Chimerix Inc. Q1 2023 Earnings Call
From an execution standpoint, we continue to open action study sites and now have regulatory approval for the protocol in nine countries. The latest approval was received a few weeks ago from the European Union and we're activating sites there now.
We remain on schedule for our first efficacy analysis in early 2025, which includes an initial overall survival assessment.
We were pleased in the meantime to have a strong showing at the American Association for cancer Research annual meeting this year with more than a dozen presentations related to the <unk> platform. Those were presented by the company and our collaborators at Brown University and the University of Michigan.
The presentation by a doctor Carl Kaufman from the University of Michigan was the highlight he presented clinical evidence of <unk> 200 one's ability to reverse the <unk> III K twenty-seven trimethyl loss. We've described previously the relationship between <unk> 200 one's molecular targets and.
The <unk> III, Kate 27 am target population, but this this goes a step further.
This is the first known example of any therapy reversing age three K 2007, and try them out the loss. This is a characteristic which you may know has been linked to tumor growth and poor prognosis. So on top of the durable tumor responses observed in the phase two dataset the overall.
<unk> advantage reported by multiple non randomized analyses of patients treated with <unk> 201, compared to all others. This provides additional confidence in the outcome of the action trial I'll, let Josh dig a little bit deeper into the science and why it matters in a moment.
We also continue to progress onto a six in the dose escalation studies, we expect the open label dose escalation to run into the first half of 'twenty 'twenty four that will both inform the dosing strategy and create the opportunity to identify other signals of activity as you recall last quarter, we reported.
An investigator assessed response in a recurrent glioblastoma patients without the <unk> III <unk> 27, a M mutation who received.
206 at one of the lower doses this signals the potential for this drug in much larger patient populations.
Paired to the Hai K 27 am glioma indication.
With that I'll turn the call over to Josh for a deeper review on all 200 one's ability to reverse this trend up a loss and 206 development.
Thanks, Mike.
So I would first like to expand on one of the novel findings from ACR that Mike alluded to is it bolsters our confidence in the probability of success of arc 201 for the treatment of <unk> 27, <unk> patients in our ongoing phase III <unk> study.
These findings suggest both in lab models and in patients' tumors that arc 201 reverses what is thought to be the <unk> III <unk> 27, and mutations pathogenic hallmark.
Put this into context, the <unk> III <unk> 27, and mutation directly causes sequestration of the PRC two enzyme that normally carries out try methylation of histone each street at position <unk> 27, as a repressive epigenetic mark to tamp down gene expression.
Said another way the H <unk> 27, and mutation found in tumors causes global loss of <unk> 27 train methylation to drive oncogenic genes oncogenic gene expression.
Turning back to the effects of <unk> hundred one we already knew there were certain mechanistic vulnerabilities associated with each <unk>, 27%.
It rationalized hypersensitivity.
This new finding demonstrates a reversal of the direct consequence of the mutation is a whole new mechanistic layer and gives us additional confidence in the potential utility of <unk> hundred one in the action study patient population.
Reversal of the <unk> 27, trimethyl loss associated with our tool when treatment was consistent.
Persistent and pervasive across patients in their tumors.
While we have documented integral blastoma activity in other patient populations. This new demonstration is particularly reassuring as it into keeps consistent biological activity at the recommended phase two dose and our targeted population.
Furthermore, recent literature demonstrates that removing the <unk> III <unk> 27, and mutation to increase <unk> 27 to <unk> metal established tumor models corresponds with the significant anti tumor effect and prolonged Asian of overall survival.
All of this data indicate that arc 201 has a direct effect on <unk> 27, a mutant glioma in patients.
It also sparks a number of scientific offshoots that are being pursued not the least of which are the implications for additional indications that exhibit loss of <unk> 27 tried muscle through several mechanisms other than the <unk> mutation.
Look forward to sharing more as the science unfolds.
Now turning quickly back to 206. This program remains on track to complete dose escalation by the first half of 2024, you will recall our prior announcement of our monotherapy objective response in a patient with non <unk> III K 27, recurrent glioblastoma, who enrolled early in dose escalation.
This is added to the enthusiasm for the program and further escalation is expected to target dosing on a twice per day three days on four days off schedule.
When possible. These studies are collecting archival tumor tissue to enabled molecular response signature studies downstream there'll be cross informed by potential signs of clinical activity in parallel laboratory investigations that are expected to collectively informed data driven path forward.
With that I'll turn the call over to Mike Andriole for a financial update.
Thanks, Ross and good morning, everyone I'll provide just a quick update on our financial performance for the quarter and our cash position.
The first quarter of 2023, we reported a net loss of $21 $4 million compared with a net loss of $24 8 million for the first quarter of 2022.
The majority of our expenses were related to research and development, which decreased to $18 $8 million for the first quarter of 2023 compared to $19 million for the same period in 2022.
Meaningful portion of our R&D spend recently has been on clinical pharmacology studies needed to support a potential future NDA filing this investment and the associated claim firm work, we're finishing positions us.
Well to prepare for a quick submission following the action study.
Regarding general and administrative expenses, we continue to manage these tightly despite above average wage inflation over the past year.
Those expenses increased slightly to $5 $7 million for the first quarter of 2023 compared to $5 6 million for the same period in 2022.
Looking forward, we expect the financial impact of our previously announced reduction in force to begin to take effect this quarter.
Turning toward our cash position. We ended the first quarter of 2023 with approximately $246 million in cash and equivalents net burn in Q1 was at the high end of what we expect for the year. As Q1 included several nonrecurring items, including severance expense upfront CRA payments associated with ramping up the <unk>.
<unk> study and expenses related to <unk>, which we paid in Q1, but won't be reimbursed by emergent until Q2.
Under our current operational plan would continue to expect year end cash of around $200 billion, which we expect will be sufficient to fund the organization into 2027, including through the primary endpoint Readouts of the phase III action study, which are expected to occur beginning in early 2025.
We also expect cash balances to be sufficient to fund the initiation of efficacy studies for <unk> hundred six should they be pursued following the ongoing dose escalation work during this period.
Importantly, we have not included any incremental non dilutive capital arising from our 10 Bucks a agreement with emergent and this forecast so any procurement exercises over this period by the U S government would generate an additional $31 million milestone per full option exercise. We also have the potential to receive royalties from international shipments September .
Mexico volumes, but during this period in summary, any proceeds from 10 Bucks a demand in the U S or internationally would be incremental to our capital plan.
With that overview I will turn the call back to Mike for closing remarks.
Well, thanks, Mike I actually will turn it to the operator and let's just open it up for questions.
Yeah.
Yeah.
Thank you at this time I would like to remind everyone in order to ask a question Press Star then the number one on your telephone keypad.
For just a moment to compile the Q&A roster.
Your first question comes from the line of Maury Raycroft from Jefferies.
Martin Your line is now open.
Hi, This is Kevin on for Maury, Thanks for taking my questions.
Just had a quick couple on 206 to start you said you expect the dose escalation to complete by the first half of next year.
Are you.
Any more color into where you're at with the escalation in terms of.
Which cohort and whether you are able to.
Amend the protocol to dose up two to three weeks and and also just in terms of when we might see data if we're going to wait until the recommended phase II.
Doses found or not.
Okay.
Yes.
Maybe Joshua Allen can add to this but.
The heska.
Escalation has continued with the once a week dosing in parallel to preparing for the more intense dose.
And so I expect that to happen.
To initiate shortly in terms of data. It's an open label trial. So we'll be able to provide updates as we have it we expected the the therapeutic window would be in doses that we could initiate either.
This year or early next year. So I think I think the notion that having some insight both into the.
The the dosing.
Schedule and how that's playing out as well as potential signals on activity are likely to be end of the first half of next year.
Okay.
Great Thanks, and for the the action Phase III you reiterated the early 2025 timeline for <unk>.
Initial data could you just give any color on how.
How that enrollment is going any feedback from investigators so far and any granularity on maybe regionally.
Got it.
How the how the trial is enrolling.
And in the U S or ex U S.
You can imagine the U S sites or active for so that's really where most of the enrollment has occurred so far where we are.
The U K and Israel or the first sites outside of the U S to follow.
With the.
Sites in Western Europe opening here over the coming weeks that will begin to ramp up there as well.
The feedback has been really positive on the.
As we've rolled this out and began to activate sites, we've actually had more interest and participation.
We anticipated initially and so that May may mean.
We have an opportunity to activate more sites than the original plan.
We'll see how that goes but so far the the patient enrollment per site per month actives is.
It has exceeded our expectations and yet.
It's early so I don't necessarily think you can count on that continuing although thats certainly the right side of the equation to be honest we are.
As we're early in the study.
Okay, great. Thank you Mike.
Thanks, Kevin.
Okay.
Okay.
Your next question comes from the line of Navin Cambria from capital One Securities. Your line is now open.
Thank you hi, good morning, Thanks for taking my question. So just a quick one on tourists expressed going back. So how many doses are you able to comment how many doses have been completed.
At.
The current regimen and less frequent dosing regimen.
I know that youre switching up to a more intense dosing that.
I don't know I don't know if theres what to add to the prior comment that Josh or.
You wanted to shift in there.
Yes.
A lot of color to add to be honest other than.
<unk>.
Where the study is moving I think there was a prior question on if were able to amend the protocol from where we are right now in that.
The answer is yes. So we previously commented the Escalations continued well that responder.
Went up to a dose of 100 milligrams that we've reported previously in future. The study aimed at moving as quickly as possible to the increased dose schedule.
Okay sure. Thanks.
And then on the update from ACR, where Dr. Kaufman presented on the mechanism of <unk> one.
It's all of the history.
I was just curious if you're able to sort of incorporate that in your finding into the actions that in some ways. So for instance, maybe not you might not be able to get tissue samples by.
Mike looking at Cte DNA or CSF, and looking indirectly get two HG levels at the increase or decrease or in some way incorporating the new finding.
I'll, let Alan and John speak to that I'll say for starters. It has no impact on our protocols, we're not amending that.
And that way and yet I do think this is a.
This is a.
A metric that can be interesting both as we think about the development of <unk> hundred one and 206, but I don't know if Alan there Josh you want to expand on that.
Knowing this is Alan I'll answer.
One thing I'll add is that we are collecting tissue on all patients that we can.
Unfortunately at this point.
Having to save this tissue until we.
Resolve the question of whether we need to <unk>. Our hope is that CTX on lapping necessary and we can use the tissue that we collect to do other additional study that will I think help the field and our understanding of the disease as well as our tier one better.
More to come after a clarified their need for the CTX.
Got it.
Oh, Okay. I was just going to quickly quickly add in addition to the tissue that Alan spoke about we're also collecting blood samples as well as Mike mentioned, we don't expect this to change anything with the protocol.
We have preserved the optionality for additional molecular assays on tumor tissue like Allen mentioned anthem on blood samples as well. So we'll have an opportunity to dig in a little little more later in the study and of course just to highlight I think that's what Mike was getting out there theres a lot of implications outside of the action trial as well as several other.
Cancers types exhibit this tried medical as losses loss as well. So we can be mindful of this as we contemplate future development not just the 201, but also to a six.
Sure.
And then just one more so with regards to.
Your participation in the Canadian <unk>, meaning.
Meaning will there be any presentations from your collaborators there.
Josh one highlight of note. We're sponsoring that you want to comment we will have it.
<unk> there.
I don't think there's meaningful data expected to be presented their addressable clarify.
That's right are our team is actively off the ground as we speak at that conference sponsoring engaging and the real focus at that stand against the <unk>.
While in that particular geography, so wouldn't expect there to be specific presentations, but a lot of conversations ongoing to stay on the extra trial.
In Canada as quickly as possible.
Okay, great. Thank you.
Thanks Laurent.
Okay.
Thank you. Your next question comes from the line of Ed White from H C. Wain.
Right and your line is now open.
Yeah.
Good morning, Thanks for taking my question.
Just going back to the action study and the sites congratulations with the European approval.
How should we be thinking ultimately of the split between U S and outside the U S sites and patient enrollment what are your goals there and I think you had said.
Initial goal was over 100 global sites.
But you just said you might have some more interest so how should we be thinking about that.
In totality.
Yes, I think Bruce.
Broadly speaking this isn't this isn't precise but we estimate most of our patients will come.
From the U S or North America same say two thirds, but obviously that there's some variability around that as we get we actually Europe Europe is opening a little bit more rapidly than we anticipated so that could impact that.
And in terms of the total number of sites.
I think 120 sites as.
Is.
Sort of well within our expectation and could potentially go slightly beyond that as I mentioned before I don't for those sized trial, we don't necessarily need that many but.
To the extent that these sites end up being productive in terms of enrolling patients that can always accelerate the.
Timelines.
And then of course, the acceleration timelines as to.
Among the best ways to preserve capital and preserve opportunity for other investments. So we're always keen to look for ways to accelerate but but yes. The short story as it could be could be north of 120, but not much.
Hey, Alan this is competitive enrollment and I can tell you when we did meet with our European plant City I know Theres a lot of interest there so.
Having Europe open as quick as we could we could definitely change that pallets, depending on the sites and the excitement.
Great. Thanks Alan.
And just thinking about the timing of data you had mentioned that.
The first OS assessment is expected in early 2025 are you still expecting.
The PFS readout sometime after that but before the second OS assessment.
And is the timing of that also in early 'twenty five or how should we be thinking about that.
Yes, you can imagine there is some variability around that Ed.
The range of what we do expect the PFS too and Thats the final PFS mind you.
To read out just after the.
The OS initial OS assessment, so still in during 2025, probably probably not early 2025, but that's certainly a potential.
That second OS would.
Has the potential to also readout during later that year with final analysis happening in 2026 so.
I do think that.
Do you think that PFS will will be second to that initial overall survival assessments.
Great. Thanks, Mike and then last question I wanted to ask is just a.
A big picture question.
Regarding onto a six based on your.
Small amount of clinical data so far but also on your preclinical data where do you ultimately.
Wanted to take the drug.
Wanted to get you to sort of compare what youre thinking as far as the ultimate markets for October six versus nine to a one <unk>.
<unk>.
What can be probably term niche opportunities.
Yeah, I'll start with that and maybe expand from there and I'll say this trend up a loss.
Finding has.
<unk> broadened our thinking there. The first comment is the fact that we've got demonstrated activity in the non H Street K 27, I'm Glioblastoma suggests there is a potential to access that segment, which is six times the size of the patient population with a mutation.
It's not to diminish the.
The.
The 5000, plus patients that have the mutation. It's a it's an orphan indication and yet it's a it's a significant opportunity in and of itself.
Going outside of that mutation.
Supply that opportunity by by about six in terms of the patients that you could you could reach.
What what becomes interesting, though is pre clinically we see broader potential for <unk>, six and so or in parallel to the sudden dose escalation identifying opportunities both where we've seen activity in models and now expanding that too.
Instead, it seems like there's a number of other opportunities.
That do present themselves that would make more sense clearly within fiennes. We've had published data on a number of non H three K 27, and you can glean almost responding to the to the drug.
When we get those pickles coming through the in the trial. So I think within CNS. It will clearly be activity opportunities outside of K 27 up distinct from that of two a month that'll be the most logical and then of course, there's non fiennes activity as well with a bunch of lab studies that will look to refine throughout the course of the year as well that could be additional fee.
Anything to add.
No nothing.
Okay. Thanks for taking my questions.
Thanks.
Hi, there congrats on the progress and thanks for taking our questions just in terms of future data updates around onto a six <unk>.
Alrighty more color granularity around your expectations for what you liked the first days that to include in terms of just like a number of patients dose levels amount of follow up anything like that.
Yeah, I think we'll be able to we we've held off until we we got into the actual dosing of this more intense to to elucidate that that strategy, but we'll be able to define that a little bit more in upcoming updates.
The I think the next thing will be essentially obviously the the focus on those trials is always the safety in Kenya, escalate safely and get into the anticipated therapeutic window. So well today no real safety signals that that will be an important to update us we go.
Oh that were previously reported and so but that opens the window for activity to be seen uhm from a from a response standpoint at any point that didn't even said it's it's it's less typical that you have a patient where you can reliably measure tumor response because of prior to.
Therapies that confound measurements as we discussed before so we've really only had a.
C. One and in that setting is actually but was was unexpected but there are other ways to measure activity via via markers and so there's the potential to do that it's important to remember that the primary goal of these.
This work is to is to define and and Ah dosing strategy and the safety profile.
But at the same time you know.
Sorry efficacy of signals as I say that will likely happen more into 2024, but we'll keep abreast of that data unfolds.
There are no further questions at this time I turned to call back over to Mike Sherman.
Great well, thanks again for joining us thanks to the chimeric scene in our collaborators for the good work that they're doing and strong execution, so far and I look forward to providing you updates in the coming months. Thank you [noise].
This concludes today's conference call you may now disconnect.
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Good morning, ladies and gentlemen, and welcome to the <unk> first quarter 2023 earnings Conference call I would now like to introduce you to your host for today's call Michelle less Paludal, Vice President of strategic planning and Investor Relations at tight metrics. Please proceed.
Yeah.
Thank you good morning, everyone and welcome to the <unk> first paradox, 2023 financial and operating results Conference call. This morning, we issued a press release related to our first quarter operating update you can access the press release and our Investor section of the website with me on today's call are president.
Yes.
Oh Officer, Ellen Melamed, Chief financial and business Officer, Mike Andriole, and Chief Technology Officer, Josh Elving before we begin I would like to remind you that the statements made on today's call include forward looking statements within the meaning of the private Securities Litigation Reform Act of 1995 and are subject to.
The risks and uncertainties and other factors these risks and uncertainties and other factors could cause actual results to differ materially from those referred to in the forward looking statements. Please refer to our filings with the SEC for a more complete disclosure of these risks and uncertainties.
This time I would like to turn the call over to our President and Chief Executive Officer, Mike Sherman.
Good morning, everyone and thanks for joining our 2023 is definitely off to a good start from an execution standpoint, we continue to open action study sites and now have regulatory approval for the protocol in nine countries.
This approval was received a few weeks ago from the European Union and we're activating sites there now.
We remain on schedule for our first efficacy analysis in early 2025, which includes an initial overall survival assessment.
We were pleased in the meantime to have a strong showing at the American Association for cancer Research annual meeting this year.
With more than a dozen presentations related to the <unk> platform.
Those were presented by the company and our collaborators at Brown University and the University of Michigan.
Presentation by a doctor Carl Kaufman from the University of Michigan was the highlight he presented clinical evidence of <unk> 200 one's ability to reverse H three K twenty-seven try not to loss. We've described previously the relationship between our 200 one's molecular targets and the <unk>.
<unk> III, Kate 27 target population, but this.
This goes a step further.
This is the first known example of any therapy reversing age three K 27 trying not the law. This is a characteristic which you may know has been linked to tumor growth and poor prognosis. So on top of the durable tumor responses observed in the phase two dataset. The overall survived.
<unk> advantage reported by multiple non randomized analysis of patients treated with <unk> 201, compared to all others. This provides additional confidence in the outcome of the action trial I'll, let Josh dig a little bit deeper into the science and why it matters in a moment.
We also continue to progress onto a six in the dose escalation studies, we expect the open label dose escalation to run into the first half of 2024 that will both inform the dosing strategy and create the opportunity to identify other signals of activity as you recall last quarter, we reported.
An investigator assess response in a recurrent glioblastoma patients without the H <unk> 27, a mutation who received.
Up to six at one of the lower doses.
Signals the potential for this drug and much larger patient populations.
Paired to the eighth Street <unk> 27 a M.
My indication.
With that I'll turn the call over to Josh for a deeper review on our 200 one's ability to reverse this trend up a loss and <unk> development.
Thanks, Mike.
So I would first like to expand on one of the novel findings from ACR that Mike alluded to is it bolsters our confidence in the probability of success of arc 201 for the treatment of <unk> 27 and <unk>.
Patients in our ongoing phase III <unk> study.
These findings suggest both in lab model and in patients' tumors that until one reverses what is thought to be the <unk> III <unk> 27, and mutations pathogenic hallmark.
To put this into context, the H, 327% and mutation directly causes sequestration of the PRC two enzyme that normally carries out try methylation of histone H Street at position K 2007, as the repressive epigenetic mark to tamp down gene expression.
Said, another way <unk> 27, and mutation found in tumors causes global loss of <unk> 27 trained methylation to drive oncogenic genes oncogenic gene expression.
Turning back to the effects of <unk> hundred one we already knew there were certain mechanistic vulnerabilities associated with H, 327%.
It rationalized hypersensitivity.
This new finding demonstrates a reversal of the direct consequence of the mutation is a whole new mechanistic layer and gives us additional confidence in the potential utility of <unk> hundred one and the actual study patient population.
The reversal of the <unk> III <unk> 'twenty seven try not the loss associated with our tool when treatment was consistent.
Persistent and pervasive across patients in their tumors.
While we have documented integral blastoma activity in other patient population. This new demonstration is particularly reassuring as it indicates consistent biological activity at the recommended phase two dose in our targeted population.
Furthermore, recent literature demonstrates that we're moving the <unk> 27, a M mutation two increased <unk> 27, <unk> methyl established tumor models corresponds with the significant anti tumor effect and prolonged Asian of overall survival.
All of this data indicate that <unk> hundred one has a direct effect on <unk> 27, <unk> mutant glioma in patients.
It also sparks a number of scientific offshoots that are being pursued not the least of which are the applications for additional indications that exhibit loss of <unk> 27 tried muscle through several mechanisms other than the <unk> mutation.
Look forward to sharing more as the science unfolds.
Now turning quickly back to 206. This program remains on track to complete dose escalation by the first half of 2024, you will recall our prior announcement of a monotherapy objective response in a patient with non <unk> III K 27, recurrent glioblastoma, who enrolled early in dose escalation.
This is added to the enthusiasm for the program and further escalation is expected to target dosing on a twice per day three days on three or four days of scheduled <unk>.
When possible. These studies are collecting archival tumor tissue to enabled molecular response signature studies downstream that will be cross informed by potential signs of clinical activity in parallel laboratory investigations that are expected to collectively informed data driven path forward.
With that I'll turn the call over to Mike Andriole for a financial update.
Thanks, Ross and good morning, everyone I'll provide just a quick update on our financial performance for the quarter and our cash position.
The first quarter of 2023, we reported a net loss of $21 $4 million compared with a net loss of $24 8 million for the first quarter of 2022.
The majority of our expenses were related to research and development, which decreased to $18 $8 million for the first quarter of 2023 compared to $19 million for the same period in 2022.
<unk> portion of our R&D spend recently has been on clinical pharmacology studies needed to support a potential future NDA filing this investment and the associated claim firm work, we are finishing positions us.
Well to prepare for a quick submission following the action study.
Regarding general and administrative expenses, we continue to manage these tightly despite above average wage inflation over the past year.
Those expenses increased slightly to $5 $7 million for the first quarter of 223 compared to $5 6 million for the same period in 2022.
Looking forward, we expect the financial impact of our previously announced reduction in force to begin to take effect this quarter.
Turning toward our cash position. We ended the first quarter of 2023 with approximately $246 million in cash and equivalents net burn in Q1 was at the high end of what we expect for the year. As Q1 included several nonrecurring items, including severance expense upfront CRA payments associated with ramping up the <unk>.
<unk> study and expenses related to <unk>, which we paid in Q1, but won't be reimbursed by emergent until Q2.
Under our current operational plan, we continue to expect year end cash of around $200 billion, which we expect will be sufficient to fund the organization into 2027, including through the primary endpoint readout of the phase III action study, which are expected to occur beginning in early 2025.
We also expect cash balances to be sufficient to fund the initiation of efficacy studies bronchiole six should they be pursued following the ongoing dose escalation work during this period.
Importantly, we have not included any incremental non dilutive capital arising from our 10 Bucks a agreement with emergent and this forecast so any procurement exercises over this period by the U S government would generate an additional $31 million milestone per full option exercised we also have the potential to receive royalties from international shipments September .
Back to volumes during this period in summary, any proceeds from 10 Bucks a demand in the U S or internationally would be incremental to our capital plan.
With that overview I will turn the call back to Mike for closing remarks.
Thank you at this time I would like to remind everyone in order to ask a question Press Star then the number one on your telephone keypad, we'll pause for just a moment to compile the Q&A roster.
Your first question comes from the line of Maury Raycroft from Jefferies.
Sorry. Your line is now open.
Hi, This is Kevin on for Maury, Thanks for taking my questions.
Just had a quick couple on 206 to start you said you expect the dose escalation to complete by the first half.
Of next year.
Are you, giving any more color into where you're at with the escalation in terms of.
Which cohort and whether you are able to.
Amend the protocol to dose up to three weeks and and also just in terms of when we might see data if we're going to wait until the recommended phase II.
Doses found or not.
Okay.
Yes.
Maybe josh or Alan can add to this but.
The.
Escalation has continued with the once a week dosing in parallel to <unk>.
Preparing for the more intense dose.
And so I expect that to happen.
That to initiate shortly in terms of data. It's an open label trial. So we'll be able to provide updates as we have it we expected the.
The therapeutic window would be in doses that we could initiate either late this year or early next year. So I think I think the notion that having some insight both into.
The dosing.
Schedule and how that's playing out as well as potential signals on activity are likely to be end of the first half of next year.
Okay.
Great Thanks, and for the the action Phase III you reiterated the early 2025 timeline for.
Initial data can you just give any color on how.
How that enrollment is going any feedback from investigators so far and any granularity on maybe regionally.
How the how the trial is enrolling.
And in the U S or ex U S.
You can imagine the U S sites or active for so that's really where most of the enrollment has occurred so far.
In the U K and Israel or the first sites outside of the U S.
To follow.
With the.
Sites in Western Europe opening here over the coming weeks that will begin to ramp up.
There as well.
Back has been really positive on the.
As we've rolled this out and began to activate sites, we've actually had more interest in participation then.
We anticipated initially and so that May may mean.
We have an opportunity to activate more sites than the original plan, we will see how that goes.
So far the the patient enrollment per site per month actives is.
It has exceeded our expectations and yet.
It's early so I don't necessarily think you'd think count on that continuing although thats certainly the right side of the equation to be honest.
We're early in the study.
Okay, great. Thank you Mike.
Thanks, Kevin.
Okay.
Your next question comes from the line of Navin Cambria from capital One Securities. Your line is now open.
Thank you hi, good morning, Thanks for taking my question. So just a quick one on tourists expressed going back. So how many doses are you able to comment how many doses have been completed.
At did the.
The current regimen, you know in less frequent dosing regimen.
I know that you're switching up to a more intense dosing that.
I don't know I don't know if theres what to add to that prior comment that Josh or I don't know if you wanted to ship in there.
Yes.
A lot of color to add to be honest other than.
<unk>.
The study is moving I think there was a prior question on if were able to amend the protocol from where we are right now in that.
Answer is yes. So we previously commented the Escalations continue dwell of that responder went up to a dose of 100 milligrams that we've reported previously in the future of the study aimed at moving as quickly as possible to the increased dose schedule.
Okay sure. Thanks.
And then on the update from ACR, where Dr. Kaufman presented on the mechanism of <unk> one.
His son.
I was just curious if youre able to sort of incorporate that in your finding into the actions that in some way. So for instance, maybe not you might not be able to get tissue samples, but like looking at Cte DNA or CSF and looking indirectly yet to HD levels at the increase or decrease or in some way incorporating the new finding.
Okay.
I'll, let Alan speak to that I'll say for starters. It has no impact on our protocols, we're not amending that.
And that way and yet I do think this is a this.
This is a.
Metric that can be interesting both as we think about the development of <unk> hundred one and 206, but I don't know if Alan there Josh you want to expand on that.
Knowing this is Alan I'll answer.
One thing I'll add is that we are collecting tissue on all patients that we can.
Unfortunately at this point.
More to come last week clarified the need for the CTX.
Got it Josh.
Okay, Great I was just.
Quickly quickly add in addition to the tissue that that Alan spoke about we're also collecting blood samples as well as Mike mentioned, we don't expect this to change anything with the protocol.
We have preserved optionality for additional molecular assays on tumor tissue like Allen mentioned anthem on blood samples as well. So we'll have an opportunity to dig in a little little more later in the study and of course just to highlight I think that's what Mike was getting at there Theres a lot of implications outside of the action trial as well as several other.
Cancers types exhibit that's tried methanol as losses loss as well. So we can be mindful of this as we contemplate future development not just the 201, but also to a six.
Sure.
Just one more so with regards to.
Joshua highlighting that we're sponsoring that you want to comment we will have a team there.
Think there's meaningful data.
Expected to be presented their address and clarify it.
That's right are our team is actively off the ground as we speak at that conference sponsoring engaging and the real focus of that standing up the trial in that particular geography. So wouldn't expect there to be specific presentations, but a lot of conversations ongoing to stay at the extra trial.
Canada as quickly as possible.
Okay, great. Thank you.
Thanks, sorry.
Okay.
Thank you. Your next question comes from the line of Ed White from H E.
Wing right Ed Your line is now open.
Good morning, Thanks for taking my question.
How should we be thinking ultimately you have the split between U S and outside the U S sites and patient enrollment what are your goals there and I think you had said.
Initial goal was over 100 global sites.
But you just said you might have some more interest so how should we be thinking about that.
In totality.
Yes.
Broadly speaking this isn't this isn't precise but we estimate most of our patients will come through from the U S or North America say say two thirds, but obviously that there's some variability around that as we get we actually Europe Europe is opening a little bit more rapidly than we.
So that could impact that.
And in terms of the total number of sites.
I think 120 sites as.
Is.
Sort of well within our expectation and could potentially go slightly beyond that as I mentioned before I don't for those sized trial, we don't necessarily need that many but.
To the extent that these sites ended up being productive in terms of enrolling patients that can always accelerate.
The timelines are.
That of course, the acceleration timelines is.
Among the best ways to preserve capital and preserve opportunity for other investments. So we're always keen to look for ways to accelerate that but yes. The short story as it could be could be north of 120, but not much.
And Allen this is competitive enrollment and I can tell you when we did meet with our European plant City on there is a lot of interest there so.
Having Europe open as quick as we could we could definitely change that talents, depending on the sites and the excitement.
First OS assessment is expected in early 2025.
Are you still expecting.
And is the timing of that also in early 'twenty five or how should we be thinking about that.
Yes, you can imagine there is some variability around that Ed.
The range of what.
We do expect the PFS. Two then that's the final PFS mind you.
Read out just after the <unk>.
OS initial OS assessment, so still in during 2025, probably probably not early 2025, but that's certainly a potential.
Does that second OS would.
Has the potential to also read out during later that year with final analyses happening in 2026.
I do think that.
Do you think that PFS will will be second to that initial overall survival assessment.
Big picture question.
Regarding onto a six based on your.
Small amount of clinical data so far but also on your preclinical data.
Do you ultimately.
Wanted to take the drug.
I just wanted to get you to sort of compare what youre thinking as far as the ultimate markets for off two of six versus October one.
Including.
What can be probably term niche opportunities.
I'll start with that and maybe expanded from there I'll say this trend up a loss.
Finding.
<unk>.
Broadened our thinking there. The first comment is the fact that we've got demonstrated activity in the non H Street K 27, I'm Glioblastoma suggests there is a potential to access that segment, which is six times the size of the patient population with a mutation that is.
Not to diminish the.
The 5000, plus patients that have the mutation.
Orphan indication in yet.
It's a it's a significant opportunity in and of itself.
Going outside of that mutation multi.
Multiply that opportunity by by about six in terms of the patients that you could you could reach.
What what becomes interesting, though is pre clinically we see broader potential for <unk>, six and so or in parallel to this that dose escalation identifying opportunities both where we've seen activity in models and now expanding that too.
And focusing on indications, where there is probably not the losses is indicated as as target opportunities theres actually some overlap where that's been demonstrated and we have preclinical data. So I think more to come on where the.
Where the focus will be in terms of indications.
Beyond Glioblastoma as we as we nail down the dosing strategy now Allen, Josh if you want to expand on that.
Yes, I think I think I agree just to say it a different way Ed I mean, I think we've seen clearly at pure <unk> is broader activity in the lab clearly a number of expansion opportunities. Some data presented at ACR shows that.
I don't think 206 is going to.
That very well need to or a follow on in the context page <unk> seven that you can clear all know sequencing both therapies in the lab doesn't seem to make a lot of sense for the data we have.
Yet to generate in vivo data that shows that adding to the top 201 of the in vivo setting for <unk>.
<unk> kept them.
It is the most logical instead it seems like there is a number of other opportunities.
That do present themselves that would make more sense.
Nearly within CNS, we had published data on a number of non <unk> III <unk> 'twenty seven unequally almost responding to the drug.
And lab models that we've seen the first proof of concept kind of come through with that one responder in the trial. So.
Like I mentioned, we will have the privilege of leading the drug play out in the broad CNS tumor space.
Molecular tissue. So that we can do signal refine that when we get those cycles coming through in the trial. So I think within CNS that will clearly be activity opportunities outside of <unk> 27 distinct from the <unk> hundred one that'll be the most logical.
And then of course, there is non CNS activity as well with a bunch of lab studies that will look to refine throughout the course of the year as well that could be additional tier two opportunities.
Alan anything to add.
No nothing.
Okay. Thanks for taking my questions.
Thanks, Ed.
Your next question comes from the line of Troy Ford from Cowen. Your line is now open.
Hi, there congrats on the progress and thanks for taking our questions just in terms of the future data updates around onto a six can you provide any more color granularity around your expectations for when you would like that first data set to include in terms of just number of patients dose levels. The amount of follow up anything like that.
Yes, I think we will be able to.
We've held off until we got into the actual dosing of this more intense.
Elucidate that that strategy, but we will be able to define that a little bit more in upcoming updates.
I think the next thing will be.
Essentially obviously the focus on those trials as always the safety and Kenya escalate safely and get into the anticipated therapeutic window. So.
To date, no real safety signals that that will be an important.
To update as we go the efficacy signals are a little bit trickier to anticipate.
We didn't expect to see a response at.
At the at the <unk>.
Most that we that we saw in patients.
Now that we've previously reported and so but that opens the window for activity to be seen.
From a from a response standpoint at any point that having been said it's it's.
Less typical that you have a patient where you can reliably measure.
<unk> response, because of prior therapies that confound measurements as we've discussed before.
So we've really only had.
A few patients where response was potential and to <unk> in that setting is actually what was unexpected but there are other ways to measure activity.
The the markers and so there is the potential to do that it's important to remember that the primary goal of these.
This work is to is to define and.
Dosing strategy and the safety profile.
But at the same time.
We're fortunate.
We get the right patients we may be able to provide additional safety signals.
Sorry efficacy signals as I say that will likely happen more into.
2024, but we will keep you abreast of that data unfolds.
Alright, great. Thanks for all the color.
Alright, Thanks, Brian .
Okay.
There are no further questions at this time I turn the call back over to Mike Sherman.
Great well, thanks again for joining us thanks to the <unk> and our collaborators for the good work that they're doing and strong execution, so far and I look forward to providing you updates in the coming months. Thank you.
Okay.
This concludes today's conference call you may now disconnect.