and administrative expenses for the second quarter of 2021 were $12.6 million, compared to $7.5 million for the second quarter of 2020. The increase in GNA expenses was primarily due to increases in personnel costs and non-cash share-based compensation.
Determined the recommended phase 2 dose <unk> $5.39 by the first quarter of 2020 to submit an IND application for <unk> 2008, or 6 by the end of 2008.2022 with that operator, we're now ready for questions.
As a reminder to ask a question you will need the plan's star 1 on your telephone.
Through all your question press, the pound or Husky, please standby, while we compile the Q&A roster.
Your first question comes from the line of Jonathan Chang from SBB Leerink. Your line is now open.
Hi, guys. Thanks for taking my questions. First question can you provide more color around how the dose levels or select for the $5.9 expansion cohorts.
Sure Jonathan and thanks for the question so.
The guidance from FDA.
And that is now sort of clue colloquially known as project Optimus.
Instruct sponsors or guide sponsors to identify the lowest dose with maximum biologic and clinical activity.
And then its guidance FDA is moving expressly away from maximum tolerated dose in the context of targeted therapies in oncology.
Mark Brasso: The net loss for the second quarter of 2021 was $33.7 million, or 51 cents per share, compared to a net loss of $20.5 million, or 40 cents per share, for the second quarter of 2020. As of June 30, 2021, we had cash, cash equivalents, and short-term investments of $567.5 million, compared with $633.3 million as of December 31st, 2020. The cash balance as of June 30th reflects the expenditure of $6.6 million to repay in full our existing debt facility at a reduced prepayment fee leveraging our strong cash. Looking ahead, we anticipate our operating expenses for the full year 2021 to be in the range of $130 million to $140 million as we continue to invest in the clinical and pre-clinical development of our pipeline, important drivers of future growth.
So that pushes towards lower doses, not higher doses MTV being kind of a relic if you will of the old chemotherapy days.
With that being said it was.
It was pretty clear that the low dose of 200 milligrams. Once daily was right because we saw robust activity that activity was highlighted at ash in particular, a couple of responses among NPM 1 mutant patients.
1 with a CR that was MRV negative the other being an MLM FES when it comes to the higher dose, we really face the choice was it 600 or 800 and.
Given the limitations of the phase <unk> study the fact that it wasn't in genetically enriched 4 Kmt <unk> mutant patients, we didnt really see a difference between those 2 doses are different enough to justify going with 800 vs 600, those 2 doses looked sort of consistent.
And per the Fda's guidance, if thats the case should go with the lower dose. So we're now at a point and we've we're actively enrolling in the phase <unk> as I mentioned in the prepared remarks at doses of 200.600.
Expect that both of the both of those doses have.
Mark Brasso: We expect our net cash use and operating activities for the full year 2021 to be in the range of $105 million to $150 million. Based on our current plans, we continue to believe that our cash, cash equivalence to Georgia investments, will be sufficient to fund current operations into 2020. With that, we'll now turn the call back over to Troy. Thank you, Mark.
Good safety and Tolerability.
They are very clean, we think either dose could potentially be a good going forward dose. The phase <unk> study is now explicitly an efficacy study and it will allow us to both select and <unk> and begin to compile patients who we believe are going to be eligible to be included in the population for.
<unk>.
Understood. Thank you.
And second question, how should investors be thinking about the cadence and the substance of 539 updates for both the escalation and expansion portions over the remainder of 2021 and in 2022.
Troy Edward Wilson: Mark. Before closing, I'd like to take this opportunity to welcome Carol Schaefer and Dr. Helen Collins to our board of directors. Carol brings more than 25 years of experience as a trusted strategic and financial advisor to the leadership teams of growing biopharmaceutical companies, most recently as vice chair of equity capital markets at Wells Fargo Security. Helen comes with more than 25 years of medical experience, most recently as Chief Medical Officer at Five Prime Therapeutics, where she oversaw the development of Fomarituzumab, a first-in-class anti-FGFR 2B antibody for the treatment of patients with gastric cancer.
Yes, great question so.
The way, we're thinking about the phase 1 experience is.
<unk> is primarily a safety study the phase phase <unk> excuse me, it's a safety study the phase <unk> is really efficacy driven study.
The phase <unk> is now close to enrollment.
We got out of it I think what we were expecting the molecule is safe and well tolerated across a range of doses.
We're seeing anecdotal activity.
But there are limitations and the limitations are.
It is not genetically enriched.
A number of patients are not efficacy evaluable, but despite that we continued to see encouraging signs of activity, including in patients who had progressed on a prior <unk> inhibitor.
And that we thought that was noteworthy.
The phase <unk> is explicitly in the <unk> and NPM 1 our goal Jonathan as we said in the prepared remarks is to have the phase <unk> cohorts fully enrolled by the end of the first quarter of next year and to be in a position where we have identified the recommended phase II dose.
Troy Edward Wilson: Carol and Helen each bring a unique perspective to the board, and we look forward to their contributions as we work to bring our oncology drug candidates to market, expand their use to larger patient populations, and create value for patients and our shareholders. I also want to take this opportunity to express my sincere appreciation to Robert Hoffman for his many contributions throughout his six years on the Currah Board of Directors. We're deeply grateful for his service as a board member and as chair of our audit committee. On behalf of everyone at Curra, we wish Robert well in his future endeavors.
We will do everything we can to 2.
To meet or exceed that timeline, but given the given what we're seeing in the screening Q and the pace of enrollment we think thats a good base case projection.
Our intent is to provide qualitative updates on this study throughout the remainder of 2021. Those will include and you've gotten some sense of that today from the commentary.
Initially you are focused on site activation you're focused on the screening funnel than youre talking about are we actually recruiting patients to the 2 arms. We are I think we will be able to give guidance both on enrollment and quantitatively. What are we seeing right I don't think we're going to be able to call out specific patients.
The very reason that this this it's our hope and our intent that this data will be considered for registration by FDA. So we have to treat it with with some <unk>, but I think we'll be able to provide guidance on enrollment and on activity or are there are there are there differences between the arms.
Troy Edward Wilson: Now, before we jump into the question and answer session, let me lay out our anticipated milestones for the remainder of the year. Complete enrollment of 24 valuable patients in the Comet-001, Phase 1B expansion cohorts by the first quarter of 2022. Determine the recommended phase two dose of KO539 by the first quarter of 2022. Submit an I&D application for KO2806 by the end of 2022. With that operator, we're now ready for questions.
That's our intent is to provide qualitative guidance and we will look to present, the 1 day and the 1 b together.
As the full phase 1 experience at a at an upcoming medical or scientific meeting.
Understood. Thank you and if I can just sneak in 1 more mostly because I don't think youll be able to.
And the chance that you can can you expand on what you mean by the early signs of clinical activity in the phase 1 expansion cohorts for a factory line. Thank you.
Sure.
I mean, there are there are a number of measures of that including.
Disease stabilization improvement of performance status, but the most notable 1 Jonathan is reduction in blast counts.
And I should just leave it at that.
Again, we don't want to be Cherry picking data, what we want to do is to leave you and the others on the call with an understanding that from our perspective.
Operator: As a reminder, to ask a question, you will need to press Star 1 on your teleps. To withdraw your question, press the pound or hash. Please time by while we compile a Q&A wrong. Your first question comes from the line of Jonathan Chang from SBB Hearing. Your line is now open.
Fact that.
What we're seeing it's early it's preliminary but what we're seeing in the phase 1 b reinforces that the dose selections of 200, 600, where the right dose selections.
Got it thank you.
Your next question comes from the line of Peter Lawson from Barclays. Your line is now open.
Jonathan Chang: Hi guys, thanks for taking my questions. First question, can you provide more color around how the dose levels were selected for the KO539 expansion cohorts?
Great. Thanks, Thanks for taking the questions Troy.
Just on.
Kind of day to.
Disclosures that we may get the ship would we get anything around.
Durability from any of the previously treated patients where we've seen them.
Troy Edward Wilson: Here, Jonathan, and thanks for the question. The guidance from FDA, that is now sort of colloquially known as Project Optimus, instructs sponsors or guides sponsors to identify the lowest dose with maximum biologic and clinical activity. And in its guidance, FDA is moving expressly away from maximum tolerated dose in the context of targeted therapies and oncology. So the push is toward lower doses, not higher doses, MTD being kind of a relic, if you will, of the old chemotherapy days.
Yes, Peter I think we're going to have to wait until we disclose the.
Until we disclosed a full phase 1 experience.
We have been thus far.
Pressed with the durability, but it's early days. This is a handful of patients. The data is preliminary I think we don't want to pick and choose we need to we need to look at durability in the context of the full clinical package and it's our intent it's our intent to enroll the <unk>.
Troy Edward Wilson: With that being said, it was pretty clear that the low dose of 200 milligrams once daily was right because we saw robust activity. That activity was highlighted at Ash, in particular a couple of responses among NPM1 mutant patients, one with a CR that was MRD negative, the other being an MLFS.
As quickly as we can and be in a position to talk about both the safety and tolerability and the efficacy profile of $5.39.
As quickly as we can at an upcoming future medical meeting.
Got you and you had mentioned a patient progressed on a prime men an inhibitor.
You kind of.
The uncertainty potentially retreat with <unk> inhibitors.
Troy Edward Wilson: When it comes to the higher dose, we really faced a choice. Was it 600 or 800? Given the limitations of the Phase 1A study, the fact that it wasn't genetically enriched for KMT2A and NPM1 mutant patients, we didn't really see a difference between those two doses, a difference enough to justify going with 800 versus 600. Those two doses looked sort of consistent, and per the FDA's guidance, if that's the case, you go with the lower dose.
Yes, so so a couple of comments Peter.
Yes, it's actually plural patients.
Not not just 1 I think it's what we're seeing is evidence of clinical activity.
The just to be clear right, let's draw a distinction between the mechanism of action and then.
1 might do in a registrational context.
That gives us confidence that just as you say.
Even in patients who have progressed on upon treatment with a prior <unk> inhibitor you are still seeing evidence of clinical benefit.
Troy Edward Wilson: So we're now at a point where we're actively enrolling in the phase 1Bs, as I mentioned in the prepared remarks, at doses of 200 and 600. We expect that both of those doses will have, you know, good safety and tolerability. You know, they're very clean.
That's fine for 1 day.
We're not expressly excluding those patients from the 1 day in all likelihood they will be excluded from the Registrational study because it goes both ways right you don't want to bias in favor of patients who might be more likely to respond you also don't want to bias in favor of patients who may have may have you may have.
Troy Edward Wilson: We think either dose could potentially be a good going forward dose. The phase 1B study is now explicitly an efficacy study, and it will allow us to both select an RP2D and begin to compile patients who we believe are going to be eligible to be included in the population for registration.
Have exhausted that mechanism of action. So I think that data is anecdotally important and it's and it. It's 1 of the pieces that gives us confidence that we have a best in class.
<unk> inhibitor, but I think as we go forward.
I wouldn't be expecting us to enrich and a lot of patients who've been on prior <unk> inhibitors is the way I would say it.
Troy Edward Wilson: And second question, what should investors be thinking about the cadence and the substance of 539 updates for both the escalation and expansion portions over the remainder of 2021 and in 2022?
Great. Thank you so much.
Sure. Thank you Peter for the questions.
Your next question comes from the line of Thiago <unk> from Credit Suisse. Your line is now open.
Thanks for taking the question I guess, just a follow up on <unk>. If you could provide any commentary on aim and how enrollment trends are tracking there.
Troy Edward Wilson: Yeah, great question. The way we're thinking about the phase one experience is, you know, phase one is primarily a safety study, phase one A, excuse me, is a safety study, and phase 1B is really an, you know, an efficacy-driven study. The phase 1A is now closed to enrollment. We got out of, I think, what we were expecting. The molecule is safe and well tolerated across the range of doses. We're seeing anecdotal activity, you know, but there are limitations. And the limitations are, you know, it's not genetically enriched.
And related to that how much has genetic screening indication has evolved over time and how that may play a role in the future combination studies.
And since we're kind of on the same topic.
If you could provide any detail on how 'twenty 8.6 could actually differ from TPG in a sense that will will you be able to address more indications.
For additional combination approaches what are some of the features that you expect to improve upon.
Thanks.
Sure Thiago.
3 good questions tucked in there so let me take those in turn.
Aim HN.
Troy Edward Wilson: You know, a number of patients are not efficacy of valuable. But despite that, we continue to see encouraging signs of activity, including in patients who had progressed on a prior Mennon inhibitor. And we thought that was noteworthy. The phase 1B study is explicitly in KMT2A and NPM 1.
Just to remind everyone on the call we made a major amendment to the protocol last year.
Where we did 2 things we removed some of the impediments to enrollment and we expanded the patient population to include all <unk> mutant patients that met we have to enroll up to 100 evaluable patients to fully meet the Registrational total.
But.
And we also did this I should say in the context of the pandemic.
Troy Edward Wilson: Our goal, Jonathan, as we said in the prepared remarks, is to have the phase 1B cohorts fully enrolled by the end of the first quarter of next year and to be in a position where we have identified the recommended phase two dose. We'll do everything we can to, you know, meet or exceed that timeline. But given what we're seeing in the screening queue and the pace of enrollment, we think that's a good base case projection.
We did see a very significant.
<unk> in primarily in screening of patients during the pandemic now that the at least the first wave of Covid is behind us.
And we've had that chance for these protocol amendments to work their way through we've seen an improvement in uptick Thiago in enrollment we are still not in a position where we can give guidance.
1 of the things that we've been experiencing is we have a conversion rate on the study of approximately 30%.
So that means out of 10, H Ras mutant patients identified we can get 3 of them on the study and that really relates to the fact that these patients are pretty fragile in the second and later lines of of head and neck squamous similar to what.
Troy Edward Wilson: Our intent is to provide qualitative updates on the study throughout the remainder of 2021. Those will include, you know, and you've gotten some sense of that today, you know, from the commentary. You know, initially, you're focused on site activation.
Similar to any trial you want to put good high quality patients on but that means we have to screen them. Thus identifying many more patients. The team is doing a terrific job of that the study is just kind of quietly marching along.
Troy Edward Wilson: You're focused on the screening funnel. Then you're talking about, you know, are we actually recruiting patients into the two arms? We are.
To your second question, which relates to the first 1 of the challenges in head and neck. In contrast to AML or say lung cancer is the genetic screening is not standard of care typically physicians do not conduct genetic screening until the patient has exhausted.
Troy Edward Wilson: I think we'll be able to give guidance both on enrollment and qualitatively, what are we seeing, right? But I don't think we're going to be able to call out specific patients for the very reason that this. It's our hope and our intent that this data will be considered for registration by FDA. So we have to treat it with some, you know, sub-sanctity. But I think we'll be able to provide guidance on enrollment and on activity.
Now typically the checkpoint inhibitors, plus or minus chemo and by the time that happens the patient may or may or may not be in a position where they are actually able to receive benefit from another therapy.
We're working to raise awareness, we're working with the.
The kols and the physicians to increase the awareness of genetic screening that's a big driver and part of what we're so excited about by combining <unk> and <unk> because.
Troy Edward Wilson: Are, you know, are there differences between the arms? That's our intent, to provide qualitative guidance, and we'll look to present the 1A and the 1B together as the full Phase 1-1 experience at an upcoming medical or scientific meeting.
And this is all sort of laid out in our corporate presentation. The combination of <unk> plus appellative goes from 5% of the head and neck population to potentially up to 50% and that 50% comprises 4 genetic subtypes HRS mutant <unk> over expressed picked <unk> CA.
Troy Edward Wilson: And if I can just sneak in one more, mostly because I don't think you'll be able to call this, but on this chance that you can, can you expand on what you mean by early signs of clinical activity in the Phase 1B expansion cohorts for 539. Thank you. Sure.
Amplified and pick <unk> mutants, we're going to start the current study, which is the combination of our pellets have been typically barnett in the pig <unk> dis regulated population, that's 1 where it's quite a bit larger it's 20%, maybe even 25% of head and neck. So you have more patients.
Troy Edward Wilson: Sure, I mean, there are a number of measures of that, including, you know, disease stabilization, improvement of performance status, but the most notable one, Jonathan, is a reduction in blast counts. And I should just leave it at that. You know, again, we don't want to be cherry-picking data. What we want to do is to leave you and the others on the call with, you know, an understanding that, from our perspective, the fact that, you know, what we're seeing, It's early, it's preliminary, but what we're seeing in phase 1B reinforces that the dose selections of 200 and 600 were the right dose selections.
From which to choose and if you have now.
1 out of 3 years or 1 out of 2 patients that may be an eligible patient for your combination. We think that will help to drive genetic screening awareness of the small molecule targeted options. So as we think about the program strategically the combination with <unk> is an important next step and it builds.
Peter Richard Lawson: Your next question comes from the line of Peter Lawson from Berkeley. Your line is now open. Good.
Peter Richard Lawson: Great, thanks for taking the questions. Troy, just on the kind of deed to disclosures that we may get this year. Would we get anything around durability from any of the previously treated patients where we've seen them?
Troy Edward Wilson: Yeah, Peter, I think we're going to have to wait until we disclose the full phase one experience. You know, we have been impressed with the durability, but it's early days. It's, you know, this is a handful of patients; the date is preliminary. I think, you know, we don't want to pick and choose. We need to look at durability in the context of the full clinical package, and it's our intent to enroll 1B as quickly as we can and be in a position to talk about both the safety and tolerability and the efficacy profile of 539 as quickly as we can at an upcoming future medical meeting.
In ancient FCC as you'll see it through the rest of this year and into next year. It's meant to go into new disease indications that represent significant patient populations and we've really never to this point not disclose though.
That's something that I would think we will disclose it will it will depend on the timing of the publication, but it'll be disclosed either later this year or early next year in the meantime, we are take we are doing steps to lay the groundwork for both preclinical and clinical studies to.
Troy Edward Wilson: Gotcha. And you mentioned a patient that progressed on a prime men inhibitor. So you're kind of seeing signs that you can potentially retreat with men, and Yeah.
Now build on those rational combinations of stis plus other targeted therapies.
Did I answer your 3 questions.
And for them all I appreciate the.
Troy Edward Wilson: Yeah, so a couple of comments, Peter. Yeah, it's actually plural patients, not just one. I think what we're seeing is evidence of clinical activity. You know, just to be clear, right, let's draw a distinction between the mechanism of action and then what one might do in a registrational context. So that gives us confidence that, just as you say, even in patients who have progressed on upon treatment with a prior Mennon inhibitor, you're still seeing evidence of clinical benefit. That's fine for 1A.
Hi.
Thank you so much I appreciate it.
Your next question comes from the line ran Benjamin from JMP Security. Your line is now.
Hey, good afternoon, guys. Thanks for taking my questions and congrats on on getting the dosing started for the phase 1 b expansion, maybe just 2 questions from me Troy 1 piggybacking.
From previous question regarding the patients who progressed on prior.
Troy Edward Wilson: We're not expressly excluding those patients from the 1B study. In all likelihood, they will be excluded from the registrational study because it goes both ways, right? You don't want to bias in favor of patients who might be more likely to respond. You also don't want to bias in favor of patients who, you know, you may have, you may have, exhausted that mechanism of action. So I think that data is anecdotally important, and it's one of the pieces that gives us confidence that we have a best-in-class men-in-in-in inhibitor. But I think, you know, as we go forward, I wouldn't be expecting us to enrich for a lot of patients who've been on prior menin inhibitors, is the way I would say it.
Troy Edward Wilson: Great! Thank you so much.
Troy Edward Wilson: Sure. Thank you, Peter, for the question.
Piagafah: Your next question comes from the line of Piagafah from Cardiff, Switzerland. Your line is now open.
Piagafah: Thanks for thinking your question.
Troy Edward Wilson: I guess just a follow-up on TP; if you could provide any commentary on AIM and how enrollment trends are tracking there. And related to that, how much has genetic screening for that indication evolved over time and how that may play a role in future combination studies.
Profile, we believe we've got the ability to push the dose the biology is is the.
Troy Edward Wilson: And since we're kind of on the same topic,
Troy Edward Wilson: If you could provide any detail on how 28-06 could actually differ from TP in the sense that we'll be able to address more indications, and explore additional combination approaches, what are some of the features that you expect to improve upon?
Biology is evolving but I think we're encouraged and we will get a much better read on this in the phase 1 b, which is actively enrolling and setting us up for registration.
Got it and then just my final question on the phase 1.
Troy Edward Wilson: Sure, Tiago, thank you. There are three good questions tucked in there, so let me take those in turn.
Current study can you just give us a little bit of color on the on the trial design here you have to start.
Troy Edward Wilson: AMHN, you know, just to remind everyone on the call, we made a major amendment to the protocol last year where we did two things. We removed some of the impediments to enrollment, and we expanded the patient population to include all H-Rs mutant patients. That meant we had to enroll up to 100 valuable patients to fully meet the, you know, registrational total. But, you know, and we also did this, I should say, in the context of the pandemic.
Re dosing tippy with a fixed dose of of alpelisib or or both.
<unk> and dosing and how about how many patients per.
Phase if you will go from the phase 1 dose escalating as well as the face too.
Yeah. Good good question. So in fact I'll draw your and everyone's attention. We've added a new slide to the corporate presentation that as a schematic of the current study.
It doesn't speak ran to your question of specific numbers of patients, but it does at least show you. The initial schematic for the for the doses and what you'll see is that a <unk> is held constant.
Troy Edward Wilson: We did see a very significant, you know, dip in, primarily in screening of patients during the pandemic. Now that the, you know, at least the first wave of COVID is behind us, and we've had a chance for these protocol amendments to work their way through, we've seen an improvement, an uptick, Tiago, in enrollment. But we're still not at a position where we can give guidance.
Continuously and tippy is dose to every other week, both being dosed as they typically are I'll just remind everyone that.
The preclinical studies that were conducted showed evidence of clinical or showed synergistic activity at doses that were below the dose of each drug has a mono therapy. So we dialed them both down by I believe to approximately 70% of the mono therapy dose and you're still seeing better activity of the combination.
Troy Edward Wilson: One of the things that we've been experiencing is we have a conversion rate on the study of approximately 30%. So that means, you know, out of 10 H.R.S. Mutant patients identified; we can get three of them on the study. And that really relates to the fact that these patients are pretty fragile in the second and later lines of head and neck squamous. Similar to what, you know, similar to any trial, you want to put good, high-quality patients on it, but that means we have to screen and thus identify many more patients. The team is doing a terrific job with the test.
It's going to take it.
It might take some tinkering ran in in the study to get that dose and schedule right.
Where you don't know until you try it it's it's difficult to model. These these toxicities, but but our team has done a significant amount of work Preclinically to show that there are a number of different doses and schedules you can give them. Both continuously you can give them both intermittently that.
Will drive activity and that will give our clinical team and the investigators the flexibility to be able to go in there and the trial is a very elegant design.
Troy Edward Wilson: that the study is just kind of quietly marching along. To your second question, which relates to the first, one of the challenges in head and neck cancer, in contrast to AML or, say, lung cancer, is that genetic screening is not standard of care. Typically, physicians do not conduct genetic screening until a patient has exhausted, now typically, checkpoint inhibitors plus or minus chemo. And by the time that happens, the patient may or may not be in a position where they're actually able to receive benefit from another therapy.
Molly Leoni RVP of clinical development took the lead on developing it and Stephen day I'll also weighed in on it but.
But it allows you to change the dose of both drugs and it and it relies on the extensive safety databases of both drugs. So we are hopeful that gives you a fairly efficient.
Chance to get to a recommended dose and schedule for the combination and given ran that were in the genetically selected population, namely either pick 3 C a mutant or pick <unk> amplified.
Troy Edward Wilson: We're working to raise awareness. We're working with the, you know, the KOLs and physicians to increase the awareness of genetic screening. That's a big driver and part of what we're so excited about by combining appellisive and tippy farnib because, and this is all sort of laid out in our corporate presentation, the combination of tippy plus appellisive goes from 5% of the head and neck population to potentially up to 50%, and that 50% comprises four genetic subtypes. H.R.R.S. Mutant, H.R.R.S.
We might get some early indications of activity. Although the study is not explicitly designed to have an efficacy endpoint any any efficacy similar to comment any efficacy at that point would just be would be anecdotal until you're you're going directly in the right direction, but that's summarized in our corporate presentation and over the next.
Few months as we lead up to the kickoff of current which again, we're expecting in queue for will give more color on on exactly the sizing of the study it's going to be pretty typical with what 1 would expect.
Perfect. Thanks, Thanks for taking my questions.
Happy to do it.
Once again, if you would like to ask a question you will need the price par 1 on your telephone.
Troy Edward Wilson: over-expressed, PIC-3CA amplified, and PIC3CA mutants. We're going to start the current study, which is the combination of L. Pelosib and Tipipiparneb in the PIC-3CA disregulated population. That's one where it's quite a bit larger.
Your next question comes from the line itself.
From calling in.
Your line is now.
Good afternoon, congrats on progress and thanks for taking our questions first.
First 1 question on 559, please won't be.
Good.
Cohorts today from a minimum requirement from a number of MLR patients.
That are enrolled or will it just be first of all patients and.
Troy Edward Wilson: It's 20%, maybe even 25% of head and neck cancers. So you have more patients from which to choose. And if you now have, you know, one out of three or one out of two patients that may be an eligible patient for your combination, we think that will help to drive genetic screening and awareness of these small molecule targeted options. So as we think about the program strategically, the combination with pellisib is an important next step.
Whether it's in care more on her.
It doesn't particularly matter.
Yeah, Phil Thanks for the question, it's actually it's the ladder of the options. So there is no explicit requirements of either NPM, 1 or MLR.
The trial has a mechanism to ensure that the 2 arms or balanced. So that you don't end up with all the NPM 1 mutant patients in 1 arm and the MLR in the other arm.
But.
It's going to largely be what we get.
Troy Edward Wilson: And it builds on, you know, the very significant clinical activity of TIPI and the encouraging clinical activity of appellate. To your third question, about 2806, so we became aware of, you know, the tippy appellasib combo is a true example of synergy. And a lot of people throw that term around, but there are, you know, specific algorithms to measure synergy. For example, you see clear synergistic activity with tippy and appellative in different genetic subtypes of head and neck squamous cell carcinoma.
If the if the early indications are.
Continue we're seeing a good mix of both populations quite.
Quite a bit different than what we saw in the phase 1 day, but of course, we're now operating at potentially many more sites and everybody is expressly looking for these patients. So I think that's the kind of color field, we might be able to provide a bit more qualitative updates in the in the months ahead.
Perfect.
The second question is a follow up to an earlier 1 when you were choosing the doses to advance to the expression cohorts you talked about the safety and Kurkowski, where you're also able to look at things like chemo generic gene expression project from new sworn gene expression.
Troy Edward Wilson: And what's interesting, and again, this is in the corporate presentation, you see synergy of TIPI plus other drugs as well, cisplatin, CDK46 inhibitors, just to mention a couple of examples. What we have found is that Farnesil-Transprase inhibitors offer the potential to go pretty impressively beyond where other small molecule targeted therapies can go. And we're being kind of circumspect about exactly what the biology is, exactly what the indications are, because this is obviously a very competitive field. We have a publication pending. We have intellectual property pending. But it was part of that initiative, Tiago, to target 2806. So TIPI is a very good drug, and 2806 is even better.
And was there any difference between the various doses that were tested in the first 1 day.
So we've looked at that as an exploratory endpoints sale. It's a good question.
And the answer is we're looking at it it really didn't factor into the dose decision. The dosing was driven first and foremost by safety and Tolerability and then secondly by clinical efficacy, we didn't use any kind of surrogate biomarker to factor into that into that decision that is work that we're doing both to help inform.
The development in MLR NPM, 1 mutant subtypes and also to understand.
What what how do you how do you think outside of the MLR NPM, 1 mutant populations and where else could you go but those are exploratory and and not really gating at all either on the selection of the 2 doses for the phase 1 B R. I think ultimately what will come out in terms of the determination of the RP Judy once we.
Have the 24 evaluable patients enrolled.
And then last question, who is actually on the determination of equivalent of trees to dose.
Proficient from each cohort each patient's approximately 8 per cent of the cohorts, who what is a clinical meaningful difference.
In response between the cohorts can you give us some sense of how you're thinking of what would differentiate 600 milligrams vs versus 200 milligrams given the relatively small size of the cohorts.
Troy Edward Wilson: It is more potent. There is less interpatient variability. We've largely eliminated the first pass effect, so it's not meant to compete with TIPIFRNED in HNSC.
Yes, it's a really good question and it's 1 that I divest.
Troy Edward Wilson: As you'll see through the rest of this year and on the Internet, it's meant to go into new disease indications that represent significant patient populations, and we've really never, to this point, not disclosed them. That's something that I would think we would disclose. It'll depend on the timing of the publication, but it'll be disclosed either later this year or early next year. In the meantime, we are doing steps to lay the groundwork for both preclinical and clinical studies to now build on those rationales. Combinations of FTIs plus other targeted therapy
Both Molly Leoni, who is now leading this program she's she's now the clinical lead for the men and program as well the Steven and the short answer fill as you kind of know it when you see it.
There isn't an explicit difference that 1 needs to see if if you don't see a meaningful difference. They look roughly the same fda's very strong guidance will be go with the lower dose that being said.
Will have the ability to either do suffer dose down as you need to.
Only if you really see a striking difference either 1 way or the other.
Troy Edward Wilson: Did I answer your three questions?
Will you selected if the 2 cohorts run out and they look comparable in terms of CRC R. H.
Troy Edward Wilson: You're dead, you guys, answer them all. I appreciate the reply. Thank you so much.
Safety and Tolerability the other parameters.
Troy Edward Wilson: Thank you so much. I appreciate it.
I think the consensus is you're going to go with the lower dose and I will say I'll reiterate this again I've said it I would say it whenever it gets asked I think we have good confidence that either of these doses as a good going forward dose. This is really now a question of refinement and.
Reni John Benjamin: Your next question comes from the line of Rand, Benjamin, from JMP.
Reni John Benjamin: Hey, good afternoon, guys. Thanks for taking the questions and congrats on getting the dosing started for the Phase 1B expansion. Maybe just two questions for me, Troy. One, piggybacking from a previous question regarding the patients who progressed on a prior Mennon inhibitor.
Is 1 of them what is the what is the optimum dose not only for this study, but this dose will then set the starting point for all future studies, which is why it's important to take the 24 patients and really get it right because it becomes the cornerstone of the program and and the entire development plan rest.
On it and then I think I think the team has it well in hand.
Reni John Benjamin: I guess I
Perfect. Thanks for taking our questions.
Troy Edward Wilson: stay on the drug due to toxicity issues as opposed to resistant mutations coming up. Am I thinking about that correctly since they're responding to another man-in inhibitor, or are there key resistant mutations that maybe K-0-539 may be inhibiting at the same time?
Happy to do it.
There are no further questions at this time I will Chinese Bath, Alright Kid, Dr. Wilson for any closing remarks.
Thank you operator, and thank you all once again for participating in the call today, we're going to be at the Wedbush Virtual Healthcare Conference next week and we'll look forward to speaking with many of you then in the meantime, if you have any additional questions. Please feel free to contact Pete Mark for myself.
Troy Edward Wilson: So I think Wren this is still an evolving story. We're not aware of mechanisms of resistance to menin inhibitors in the form of point mutations. These are not like tyrosine kinase inhibitors where you can develop a gatekeeper mutation or something. But it's important to note the patients who come on to our study have, you know, active progressive disease at the time they come on the study. So it's not that they were discontinued from another study due to talks; it's that they actually progressed and then came into our study. And, you know, I don't, we were, this is still kind of an open question in our minds, right?
Thank you and have a good evening everyone.
This concludes today's conference call. Thank you for participating you may now disconnect.
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Troy Edward Wilson: It is, will patients respond to one minute inhibitor when they've perhaps progressed on another? I think what it potentially does is it reinforces this notion that, given the wide therapeutic window, we can push the dose very hard on this compound. And that's the endemic. Both by, you know, these are anecdotal reports. We don't want to make too much of them, but also the fact that we have seen activity outside of the MLLR and the NPM1 mutant context.
Troy Edward Wilson: And, you know, that may ultimately best be addressed through combinations. But, you know, we've said very consistently that we believe we've got the best-in-class safety profile. We believe we've got the ability to push the dose. The biology is, you know, the biology is evolving, but I think, you know, we're encouraged, and we'll get a much better read on this in phase 1B, which is actively enrolling and setting us up for registration.
Reni John Benjamin: Got it. And then just my final question on the phase one current study, can you just give us a little bit of color on the trial design here? Do you have to start a, you know, redosing tippy with a fixed dose of Alpilib, or are both, you know, changing in dosing, and how about a
Reni John Benjamin: About how many patients
Reni John Benjamin: per, you know, phase, if you will, for the phase one dose escalating as well as phase two.
Troy Edward Wilson: Yeah, a good question. So, in fact, I'll draw your and everyone's attention to it.
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Troy Edward Wilson: We've added a new slide to the corporate presentation that is the schematic of the current study. It doesn't speak, ren, to your question of specific numbers of patients, but it does at least show you the initial schematic for the doses. And what you'll see is that the pellisive is held constant. It's dosed continuously, and TIPI is dosed every other week, both being dosed as they typically are.
Troy Edward Wilson: I'll just remind everyone that the pre-clinical studies that were conducted showed evidence of clinical activity or showed synergistic activity at doses that were below the dose of each drug as a monotherapy. So we dialed them both down by, I believe, to approximately 70% of the monotherapy dose, and you're still seeing better activity of the combination. It's going to take it's going to it might take some tinkering, Bren, in the study to get the dose and schedule right. You know, you don't know until you try it.
Troy Edward Wilson: It's difficult to model, you know, these toxicities, but our team has done a significant amount of work preclinically to show that there are a number of different doses and schedules. You can give them both continuously. You can also give them both intermittently, and that will drive activity. And, you know, that will give our clinical team and the investigators the flexibility to be able to go in there. And the trial is a very elegant design.
Troy Edward Wilson: You know, Molly Leone, our VP of clinical development, took the lead on developing it, and Stephen Dale also weighed in on it. But it allows you to change the dose of both drugs. And it relies on the extensive safety databases of both drugs, so we're hopeful it gives you a fair chance. efficient chance to get to a recommended dose and schedule for the combination. And given Wren that we're in the genetically selected population, namely either PIC 3CA mutant or PIC3CA amplified, we might get some early indications of activity, although the study is not explicitly designed to have an efficacy endpoint.
Troy Edward Wilson: Any efficacy, similar to comment, any efficacy at that point would just be anecdotal and tell you you're going in the right direction. But that's summarized in our corporate presentation, and over the next few months as we lead up to the kickoff of current, which again we're expecting in Q4, will give more color on exactly the sizing of the study. It's going to be pretty typical with what one would expect.
Reni John Benjamin: Terrific. Thanks. Thanks for taking the questions.
Operator: Once again, if you would like to ask a question, you will need to press play on your television. Your next question comes from the line Phil Nadu from Colin and Cole.
Phil Nadu: Good afternoon, congratulations on the progress, and thanks for taking our questions. First, one question on 539's Phase 1B, the cohorts, do they have a minimum requirement for the number of MLLR patients that are enrolled, or will it just be the first of all patients, and whether it's NPM 1 or MLR doesn't matter.
Phil Nadu: Yeah, Phil, thanks for the question. It's actually the latter of the two options. So there is no explicit requirement for either NPM 1 or MLLR.
Troy Edward Wilson: The trial has a mechanism to ensure that the two arms are balanced so that you don't end up with all the NPM 1 mutant patients in one arm and the MLLR in the other arm. But, you know, it's going to largely be what we get. If the, you know, if the early indications are, you know, continue, we're seeing a good mix of both populations. Quite a bit different than what we saw in the Phase 1A, but of course, we're now operating at potentially many more sites, and everybody is expressly looking for these patients. So I think that's the kind of color, Phil, we might be able to provide a bit more qualitative updates in the months ahead.
Phil Nadu: Perfect. Then, the second question is a follow-up to an earlier one. When you were choosing the doses to advance into the expansion cohorts, you talked about safety and clinical efficacy. But were you also able to look at things like leukemogenic gene expression, for example, MIS 1 gene expression? And was there any difference between the various doses that were tested in Phase 1A?
Troy Edward Wilson: So we've looked at that as an exploratory endpoint, Phil. It's a good question, and the answer is, we're looking at it.
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Troy Edward Wilson: It really didn't factor into the dose decision. The dosing was driven, first and foremost, by safety and tolerability, and then secondly, by clinical We didn't use any kind of surrogate biomarker to factor into that decision. That is work that we're doing, both to help inform the development of MLLR and NPM1 mutant subtypes and also to understand, you know, how do you think outside of the MLLR and NPM1 mutant populations, and where else could you go?
Troy Edward Wilson: But those are exploratory and not really gating at all, either on the selection of the two doses for phase one or, I think, ultimately, what will come out in terms of the determination of the RP2D once we have the 24 valuable patients enrolled.
Phil Nadu: Got it. And then the last question is actually on that determination of the recommended phase two dose. With 12 patients in each cohort, each patient is approximately 8% of the cohort, so what is a clinically meaningful difference in response between the cohorts? Can you give us some sense of how you're thinking of what would differentiate 600 milligrams versus 200 milligrams, given the relatively small size? Yeah, it's a really good question.
Troy Edward Wilson: Yeah, it's a really good question, and it's one that I've asked, you know, both Molly Leone, who's now leading this program, and she's now the clinical lead for the Mennon program, as well as Stephen.
Troy Edward Wilson: And the short answer, Phil, is you kind of know it when you see it. There isn't an explicit difference that one needs to see. If you don't see a meaningful difference, they look, you know, roughly the same.
Troy Edward Wilson: FDA's very strong guidance will be to go with the lower dose. That being said, you know, you know, you know, you will have the ability to either dose up or dose down as you need to. Only if you really see a striking difference, either one way or the other, will you select it? If the two cohorts run out, and they look comparable in terms of CRCRH and safety and tolerability, and the other parameters, I think the consensus is that you're going to go with the lower dose.
Troy Edward Wilson: And I will say, I'll reiterate this again, I've said it, you know, I say it whenever it gets asked. I think we have good confidence that either of these doses is a good starting dose. This is really now a question of refinement and is one of them, you know, what is the optimum dose not only for this study, but this dose will then set the starting point for all future studies, which is why it's important to take the 24 patients and really get it right, because it becomes the cornerstone of the program, and the entire development plan rests on it. And I think the team has it well in hand.
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Operator: There are no further questions at this time. I will turn it back over to Dr. Wilson for any closing remorse.
Troy Edward Wilson: Thank you, operator. And thank you all once again for participating in the call today. We're going to be at the Wedbush Virtual Healthcare Conference next week, and we'll look forward to speaking with many of you then. In the meantime, if you have any additional questions, please feel free to contact Pete, Mark, or myself. Thank you, and have a good evening, everyone.
Operator: This concludes today's conference call. Thank you for participating. You may now discuss.
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