Q3 2023 Wave Life Sciences Ltd Earnings Call
Good morning, and welcome to wave Life Sciences third quarter 2023 financial results Conference call. At this time all participants are in a listen only mode. As a reminder, this call is being recorded and webcast now I'll turn the call over to Kate Walsh, Vice President Investor Relations at Corp.
Current affairs. Please go ahead.
Thank you operator, good morning, and thank you for joining us today to discuss our recent business progress and review with third quarter 2023 financial results.
And me today are Dr. Paul Bono, President and Chief Executive Officer, Calmer, and Chief Financial Officer, and really quite Chang Chief Development Officer Soccer, Ginnie Yang SVP translational medicine, and Dr. Sandra Buggy Chief Technology Officer.
Yes release issued this morning is available on the investors section of our website Www Dot wave life Sciences Dot com.
Before we begin I would like to remind you that discussions during this conference call will include forward looking statements.
Shipments are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 22, and our quarterly report on Form 10-Q.
Order ended September 32023, we undertake no obligation to update or revise any forward looking statement for any reason I'd now like to turn the call over to Paul. Thanks, Keith Good morning, and thank you all for joining us on today's call I will begin with opening remarks next Anne Marie will provide an update on our clinical trial finally, I will review our financials.
We will then open up the call for questions John.
Sandra engineered will also be available for questions.
In the third quarter, our team made tremendous progress advancing our pipeline of novel RNA about it.
Since our last update we have brought our first in class RNA editing therapeutic program W. V E zero zero fixed for 88 into the clinic, we outlined our strategy for growth that our annual R&D day, including announcing a new wholly owned SA RNA program.
Targeting in hip and knee for metabolic disorders, including obesity, and we continue to advance our clinical trials in DMD and H D.
Looking ahead to 2024, we are approaching a transformative year for wave, but we will deliver key data sets for all three of our clinical program and selected in hip and knee clinical candidates.
Starting with W V.
Today, we are announcing the approval of multiple clinical trial application or Cta and the initiation of a restoration program, which will investigate WV easier thick the industry's first ever clinical RNA editing candidates for Alpha one antitrypsin deficiency, where a T D.
This is another significant milestone for wave patients in the field of nucleic acid.
We remain on track to begin dosing healthy volunteers this quarter and that Anne Marie will describe in more detail later. The restoration program is designed to enable a highly efficient path to proof of mechanism.
Our excitement for W V E or there.
Is grounded in the strong preclinical profile, we have observed to date, we've achieved remarkable potency and durability of editing with convenient subcutaneous dosing in our preclinical studies.
Because of our unique fully chemically modified oligonucleotide and their ability to effectively recruit meet our enzymes.
W. E zero six precisely correct. The P. IV mutation on the transcript with nobody's vendor of it.
Contract genome editing technologies rely on hyperactive exogenously delivered artificial enzymes that can result in significant irreversible collateral bystander editing with DNA youll being not only the potential for permanent off target edits to DNA, but I used to forms of protein with differential function.
Oh, it's mixed contained the galvanic conjugated a highly specific and elegant delivery to all that is well validated through multiple approved silencing therapeutics on the market for.
For <unk>. It is a significant advantage to have a stable and optimized candidate that can leverage jelinek and avoid lipid nanoparticles, which have their own challenges require intravenous dose.
With current therapies, largely confined to treating other pulmonary or in the future hepatic manifestations of the disease the unmet need in ATB remains high.
Even with the limitations of available therapies, the pharmaceutical market for ATB is substantial with augmentation therapy alone accounting for over $1 billion in sales per year.
Our partner GSK has a long history and clear leadership with respiratory medicine development and commercialization and together with its differentiated profile. We believe this program is in a strong position and we look forward to delivering proof of mechanism data next year as a reminder, under the terms of our collaboration wave is also eligible to receive.
<unk> near term clinical milestones, starting this year, which have the potential to add substantially to our balance sheet.
Clinical proof of mechanism with <unk> would serve to meaningfully Derisked. This novel modality I will continue to unlock value for our emerging pipeline of RNA editing programs.
As we shared at our R&D day, we are actively building a pipeline of wholly owned therapeutic candidates.
Nine to either correct or up regulate mrna across a range of high impact targets.
We presented both in vivo and in vitro data on several of these targets, which all offer efficient path to clinical proof of concept and.
And represent meaningful commercial opportunities for both rare and common disease indications.
We look forward to continuing to share data on these exciting programs over the course of 2024.
Beyond <unk>, our strategic collaboration with GSK continues to make meaningful progress the wave and GSK teams continue to work to advance multiple targets and is our partner share during our R&D day. This work spans multiple modalities beyond RNA editing, including silencing using SA RNA.
As a reminder, GSK paid 100% of the cost related to target validation REIT partner program and wave is eligible for up to $2 $8 billion milestone not inclusive of a six and additional tier royalty payments.
At R&D day, we also announced our first fully owned program to emerge from the collaboration.
<unk> conjugated SA RNA program targeting <unk> inhibitor to treat metabolic disorders, including obesity.
Inhibit he is a particularly exciting target given its strong supporting genetic evidence.
Inhibiting <unk> loss of function heterozygous carrier exhibit healthy metabolic profile, including reduced hip to weight ratio improved lipid profile reduced odds of coronary artery disease and type two diabetes.
G. L. P. One therapeutic have established a substantial market opportunity for weight loss therapeutics.
We estimate there are more than 47 million people in the United States, and Europe with metabolic disorders, including obesity.
<unk> ones are becoming standard of care for weight loss, they come with several drawbacks, including loss of muscle mass depression of the general reward system and poor tolerability with discontinuation rates as high as 70% there is a need for more therapeutic options, including long term maintenance.
We believe that therapeutic approach for obesity that improves metabolism.
Increases bat lots, while maintaining muscle map offers the potential for an infrequent dosing and does not affect the general reward system would be ideal.
This is what we aim to achieve with our IBD program.
At R&D day, we presented the first in vivo data supporting preclinical proof of concept for this target.
We achieved inhibiting silencing well beyond the 50% therapeutic threshold, which led to substantially lower body weight and substantial reduction of betrayal back in <unk> as compared to control.
These are the first in vivo data to demonstrate if you need violent.
With the phenotype of heterozygous loss of function carriers.
Since R&D day, we've identified potent and highly specific leads using our new chemistry format and are rapidly advancing towards our goal of selecting an inhibitor clinical candidate by the fourth quarter of 2024.
Notably because of the levels of inhibiting <unk> protein and other relevant clinical biomarkers can be readily measured in Europe, we believe the path to accessing target engagement and clinical efficacy can be straightforward and achieved in a relatively short period of time.
As a reminder, our collaboration allows wave to leverage gsk's genetically validated targets to advance at least three program, meaning we have an additional two slots open for new wholly owned program.
Turning to DWP and by three one and <unk> three we continue to advance our clinical DMD and HD program and are on track to deliver key data from both programs in 2024.
For DMD with WB and by three one we aim to provide a treatment option that delivers convenient safe production of endogenous functional Becker like yesterday, and ultimately meaningful clinical benefit for all patients amenable to exon 53 skip it.
There remains significant questions around the functional benefit of micro or mini dystrophin, and we recognize the urgency to deliver more therapeutic options for these patients.
We look forward to evaluating the translation of our best in class exon skipping a functional dystrophin protein in 2024.
And Huntington's disease, we believe <unk> is the most promising assets in the field.
To date, we have demonstrated successful translation of our compelling preclinical data to the clinic with reduction of mutant Huntington and preservation of Wild type Huntington after a single dose in humans.
We have robust evidence from multiple preclinical studies, including LHC studies that support the ability of our oligonucleotides to achieve significant exposure level throughout the CNS.
As we look ahead to the first multi dose data from our select HD clinical trial next year, we anticipate potent and durable knockdown of mutant Huntington, while sparing wild type protein similar to what we observed in our GP reduction in our <unk> program, when we transition from single to multi dose.
Emory will speak more select HD at our other clinical development program and I would now like to turn the call over to her and Marie. Thank you Paul its a truly exciting time to be at wave as we are continuing to validate the translation of our platform and the Kinect <unk>.
Getting with waves the reserve stays down that conjugate you Dana or RNA editing oligonucleotides for IHG D. We have now received approval for multiple clinical trial applications. A cta this accomplishment that RNA editing oligonucleotides can leverage established regulatory pathway and wave.
There was a mistake, especially become the best RNA editing oligonucleotides to enter the clinical trials.
Today, we are announcing the initiation of a restoration clinical program, which is comprised of two interconnected portion restoration one healthy volunteers.
<unk> G for individuals with AA and have the homozygous PIV mutation.
The healthy volunteer cohorts, along with our PD modeling and lymphoma dose that can rapidly in April initiation and D. D patients at the level expected to engage targets, thereby enabling efficient delivery of proof of mechanism.
By detection of attitude protein and Cameron.
Frustration chain patients will have multiple assessments of Sharon MAA throughout the low medium and high dose cohort, meaning it is possible to achieve proof of mechanism for completion of the whole trial and potentially prior to completion of the first cohort restoration. One is now underway and we can expect to initiate dosing in healthy.
Volume change this quarter and delivery of proof of mechanism data in patients with <unk> in 2024.
Moving onto BMD I'll start with a quick reminder of the clinical data that drives their excitement in this program.
And patient muscle biopsy collected from our proof of concept study, we observed a mean, 53% of exon skipping a six week following three doses of <unk> three one every other week.
Since exon skipping and resulting dystrophin production improves the cellular environment to enable more skipping on dystrophin significant non linear increases in dystrophin may be expected given the amount of exon skipping we've seen this non linear relationship between exon skipping and dystrophin production has been observed that mosquitoes.
Furthermore, high tissue concentrations of <unk>, one five myobloc and especially in such lifestyle, which of the progenitor cells, new myobloc speak to promise of achieving best in class dystrophin protein expression.
We are advancing forward 53 are potentially registrational phase III trial of <unk> three one.
The open label trial is evaluating can make picking doses have been by three one administered every other week.
Powered to assess functional indulgence dystrophin expression of 24% and 48 weeks of treatment, which will be the trials primary endpoint.
The trial will also evaluate safety and Tolerability pharmacokinetics, and digital and functional endpoints.
We remain on track to deliver dystrophin protein data in 2024, which if positive would support our plans to file for accelerated approval in the U S.
These data would also accelerate our clinical development plans to build a wholly owned multi X on DMD franchise beyond exon 53.
We have generated in vitro dystrophin restoration data for follow on exon skipping compounds that together would address up to 40% of the DMD population.
These follow on compounds are all designed with Pn chemistry and have demonstrated high levels of excellence keeping under strict and production restoration in in vitro studies.
Turning to wave the Missouri, three our first in class allele selective commented up behind you can see our H D.
She is a devastating debate on whether there is there are three offers an optimal treatment approach as it reduces the toxic mutant Huntington protein, while preserving the healthy wild type pricing.
As a reminder, this program is part of an active collaboration with Takeda in the third quarter, we achieved a milestone from this collaboration which pertained to the positive results from a non clinical study of <unk> in non human primates.
This study showed significant tissue exposure levels of <unk>, three and the deep brain regions, including strong and bolstered our existing dataset that confirm the ability of our oligonucleotides distribute to the areas of CNS imported for H D.
Coupled with the already demonstrated main mutant Huntington CSF single dose reduction of approximately 5% compared to placebo.
<unk> and HP results further reinforce our confidence in this program.
I'm excited to share that we've now completed enrollment to the 30 milligram multi does Q eight week cohort comprised of 24 HD patients.
I have enrolled patients from the single dose cohorts I'm fully enrolled with the multi dose cohort, which is critical to inform the decisions on this program. We will now evaluate the completed single dose and multi dose cohorts simultaneously.
We expect to report the SaaS milligram multi dose data with extended follow up along with all single dose data in the second quarter of 2024.
We also expect these digested enabled decision, making on the program and supports our option package that you pay them.
In summary, I'm proud of our team's accomplishments this year I'm truly excited for the year ahead during which we will have high impact <unk> out across all three of our clinical trials.
With that I'd like to turn the call over to our CFO Carl Moron can provide an update on our financials.
Thanks Anne Marie.
We recorded $7 $3 million of net income for the third quarter of 2023 as compared to a net loss of $39.0 million in the prior year quarter.
This year over year change was primarily driven by increased revenue under both our GSK and Takeda collaborations.
Under the Takeda collaboration we earned $7.0 million for the achievement of a non clinical milestone for <unk> III.
Additionally, we recognized 28 points here of $1 million from Takeda related to the discontinuation of <unk>, four and $14 $3 million under the GSK collaboration.
Research and development expenses in the third quarter of 2023 were 31 $6 million as compared to $27 6 million in the prior year quarter.
This increase was primarily driven by increased external expenses related to all three of our clinical programs.
G&A expenses in the third quarter were $13 1 million as compared to $11 $6 million in the prior year quarter, primarily due to increased spending on professional and consulting expenses.
We ended the third quarter with $139 $9 million in cash and cash equivalents.
Subsequent to the end of the quarter, we received 7.0 million ish for the achievement of the previous discussed by us So we.
We expect that our cash and cash equivalents will be sufficient to fund operations into 2025.
As a reminder, we do not include any future milestones.
And our cash runway.
But we do have the potential to achieve meaningful near term milestone payments this year and beyond including clinical development milestones related to <unk> I will turn the call back over to Paul.
Thank you Kyle.
With the most versatile RNA medicines platform in the industry best in class chemistry, and our pipeline of transformative medicines wave is approaching an exciting inflection point.
As we approach 2024, I'd like to recap the many near term milestones, we expect to deliver next year.
We expect to deliver and share the first ever clinical proof of mechanism data for RNA editing with WB. There is aerospace we expect to deliver dystrophin data from our potentially Registrational forward 53 clinical trial, and we expect to deliver data from the multi dose collect HD cohort with extended follow up along with all single dose data we.
So expect to select a clinical candidate for inhibited by the fourth quarter of 2024, thereby supporting our goal of collecting five new clinical candidates by year end 2025.
Together, we are re imagining what's possible and patients and we look forward to continuing to share our progress with you and with that we'll turn it over to the operator for Q&A.
Certainly ladies and gentlemen, if you do have a question at this time. Please press star one on your telephone. If your question has been answered and you'd like to remove yourself from the queue simply press Star. One again, our first question comes from the line of Steve <unk> from Raymond James Your question. Please.
Hi, good morning, Thanks for taking the questions wanted to first ask about.
The satellite cell histology that you spoke about and showed at R&D day.
For the 501 program of course.
I'm curious if that's something that.
Like can you look for dystrophin protein as well directly in those cells by IHT or something is that something that you would do in the ongoing phase II clinical study and lastly.
Lastly, do you think.
DMD experts are regulators would view that as a meaningful clinical biomarker at this point or is it still sort of academic and speculative what the meaning of that is.
So thank you for the question. So I think if we think about the importance of the satellite solid data.
Do think it helps to drive dystrophin production along the full muscle.
Muscle so muscles are composed of the <unk>, but also the satellite cells, which repopulate the muscle cells. So if we do think about looking for dystrophin and in terms of assessing.
Immuno histochemistry standing for dystrophin that will obviously be something we look for in the next study. However, the most important meaningful biomarker for us will be western blot dystrophin that we can quantitatively assessed against our peers, but I think in the totality of the treatment and I think this is what's really important around the satellite cell production.
With newborn screening growing in the U S. We now know newborn screening is growing in Europe. If you think about treating patients much earlier in the process for the loss of ambulation before.
And the point before the disease, what historically had been diagnosed being able to treat those boys earlier and get exposure to the repopulating cells in the body. We think is a critical part of the treatment paradigm. So.
I think it's an exciting piece because it demonstrates the potential of our <unk> in pn, Kevin to distribute broadly in the muscle and not just the select belt, we think long term it treats to the totality of the treatment of the disease, but will obviously be something that will be assessed in the subsequent study and I think it's important that it was also identified in all three boys. So this wasn't a unique finding it.
A particular boy on the original study so I think it's going to be compelling as we look at it in the 453 study.
Okay, that's great.
I want to ask separately also about.
One anti Trypsin program, just a preface the question I noticed in Telia.
This morning, just hold the development of their knockout approach.
Targeting liver phenotype. They are advancing their lung phenotype program only and then of course, the RNA approaches focused on liver. So it seems like.
There is an opportunity here for wave for RNA editing to.
Really demonstrate.
That you can.
Two birds with one stone so to speak and treat both lung and liver phenotype, maybe even within the same patient.
Im curious if thats a focus.
Maybe the initial patients you would enroll if that's even possible to sort of enrich for that.
Really in general thinking about the market, how many patients kind of fit into this category, where they could benefit from a therapy that addresses both lung and liver phenotypes at once.
No. It's a phenomenal question, obviously, an interesting update today I think the other interesting nuance that we're also trying to affect from that.
And then the announcement today of our regulatory filings, where we can say actually we think RNA editing is being treated very similar at the other oligonucleotide with a shift from a <unk>.
IND filing to a Cta filing for London. So I think there's a lot of questions still around DNA editing.
And versus RNA editing, but to your point on liver versus lung I think we agree from the beginning year important point that it's about the totality of treatment for ADHD, we don't want to exclude.
Obviously, there's a protein expression threshold, so again, beating two birds with the same hand being able to elevate that restored protein function.
Protect one, but obviously as we've shown over time to that wild type protein allows the Z protein to come out of the liver and improved liver function. The other thing we've seen and I think this is an important point again for the repeat dosing that comes with RNA editing as we have shown that sells get healthier and so this ability when you repeat dose.
But you don't have to try to capture all of the sales on that single infusion and then watch the other hepatic necrosis as they are in.
Injured.
To restore healthy habit sites over time, which continues to make more protein and improve the production over time as well.
So I think if we think about again the totality of the treatment for this important disease. So like a 100000 patients in the U S and Europe, having a treatment that singularly treat both liver and lung.
And the word means that we're going after I think gives a is it really exciting promise for these patients.
And thanks, so much.
Thank you one moment for our next question.
And our next question comes from the line of Salim Syed from Mizuho. Your question. Please.
Great. Good morning, Paul Thanks for the update and the question.
For me on DMD since for.
Important year for the next year 'twenty for them in the space just curious to get your views.
If you can.
Talk about typically you've talked about this throughout the compound <unk>.
Tolerated approval, we had a controversial ad com.
And it failed to hit on the primary and.
And embark and then about $70 million in sales in quarter.
Quarter, one right.
Just curious any implications there are nuances to your updated thoughts on either regulatory or commercial.
As it relates to the space.
I mean, I think and I think this is an important point you bring up which is that patients need new treatments, whether or not that was gene therapy coming to market I think over existing skippers I think patients need new treatment and recognize that they are underserved we had.
Very interesting discussions with <unk> with the patient community and I think there is a hunger for improved dysfunctional dystrophin and so I think as we look at the state I, obviously can't comment on.
Individual regulatory discussions, but what I can say is we are resolutely focused on driving as much functional dystrophin protein as possible and seeing that translate the functional benefit for these boys not just in the U S and I think that's another thing we routinely here is the frustration outside the United States, where we're engaged with the patient commute.
80 to watch in the U S. As these accelerated approvals medicines that you pointed out are getting onto market, but because they haven't finished the complete study or not.
Not going to treat patients outside the United States. So as we think about the totality of our program both a U S strategy, but ultimately delivering functional proteins. So that we can see that translation to boys globally not just those that are amenable to <unk> 53, but again, our thesis of being able to expand that beyond 53 across 40% of <unk>.
Yes.
I think thats, our core focus so we've seen that with the initial data. We're excited about $4 53 in terms of delivering protein data and really providing substantial opportunities for these boys with DMD.
Got it thanks Paul.
Yeah.
Thank you one moment for our next question.
And our next question comes from the line of Joon Lee from <unk> Securities. Your question. Please.
Good morning. This is awesome one for Sharon thanks for taking the questions.
I'm just wondering do you plan to optimize the guide molecules for cost 12 to a cash nine using a platform now that you've demonstrated progress in R&D.
<unk> RNA editing.
And then just on inhibiting E.
The timeline is now 42 parts of the D C.
I'm just wondering do you think you could have progressed faster within EXL.
Thank you.
So can you repeat the second question I just wanted to make sure.
Oh, Yes, I'm just wondering if you could just elaborate a little bit.
If you think you could have progressed faster with an antisense oligonucleotide as opposed to in the RNA approach for the <unk> inhibitor program. Thank you.
Oh, okay.
Sorry, I'll take the last one.
I just want to make sure you are inhibiting E. Because it was not clear if with ADT or inhibited. So youre, saying could we have gone faster for an ASR no I think actually our experience in <unk> and as we shared earlier in our collaboration with Janssen, we've been working in.
<unk> SA RNA for a while now with our format. So I don't think that there is any.
Any speed disadvantage by pursuing SA RNA for the inhibitor program in fact I think.
We are quite on track and I think competitive in the field right now and that they are there and I think yes.
As we've always said, having multiple modalities, let this really evaluate what is the best modality for treating with given disease and I think what we've seen and not just potency the durability the gallon neck in hepatocytes on violent thing I think we actually have the best modality and.
Format, frankly to treat this where we can think about potential for biannual or annual dosing. So I think we've got a competitive program here I think our goal is to stay ahead of.
In the space and we'll continue to watch it.
To your first question, it's an interesting one because as we think about the power of <unk> and we have discussions with numerous companies around our GMP manufacturing capability and process development I do think we have the ability to work in these spaces, what I don't want that to be translated to on this call is that way is going to work on Harley control guide strengths are Christopher REIT, but.
I think that capability, we have in collaboration to apply our chemistry, and our IR manufacturing knowhow and our process development across multiple formats in oligonucleotides.
Definitely translatable.
I think our focus right now is RNA editing in the cases, we shared earlier.
Sort of advantage it but.
Protests were taking our chemical modifications again proprietary debate are definitely transferable across other oligonucleotide space.
Thank you and then just one more so I noticed that the single dose data, let's say, which means youre going to get it this quarter.
Now I'm going to come out with the multi dose data in the second quarter of 2024, if you could just elaborate little bit on that thank you.
I'm happy to Emory.
Yes sure. So the single day does stay turn not informative.
And as we've rolled out of a single dose data into the multi dose cohort and when you involve multi dose cohort will be doing them out together because these are the important data enabling decision making.
Yes, I mean, just to follow up on that I mean, the study that the single dose is complete.
When we cut data and I think this has been discussed before it is critical when you do assessments of data, particularly on the study that they go to evaluate all patients simultaneously to avoid any discrepancies across the assay in comparison and so with that completed the Emory point with those patients having rolled over and are fully enrolled 30 milligram repeat dose cohort.
Those repeat dose data as we've shared earlier on prior calls are going to be critical and informing them that step of the program.
Thank you very much Paul.
Yes.
Thank you one moment for our next question.
And our next question comes from the line of Joseph Joseph Schwartz from Leerink Partners. Your question. Please.
Thanks, very much so given what we recently saw from embark I was wondering if we could get your opinion on the merit of NSA has a functional assessment and.
What other endpoints do you think.
It could be more informative if any.
And what functional assessments will you be focusing on now in the $4 53 study and what is the bar for.
Success on each and then I have a follow up thank you.
I think the first and it's a great question, Joe I mean, I think when we look at these data at the beginning for US the translation between and we think about Becker like functional dystrophin is <unk>.
Making functional dystrophin should translate to a functional benefit it was always a question. We remember the AD com that was one of the fda's questions up wouldn't micro dystrophin actually translate to a functional benefit I think incentive across the reviewers with no.
So I don't think this is necessarily the application of saying well how do you make the Northstar the endpoint better our focus is on how do you make the protein better and thats been creating functional protein. So our view is we're not changing our functional endpoints, we're going to look at Northstar or we're going to look at other digital endpoint, we're looking at a whole host of endpoint.
Function, but it gets back to the primary driver of the biology of the disease. The reason, we're developing exon skipping oligonucleotide at.
For DMD is because the premise of the biology foundational. It was how can you create becker like functional protein that has all of the properties that are required there. So I think our goal is to deliver on that protein.
Then look at the translation of that into function.
And when you do your.
Muscle.
Histology biopsy analyses.
Do you think there is any potential to see evidence of.
<unk>.
A differentiated profile from having more activity in the satellite cells on the muscle cell architecture, given what you said about.
The actual protein that can be produced.
As a result.
So really interesting question. So obviously, one we will have longer duration REIT a follow up in terms of that forward 53, then the three doses at six weeks, which is a more static time point and so there are opportunities to see the evolution of satellite that was the evolution of where district located the important thing obviously is the quantitative function.
Protein and then looking at endpoints beyond that but there are interesting discussions happening I know in muscle biology thinking about population and translation of satellite cells into how that dystrophin translates onto the <unk>, how do you actually expand dystrophin coverage of Irobot.
Again, a lot of that work being academic I think the fact is the fact that we get there actually should let us be able to look at dystrophin architecture over time and those are interesting continued academic experiments to really think about that translation to function.
The most important endpoints for us should be the quantity of dystrophin that we produce and the translation of functional endpoints, but again when you see that.
That opens up a lot of possibilities than to continue to look and understand better the dystrophin biology, and ultimately the translation of that.
Makes sense, thanks for taking my questions.
Yes.
Thank you one moment for our next question.
And our next question comes from the line of <unk> Yang from Jefferies. Your question. Please.
Thank you another question on DMD, So when you produce this.
Welcome Kim and obviously.
At close to full length versus micro dystrophin.
<unk>.
You mentioned there is a there are lukach stomach testing can.
Assess functionality of a protein itself when you measure the protein levels.
You assume that the protein.
Is functional.
Yeah. So when one dystrophin protein is translated to the outside of the cell at that point, that's the function of appropriate after.
That's why this protein takes time to both produce and then located south onto the <unk>.
External part of it is that right. So I think that's the piece overtime that is that is the functional protein when I was talking about the academic work that's more on how that how that distribution takes place over time.
And obviously it will be important as we study that we have longitudinal both the 24 and 48 week opportunity to really look at the progress not just in the quantity, but in distribution I think those are the points that will be interesting to assess over time, obviously the key metric as we think about the potential for accelerated approval filing will be the quanta.
Or has that been on western blot propane.
Functionality of the protein is definitely something.
We will obviously look at the distribution of the protein in the cell.
Just from a logical point of view you would expect that a protein which is as close as possible to the 19th district is most likely to be functional and I think with these data. We can say the import data really significant questions as to whether my credit discipline has stability completed the election benefit.
Thank you and then you mentioned that obviously if it isn't.
Need for new treatments for DMD patients so given what's out there while we have seen.
What level do something levels do you think you need in order to file for approval can be differentiated.
Commercially.
It would be differentiated commercially I think there are several several ways to differentiate it obviously one for exon 53, which is the immediate commercial space, we'd be entering we are powering the study to ensure that we can deliver greater than 5% that's.
That's the commercial threshold within the exon 53, we believe based on our levels of transcript and the time and duration. We're treating that we should be able to see that level of protein above that current threshold as we talked to patients and physicians. There is other areas of points of differentiation, even amongst the current program. So we're already less.
And in terms of dosing administration as we talk to these patients about impact on their life in terms of travel a transit cost.
Having weekly IV infusion versus whether it's biweekly and as we saw in our data from part a 25 day half life means the potential for monthly or less frequent treatment that in and of itself as we talked the families of the huge advantage. So we see that in the profile of the stability of Archrock.
We have a profile in terms of safety.
Safety, two and at least in the early pieces that tells us that we shouldnt look differently than the existing standard of care. So we can provide these patients an opportunity to switch with less frequent administration and substantially more protein, which is what we are powered to see and the ability to get the satellite cells and the fact that we see higher levels and I think we need to go back to remember.
That data at 53% transcript was seen in skeletal muscle.
We've shared data that showed that we see substantially full tire transcripts production in both our <unk> and in our double knockout mice are diaphragm. So we think about the overall profile differentiated profile from the existing standard and what's going to be important to patients with high levels of cardiac distributions and muscle protein dystrophin.
High levels of diaphragmatic protein expression that treats the underlying respiratory cardiopulmonary complications that these patients suffer from in addition to the high levels of skeletal muscle concentrations. So the totality of the profile and I know people tend to think about all exon skipping is being the same the profile and reason we started this probe.
Graham after our prior experiences here is not just because of the quantity of dystrophin, but the localization the exposure profile.
<unk> from the existing exon skipping therapies without the need for conjugates in the other.
Modalities that potentially impact liabilities on those molecules compared to standard of care.
Thank you and then last question is on IAA TD RNA editing.
And you deliver a proof of mechanism data.
In 2024 can you kind of talk about the level of data, we'll see in terms of a number of our patients.
That data we would see.
To determine proof of mechanism. Thank you.
I'll, let Anne Marie defined kind of I think it's important that we benchmark proof of mechanism, obviously, a lot more update to your other questions in terms of numbers and designs as the study progresses, but you want to talk about.
Sure.
Im impressed with magic mechanism is detection of attitude protein in serum and that would be a very significant mall trends evidenced.
Evidence that Aegon NV.
The same kind of translate into humans.
Our study we have multiple assessments of MAA throughout the cohorts light medium light and so we can achieve proof of mechanism as soon as we get catch it.
Before the completion of the trial and potentially before patient cohort.
Thank you.
Thank you.
Moment for our next question and as a reminder, ladies and gentlemen, if you have a question at this time. Please press star one one.
Our next question comes from the line of Casey from RBC. Your question. Please.
Oh, great. Thanks for taking our question Lisa answer Luca.
Just a couple on <unk>, you mentioned that multiple Cta as have been accepted just wondering if you can share which geographies you have cleared the cta.
<unk>.
Hi.
That data I know youre expecting to dose healthy volunteer soon.
Given there is no mutation to correct in healthy volunteers what clinical.
Clinical information are you hoping to gain from these subjects and what will help inform further treatment in <unk> patients.
Sure.
The first clinical trial site.
Okay.
<unk> coming.
To your question about what we expect to get from the volunteer study well. The volunteer study has been designed to.
Q&A bless to most rapidly achieve doses in patients that we would expect to see target engagement and so it's really designed for efficiency and speed.
The volunteer study willing form.
In the patient study and also of course.
And Tolerability.
If you think about it the goal is to get very quickly too.
First low dose cohort and the patient arm, which is where we modeled to anticipated initially engaging target. So there is a combination of how quickly can we enroll and established both safety and PK and tie that over to our preclinical modeling on PD.
This translated across multiple clinical programs to date.
And to be able to affirm how do we get quickly to starting at a patient cohort, where we would expect to anticipate engaging target. So this idea of kind of rapidly starting as opposed to building up and patients to get to a part where you eventually engage target I think became.
A really elegant job of bringing those pieces together to expedite getting to that proof of mechanism inflection as quickly as Bob.
Thanks, Paul.
If I may just on the milestone can.
Can you give us a sense of the cadence of the milestone payments from GSK for the pro.
Graham Thanks.
Sure I mean, I think obviously, we cant breakdown like.
But we can say is.
As we've said publicly.
We have milestones for the program as we move through the clinic. Some of these are execution milestones in some of these are data inflection milestones, we anticipate milestone payments in 2023, and then 2024 and beyond so at the most I can say.
But given the progress the team is making I think it's pretty clear to see a path to how we're going to move through that cadence of potential milestones.
Perfect. Thanks for taking our questions.
Sure.
Thank you.
It does conclude the question and answer session of today's program I'd like to hand, the program back to Dr. Paul <unk> for any further remarks.
Thank you all for joining the call. This morning, I also want to thank our employees for their efforts towards delivering life changing treatments for people battling devastating diseases, we have an exciting year on the horizon and we look forward to keeping you all updated on our progress have a great day.
Thank you, ladies and gentlemen for your participation in today's conference. This does conclude the program you may now disconnect good day.
Okay.
Okay.
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