Q2 2022 Kura Oncology Inc Earnings Call
Please stand by good day and welcome to the correct oncology second quarter 2022 Conference call. Today's conference is being recorded at this time I would like to turn the conference over to Pete de Spain, Senior Vice President of Investor Relations. Please go ahead Sir.
Please stand by.
Good day and welcome to the Kura Oncology, second quarter 2022 conference call.
Today's conference is being recorded.
At this time, I would like to turn the conference, over to Pete de Spain, Senior Vice President of Investor Relations.
Sure.
Thank you Sarah good afternoon, and welcome to Curl oncology second quarter 2022 conference call. Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer, and Tom Doyle, Our senior Vice President of Finance and accounting.
Please go ahead, sir.
Thank you, Sarah.
Good afternoon and welcome to Kura Oncology's, second quarter 2022 conference call.
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 <unk> filings with the SEC, which are available.
Joining me on the call are Dr.
From the FCC or on the Kura oncology website for information concerning risk factors that could affect the company with that I will now turn the call over to Troy.
Troy Wilson, our President and Chief Executive Officer, and Tom Doyle, our Senior Vice President of Finance and Accounting.
Before I turn the call over to Dr. Wilson, I'd like to remind you that today's call will include forward-looking statements based on current expectations.
Thank you Pete and thank you all for joining us this afternoon.
Such statements represent management's judgment as of today, and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website, for information concerning risk factors that could affect the company.
With that, I will now turn the call over to Troy.
Last year as we continue the dose escalation with our Menin inhibitor is just a minute in an all comer population of patients with relapsed or refractory acute myeloid leukemia, we saw FDA feedback regarding the design of our registration directed trial in the context of those discussions FDA advised we spend more time in our phase one study.
Identify an optimal dose guidance. We now know was part of a broader FDA initiative in oncology drug development aptly named project Optimists in.
In agreement with FDA, we enrolled a phase <unk> study with two dose expansion cohorts 200 milligrams to 600 milligrams. Each comprised of 12 patients with MTN <unk> mutants four Kmt <unk> rearranged relapsed refractory AML I am pleased to report with nearly completed our assessment of these patients.
In the expansion cohorts for efficacy safety and Tolerability as well as pharmacokinetics and exposure and we believe we have identified a recommended phase II dose preserved demanded.
We're working diligently to gather the data package for submission to FDA and look forward to sharing the recommended phase II dose for just a minute later this year pending the agency's review along with topline data from the Phase <unk> study with a more complete dataset reserve for presentation at a medical meeting in the fourth quarter.
In the meantime enrollment in Commerce 001 has continued and we're pleased to announced that we've enrolled an additional 18 patients in a phase <unk> study in less than three months of what we believe to be the recommended phase II dose and indication of the continued enthusiasm surrounding <unk> among investigators and patients.
Thank you, Pete, and thank you all for joining us this afternoon.
We continue to believe data from all patients treated at the recommended phase two dose will have potential to contribute to the registrational patient population.
Last year, as we continued in dose escalation, with our Menin inhibitors, Zifta-Menin, in an all-comer population of patients with relapsed or refractory acute myeloid leukemia, we sought FDA feedback regarding the design of our registration-directed trial. In the context of those discussions, FDA advised we spend more time in our Phase I study to identify an optimal dose.
Guidance we now know was part of a broader FDA initiative, in oncology drug development, aptly named Project Optimus.
In parallel with our efforts to advance <unk> monotherapy, we have been working to operationalize a series of combination studies in the relapsed and frontline settings. We've designed these studies to assess the safety Tolerability and therapeutic activity is just a minute in combination with current standards of care in AML, including <unk>.
In agreement with FDA, we enrolled a Phase Ib study, with two dose-expansion cohorts, 200 milligrams and 600 milligrams, each comprised of 12 patients with NPN1 mutant or KMT2A rearranged relapsed refractory AML. I'm pleased to report we've nearly completed, our assessment of these patients in the expansion cohorts for efficacy, safety, and tolerability, as well as pharmacokinetics and exposure, and we believe we've identified a recommended Phase II dose for Zifta-Menin.
We're working diligently to gather the data package, for submission to FDA and look forward to sharing the recommended Phase II dose for Zifta-Menin later this year, ending the agency's review, along with top-line data from the Phase Ib study, with a more complete data set reserved for presentation at a medical meeting in the fourth quarter.
In the meantime, enrollment in COMET-001 has continued, and we're pleased to announce that we've enrolled an additional 18 patients in the Phase Ib study in less than three months at what we believe to be the recommended Phase II dose, an indication of the continued enthusiasm surrounding Zifta-Menin among investigators and patients.
<unk> three inhibitors and standard induction cytarabine ribbon chemotherapy, commonly referred to as seven plus three we remain enthusiastic about the potential for <unk> in the treatment of acute leukemias as we prepare to transition into the phase III registration directed portion of comment 001 and initiate our.
We continue to believe data from all patients, treated at the recommended Phase II dose will have potential to contribute to the registrational patient population.
In parallel with our efforts, to advance Zifta-Menin as a monotherapy, we've been working to operationalize a series of combination studies in the relapsed and frontline settings. We've designed these studies to assess the safety, tolerability, and therapeutic activity of Zifta-Menin in combination with current standards of care in AML, including venetoclaxonase of cytidine, FLT3 inhibitors, and standard induction, cytarabine-donorubicin chemotherapy, commonly referred to as Cetin plus 3.
Combination studies pending determination of a recommended phase II dose.
We remain enthusiastic about the potential for Zifta-Menin, in the treatment of acute leukemias as we prepare to transition into the Phase II registration-directed portion of COMET-001 and initiate our combination studies pending determination of our recommended Phase II dose.
Although our MENIN program continues to capture much of the attention, we remain just as motivated, by opportunities for farnesyl transferase inhibition in oncology. One of the first therapeutic applications of an FTI as a targeted therapy was via direct, inhibition of an oncogenic protein, namely HRAS. We've demonstrated the potential for tififarnib to drive durable responses in recurrent and, metastatic HRAS mutant head and neck squamous cell carcinoma, or HNSCC, and our ongoing, AIM-HN registration-directed trial continues in that indication.
Although our Menin program continues to capture much of the attention we remain just as motivated by opportunities for Farnesol transfer <unk> inhibition in oncology.
One of the first therapeutic applications of an STI as a targeted therapy with via direct inhibition of an oncogenic protein, namely HRS, we have demonstrated the potential for typify it to drive durable responses in recurrent and metastatic <unk> mutant head and neck squamous cell carcinoma, or <unk> FCC and our ongoing <unk>.
<unk> registration directed trial continues in that indication more recently, we've begun efforts to build upon the initial monotherapy activity of <unk> with a focus on overcoming drug resistance late last year. We initiated the current HN study designed to evaluate the combination of <unk> and El <unk> and inhibitor of <unk> kinase.
More recently, we've begun efforts to build upon the initial monotherapy activity of tififarnib, with a focus on overcoming drug resistance. Late last year, we initiated the current HN study designed to evaluate the combination, of tififarnib and alpelasib, an inhibitor of PIATRI-KINASE-alpha, in selected HNSCC patient cohorts. We believe that HRAS and PIATRI-KINASE-alpha are codependent oncogenes in HNSCC, and the, combination of the two inhibitors has potential to provide improved antitumor activity relative to the inhibition of either target alone.
Help us in selected <unk> FCC patient cohorts.
We believe that HRS and <unk> kinase Alpha are codependent, oncogene, and <unk> FCC and the combination of the two inhibitors has potential to provide improved antitumor activity relative to the inhibition of either target alone. The combination also has potential to increase the total addressable population.
The combination also has potential to increase the total addressable population for tififarnib, to as much as 50% of patients with recurrent and metastatic HNSCC.
Particularly foreign it to as much as 50% of patients with recurrent and metastatic HSBC.
The initial cohort of the current HN study includes patients with <unk> III CA dependent <unk> FCC and I am pleased to report that we recently dosed the first patient and a second cohort comprised of patients with HRS overexpression. Our goal with the current HN trial is to identify a recommended phase II dose and schedule for the combination.
The initial cohort of the current HN study includes patients with PIK3CA-dependent HNSCC, and I'm pleased to report that we recently dosed the first patient in a second cohort comprised of patients with HRAS overexpression. Our goal with the current HN trial is to identify a recommended phase two dose and schedule, for the combination in each patient cohort.
<unk> in each patient cohort, we're encouraged by the preliminary safety and Tolerability of the combination as well as early evidence of clinical activity and we believe we may be in a position to share preliminary proof of mechanism data from patients in the <unk> III CA dependent <unk> FCC cohort later this year.
We're encouraged by the preliminary safety and tolerability of the combination, as well, as early evidence of clinical activity, and we believe we may be in a position to share preliminary proof-of-mechanism data from patients in the PIK3CA-dependent HNSCC cohort later this year.
Beyond HNSCC, we continue to elucidate the role of FDIs in preventing or delaying the, emergence of resistance for certain classes of targeted therapy with potential to drive deeper and more durable responses in large solid tumor indications.
Beyond <unk>, we continue to elucidate the role of <unk> in preventing or delaying the emergence of resistance for certain classes of targeted therapy with potential to drive deeper and more durable responses in large solid tumor indications.
One of these emerging combination opportunities was unveiled earlier this year at the American, Association for Cancer Research annual meeting. The preclinical data generated through a collaboration within CIRM support potential for tipifarinib, to prevent emergence of resistance to osimertinib and other potent EGFR inhibitors in EGFR mutant non-small cell lung cancer.
One of these emerging combination opportunities was unveiled earlier this year at the American Association for cancer Research annual meeting the preclinical data generated through a collaboration with <unk> support potential for <unk> to prevent emergence of resistance to <unk> and other potent egfr inhibitors and Egfr mute.
Non small cell lung cancer, we're preparing to initiate a phase one study of <unk> in combination with <unk> in Egfr mutated non small cell lung cancer, which we call current lung later this quarter.
We're preparing to initiate a phase one study of tipifarinib in combination with osimertinib, in EGFR mutated non-small cell lung cancer, which we call current lung, later this quarter.
We intend to perform initial clinical evaluation of tipifarinib and osimertinib to gather valuable, experience and data, while in parallel advancing KO2806, the lead development candidate in our Next Generation FDI program, through IND-enabling studies. KO2806 represents a Next Generation Farnesyl transferase inhibitor with improved PK, exposure, and bioavailability relative to tipifarinib.
We intend to perform initial clinical evaluation of <unk> together valuable experience and data while in parallel advancing Kao 28, six lead development candidate in our next generation STI program through IND, enabling studies.
26 represents a next generation parcel <unk> transferase inhibitor with improved PK exposure and bioavailability relative to typify it.
In addition to combining FTIs with EGFR inhibitors, we continue to investigate combinations with, other potent targeted therapies in preclinical studies that may represent additional opportunities.
In addition to combining <unk> with Egfr inhibitors, we continue to investigate combinations with other potent targeted therapies in preclinical studies that may represent additional opportunities we intend to evaluate <unk> in combination with these targeted therapies and we remain on track to submit an IND application for.
We intend to evaluate KO2806 in combination with these targeted therapies, and we remain, on track to submit an IND application for KO2806 in the fourth quarter.
<unk> thousand 806 in the fourth quarter with that I'll now turn the call over to Tom for a discussion of our financial results.
With that, I'll now turn the call over to Tom for a discussion of our financial results.
Thank you, Troy, and good afternoon, everyone.
Thank you Troy and good afternoon, everyone I'm happy to provide a brief overview of our financial results for the second quarter 2022.
I'm happy to provide a brief overview of our financial results for the second quarter, 2022.
I invite you to review our 10-Q file today for a more detailed discussion. Research and development expenses for the second quarter of 2022 were $24.3 million, compared to $21.1 million for the second quarter of 2021. The increase in R&D expenses was primarily due to increases in our clinical trial cost, related to our ZYPTO program and personnel cost.
Might you to review our 10-Q filed today for a more detailed discussion.
Research and development expenses for the second quarter of 2022, or $24 3 million compared to $21 1 million for the second quarter of 2021.
The increase in R&D expenses was primarily due to increases in our clinical trial cost related to our <unk> program and personnel cost.
General and administrative expenses for the second quarter of 2022 were $11 1 million compared to $12 6 million for the second quarter of 2021.
General and administrative expenses for the second quarter of 2022 were $11.1 million, compared to $12.6 million for the second quarter of 2021. The decrease in G&A expenses was primarily due to the decreases in personnel cost and, professional fees.
The decrease in G&A expenses was primarily due to the decreases in personnel costs and professional fees.
Net loss for the second quarter of 2022 was $34 8 million compared to a net loss of $33 7 million for the second quarter of 2021.
Net loss for the second quarter of 2022 was $34.8 million compared to a net loss of $33.7, million for the second quarter of 2021.
As of June 32022, we had cash cash equivalents and short term investments of $453 million compared to $518 million as of December 31, 2021.
As of June 30, 2022, we had cash, cash equivalents, and short-term investments of $450.3 million, compared to $518 million as of December 31, 2021.
Based on our operating plan, we continue to believe that our cash, cash equivalents, and short-term investments will fund current operations through 2024.
Based on our operating plan, we continue to believe that our cash cash equivalents and short term investments will fund current operations through 2024.
With that, I now turn the call back over to Troy.
With that I'll now turn the call back over to Troy.
Thank you, Tom.
Tom before we jump into the question and answer session. Let me lay out our anticipated milestones for 2022 for our Menin inhibitor program determined the recommended phase two dose for <unk> in consultation with FDA and report topline data from the Phase <unk> study later this year.
Before we jump into the question and answer session, let me lay out our anticipated milestones, for 2022. For our Mennon inhibitor program, determine the recommended phase 2 dose for ZYPTO-Mennon, in consultation with FDA, and report top-line data from the Phase 1b study later this year.
Present updated data from comment Zero-zero won at a medical meeting in the fourth quarter and for our STI programs initiate the phase one current lung study of <unk> plus <unk> this quarter and submitted new investigational new drug application for <unk> hundred $28 six in the fourth quarter with that Sarah we're now ready for <unk>.
Present updated data from Comet-001 at a medical meeting in the fourth quarter.
And for our FTI programs, initiate the Phase 1 current lung study of Tipifarnib plus Osimertinib, this quarter, and submit an investigational new drug application for KO-2806 in the fourth quarter.
With that, Sarah, we're now ready for questions.
<unk>.
Thank you.
Thank you if you'd like to ask a question today. Please take note by pressing star one on your telephone keypad.
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Again, please press star 1 to ask a question, and we'll pause for just a moment to allow, everyone an opportunity to signal for questions.
Again, Please press star one to ask a question then we'll pause for just a moment to allow everyone an opportunity to take no for question.
And we'll take our first caller from Jonathan Chang, SVB Securities.
And we will take our first caller from Jonathan King.
<unk> be security.
Hi, guys.
Thanks for taking my question.
Hey, guys. Thanks for taking my questions.
First question, on timing of the top lines of DOMINIUP data, can you provide any additional, color on how you're thinking about when to disclose the top line data?
First question on timing of the topline Cisco amount of data you can provide any additional color on how you're thinking about when to disclose the top line data.
Sure, Jonathan, thanks for the question.
Sure Jonathan Thanks for the question.
As we as we indicated Jonathan our goal here is to determine the recommended phase II dose in consultation with FDA.
As we indicated, Jonathan, our goal here is to determine the recommended phase two dose, in consultation with FDA.
We're at a point, where we are completing our assessment and preparing to submit the package to FDA that should happen. Shortly what we don't have as much visibility into is the process and the timeline by which FDA reviews that.
We're at a point where we are completing our assessment and preparing to submit the package to FDA.
That should happen shortly.
What we don't have as much visibility into is the process and the timeline by which FDA, reviews that.
Unlike, for example, in the case of an IND submission, there isn't a 30-day clock.
Unlike for example in the case of an IND submission there isn't there isn't a 30 day clock.
We certainly believe that we're going to submit a package that should address all of their, questions.
We certainly believe that we're going to submit a package that should address all of your questions. We will stand ready if they have additional questions.
We'll stand ready if they have additional questions or need us to look at the data in any different way.
Need us to look at the data in any different way at this point I think that the best we can say is we're probably looking at late in Q3.
At this point, I think that the best we can say is we're probably looking at late in Q3. It could potentially slip into Q4, just depending on the timing with FDA.
It could potentially slip into Q4, just depending on the timing with FDA.
Okay.
Got it.
Got it.
Thank you.
Thank you and I guess are you able to provide any color on the identification of the <unk> and the regulatory interactions I guess, what boxes remain to be checked before officially declaring the RPT.
I guess, are you able to provide any color on the identification of the RP2D and the, regulatory interactions?
I guess, what boxes remain to be checked before officially declaring the RP2D?
Yes.
Yeah.
Yeah.
Maybe just to take a quick step back, we undertook this Phase 1b study really as an exercise, in dose optimization.
So maybe just to take a quick step back.
We undertook this phase <unk> study really as an exercise and dose optimization.
This is part of the FDA's initiative around Project Optimist.
And this is part of the Fda's initiative around project Optimus, It's becoming standard for targeted therapies I can tell you is our view now having conducted the phase <unk> and the phase <unk> that the phase <unk> was absolutely the right thing to do.
It's becoming standard for targeted therapies.
I can tell you it's our view, now having conducted the Phase 1a and the Phase 1b, that, the Phase 1b was absolutely the right thing to do. We've gathered a tremendous amount of information about the clinical activity, the safety and, tolerability, the PK, in addition to how to manage the on-target AEs, such as leukocytosis and DS. It was absolutely the right thing to do.
We gathered a tremendous amount of information about the clinical activity safety and Tolerability.
The PK in addition to how to manage the on target aes such as leukocytosis in DFS.
It was absolutely the right thing to do I think we're going to emerge from this in our view with a very strong data package supporting the recommended phase II dose, we still want to jump the gun at this point.
I think we're going to emerge from this, in our view, with a very strong data package, supporting the recommended Phase 2 dose.
We just don't want to jump the gun at this point.
And it isn't so much Jonathan a check the box exercise as it is the FDA is looking for information relating to clinical activity safety and Tolerability PK and exposure really across all of the patients enrolled in the study to this point, but with a particular emphasis on the phase <unk> patients and.
It isn't so much, Jonathan, a check-the-box exercise as it is the FDA is looking for information, relating to clinical activity, safety and tolerability, PK and exposure, really across all the patients enrolled in the study to this point, but with a particular emphasis on the Phase 1b patients, and integrating that and analyzing that to really make a strong recommendation that supports advancement as a monotherapy and that sets the dose for any and all future combination studies.
Integrating that and analyzing that to really make a strong recommendation that supports advancement as a monotherapy and that sets the dose for any and all future combination studies. That's why this is so critically important and I can't stress enough I think we did although it took a bit long.
That's why this is so critically important.
I can't stress enough.
I think we did, although it took a bit longer, given the profile we had with Zipta-Meniv, and given what we were seeing, absolutely the right experiment.
<unk> given the profile, we had was <unk> and given what we are seeing absolutely the right experiment to do.
Got it.
Thank you.
Okay.
Got it. Thank you and just last question for me.
On the additional 18 patients enrolled and comments here zero one since may.
Many of these patients could we see data on for the topline disclosure and for the fourth quarter Medical meeting presentation. Thank you.
Yeah. That's a good question Jonathan So it's been our intent from the beginning and then this was actually guidance that we received from FDA to conduct the phase one be using the same endpoints as will ultimately be used in the registrational portion of the phase III as.
As such the data that we're gathering is to use it for lack of a better word. It's sanctified right. These are patients that we hope and expect will be part of the registrational totals and we're certainly treating them as such that that's partly perhaps it's helpful to have people understand is you really need to make sure.
The data coming from the sites is robust it's clean you've checked it.
This ultimately we hope will become part of the submission that's true also Jonathan for the additional 18 patients.
Of course, all subsequent patients we would enroll so we're balancing here.
Is there is there incremental value ensuring additional data versus the time lost of then having to potentially replace those patients.
Put at risk when Youre sharing data from sanctified patients in a registration enabling study you put those patients at risk if you keep doing data cuts.
So at this point I'm, not expecting Jonathan that youre going to see more than the initial 12 patients in each cohort in the top both topline sorry in the top line results at Ash Youll see of course, the data from the phase <unk> and the phase one b, it's not our current expectation that we will go beyond the initial <unk>.
<unk> patients in each cohort at this point we.
We might be able to speak qualitatively to it but we don't want to we're doing everything we can to try to maintain momentum and close the gaps and we don't want to put those patients at risk.
And just last question for me.
Makes sense, thanks for taking the questions.
Our pleasure Jonathan Thank you.
On the additional 18 patients enrolled, in Comet 001 since May, how many of these patients could we see data on for the top line disclosure and for the fourth quarter medical meeting presentation?
Thank you and next we'll move on to Thiago.
With credit Suisse.
Thank you.
Great. Thanks, Thanks for taking the question congrats on the progress. So I understand you might be fairly limited in what you can share at this point, but to the extent that you can provide any qualitative comment, though wondering about the enrollment proportion between the two genetic subtypes that is consistent with prior competitor experience I don't know if you can also talk about <unk>.
Yeah, that's a good question, Jonathan.
Since CF efficacy response between those two subpopulations.
And perhaps just trying to understand a little bit better the future for the STI franchise. So if you have 20 806 is expected to enter clinic in Q4, perhaps Q1, depending on how that shakes out with the IND filing.
So it's been our intent from the beginning, and, this was actually guidance that we received from FDA to conduct the phase 1B using the same endpoints as will ultimately be used in the registrational portion of the phase 2.
As such, the data that we're gathering is, you know, to use a, for lack of a better, word, it's sanctified, right?
These are patients that we hope and expect will be part of the registrational totals.
And we're certainly treating them as such.
That's partly perhaps what, you know, it's helpful to have people understand is you really need to make sure the data coming from the sites is robust, it's clean, you've checked it.
And you have recently initiated the combo trials for <unk> TP right with both <unk> and <unk>.
We expect to develop the same combo simultaneously when it makes sense established proof of concept with TP, perhaps progressed with $28 six for a registrational trial.
If there is any characteristics that would make <unk>, a better candidate for giving combo or how that's going to evolve over time. Thanks.
Yes, Thiago. Thanks, Thanks for that it's a three part question. Let me take let me take you through the parts and turn so on your first question around enrollment.
You know, this ultimately, we hope, will become part of the submission.
That's true also, Jonathan, for the additional 18 patients and, of course, all subsequent patients we would enroll.
Ebbs and flows.
So we're balancing here, you know, is there incremental value in sharing additional data versus the time lost of then having to potentially replace those patients.
I'd say, we see a pretty healthy balance between NPM, one Kmt <unk> rearranged patients.
You put at risk when you're sharing data from sanctified patients in a registration-enabling study.
You put those patients at risk if you keep doing data cuts.
Again, it ebbs and flows kind of at any given point in time, it seems enrich gene Kmt <unk> rearrange to AML patients relative to what the overall epidemiology might suggest you would expect it to be roughly four 5% to one we're seeing more of kind of an equal weighting if you will but.
A lot of interest among physicians, who want to want to enroll both populations.
I think I think we're going to continue to see strong enrollment as we transition into phase II in those ultimate registrational cohorts relating to activity. What I can tell you. There is our thoughts are remained consistent that we're thinking of the cohorts as being approximately the same size, namely 50 to 75.
Patients each.
That should tell you that statistical design should tell you, we're looking to meet or exceed really the same the same bogey right and that is 20%, 30% CR cri rate, 4% to six month's durability transfusion independence as a secondary endpoint, we think that number of patients is probably in the right range.
To allow us to deliver.
To deliver successful phase II cohorts in both the <unk> and the NPM one.
So thats as much as I think we can say of course, we will have the flexibility to be data driven.
The third part of your question that relates to the strategy around the FTE is you make an important point and.
You're really we're really trying to solve several things simultaneously. So the first is data generation.
I think our mindset has evolved to the highest best use of Stis may be in combination with these other targeted therapies you have seen <unk> Alpha youll see youre going to see Egfr, we have we hope a third and even a fourth that youll see later this year or early next year. So part of that is just.
Data generation does the clinical data recapitulate, what you see pre clinically we have got some very exciting preclinical data. The second is how do you think about development and commercialization regionally or globally I think we feel pretty comfortable that we could take a tipping point about policy combo forward in the U S and Europe should the data support.
That into a registrational study in the recurrent metastatic Senate, obviously, we would need to have alignment with novartis with whom we are in a clinical collaboration we have a very good relationship with them on this program and look forward to working with them.
That's a bit of a special case Thiago I think as we think about <unk> nib or other opportunities. That's where you begin to think about 2008 O six and so what youre seeing with the current lung study is a chance to learn or are we seeing the early in <unk> that are consistent with the preclinical data around the op.
<unk> to delay the onset of resistance to <unk>. If we do if we see encouraging data the intent would be to slingshot $28 six around chippy and take that forward with <unk> that is.
It's no surprise to anyone that has a massive potential opportunity even if we assume we're targeting only 20 or 30% of the <unk> population, but given given this is completely novel biology novel furnace related targets. We thought there was value in derisking it clinically with Tippi, while we put the work in.
And I alluded to selected combinations in the phase one study for 26, you can imagine that an egfr inhibitor will be in that mix.
So Thiago we'll continue to we've got we've got preclinical work, we've got clinical tools, we can think strategically and commercially ultimately I think we're optimistic the 26 is a better STI, but the unmet need in recurrent metastatic head and neck is so great that if we see if we see.
<unk>.
Compelling data that supports moving forward with <unk> I think we will and then we will look to beat our own data, but we will put that in our bucket of high class problems, if thats, where we ended up with it.
And I answered that I think I answered the three parts of your question, but certainly intended to address elements of it.
Thanks again for taking the question I appreciate it.
Pleasure.
Thank you.
We'll move on to Peter Walton Barclays.
Great. Thank you thanks for taking the questions.
200 <unk>.
And the Gram dose.
Which do you think central Alberta for first landing combination use.
And then Dan.
And we think you will see an inflated the Q.
The Manning gay kill anything that makes you incrementally more positive for a conventional loan packages.
Yes, it's a good question Peter so.
Maybe to take a step back to the first part of your question. What we're really looking for first and foremost is safety and Tolerability right that this is still ultimately a phase one study.
Efficacy remains even though we are conducting a pursuant to registrational endpoints.
We're all in such a rush, but ultimately it is still a safety study we feel like we had a good safety window at both doses, we have the ability to dose at either dose and potentially to move between them as needed. So that I think is first and foremost we've been looking at clinical activity PK exposure.
Pharmacodynamic markers as well and.
We're looking forward to sharing that with you you'll get it youll get a glimpse of it in the top line Youll get a much more fulsome picture at Ash I think it's a very nice set up for a monotherapy and potentially in combination we're feeling as I as I said in response to Jonathan's question. It was the right experiment to run one of the things.
So at this point, I'm not expecting, Jonathan, that you're going to see more than the initial 12 patients in each cohort in the top, both top line, sorry, in the top line results.
We've learned as we've transitioned from 100% <unk> is we see leukocytosis, we see.
At ASH, you'll see, of course, the data from the Phase 1a and the Phase 1b.
It's rare, but we see cases of differentiation syndrome to the uninitiated leukocytosis can look like progression and you say you have a patient who has failed three or four lines of prior therapy. They go on amended inhibitor you start to see leukocytosis, which means it looks like the accounts in the periphery are going up.
We've learned is that as not necessarily progression thats actually the sales doing exactly what they are programmed to do when you block <unk> in MLR interaction, they're moving into the periphery and then they lived there for a couple of weeks and begin to die off so that kind of learning Peter is invaluable both as a monotherapy.
Setting up for success and then thinking about in combination if you start to see things in combination.
You need to really understand okay, which element of the combo is it coming from.
<unk>.
It's not our current expectation that we'll go beyond the initial 12 patients in each cohort.
With respect to the second part of your question.
Our enthusiasm continues.
I'm tryin', hopefully I'm, succeeding and just maintaining a very steady course, we remain encouraged about the potential prezista minute. We're looking forward to sharing the data we are very very much living this experience of project Optimus and.
We look forward to sharing the data with the FDA and hopefully gaining their alignment I think we'll be in a good position come the topline data and ultimately the presentation at a medical meeting to to be able to support the idea that there's a strong path forward here as a mono monotherapy and potentially.
We're very well setup in combination to be best in class. So time will tell.
Okay.
Great. Thanks, so much.
Our pleasure thank you Linda.
Well move on next to Roger song with Jefferies.
Great.
Thank you for taking the question.
Maybe just a couple clarifications from.
Troy So first of all I see.
What you said is these things may you're starting.
Additional 18 patients in the <unk>.
Alone. So maybe just to clarify that's the case, maybe that imply you already decide <unk> in may based on the profile you have.
Yeah.
That time.
Yes, Roger and I am going to be very different here or two to the FDA on this.
Protocol as was originally agreed to with the FDA gave us the flexibility to enroll.
12 patients at each of the two doses and then to continue enrollment.
In either cohort depending on the way the data went.
And so we've done exactly that we've enrolled 24 patients that were nearly completed the assessment. We've continued enrolling at at what we believe to be the optimum dose I want to choose my words carefully out of respect for the agency.
We'll be able to come back and tell you that is the recommended phase two dose once we have their alignment, but obviously, we feel at this point that the data is trending in the right direction that we want to try to both give every patient the best chance for clinical benefit or benefit risk. If you will and as I've said in response to.
At this point, you know, we might be able to speak qualitatively to it, but we don't want to – we're doing everything we can to try to maintain momentum and close the gaps, and we don't want to put those patients at risk.
To the earlier question to try to close any gaps on enrollment and maintain the momentum for the program.
Makes sense.
Okay.
Excellent. Thank you.
Okay and.
Our next question is related to the <unk>.
The regulatory interactions.
Understanding you have now final data analysis for those 24 patients.
But have you.
Scott any kind of <unk>.
A device or having any discussion with the FDA regarding this.
Two D package.
And kind of are.
Side, what kind of data you want to improve in that package.
Yes, Thats a very good question Roger so.
As part of the discussions when we were agreeing with FDA on the design of the Phase <unk> study.
They were very clear on what they were looking for as far as the data coming out of the phase one b and in terms of assessing benefit risk and I've characterized that in kind of the three columns of efficacy.
Can see data safety and Tolerability PK and exposure.
And then any other data we want to include to help support the benefit risk at.
What we what we would feel is the appropriate recommended phase II dose nothing there has changed.
We have regular interactions with the FDA I don't want to get into the specifics, but nothing on that guidance has changed at all where we are is this data has to be this data has to be against sanctified right. These are patients that we hope and expect will ultimately be able to be included in our registrational package. So as we're pulling.
Data out of the site as we're pulling it out of the vendors.
We have to make sure it's clean we have to make sure. It all ties out I don't think the answer is going to change Roger between now and when we ultimately submit the package, but the FDA is looking for a level of credibility of excellence of professionalism that we intend to meet or exceed and they were clear with their instructions on what theyre looking for.
We're going to deliver them that we're also going to then Roger is as every company I suspect does we will prepare for any other questions. They might have right. So they get the data do they want to look at it a different way do they maybe have a question about.
Cutting it this way or that way. This is the kind of scenario planning that you do and our team is all over that will be ready to.
To provide the FDA any additional information that they need or any further analysis to help support the recommended phase II dose, we found them to be very collaborative and to be very clear on what they need and we're hoping we can move through this as efficiently as possible.
Okay.
Yes, that's very good great.
Maybe just very quick last one.
Maybe just to confirm this additional 18 patients on that.
Our optimal dose additional 18 patients won't be part of this docket would you package all FDA, requiring all know asking for the data from those 80 patients.
Yes.
So just to be clear Roger the FDA has I'm going to I'm going to rely on my legal background here. The FDA has jurisdiction over every patient on every study right. So they can ask they can ask whatever they want to ask it particularly as it pertains to safety. If there are safety updates you are obligated to share that.
With them, but but let's go back to the point of the exercise we believe that the 24 patients who comprised the phase one b population at the 200 600 milligram dose R. R.
Are going to be what's needed, we'll provide any additional safety updates as needed but.
We're not expecting to have to keep doing to keep doing data cuts. Obviously, if the FDA asks were of course going to work with them and supply, but that's not the expectation going in.
Okay. Okay, great I think that's upon us. Thank you. Thank you Troy.
Thanks Roger.
Thank you and next we'll move on to Lee website with Cantor Fitzgerald.
Thanks for taking the questions.
Hey, guys. Thanks, so much for taking my questions I guess, one question on symptomatic and finishing enrollment in may and now.
August I guess.
Or differentiation Cingal, we know that typically occurs early in treatment. So I guess I'd say.
Is that right.
Right now for I.
I guess serious cases.
Our pleasure, Jonathan.
Yes, I'm glad you asked that question.
So just to remind everybody.
We were earlier this year on a partial clinical hold related to a case of differentiation syndrome at that point, we implemented some revised guidance around how to manage differentiation syndrome.
Thank you.
Thank you.
And.
It's been our experience Lee as the trials continued to enroll that although we do see differentiation syndrome, it's relatively rare and infrequent, but in cases, where you see it the severity of the DFS appears to be less now than it was prior to the implementation of the revised <unk> guidance.
And our goal all along has been this is so leukocytosis and differentiation syndrome are on mechanism Aes right. If you will they are the <unk>.
Sales are doing exactly what you are programming them to do.
Our goal is to try to.
Provide the investigators the clinicians with the tools to keep any cases of DFS or leukocytosis.
Great one great to kind of mild to moderate keep it away from the more severe grades I think we've been more successful in that as the trial has gone on we've learned a lot.
Of course, the physicians, who have the greatest facility are the ones who have the most experience with the drug not unlike what we've seen for example, with venetic Claxton tumor lysis syndrome took a while for the <unk>.
For investigators to develop an expertise and understanding of what to look for and how to mitigate it so I would say not only.
Are we seeing less perhaps less frequent but certainly less severe DFS.
And thats trending in the right direction that should also only get better as we move into certain combinations with site reductive agents because that's one of the means of mitigating DFS is to provide something like cytarabine as a way of managing count. So that's why I think we're optimistic that we're on track.
To be as good as if not better than our competition. The arrows are at this point.
It's an ongoing trial, but the arrows are going in the right direction.
Okay, great. Thank you for the color.
I guess my second question is about.
TB combination.
Shen <unk>.
One I guess current had a next study.
Some preliminary I guess.
That activity, so I wonder if you can make.
A little on that I guess, what have you.
For that gave you the confidence that.
Hey activity Israel.
Can you remind us what the benchmark.
So I guess.
You mentioned that in my.
Hi, guys presenting some data later this year.
At this time.
What we should expect.
Sure. So good good good question three another three part question, let me take one on each of them in turn so so typically we've worked me me and several others here, we've worked in and around the map kinase pathway kinase pathways for a long time.
On different agents by and large the industry has not been successful at combining inhibitors of the map kinase pathway in the <unk> pathway due to due to overlapping toxicity. So first and foremost the fact that we're seeing an acceptable safety and Tolerability profile is a big I think a big advance that wasn't clear thus far.
I would have assigned the greatest amount of risk.
Preclinical models are only so good at predicting toxicity, we're at a point, where we are in dose escalation and we remain encouraged by what we're seeing as far as safety and Tolerability, that's usually been kind of a stopping point for most combinations on these pathways, but equally.
Equally important and perhaps more intriguing is we're seeing early evidence of clinical activity. So what do we mean by that.
If you will tumor regression.
Clinical endpoint now when we talk about proof of mechanism. What we're looking for is examples in a handful of patients that really recapitulate. The preclinical data that we've published you can see it in our corporate presentation. It's available on the ACR presentations on our website you see synergistic activity.
Combining our palisade <unk> in each of the four subsets in head and neck cancer, the two <unk> dependent and the to pick three CA dependent you see synergistic activity across all four subsets even early in dose escalation Lee we're seeing some early evidence that that is trending in the right direction and I'll just.
To remind you in the pit III CA population.
Typically foreign or is inactive and our policy really drive stable disease. So if youre seeing tumor regression if youre seeing response durable response, that's trending in the right direction. That's the way to think about a potential data update later this year I would contrast that with what we would term as proof of concept.
Proof of concept, we usually.
Keep as you.
You reach a recommended phase two dose and schedule and then you do an expansion cohort such that you can get closer to what you would think of as an overall that's proof of concept I wouldn't look for that data until probably middle of next year, but that your final question is kind of what's the what's the threshold. So.
The the threshold for success in our view if you're in the range of 30% objective confirmed responses and above youre in.
In the right range to be able to think about taking this combination forward relative to the existing standards of care in the recurrent and metastatic head and neck.
<unk>.
Right now the three approved agents are our Opdivo keytruda and Cetuximab are <unk>. They provide monotherapy is kind of in the teens, maybe the low twenty's. If you could do better with an all oral regimen, we think that would be a big deal and to remind you potentially allow us to treat up to 50% of recurrent.
Static head and neck.
And next, we'll move on to Tiago Fonts with Credit Swift.
Great. Thank you so much.
Thank you and next we'll move on to rain.
Then Jim.
Can men with JMP securities.
Great.
Hey, good afternoon, everyone. Thanks for taking the questions and congrats on the progress.
Thanks for taking the question.
Maybe just starting off with <unk>.
FTA review again.
Trying to just get a better handle or are you looking for them to confirm kind of your <unk>.
<unk> that you have selected in the go forward strategy or are you looking for something more guidance oriented alright. So you give them both the datasets in U.
It's more of like a collaborative effort to decide what it what the go forward <unk> should be.
Congrats on the progress.
So I understand you might be, fairly limited in what you can share at this point, but to the extent that you can provide any qualitative comments, wondering about the enrollment proportion between the two genetic subtypes, if that is consistent with prior competitor experience.
Yes, Ron I. Appreciate the question, we're not we're looking for FDA, we're looking for FDA input, but we're looking for SBA too.
To analyze and hopefully to agree with our recommendation, we're going to we're going to give them a recommendation and let them respond to that.
Rather than seeking.
Seeking their input sort of making it a jump ball. If you will we're not we're not going to do that just to remind everyone FTA needs to agree with any registrational plan, which means they have to agree with the registrational dose and so this is the predicate to starting the registrational portion of the common 001 study or <unk>.
I don't know if you can also talk about consistency of efficacy response between those two subpopulations.
And perhaps just trying to understand a little bit better the future for the FTI franchise.
<unk> and <unk> combination study, but to your specific question Ren we will put to them.
So if you have 2806 expected to enter clinic in Q4, perhaps Q1, depending on how that shakes, out with the IND filing, and you have recently initiated the combo trials for TP, right, with both PI3K and GFR, do you expect to develop the same combo simultaneously?
<unk> heroes are here's what we believe is the minimal safe and efficacious dose pursuant to project Optimists, Here's the data supporting that.
Would it make sense to establish proof of concept with TP and perhaps progress with 2806 for a registrational trial?
And seek their feedback and address any questions. That's the way. We're that's the way we're intending to do it got.
So, I'm curious if there's any characteristics that would make TIPI a better candidate for, a given combo or how that's going to evolve over time.
Got it and then as part of this discussion.
Thanks.
Will you be.
Talking about the Registrational study and getting kind of like the FCA blessing on that or is that a subsequent discussion.
Yeah, Thiago, thanks for that.
After this is completed.
It's a three-part question.
No youre absolutely right rents so its option one in your in your options, we will look to gain alignment from the FDA on the path forward.
Let me take each of the parts in turn.
In the in the Registrational study as a monotherapy.
So on your first question around enrollment, you know, it ebbs and flows.
Okay.
And then just switching gears real quick to the current lung study that'll that'll be started can you talk a little bit about.
I would say we see a pretty healthy balance between NPM1 and KMT2A rearranged patients.
You know, again, it ebbs and flows kind of at any given point in time.
From the preclinical work do you have a sense.
How exactly or what type of specific resistant mutations seem to be impacted by to be seen.
Seem to recall that like $2 79.
790 <unk>.
I think it's 790 <unk> mutations are the typical mutations that were they were looking for the confer resistance to Oc.
Just kind of trying to get a sense about that and then I know that youre going to be measuring Cte DNA.
As a biomarker.
For efficacy, but can you also use that as a biomarker to follow resistance.
Yes, so so both really good questions around.
It seems enriched in KMT2A rearranged AML patients relative to what the overall epidemiology, might suggest.
So what is what does it seems to be evolving to is let's let's step away from Egfr and even for most of America for just a second.
The.
You'd expect it to be roughly, you know, four or five to one.
We're seeing more of kind of an equal weighting, if you will, but a lot of interest among physicians, who want to enroll both populations.
You often ask the question if you have a potent signal transduction inhibitor like <unk> or <unk>. For example, why don't we Ccr's right why do we see Prs.
So, you know, I think we're going to continue to see strong enrollment as we transition, into phase two in those ultimate registrational cohorts.
Relating to activity, what I can tell you there is our thoughts remain consistent that, we're thinking of the cohorts as being approximately the same size, namely 50 to 75 patients each.
That should tell you, you know, that statistical design should tell you we're looking to meet, or exceed really the same bogey, right? That is 20 to 30% CRCRH rate, four to six months durability, transfusion independence, as a secondary endpoint.
We think that number of patients is probably in the right range to allow us to deliver, successful phase two cohorts in both the KMT2A and the NPM1.
This is a question I've been asking myself for the better part of 15 years since I've been working across various targets and one potential mechanism is there are a subset of cells that are called drug tolerance cells. When you hit them with a potent signal transduction inhibitor like <unk>. There is a sub population that you just don't kill and.
So that's, you know, as much as I think we could say.
Of course, we'll have the flexibility to be data-driven.
On the third part of your question that relates to the strategy around the FTIs, you make, an important point, and we're really trying to solve several things simultaneously.
So the first is data generation.
You know, I think our mindset has evolved to the highest best use of FTIs may be in, combination with these other targeted therapies.
The reason a reason you don't kill them is those sales actually fundamentally re wire <unk>.
You've seen PIATRI-KINES-ALPHA, you're going to see GFR.
We hope a third and even a fourth that you'll see later this year or early next year.
So part of that is just data generation.
They actually Dedifferentiate and they were able to cycle in the presence of <unk> and the reason and the way that they get into that drug tolerance state is through a furnace related protein one of the ROE proteins.
Does the clinical data recapitulate what you see preclinically?
We've got some very exciting preclinical data.
When once they've developed some sort of resistance mutation rent than they re differentiate and then they can take off in the presence of <unk> or another Egfr inhibitor post imatinib happens to be the 800 pound gorilla, which is why it's the one we've started with but.
The second is, how do you think about development and commercialization regionally or globally?
But that.
That re differentiation in that exit of drug tolerance is also foreign installation dependent. So so now when you combine <unk> plus <unk> in patients who haven't seen ost emerge nib, what the preclinical data says happens is you prevent those drug tolerance cells.
I think we feel pretty comfortable that we could take a tippi-farnabel-pelicib combo, forward in the U.S. and Europe, should the data support that, into a registrational study in the recurrent metastatic setting.
Obviously, we would need to have alignment with Novartis, with whom we're in a clinical, collaboration. We have a very good relationship with them on this program and look forward to working, with them.
That's a bit of a special case, Tiago.
From entering a state of drug tolerance, so they become more susceptible to <unk> now I don't know if clinically we're going to be able to drive Crs. We have some preclinical data that suggests in some context, that's possible, but the way it appears to manifest itself and it's not just Egfr is EG, we it appears any egfr.
Liberty <unk> Alpha inhibitors, BRAF inhibitors, you'll potentially see other potent signal transduction inhibitors. Later this year you are preventing drug tolerance, and therefore, you are preventing or delaying the onset of resistance because youre not giving this subpopulation of chance to sit there and cycle and develop drug resistance. So.
The key is you've got to hit it before the resistance happens if you wait until the resistance happens the way most other therapies work you've waited too long the beauty of it of course is the hope is you could take post these 18 months or 19 months median PFS and go 50% greater that would be a huge <unk>.
Vance for patients and we're not the only ones trying to do this but I think what will be significant is oce is just the tip of the iceberg, it's a pretty big chip, but it's the tip of the iceberg. We're increasingly encouraged that this is a phenomenon of foreign installation dependent drug tolerance, that's true across multiple.
Small molecule drug targets, which really sets up the TP 2806, as a story thats going to pay dividends over the next 2345 years.
I think as we think about osomertinib or other opportunities, that's where you begin to, think about 2806.
And so what you're seeing with the current lung study is a chance to learn, are we seeing, the early indicia that are consistent with the preclinical data around the opportunity to delay the onset of resistance to osomertinib?
If we do, if we see encouraging data, the intent would be to slingshot 2806 around tippi, and take that forward with osomertinib.
Got it.
Which.
It leads me to.
Focusing on what Youre going to look for particularly for a go no go decision because it seems like median PFS would be way too long.
Yes, and no. So I'm sorry, you reminded me that I in my long winded answer I didn't answer your <unk> question. So we will be looking at Cte DNA astrazeneca and the and the clinical investigators understand the Cta Cta DNA profile for everyone else on the call. This is circulating tumor DNA.
And what it allows you to do is you don't have to do with solid tumor biopsy you could do it blood based you can both watch disappearance of the mutant allele.
So in this case T 790 M. You can also watch for re emergence of resistance <unk> and it's a way to kind of gauge how it's equivalent to <unk> negativity if you will.
In the AML incidence.
We're going to be looking at that Ren if we if things start to go in the right direction I think will accelerate but ultimately PFS is the right endpoint.
And the downside of that is <unk> has a very long PFS. The upside is it's a huge opportunity and one where at $28. Six <unk> combo. We think potentially provides really a significantly better clinical benefit over a smart <unk> alone there will be we're asking ourselves the question Ren.
That is a, you know, it's no surprise to anyone, that is a massive potential opportunity, even, if we assume, you know, we're targeting only 20 or 30 percent of the osomertinib population.
And I want to acknowledge.
We recently re titled Kirsten flowers to be both Chief commercial officer, and Chief Corporate strategy Officer, We're looking for other instances of this where we can get an endpoint even faster. So can you for example, let's take <unk>. For example could you go from six to eight months median median.
At time to relapse to extend that out maybe 10 months or 12 months I would say stay tuned on that a lot of preclinical work going there, but that that would go alongside and help support this idea and we've come just such a long way from targeting <unk> to now targeting the ROE proteins rather.
But given this is completely novel biology, novel farnesylated targets, we thought there, was value in de-risking it clinically with tippi while we put the work in.
But.
And I alluded to selected combinations in the phase one study for 2806.
So this whole family of uniquely furnace related proteins that drive drug resistance.
It's a nice story.
And we look forward to sharing more of it is probably early next year on the other side of the men and updates.
Got it.
Final question for Us.
Foreign installation continues to I guess.
Game and more and more popularity, we're noticing more papers.
You know kind of focusing in on on this mechanism of action, especially in different diseases, including neurological ones like all timers alike.
I know that you guys don't necessarily want to branch out there, but I'm kind of curious do you have any BD discussions do you have any inbounds.
With interest kind of.
The partner your.
Library.
Okay.
So yes, so I don't want to speak to specific discussions Ren the papers that youre describing out of the University of California, Santa Barbara very provocative.
Relating to the Tau proteins and foreign installation.
One of the things that we're doing ran is I don't know if its 28 or six but I'll just say colloquially it could be 20, 807 is a brain blood brain penetrant blood brain barrier Penetrant FTR.
Let me not talk get to the partnering discussions once you have a hammer and you show that in this case you show you can block FTE Farnesol transfer price.
People.
Francis boroughs in our translational team have a huge number of collaborations ongoing <unk> one came from in <unk> and <unk>.
France, who came to us really with insights into foreign installation biology specific proteins and they needed the molecular expertise they needed the drugs, which we provided we have other examples of that so I would say stay tuned.
Great. Thanks for taking the questions.
Pleasure.
Thank you and once again, if you would like to ask a question today you may do so.
Star one.
And next we will take Eva.
<unk> <unk> with Cowen.
Hi, Thanks for taking our questions.
Back to the upcoming topline disclosure Francisco I know you had previously mentioned that it will include composite CR can you remind us is it will also include MRI status or any of the PK and exposure data.
Yes, thanks for the question so.
The.
Yes.
As far as the topline data.
We're expecting Crs CRH CRC rate.
We haven't yet decided to be perfectly Frank on an <unk> status.
We're encouraged by what we're seeing but we just that's one where we just haven't made a determination. If you don't see it in the top line Youll see it at Ash I think the PK exposure it really isn't appropriate for a topline cut that's probably more appropriate for a more fulsome discussion of the clinical data at ash, So I'll, probably hold that off until then.
Great. Thank you and will the efficacy be broken down by genetic subtypes.
It will.
Yes, it will and Youll see it youll see it certainly I think both in the top line and at Ash.
Great. Thank you and just one more point of clarification you had mentioned.
In your remarks that you expect 50 to 70 patients in each of the Registrational cohorts for each genetic subtype.
Would this be in addition to the.
<unk> 30 from the phase one be it the RPT since those patients can be counted registrational data.
Yes, so I think.
The question is we're going to need to have 50 to 75 patients who meet the criteria for inclusion right Thats, the focus and Thats literally falls out of that of the 20% to 30% CR CRH rate.
<unk>.
That debt that we're aiming for.
The patients that had been rolled up to the up to this point are a mix of the two genetics.
So we know in total we're going to need approximately 50 to 75 patients for cohort. We're obviously trying to get as many as we can but sometimes.
Patients will get knocked out for you or the FDA won't allow you to count them. So oftentimes you'll over enroll a bit just to ensure that that happens, but we just my that's our way of saying.
Related to this question of are you seeing kind of equivalent activity between the two the two genotypes. The best way, we think to answer that is to say we're planning on running similarly sized cohort. So that should tell you something right without getting into the specifics.
Perfect. That's very helpful. Thank you.
Our pleasure thank you Eva.
Thank you and there are no further questions that will conclude our question and answer session. Today I would now like to turn the conference back over to Dr. Troy Wilson, President and Chief Executive Officer for any additional or closing remarks.
You can imagine that an EGFR inhibitor will be in that mix.
So Tiago, we'll continue to, you know, we've got preclinical work, we've got clinical tools, we can think strategically and commercially.
Ultimately, I think we're optimistic that 2806 is a better FTI, but the unmet need in, recurrent metastatic head and neck is so great that if we see, you know, compelling data that supports moving forward with tippi and alpelasib, I think we will.
And then we'll look to beef our own data.
But, you know, we'll put that in our bucket of high-class problems if that's where we end up.
Did I answer that?
Thank you Sarah and thank you all once again for joining our call today, we will be participating in the Wedbush pack grow health care Virtual conference next week look forward to seeing a number of you there in the meantime, if you have additional questions. Please feel free to contact Pete Tom or me.
I think I answered the three parts of your question, but tell me if I missed anything.
Yeah, thanks again for taking the question.
Appreciate it.
Pleasure.
Thank you.
And next we'll move on to Peter Lawson, Barclays.
Great.
Thank you.
Thank you.
Okay.
Thanks for taking the questions.
And the next question is related to the regulatory interruption.
But let's go back to the point of the exercise.
Troy, just a few hundred and 600 milligram dose.
You have not final your data analysis for those 24 patients.
We believe that the 24 patients who comprise the Phase 1b population at the 200 and 600 milligram dose are, you know, are going to be what's, needed.
Which do you think is better, for first lining combination use?
But have you got any kind, of a device or having any discussion with the FDA regarding this RP2D package and kind of decide what kind of data you want to include in that package?
We'll provide any additional safety updates as needed, but we're not expecting, you know, to have to keep doing data cuts.
And then is there anything you're seeing in the data, that makes you, the manning data, anything that makes you incrementally more positive or incrementally more negative?
Yeah, that's a very good question, Roger.
Obviously, if the FDA asks, you know, we're of course going to work with them and comply, but that's not the expectation going in.
Yeah, it's a good question, Peter.
So, as part of the discussions when we were, agreeing with FDA on the design of the phase 1B study, you know, they were very clear on what they were looking for as far as the data coming out of the phase 1B in terms of assessing benefit risk. And I have characterized that in kind of the three columns of efficacy data, safety and tolerability, PK and exposure.
Very good.
So maybe to take a step back, to the first part of your question, what we're really looking for first and foremost is safety and tolerability, right?
And then any other data we want to include, you know, to help support the benefit risk at, you know, what we would feel is the appropriate recommended phase 2 dose.
Okay, great.
This is still ultimately a phase one study.
Nothing there has changed.
I think that's it from us.
Efficacy remains, even though we are conducting it, pursuant to registrational endpoints, we're all in such a rush, but ultimately it is still a safety study. We feel like we have a good safety window at both doses.
You again and have a good evening everyone.
We have regular interactions with the FDA.
We have the ability to dose at either dose, and potentially to move between them as needed.
I don't want to get into the specifics.
So that I think is first and foremost.
But nothing on that guidance has changed at all.
Thank you.
We've been looking at clinical activity, PK and exposure, pharmacodynamic markers as well.
Where we are is this data has to be, you know, this data has to be, again, sanctified, right?
Thank you, Troy.
And we're looking forward to sharing that with you.
These are patients that we hope and expect will ultimately be able to be included in a registrational package.
Thank you and that does conclude today's teleconference.
Thanks, Roger.
You'll get a glimpse of it in the top line.
So, as we're pulling data out of the sites, as we're pulling it out of the vendors, you know, we have to make sure it's clean.
And that does conclude today's teleconference.
Thank you.
You'll get a much more fulsome picture at ASH.
We have to make sure it all ties out.
And next we'll move on to Leigh Watzak with Cantor Fitzgerald.
I think it's a very nice setup for a monotherapy, and potentially in combination.
I don't think the answer is going to change, Roger, between now and when we ultimately submit the package.
Hey, guys.
We do appreciate your participation.
We're feeling, as I said, in response to Jonathan's question, it was the right experiment to run.
But the FDA is looking for a level of credibility, of excellence, of professionalism that we intend to meet or exceed.
Thanks so much for taking my questions.
Your participation you may now disconnect.
One of the things that we've learned, as we've transitioned from 1A to 1B is we see leukocytosis.
And they were clear with their instructions on what they're looking for.
I guess one question on symptomatic.
We see, it's rare, but we see cases of differentiation syndrome.
We're going to deliver them that.
You may now disconnect.
I mean, you're finishing enrollment in May, and now we're in August.
To the uninitiated, leukocytosis can look like progression.
We're also going to then, Roger, as every company, I suspect, does, we'll prepare for any other questions they might have, right?
I guess for, you know, differentiation syndrome, we know that it typically occurs early in treatment.
And you have a patient who's failed, three or four lines of prior therapy. They go on a menin inhibitor.
So, they get, the data.
So, I guess is it safe for us to assume that, like, there's less risk now for seeing, I guess, serious cases?
You start to see leukocytosis, which means it looks like the counts in the periphery are going up. What we've learned is, that is not necessarily progression. That's actually the cells doing exactly, what they are programmed to do when you block them in an MLL interaction. They're moving into the periphery, and then they live there for a couple of weeks and begin to die off.
Do they want to look at it a different way?
Okay.
Yeah, Leigh, I'm glad you asked that question.
So that kind of learning, Peter, is invaluable, both as a monotherapy and setting up for success, and then thinking about in combination.
Do they maybe have a question about, you know, cutting it this way or that way?
Sure.
So, just to remind everybody, you know, we, were earlier this year on a partial clinical hold related to a case of differentiation syndrome. At that point, we implemented some revised guidance around how to manage differentiation syndrome.
If you start to see things in combination, you need to really understand, okay, which element of the combo is it coming from?
This is the kind of, you know, scenario planning that you do.
And, you know, it's been our experience, Leigh, as the trials continue to enroll, that, you know, although we do see differentiation syndrome, it's relatively rare and infrequent.
With respect to the second part of your question, our enthusiasm continues.
And our team is all over that.
But in cases where you see it, the severity of the DS appears to be less now than it was, prior to the implementation of the revised DS guidance.
I'm trying, and hopefully I'm succeeding, in just maintaining a very steady course.
We'll be ready to, you know, to provide the FDA any additional information that they need or any further analysis to help support the recommended phase two dose.
And our goal all along has been, you know, this is...
We remain encouraged about the potential for ZIF-demented.
We found them to be very collaborative and to be very clear on what they need.
So, leukocytosis and differentiation syndrome are on mechanism, AEs, right, if you will.
We're looking forward to sharing the data.
And we're hoping we can move through this as efficiently as possible.
The cells are doing exactly what you're programming them to do.
We are very, very much living this experience, of Project Optimus, and we look forward to sharing the data with the FDA and hopefully gaining their alignment.
Yeah, that's very good.
Hum.
Our goal is to try to provide the investigators, the clinicians, with the tools to keep any, cases of DS or leukocytosis, you know, at grade 1, grade 2, kind of mild to moderate, keep it away from the more severe grades.
I think we'll be in a good position come the top-line data, and ultimately the presentation at a medical meeting to be able to support the idea that there's a strong path forward here as a monotherapy, and potentially we're very well set up in combination to be best in class.
Great.
I think we've been more successful in that as the trial's gone on. We've learned a lot.
So time will tell.
Let me just very quick, last one, maybe just confirm this, additional 18 patients on the, you know, optimal dose, additional 18 patients won't be part of this RP2D package, or FDA not requiring or not asking for the data from those 18 patients?
And, of course, the physicians who have, you know, the greatest facility are the ones who have the most experience with the drug, not unlike what we've seen, for example, with venetoclax and tumor lysis syndrome.
Great.
Yeah, so just to be clear, Roger, the FDA has, you know, I'm going to rely on my legal, background here.
It took a while, you know, for investigators to develop, you know, an expertise and an understanding of what to look for and how to mitigate it.
[music].
Thank you so much.
The FDA has jurisdiction over every patient on every study, right?
So I would say not only are we seeing perhaps less frequent, but certainly less severe DS, and that's trending in the right direction.
Our pleasure.
So they can ask whatever they want to ask, and particularly as it pertains to safety, if there are safety updates, you know, you're obligated to share that with them.
That should also only get better as we move into certain combinations with cytoreductive, agents, because that's one of the means of mitigating DS is to provide, you know, something like cytarabine as a way of managing counts.
Thank you.
So that's why I think we're optimistic that, you know, we're on track to be as good as, if not better, than our competition.
And next, we'll move on next to Roger, Song with Jeffreys.
The arrows are at this point, you know, it's an ongoing trial, but the arrows are going in the right direction.
Great.
Okay, great.
Thank you for taking the question.
Thank you for the color.
Maybe just a couple clarifications from Troy.
I guess my second question is about, you know, TB combination.
So first of all, I see what you said is since May, you're starting to enroll an additional 18 patients in the RP2D arm alone.
And you mentioned from the states when I guess current head and neck study, you've seen some preliminary, I guess, activity.
So maybe just can you clarify that's the case?
So, I wonder if you can expand a little on that.
Maybe that implies you already decided RP2D in May based on the profile you have been seeing that time?
I guess, what have you seen so far that gives you the confidence that the activity is real?
Yeah, Roger, and I'm going to be very deferent here to the FDA on this.
And maybe remind us what a benchmark is.
The protocol, as was originally agreed to with the FDA, gave us the flexibility to enroll, you know, 12 patients at each of the two doses and then to continue enrollment, you know, in either cohort, you know, depending on the way the data went. And so we've done exactly that. We've enrolled, you know, the 24 patients that where we nearly completed the assessment.
And also, I guess, you mentioned that you might, I guess, present some data later this year.
We've continued enrolling at what we believe to be the optimum dose.
Can you give us a sense of what we should expect?
I want to choose my words carefully out of respect for the agency.
Sure.
You know, we'll be, able to come back and tell you that is the recommended phase two dose once we have their alignment.
So, good question.
But obviously, we feel at this point that the data is trending in the right direction, that we want to try to both give every patient the best chance for clinical benefit or benefit risk, if you will.
Another three-part question.
And as I said, in response to the earlier question, to try to close any gaps on enrollment and maintain the momentum for the program.
Let me take one, each of them in turn.
Excellent.
So, typically, you know, we've worked, me and several others here, we've worked in and around the MAP kinase and pF3 kinase pathways for a long time on different agents.
By and large, the industry has not been successful at combining inhibitors of the MAP kinase pathway and the pF3 kinase pathway due to overlapping toxicity.
So, first and foremost, you know, the fact that we're seeing an acceptable safety and tolerability profile is a big, I think, a big advance.
So, that wasn't clear.
That's where I would have assigned the greatest amount of risk because, you know, preclinical models are only so good at predicting toxicity.
We're at a point where we are in dose escalation, and we remain encouraged by what we're seeing as far as safety and tolerability.
That's usually been kind of the stopping point for most combinations on these pathways.
But the equally important and perhaps more intriguing is we're seeing early evidence of clinical activity.
So, what do we mean by that?
Well, that's, if you will, tumor regression, you know, that's a clinical endpoint.
Now, when we talk about proof of mechanism, what we're looking for is examples in a handful of patients that really recapitulate the preclinical data that we've published.
You can see it in our corporate presentation.
It's available on the AACR presentations on our website.
You see synergistic activity combining alpelesib and tipifarniv in each of the four subsets in head and neck cancer, the two HRAF-dependent and the two PIK3CA-dependent. You see synergistic activity across all four subsets.
Even early in dose escalation, Lee, we're seeing some early evidence that is trending in the right direction.
And I'll just remind you, in the PIK3CA population, tipifarniv is inactive, and alpelesib really drives stable disease.
So, if you're seeing tumor regression, if you're seeing, you know, response, durable response, that's trending in the right direction.
That's the way to think about a potential data update later this year.
I would contrast that with what we would term as proof of concept.
Proof of concept we usually keep as you reach a recommended phase two dose and schedule, and then you do an expansion cohort such that you can get closer to what you would think of as an ORR.
That's proof of concept.
I wouldn't look for that data until probably middle of next year.
But your final question is kind of what's the threshold?
So, you know, the threshold for success in our view, if you're in the range of 30% objective, you know, confirmed responses and above, you're in the right range to be able to think about taking this combination forward relative to the existing standards of care in the recurrent and metastatic head and neck.
It's, you know, right now the three approved agents are Updevo, Keytruda, and Tatuximab or Herbitux.
They provide monotherapies kind of in the teens, maybe the low 20s.
If you could do better with an all oral regimen, we think that would be a big deal.
And to remind you, potentially allow us to treat up to 50% of recurrent metastatic head and neck.
Great.
Thank you so much.
Thank you.
And next, we'll move on to Ren Benjamin with JMP Security.
Hey, good afternoon, everyone.
Thanks for taking the questions, and congrats on the progress.
Maybe, Troy, just starting off with this FDA review again, I'm trying to just get a better, handle.
Are you looking for them to confirm the RP2D that you have selected and the go-forward strategy, or are you looking for something more guidance-oriented? So, you give them both the datasets, and it's more of like a collaborative effort to decide what the go-forward RP2D should be.
Yeah, Ren, I appreciate the question.
We're looking for FDA's input, but we're looking for FDA to analyze and hopefully to agree with our recommendation.
We're going to give them a, recommendation and let them respond to that rather than seeking their input, sort of making it a jump ball, if you will.
We're not going to do that.
Just to remind everyone, you know, FDA needs to agree with any registrational plan, which means they have to agree with the registrational dose.
And so, this is the predicate to starting the registrational portion of the Comet-001 study or starting any combination study.
But to your specific question, Ren, we will put, to them, here is what we believe is the minimal safe and efficacious dose pursuant to Project Optimist. Here's the data supporting that, you know, and seek their feedback and address any, questions.
That's the way we're intending to do it.
Got it.
And then, as part of this discussion, will you be, you know, talking about the registrational study and getting kind of like the FDA blessing on that?
Or is that a subsequent discussion, you know, after this is completed?
No, you're absolutely right, Ren.
So, it's option one in your options.
We will look to gain alignment from the FDA on the path forward in the registrational, study as a monotherapy.
Perfect.
Okay.
And then, just switching gears real quick to the current lung study that'll be started.
Can you talk a little bit about, you know, from the preclinical work, do you have a sense how exactly or what type of specific resistant mutations seem to be impacted by TIPI?
I seem to recall that, like, T790M, C, I think it's 797S mutations are the typical mutations that we're looking for that confer resistance to OC.
Just kind of trying to get a sense about that.
And then, I know that you're going to be measuring ctDNA as a biomarker, you know, for efficacy, but can you also use that as a biomarker to follow resistance? Yes.
So, both really good questions, Ren.
So, what this seems to be evolving to is, let's step, away from EGFR and even from osomertinib for just a second.
The You often ask the question, if you have a potent signal transduction inhibitor like, Osimertinib or a KRAS, for example, why don't we see CRs, right?
Why do we see PRs?
This is a question I've been asking myself for the better part of 15 years, as I've been, working across various targets. And one potential mechanism is there are a subset of cells that are called drug-tolerant, cells.
When you hit them with a potent signal transduction inhibitor like Osimertinib, there's a subset, of cells, there's a subpopulation that you just don't kill.
And the reason, a reason you don't kill them is those cells actually fundamentally rewire.
They actually de-differentiate and they are able to cycle in the presence of Osimertinib.
And the reason, and the way that they get into that drug-tolerant state is through a, farnesylated protein, one of the Rho proteins.
Once they've developed some sort of resistance mutation, REN, then they re-differentiate, and then they can take off in the presence of Osimertinib or another EGFR inhibitor.
Osimertinib happens to be the 800-pound gorilla, which is why it's the one we've started with.
But that re-differentiation and that exit of drug tolerance is also farnesylation dependent.
So now when you combine Osimertinib plus tipifarnib in patients who haven't seen Osimertinib, what the preclinical data says happens is you prevent those drug-tolerant cells from entering a state of drug tolerance. So they become more susceptible to Osimertinib.
Now I don't know if clinically we're going to be able to drive CRs.
We have some preclinical data that suggests in some context that's possible.
But the way it appears to manifest itself, and it's not just EGFR, it appears any EGFR, inhibitor, ALK inhibitors, BRAF inhibitors, you'll potentially see other potent signal transduction inhibitors later this year, you're preventing drug tolerance and therefore you're preventing, you're delaying the onset of resistance because you're not giving this subpopulation a chance to sit there and cycle and develop drug resistance.
So the key is you've got to hit it before the resistance happens.
If you wait until the resistance happens, the way most other therapies work, you've, waited too long.
The beauty of it, of course, is, you know, the hope is you could take OC's 18-month or, 19-month medium PFS and go 50% greater. That would be a huge advance for patients.
And we're not the only ones trying to do this.
But I think what will be significant is OC is just the tip of the iceberg.
It's a pretty big tip, but it's the tip of the iceberg.
We're increasingly encouraged that this is a phenomenon of farnesylation-dependent drug, tolerance that's true across multiple small molecule drug targets, which really sets up the TIPI 2806 as a story that's going to pay dividends over the next two, three, four, five years.
Got it.
Which leads me to focus in on what you're going to look for, particularly for a go-no-go, decision.
It sounds like medium PFS would be way too long.
Yes and no.
So, I'm sorry.
You reminded me that I, in my long-winded answer, I didn't answer your ctDNA question.
So, we will be looking at ctDNA.
AstraZeneca and the clinical investigators understand the ctDNA profile.
For everyone else on the call, this is circulating tumor DNA. And what it allows you to do is you don't have to do a solid tumor biopsy.
You can do it.
It's blood-based.
You can both watch disappearance of the mutant allele, so in this case, T790M.
You can also watch for re-emergence of resistance alleles.
And it's a way to kind of gauge how, you know, it's equivalent to MRD negativity, if you, will, in the AML instance.
We're going to be looking at that, Ren.
If things start to go in the right direction, I think we'll accelerate.
But ultimately, PFS is the right endpoint.
And you know, the downside of that is, OC has a very long PFS. The upside is, it's a huge opportunity and one where a 2806-osomertinib combo, we think, potentially provides really a significantly better clinical benefit over osomertinib alone.
There will be, we're asking ourselves the question, Ren, and I want to acknowledge, you know, we recently retitled Kirsten Flowers to be both Chief Commercial Officer and Chief, Corporate Strategy Officer.
We are looking for other instances of this where we can go get an endpoint even faster.
So can you, for example, like take KRAS, for example.
Could you go from six to eight months median, you know, time to relapse to extend that out, maybe, you know, 10 months or 12 months?
I would say stay tuned on that.
We've got a lot of preclinical work going there, but that would go alongside and help, support this idea.
And we've come just such a long way from targeting HRAF to now targeting the Rho proteins, REB, you know, this whole family of uniquely farnesylated proteins that drive drug resistance.
It's a nice story.
And we look forward to sharing more of it probably early next year on the other side, of the menin update.
Got it.
There's one final question for us.
You know, pharnosphalation continues to, I, guess, gain in more and more popularity.
We're noticing more papers, you know, kind of focusing in on this mechanism of action, especially in different diseases, including neurological ones like Alzheimer's and the like.
I know that you guys don't necessarily want to branch out there, but I'm kind of curious, do you have any BD discussions?
Do you have any inbounds with interest, kind of, to partner your FTI library?
So, yeah, so I don't want to speak to specific discussions, Ren.
The papers that you're describing, out of the University of California at Santa Barbara are very provocative, relating to the tau proteins and pharnosphalation.
One of the things that we're doing, Ren, is, and I don't know if it's 2806, but I'll just say, colloquially, it could be 2807, is a blood, brain penetrant, blood brain barrier penetrant FTI.
So, you know, let me not sort of talk yet to the partnering discussions.
Once you have a hammer and you show that, in this case, you show you can block FT, pharnosyltransferase, people, you know, Francis Burroughs and our translational team have a huge number of collaborations ongoing.
The Osimertinib one came from Inserm in France, who came to us, really, with insights into pharnosphalation biology, specific proteins, and they needed the molecular expertise.
They needed the drugs, which we provided.
We have other examples of that.
So I would say stay tuned.
Great.
Thanks for taking the questions.
Pleasure.
Thank you.
And once again, if you would like to ask a question today, you may do so by, pressing star 1.
Next, we will take Ava Privatera with Cohen.
Hi.
Thanks for taking our questions.
Back to the upcoming top-line disclosure for ZIFTO, I know you had previously mentioned that it will include composite CR. Can you remind us if it will also include MRD status or any of the PK and exposure data?
Yeah, Ava, thanks for the question.
So as far as the top-line data, you know, we're, expecting CR, CRH, CRC rate.
We haven't yet decided, to be perfectly frank, on MRD status.
You know, we're very encouraged by what we're seeing, but that's one where we just haven't, made a determination.
If you don't see it in the top-line, you'll see it at ASH.
I think the PK and exposure really isn't appropriate for a top-line cut.
That's probably more appropriate for a more fulsome discussion of the clinical data at ASH.
So I'd probably hold that off until then.
Great.
Thank you.
And will the efficacy be broken down by genetic subtypes?
It will.
Yes, it will.
And you'll see it certainly, I think, both in the top-line and at ASH.
Great.
Thank you.
And just one more point of clarification, you had mentioned... And in your remarks that you expect 50 to 70 patients in each of the registrational, cohorts for each genetic subtype, would this be in addition to the 30 from the Phase 1B at the RP2D since those patients can be counted as part of the registrational data?
Yeah.
Yeah, so I think the question is we're going to need to have 50 to 75 patients who meet, the criteria for inclusion, right?
That's the focus.
And that literally falls out of the 20 to 30% CR-CRH rate that we're aiming for.
You know, the patients that have been rolled up to this point are a mix of the two genetics.
So we know in total we're going to need approximately 50 to 75 patients per cohort.
We're obviously trying to get as many as we can, but, you know, sometimes, you know, patients will get knocked out or, you know, the FDA won't allow you to count them.
So oftentimes you'll over-enroll a bit just to ensure that that happens.
But we just, you know, that's our way of saying, you know, related to this question of are, you seeing kind of equivalent activity between the two genotypes, the best way we think to answer that is to say we're planning on running similarly sized cohorts.
So that should tell you something, right?
Without getting into the specifics.
Perfect.
That's very helpful.
Thank you.
Our pleasure.
Thank you, Eva.
Thank you.
And there are no further questions, so that will conclude our question and answer session, today.
I would now like to turn the conference back over to Dr.
Troy Wilson, President and Chief, Executive Officer, for any additional or closing remarks.
Thank you, Sarah.
And thank you all once again for joining our call today.
We'll be participating in the Wedbush-Pathgrow Healthcare Virtual Conference next week.
Look forward to seeing a number of you there.
In the meantime, if you have additional questions, please feel free to contact Pete, Tom, or, me.
Thank you again, and have a good evening, everyone.
Thank you.