Entrada Therapeutics Aktie

Thank you. Good morning. Thank you for joining us. I'm Paul Choi, and I cover the mid-cap biotech sector here at Goldman Sachs. Joining us here at the Goldman Sachs Global Healthcare Conference is Entrada.

Before we begin, I'm required to make some certain disclosures. These disclosures pertain to investment banking and other relationships that we may have with companies discussed here at the conference. For anyone listening or who are clients at the firm that are attending, these disclosures are available to you on our research portal. We are prepared to read them aloud, but they are available for you through our Goldman Sachs Research.

And with that, it's our pleasure to have Entrada here. And maybe what we'll do is start at a high level with Dipal here and maybe talk about for those who are new to the Entrada story and/or maybe the DMD space, can you maybe walk us through what is the EEV platform and what, I guess, in the earlier preclinical data has made you excited about its potential?

Sure. Yes. Thanks, Paul, and thanks to the Goldman team for -- asking us to participate. So the Entrada Therapeutics story starts back in 2016. But when we start to think about what is so special about this company, it starts with the Endosomal Escape Vehicles or EEVs, which are essentially a family of cyclic cell-penetrating peptides that have these remarkable and unique properties that allow us not only to get into the cell, but to get out of the early endosome with efficiencies that have not been seen before.

So why is that important? These EEVs can be conjugated to a lot of different things. So in this case and in our DMD and DM1, we're talking specifically about oligonucleotide. So conjugating the 2 together or chemically synthesizing the 2 together allow us to get out of the early endosome with deficiencies that are much, much, much greater than conventional biologics or conventional other therapeutics, upwards of 50%. And what that allows us to do then is to get to the muscle in a much more efficient concentrated way that allows us to hopefully affect change to the disease.

And in this case, with DMD, it allows us to affect the dystrophin levels. It allows us to affect the function of those muscles for those children as well, too. So it starts with DMD. It goes into myotonic dystrophy type 1, which is DM1 partnered with Vertex. And then there's a whole plethora of other diseases that we can also address via EEVs and also other modalities.

Okay. Great. Maybe starting with the DMD space. You talked a little bit about oligonucleotides. And we know, obviously, there are certain exon skippers that are already approved and commercially available in the space. So can you maybe talk about what, in your view, solidifies the EEV and using the cyclic peptides to deliver these medicines as potentially differentiating or what could be potentially best-in-class in this category?

Yes, it's a great question. I mean if you take a step back and look at DMD, in the U.S., it's a $5 billion market by itself Ex-U.S., you multiply that by at least 2. And so it's a huge market with a profoundly unmet clinical need. And there are companies that are going after DMD with a variety of different approaches, whether it's naked oligonucleotides, conjugated oligonucleotide, gene therapy, et cetera.

What makes it interesting and what makes our approach even interesting is the preclinical data that has translated remarkably to clinical data. So first and foremost, when you go after a pediatric disease or mostly a pediatric disease like DMD, where there's a deficiency within the dystrophin protein, you want to establish safety. Safety is the most important thing to be able to establish for these patients, especially the younger ones. Safety plus functional benefit.

Functional benefit in this case, is measured by an increase in dystrophin initially. That's what conventional thought always was. And so for us, what we're happy to see is that within our preclinical data, we've been able to translate from the canonical mouse models all the way through NHP to a healthy normal volunteer adult study into our recently released Cohort 44 patient data, we see this consistent translation around safety.

What we're starting to understand is that the dystrophin relationship to functional benefit is pretty complicated. And I think other approaches would also say the same thing. But what becomes really important is changing the lives of these patients with an established and safe medicine. And I think that's what's exciting about Entrada's EEV approach.

Can you maybe just remind us where you are in terms of overall clinical development versus some of the other modalities that are in the clinic? And just maybe before going to the next question, that's the level test.

So DMD is a cascade of different mutations that's in a variety of exons. There's 5 major mutations, but then there's a lot of different mutations below that. We're going after exons 44, 45, 50 and 51. Our exon 44 program just released its first multiple ascending dose patient data. That is -- we're going to continue with our Cohort 2, and then we'll go to a Cohort 3.

We're a little bit behind the competition, so to speak there. But once again, at the end of the day, what a patient will choose and what a PI will choose is a drug that has both the safety and the functional benefit. Our cohort 1, 45 data for our exon 45 program is likely the first-in-class and hopefully best-in-class, when it comes to that exon as well, too.

And those data for the first cohort will read out the middle part of this year and then 50 and 51. So we're right in the middle of this right now and going against a lot of other really interesting companies and really interesting approaches. At the end of the day, Paul, when we've talked about this extensively, the more approaches the merrier, right? Because at the end of the day, I think all of us are aligned on the same exact thing to bring treatments and a variety of treatments to these patients that have these diseases.

Okay. Great. You mentioned something earlier, which is key in development of DMD drugs, which is safety. And notably, there's always been sort of this historical concern with exon skippers with regard to liver toxicity and just what comes and what you can discover with dose escalation. Can you maybe remind us what you've seen so far? Natarajan, if you want to turn it over to you and just how you think about escalation here and what the safety data to date show?

Yes. So the safety data has been very clean for us. So we haven't seen any SAEs. We have not seen any AEs that lead to patients dropping from the trial. When we looked at PMO as a class of drugs, the main toxicity is kidney. And we have looked at all the kidney parameters like GFR (sic) [ eGFR ], magnesium levels, Cystatin C. You cannot even differentiate between placebo and treated.

So it's that clean. When it comes to liver toxicity, it is more for the PS chemistry rather than for the PMO chemistry. And of course, we didn't see any liver toxicity and we didn't expect any. Similarly, AAV has liver toxicity, but the modality that we are using, we didn't expect any liver toxicity and we didn't see any liver toxicity.

Right, just given the difference between a vectoral approach and what you guys are doing?

Yes. And I think that's a really interesting point, right? So when you start to think about diseases that have such a profound unmet clinical need, it becomes an analysis for the PIs and of course, the families around risk versus benefit. And I think the risk part usually comes up with safety, right? And so in our first cohort 44 data, which was 8 patients, as Natarajan said, we saw no safety concerns whatsoever.

When you start to think of some of the other programs that are out there, they've all had safety concerns. And so that's a huge differentiation right now at this early stage in development. And so we're really pleased with that. And once again, going back to one of your original questions, we saw all this solid safety within preclinical models. And so we're happy and this is what gives us a level of confidence that it will continue to translate as we get further and further into the clinic.

Okay. You mentioned for your exon 44 program, you recently top line Cohort 1 data. Can you maybe summarize for us what you saw in terms of your PK/PD and sort of early efficacy signals and just how you're thinking about the biomarker results to date?

Yes. So I think Natarajan and I will both take this. So I think when we looked at these data, there were 3 components of data, frankly, in this order, right, safety, which I think we've already mentioned it quite the times. So that's been confirmed. The second really was dystrophin production. And let me come back to that. The third was functional benefit. We believe that we would see dystrophin production in the double digits. We did not see that. And we know why we didn't see it, and we're confident as to when we will see it as we get into Cohort 2.

Nataraj will speak a little bit more about why we didn't see the dystrophin levels. But what was interesting was the functional benefit. We did not expect to see functional benefit this early at day 127 within these patients. And what we saw was statistically significant functional benefit as measured by 2 factors, one called time to rise and the other called time to rise velocity, which are robust and clinically relevant endpoints that regulators have all approved.

We also saw meaningful trends within 10-meter walk. So the question becomes, well, how did we see functional benefit with low dystrophin levels. And I think that's what the market is grappling with right now. And I think it comes back down to the importance of the relationship between dystrophin and functional benefit. But perhaps it's not a one-to-one correlation. Perhaps it's actually more complicated than that.

And I think what becomes interesting from the Entrada perspective is our preclinical data that shows the ability to get into these quiescent satellite cells and activate those satellite cells to be able to regenerate muscle. And right now, preclinically, we've proven it. Clinically, we're looking into that as to perhaps that's the reason why we were able to see functional benefit earlier.

At the end of the day, Paul, PIs patients, that's not -- the reasons why are not the important ones. That's for us, right? That's for us, for you, for our investors to understand. But from a product perspective, a potential therapeutic perspective, what they are seeing is safety and early functional benefit. They don't care as much as to whether or not it's double-digit dystrophin. You can have 25% dystrophin, but if you have mediocre functional benefit, then what's the point, right?

So for us, we have to explain that a little bit better. We have to learn about that a little bit better. And I think in time and with data, we'll be able to understand that better. But DMD is a complicated disease. So let's talk about the dystrophin levels and our projections and why we think that we're going to get back to where we need to be.

Yes. Maybe, Natarajan, you can walk us through what your -- before you went into the clinic, how you modeled it and then just kind of how that's different actually in the clinic with regard to PD?

So we had a robust data set to model what we were going to get in DMD patients. So we had nonclinical studies. We had NHP, other NHP sub-chronic tox, and we had other NHP studies, and then we had normal human volunteer study. So we could get a correlation between plasma exposure, muscle exposure, exon skipping.

And then we use that to project what exposures we would get in patients and how that could translate into muscle exposure and exon skipping and eventually dystrophin. What we saw in the Cohort 1 is that the exposures that we got was half of what we expected based on our normal human volunteer study and NHP study. And of course, the dystrophin level was -- it went from 4-point-some percent to 6-point-some percent about 2% increase or 50% increase from baseline.

So the reason for that turns out that when we went back and looked at the pediatric juvenile NHP, there was, again, low exposures in the pediatric population. So probably the differences in the kidney volume versus total volume contributes to low exposure in younger subjects compared to older subjects. So essentially, what has happened is that we have rightly shifted our projections based on our new model using pediatric or juvenile NHP where what we expected in Cohort 1, we would now get in Cohort 2 because we just need a linear increase in exposure, which is then double our dose should happen, and that should result in eventually having the double-digit dystrophin that we had projected for Cohort 1.

I actually just thought of a question. I don't know, you talked about the descriptive statistics showing functional benefit. But I'm just sort of curious on things like time to rise and the velocity of the time to rise. But I'm just sort of curious, if you actually took a look at the sort of completeness and length and sort of quality of the dystrophin that was produced and any comments there that might potentially explain the delta between the level of increase versus the functional outcomes?

Yes. In terms of quality of dystrophin, we do expect for majority of the patients, we do expect the quality of the dystrophin to be good. This is based on a lot of analysis that we have done from DMD, which is a related disease, where there is in frame deletions where when you have 44 amenable patients, majority of them produce a protein that is robust.

But I think the difference here, I think, is more exposure into the satellite cells because DMD is a 2-hit disease, where the first hit is to the mature fibers, which causes muscle break down and fat cells and necrosis occupying that space because of lack of regeneration, which is due to inactivation of the satellite cells activation, right? So I think the ability to get to satellite cells and activate them, I think, is playing more of an important role here.

I think the interesting thing, Paul, because we spent a lot of time on this as well with you, your team and the company is there's no biology risk here, which is what gives us confidence, right? So at the end of the day, we do believe the dystrophin levels will come up. That is important, and we'll get there with the second cohort.

This was a projection [ means ] more than anything. Now that we have the right data, this juvenile NHP data that Natarajan is referring to is a 55-week study. We got those data right about the same time we needed to share the data as well, too. Since they sit right on top of each other based upon the concentrations, we feel as though that will allow us to be able to get -- that's what's giving us the confidence around Cohort 2.

But what's interesting, once again, going right back to what Natarajan said was we -- when we start to think of Cohort 2 success for 44, which will come by the end of this year, we think of it in 3 ways. One, we want the maintenance of a favorable safety profile. And that's no small feat considering we're doubling the dose to 12 mg per kg.

So if we do that, that's huge once again, from a risk-benefit perspective. The second becomes getting those dystrophin numbers into those double-digit range. And I think Natarajan explained that with the right shifting. And the third is the maintenance of functional benefit. If we can maintain functional benefit, that is a big deal, right? Because these patients, especially the patients that we are observing once again, in this first cohort, we the patients that we had had a baseline dystrophin that was much lower than what Avidity and what NS Pharma saw. We had 4% versus their 7% to 10%. If we can maintain that functional benefit, that's a big deal, right? And so -- and we'll know that in the next several months. So we're excited about this.

Great. So maybe just to clarify, both in terms of timing and potential magnitude of changes. You talked about a right shift in your data expectations based on what you've learned from Cohort 1 and your updated NHP modeling. So can you maybe -- again, not to necessarily put you in a corner, but just help us think through what the 12 mg and the 18 mg dose might look like based on your updated information.

Yes. I mean I could start. I mean I think we for the second cohort with the 12 mg per kg, it really depends upon what the baseline looks like, right? Because we don't want to be [ acute ] with these numbers. But if you really want to look at this, if we had baseline dystrophin levels of what Avidity or NS Pharma had, then we would have double digits.

So there's acuteness there that we're not trying to go for. When we say double digits, we mean double digits, right? We think we're going to get there at 12 mg per kg. At 18 mg per kg, if we have to go to 18 mg per kg, and I think there's a big hit, right, based upon what the safety and functional benefit look like at 12 mg per kg, that's where you get like to the 25% plus, right?

But it might not be necessary because the important thing here is are we getting into the satellite cells? Is that what's affecting the functional benefit in a positive way? We know that the antibody approaches can't get into the satellite cells just it's not expressed on the antibody itself, right? Or it's not expressed on -- maybe speak -- the surface, right. So we already know that, that's a differential, right?

And so for us, if at 12 mg per kg, we achieve what I laid out, which is a favorable safety profile, double-digit dystrophin production, so above 10% and then a maintenance of functional benefit with the types of cost of goods sold that we have with the types of efficiencies around manufacturing that seem to be delaying the BLA for Delzota, that's a big win for us. And then if we have to go to 18 mg per kg, we can go to 18 mg per kg. We just don't know if we need to do that, but we're prepared to...

Okay. Can I just play devil's advocate here? And let's say, you go to 18 mg and you have no safety events or DLTs that keep you from theoretically going higher. What's the rationale for not -- for stopping there versus a 24 mg dose or 28 mg dose...

That's a very fair question.

You could optimize theoretically, if the curve is linear or algorithmic.

You'll keep on pushing it...

Can you keep on pushing it to get to almost a wild-type level of impression here?

One, there is the possibility to do that. So the tox data and the Cohort 3 data will determine that whether we can go in and we have probably good confidence that we could go with that. The question is, do we have to go there? I think based on the revised model that we have, even at 12 milligrams per kg, we should hit both the aspects of it, the addressing the dystrophin level in the fibers and addressing the dystrophin levels in satellite cells, we already -- which we already seem to be doing.

So I think, yes, we can probably move based on safety in third cohort. But I think most likely, we don't have to go beyond 18 mg.

I think the other thing is we -- if we continue to show what we've shown, right? So safety, dystrophin getting there, functional benefit, early but sustainable functional benefit, I think there will be a fair amount of pressure from the patient groups as well, too, to say, can we get access to drugs?

And we're already seeing that. A lot of rare disease companies see compassionate use requests, expanded access requests, things like that. I think if we continue the momentum that we have here, albeit the setback last month, but we catch up to that, then there's going to be a lot of good pressure on us to say, let's get this out to the patients as soon as we can.

Okay. Maybe just to wrap on the 44 program. Can you remind us what, if any, updated long-term follow-up you'll present on Cohort 1 and when that will be and then when Cohort 2 data might come?

Yes. So that's a great point. So we're excited. I mean we'll have our open label at 6 mg per kg data readout before the end of this year. So that's going to be a very important readout because it's going to be roughly 1 year on drug. So multiple doses, of course. And so it will be interesting to see. And at that data point, when we share that data, we'll also share a more robust analysis of the functional measures, right?

So there's a whole -- in our corporate presentation, there's a whole list of functional measures that we're looking at that we will be able to read out on. So we'll give a much more fulsome view. I mean the Cohort 1 data was supposed to be more of a snippet, but the open label will explain a lot more. And remember, open-label only -- and all 8 patients have converted to the open label.

Open label will only measure really 2 things. It's going to measure safety and functional benefit. There's no dystrophin level that's being measured in the open label. And so that will come out before the end of the year. Cohort 2 data at 12 mg per kg is coming out at the end of this year as well, too. We're continuing to monitor it. I think it's an exciting data set. And so those 2 data sets by the end of this year can be very telling for 44.

Okay. Does it make sense to present them simultaneously?

It's something that we're working on right now internally. The question becomes -- and just I think all companies -- all companies face is that when you're running these studies, you're getting into the winter, so you're getting into the holiday period. And so you just want to make sure that you can present that correctly. And so we're keeping an eye on it in terms of how best to present it, where to present it, things like that.

You referenced some competitors earlier, including Avidity and NS. And so the space is obviously very actively invested in right by the industry. But how do you think about the market, especially given the context of what's happened with some of the Sarepta products, specifically with ELEVIDYS and just, I guess, upon market entry for yourselves and other companies, how do you think about positioning and just sort of timing to market?

I mean data wins, right, at the end of the day. I think, unfortunately, what we've seen over the past year -- well, more than the past year, over the past 5 years really is DMD is difficult. It's a difficult disease that was not fully explained by the first-generation movers like Sarepta, that's okay, right?

We're learning a lot more about it, right? So then Delzota comes in and shows us remarkable dystrophin production. And let's call it what it is. It was remarkable dystrophin production, albeit at a safety -- at a 5 mg and a 10 mg per kg dose that is kind of difficult to understand because you don't know what's 5 mg per kg or what's 10 mg per kg. They pulled a lot of their data. They have safety concerns. It's an antibody, how do you manufacture that much antibody. So there's pluses and minuses.

ELEVIDYS set gene therapy back, right? And I think that hurt the patient groups a lot as well, too. And they're trying to come back, for years people had asked us, do you think that an exon skipper can be added on top of gene therapy? I think it's the other way around now. I think it's going to gene therapy be added on top of an exon skipper.

I think 5 years ago, if you look at some of the stuff that I've said and Natarajan has said, the flexibility of this approach, the ability to start, stop, increase, decrease, dose, things like that becomes really important to be able to match up to a patient's own journey. What hasn't stopped is the fact that it's a $5 billion market in the U.S. that is underpenetrated and that patients are clawing and desperate for a drug that not only works, but also has that flexibility and those characteristics that marketing teams usually put out, but sometimes they're not supported by data.

I think we have the opportunity to be that -- in that mix, right? And so I think for us, yes, competition is good, right? But that doesn't mean that -- like I'll give an example of my former company with Amicus Therapeutics, right? With Fabry disease and Pompe disease, they certainly weren't the first to market. And some, they weren't the second to market. But they were able to carve out a very lucrative and meaningful business because of the data profile, right?

And I think for us, I think that's what's going to drive the safety plus functional benefit when it comes to 44 and 45 ultimately, that's what's going to drive utility of the hopeful of the drug in the years to come. And we're seeing that within our clinical trials. We're seeing a tremendous amount of excitement.

We released last week our -- a press release around a data monitoring committee for our exon 45 program, which is very difficult exon and the data monitoring committee essentially said, go to 10 mg per kg, it's a 5 mg per kg study, as you know, but go to 10 mg per kg, and there's an influx of e-mail. So the patients, the PI -- I think even with the competitive landscape are -- still the bar has not been fully met. And I think that's where we can kind of come in here.

Since you mentioned the 45 program, I want to ask the construct is fundamentally the same between -- with the 44 program, but can you maybe talk about the translatability and maybe what you learned from your early PK work on the 44 program in the clinic. You also referenced that your data monitoring committee recommended dose escalation here to the next dose. And so are there any particular learnings that you would communicate from the 44 program about the 45 program to investors?

Yes. I mean I think I'll start, and Nataraj, please jump in as well, too. We've always said that the 45 program would be -- we didn't expect to see and we still don't expect to see the levels of dystrophin that you would see in 44. First -- and why is that, right? So first, the baselines are usually much lower, right? And when I say much lower, I mean like just above 0, right?

Now the caveat is that in 44, we had 4%, where we thought we'd had 7% to 10%. So it moves, right? But I still think that, that would be consistent with 45. So if you have a baseline of less than 1% of dystrophin, then we've also said that our expectation ultimately, not with the first cohort, but ultimately would be to get into the single digits dystrophin above, which would be huge, right, because casimersen, AMONDYS 45 barely shows any dystrophin production, right, because it's a difficult disease.

So for us, in this first cohort, we want to establish this safety. Safety is no small feat here. And I think the DMC result from last week puts us on a path where we believe that we are establishing safety here. And we're excited about that, right? Dystrophin functional benefit, that will come in time. It may not come in that first cohort, but that's okay, right? For us, if we establish full safety, that in itself, plus which cannot be -- I have to emphasize this as much as I can, the dosing around 45 drug is once every 6 weeks. The dosing around casimersen is once a week.

That dosing difference, that regimen is huge, right? We start to think about quality of life. We start thinking about you don't have to go and get infused every week for a 6-year-old kid, 7-year-old kid. I think there are so many characteristics around this 45 program that if we establish consistent safety in that first cohort, safety plus a dosing regimen, which is every 6 weeks, that alone is a huge win. And then in Cohort 2 and then maybe Cohort 3, we'll start to see some of that functional benefit and dystrophin start to move in a more meaningful way.

Great. In our remaining time, I want to talk about some of your other programs, including 670, which you've partnered with Vertex. Can you maybe just remind us of what are Entrada's obligations under this partnership?

Yes. So we entered this partnership a few years back, and our job is really to take the preclinical work up in IND. So that's all been completed, right? And so our obligations essentially to date have been completed. And so we are now -- we are now waiting, of course, for the study to read out, this MAD study to read out, which Vertex has publicly declared that, that will come out in the second half of this year.

So our obligations are done. We think we partnered a really good drug here that 110,000 patients in the world have DM1. And we are eagerly awaiting those results in the second half of this year.

Okay. Great. With regards to the DM1 program, to help maybe guide investors who are following it maybe from the Vertex side as well as from your side, can you talk about the translatability of the 44 or 45 program data you've seen to date internally and how that may read across to DM1.

You want to take that?

Yes. So when we think about it uses the same EEV. So the safety should translate across the platform, and we have seen that in preclinical studies. So that's -- we have established safety at 6 milligrams per kg, I think, in both normal human volunteers and in patients. So that should translate.

The second thing is that this is a difference between -- it's a different disease, right? I think DM1 is a very different disease compared to DMD. And the patients are not pediatric patients, they're adult patients. So we don't expect this -- the exposure differences that we have seen in pediatrics to translate that.

So I think between safety and exposure, we are expecting good splice correction. We have seen -- I think we've had the most robust preclinical data with a panel of over 20 genes that we have shown splice correction. So I think it should, in our opinion, translate in the clinic as well.

I think what becomes important in DM1, and it's probably a better question for Vertex, but taking a step back is also safety plus functional benefit ultimately, right? And so spliceopathy gets -- it's still kind of difficult to understand what that means. And so I think as they return those results or present those results, we'll be very interested to see how this pans out within an increasing competitive dynamic as well.

Great. With all small and mid-cap biotech cash runway is always a classic question. So can you remind us if assuming the DM1 MAD data are positive, how that potentially helps your cash position down the road there? Is there milestones tied to this particular readout?

So we haven't disclosed what the milestones are in terms of the individual milestones, but the aggregate is pretty significant. So what I can say is that our cash runway goes into Q3 of 2027, and it does not include any milestones for the DM1 collaboration. Anything above and beyond would -- and it's significant in terms of the milestones would just add to that cash runway.

Okay. Maybe in our last minute or 2 here, you've talked about other applications. You started for your EEV platform, we started talking a little in the past about ophthalmology and other things like that. Can you maybe just walk us through what sort of early development you have there and just in terms of other areas and just kind of what you might disclose to the Street in the coming, call it, a year or 1.5 years?

Yes, we're super excited about the ophthalmology franchise. I'm going to let Natarajan talk about the inherited retinal diseases specifically Usher syndrome type 2A.

Yes. So we had already nominated a candidate for USH2A with a significant type of patient population and the preclinical data that we have seen is quite good. It is, first of all, IVt injection, and there may be a possibility of once in a quarter injection. So it is looking very attractive from that.

So we are about to -- by this year to nominate candidate for another inherited retinal disease as well. It just talks about the platform and our ability to work on this exon skipping and steric blocker space, where we are able to get deep tissue penetration and get very robust target engagement. So I think that is enabling us...

In the [indiscernible].

Yes, indeed.

And I think we'll share more as the year goes by. Neither one of those programs will enter the clinics this year, but we do expect them to start to robustly move into clinical development. We're figuring out the plan. We have to talk to the regulators. There's a global approach here as well.

So we're looking for those efficiencies because once again, 15,000 -- 10,000 to 15,000 patients, but with a remarkable unmet clinical need as well. So we're excited about that as it leverages not only core expertise within exon skipping, but it also allows us to obviously branch out and show the applications of the Entrada capabilities in it's other diseases.

Yes. I think just given the frequency of how often patients get VEGF injections for AMD or DME, it doesn't even have to be a quarterly, right, necessarily.

Exactly right. Yes.

Okay. Well, we're out of time. So my thanks to the Entrada team for joining us.

We appreciate it, Paul. Thank you.

Thank you.

Welcome to the Entrada Therapeutics Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Karla MacDonald, Chief Corporate Affairs Officer. Please go ahead.

Good morning, everyone, and thank you for joining us today. I'm Karla MacDonald, Chief Corporate Affairs Officer at Entrada Therapeutics. Today, we will be reviewing the positive top line results from Cohort 1 of participants living with Duchenne muscular dystrophy or DMD, treated with ENTR-601-44 in our Phase I/II ELEVATE-44-201 study.

Our news release, along with the accompanying slides can be found in the Investors section of our website.

Before we begin, I would like to note that we will be making some forward-looking statements during our presentation within the meaning of the U.S. Securities Act of 1934. These statements are based on Entrada's current beliefs and assumptions, are subject to risks and uncertainties and are not guarantees of future performance. Further, we undertake no obligations to revise or update any forward-looking statements.

We encourage you to review our SEC filings for more information.

Speaking on today's call are Dipal Doshi, our Chief Executive Officer; Dr. Natarajan Sethuraman, our President of Research and Development; and Dr. Laurent Servais, Professor of Pediatric Neuromuscular Diseases at the University of Oxford. Dr. Servais is an expert in the treatment of DMD and other neuromuscular diseases and serves as an investigator in our ELEVATE-44-201 study.

We are thrilled to have him on the call with us today. Also, Nate Dowden, our President and Chief Operating Officer; and Kory Wentworth, our Chief Financial Officer, are on the line to answer any questions.

Turning to today's agenda. Dipal will begin with an introduction and overview of our development strategy for our DMD franchise. Dr. Servais will then discuss the urgent need for new therapies for people living with Duchenne. Following his remarks, Natarajan will review the Cohort 1 top line results and outline the next steps for our ELEVATE-44-201 study. Dipal will conclude by reviewing the upcoming clinical milestones across our pipeline before opening the call for questions.

I will now turn the call over to our Chief Executive Officer, Dipal Doshi.

Thank you, Karla. Good morning, everyone, and thank you for joining us. Today marks an exciting and important moment for Entrada. We are incredibly pleased to share positive top line results from Cohort 1 of our Phase I/II ELEVATE-44-201 study, evaluating ENTR-601-44 in ambulatory individuals with a confirmed mutation in the DMD gene amenable to exon 44 skipping. This is the first data readout from this important clinical trial, and we are encouraged by the results we have seen to date.

We are also honored to be joined by Dr. Servais, who will provide clinical context for the data we are sharing today. Taking a step back, Entrada is a clinical stage biopharma company developing proprietary genetic medicines to deliver best-in-class outcomes in high unmet need diseases. As we look at the year ahead, Entrada is positioned to have a milestone-rich 2026. We have a deep and expanding pipeline with multiple value inflection points in 2026, including four clinical catalysts in DMD and DM1 with additional pipeline expansion efforts ongoing. Our programs are differentiated in untapped markets.

Notably, in our DMD program, we are pursuing an accelerated approval strategy in a market with profound unmet patient need. Additionally, our ENTR-601-44 program has progressed to the second cohort at the increased dose of 12 mg per kg at the recommendation of an independent data monitoring committee. Today's Cohort 1 data, our ELEVATE-44-201 open-label period data as well as the Cohort 2 data by year-end 2026 have the potential to derisk and establish proof of concept across our neuromuscular programs.

With the cash runway into the third quarter of 2027, we are well capitalized to realize our value catalysts.

On Slide 6, our efforts to establish a new class of genetic medicines have enabled us to build a growing and diverse pipeline of therapeutics focused on disease areas with a substantial patient population and a significant unmet medical need. Specifically, we're pleased to share positive top line results from Cohort 1 of the ELEVATE-44-201 study. Natarajan will dive deeper into the data, but at a high level, results demonstrated a favorable safety and tolerability profile and meaningful potentially differentiated functional benefits in participants treated with ENTR-601-44.

We're on track to report data from the open-label period and from Cohort 2 at 12 mg per kg by the end of the year. In December, the FDA also granted rare pediatric disease designation to ENTR-601-44. Moving along, we are also currently dosing patients in our ELEVATE-45-201 study and expect this to be both a best-in-class and first-in-class program to meet the needs of a large segment of the DMD community. We expect to deliver data from Cohort 1 in mid-2026. Our ENTR-601-50 candidate received regulatory authorization from the U.K.'s HRA and Research Ethics Committee.

And for both ENTR-601-50 and ENTR-601-51, we expect to submit additional regulatory applications and obtain authorization following the review of data from the ongoing studies of our lead programs. Our partners at Vertex continue to enroll and dose the MAD portion of the GALILEO global Phase I/II clinical study of VX-670 in people with DM1.

The study assesses both safety and efficacy and is on track to complete enrollment and dosing in the trial and share results in the second half of 2026.

Beyond the strong progress in our clinical programs, we've generated positive preclinical data for programs focused on ocular and metabolic diseases, which include new moieties. This includes the advancement of two novel Oligonucleotide based programs for the potential treatment of inherited retinal diseases, where there is a high unmet need.

The first ocular candidate, ENTR-801, an exon 13 skipping therapy targeting a subgroup of patients with Usher syndrome or Usher 2A was announced in December 2025. We expect to name a second clinical candidate in an ocular disease in the second half of 2026.

On Slide 7, I will now turn the call over to Dr. Servais, who is a Professor of Pediatric Neuromuscular Diseases at the University of Oxford. Current President of the World Muscle Society and serves as an investigator in our ELEVATE-44-201 trial.

Dr. Servais will discuss the urgent need for new therapies for people living with DMD and what the initial Cohort 1 results mean for the DMD community.

So thank you very much, Dipal. And before going into what is actually Duchenne muscular dystrophy, I would like to show you one of my patients with this condition is 4.5 years old. And as you will see, he has a lot of difficulties to climb stairs. We would like to do it as fast as possible, but he needs the padister, needs to push on his leg to be able to climb the stairs. And we know that unfortunately, things are not going to be better with time. And this proximal weakness will be more and more obvious with time. And this young boy unfortunately, will lose the ability to plans and to rise from floor and eventually will lose ambulation between the age of 10 and 20.

So Duchenne muscular dystrophy is related to a mutation into the dystrophin gene.

And the dystrophin gene includes a protein that is called dystrophin and dystrophin is a giant. It's a very big protein. And it's actually the shock absorber of the muscle cell, but not only. Yes, the main function is shock absorbing, but also it binds with several very important protein. And that's why it is that important if we try to restore dystrophin to try to keep the main domains and eventually to get the longest dystrophin as we can when we try to restore dystrophin.

And what happened in a car, if you don't have shock absorber, it breaks, right? The very same applies to a muscle cell. If shock absorber is missing, the muscle cell can be destroyed and then you have a process of necrosis and regeneration that characterize dystrophy in general. So Fortunately, we have stem cells that can multiplicate and give a new muscle cells. But unfortunately, the genetic defect is already also present in the stem cells. And you have a kind of very accelerated turnover of the muscle cells.

And the problem of Duchenne muscular dystrophy is that it affects all muscle, including heart, right? And the burden for the family, for the kids, of course, but for the family and also for the society is huge. It starts with contractors and that needs physiotherapy and sometimes even orthopedic management. Those kids will need mobility support like because of the steroids, they will have endocrine issues. And because of steroids and because of the immobility, they could have bone health issues because of the weakness they can develop with scoliosis, insufficiency to ventilate and then respiratory issues. some of these kids may also present with cognitive issues and eventually heart problems.

So it is a very complex condition that will represent for the family and for the society, a very significant burden. It's very interesting to figure out that some patients may slightly milder phenotype and lose ambulation 4 to 5 years older than the others. And those are the patients who are skippable for the 44. And why do these patients present this difference in loss of ambulation is because they naturally express 5% of dystrophin. So we know that if we could express something like 5% of dystrophin and if we could do it since birth, then we could be potentially instrumental on the age of loss of ambulation. And if we can express more than 5%, it will make a lot of sense for the patient and for the family.

And that's why I think it's very exciting to see products that even at the low dose may induce a significant exon skipping and some dystrophin expression, which is in line with the exon skipping that is observed. Of course, we need a longer exposure to the drug because we also know that with time, the amount of dystrophin that is expressed by drugs that promote exon skipping will increase. And I'm very excited with the fact that escalating the dose could allow to improve more exon skipping and more dystrophin in these boys. Thank you for your attention.

Thank you, Dr. S. We very much appreciate your continued support as we advance our clinical programs in DMD. Today, I'm very excited to share the top line results from Cohort 1 of our ongoing ELEVATE-44-201 trial. First, let me go through key takeaways from our data. We met the primary objective of the study with favorable safety and tolerability of ENTR-601-44 at 6 milligrams per kg dose. All eight patients have transitioned to open-label portion of the study. Markers of kidney function were within normal range and comparable to placebo. We were surprised and highly encouraged to observe earlier-than-expected functional responses, a statistically significant improvement in treated participants time to rise velocity versus placebo.

Time to rise velocity is an approvable clinical endpoint in Phase III studies. We have seen positive changes in TTR velocity across the majority of participants irrespective of the severity of the disease or age. We have also observed lower-than-expected plasma exposure and consequently lower dystrophin levels in pediatric DMD patients when compared to the exposures we have seen in healthy adult volunteers and adult NHP. This, however, is consistent with the exposure data we recently received from our [indiscernible] studies.

As such, we have updated our PK modeling and believe the plasma exposures will be significantly increased in Cohort 2, resulting in higher muscle concentration, exon skipping and dystrophin production. We believe we have a highly differentiated delivery mechanism, including ability to access [indiscernible] satellite cells, which are critical drivers of muscle regeneration and repair. This unique mechanism of action may explain why dystrophin levels in Cohort 1 were sufficient to improve time to rise velocity. Ultimately, the goal of any therapy is functional benefit, and that is why these early results with ENTR-601-44 are uniquely important.

Now I would like to provide some background on our drug candidate, ENTR-601-44, which is an investigational genetic medicine and review the trial design. ENTR-601-44 is designed to address the underlying cause of Duchenne, facilitating the production of functional dystrophin from mRNAs with directed reading train. ENTR44 is a proprietary endosomal escape vehicle conjugated oligonucleotide. The oligo sequence is optimized for skipping exon 44 for patients with the mutation in the DMD gene that is amenable for exon 44 skipping. This comprises approximately 8% of the Duchenne patient population globally.

ELEVATE-44-201 is a global 2-part randomized double-blind, placebo-controlled Phase I/II study, evaluating the safety, tolerability and effectiveness of ENTR-601-44 in ambulatory participants ages 4 to 20 who are exon 44 skip vulnerable. Multiple ascending dose Part A portion of this study evaluates the safety, pharmacokinetics, pharmacodynamics and functional parameters following intravenous administration of ENTR-601-44 to study participants in U.K. and EU.

There are 3 cohorts in this study. Today, we will be talking about Cohort 1 results. and the Cohort 1 portion of the study enrolled 8 participants ages 6 to 17. They were randomized 3:1 to receive ENTR-601-44 at a dose of 6 milligrams per kg or placebo administered through intravenous infusion.

During this double-blind period, doses were administered on days 1, 43 and 85. Muscle biopsies were performed at the time of screening and six weeks post the last dose. Following the initial 3-dose administration in Part A, all participants continued to the Phase II portion of open-label portion of the trial for evaluating safety and efficacy over a longer period of time. This study is designed to enable registrational conversation with the FDA, leveraging the accelerated approval pathway. Future Phase III confirmatory studies are expected to enable full approval in the U.S. and beyond.

Let's look at the demographics and baseline characteristics of Cohort 1 participants. The average age of treated participants in the study was 9.3 years. Per protocol, all participants were ambulatory, all were on stable doses of steroids. Baseline dystrophin in both placebo and treated population were lower than what has been reported for other exon skipping clinical studies. This is important to note as dystrophin increases after treatment generally correlate with higher baseline dystrophin levels.

Now let us look at the safety data. We saw very favorable safety and tolerability, the primary endpoint of our study with ENTR-601-44 at 6 milligrams per kg. All patients -- all treatment-emergent adverse events or TEAEs were mild to moderate, with most common AE being headache. There were no reported serious adverse events or SAEs and no adverse events leading to discontinuation from the study. Importantly, no renal safety concerns were observed in the study participants who received ENTR-601-44.

All Eight Cohort 1 participants have now transitioned to open-label portion of the study. We are pleased to see markers of kidney function, including eGFR, cystatin C and magnesium were in normal ranges and comparable to placebo, reinforcing the strong safety profile of ENTR-601-44 in patients with Duchenne at 6 milligrams per kg dose. Let's change gears and review the PK and biomarker data. We observed a lower-than-expected plasma Cmax and AUC or area that curve in pediatric DMD patients, about 50% less than levels seen in healthy adult volunteers and healthy NHPs.

This, however, is consistent with the recently received PK data in juvenile NHPs. However, in juvenile NHPs, there was more than dose proportional increase in plasma AUC at higher doses. We believe that the low plasma exposure at the starting dose of 6 milligrams per kg in Cohort 1 resulted in lower exon skipping, about 2.3% above baseline and dystrophin levels about 2.3% above baseline in pediatric patient population.

As I mentioned before, the baseline dystrophin was lower in one patient than what we had reported. What has been reported in other studies. At day 127, six weeks post the last dose, the dystrophin level in treated patients was approximately 6% -- while we were surprised to see significant differences in exposures between juvenile and adults, the consistency seen between NHPs and humans fully explains the difference and gives us confidence that we will see meaningful plasma exposure in Cohort 2, which we expect will deliver higher exon skipping, higher levels of dystrophin and sustained gains in muscle function.

We originally projected PK and exon skipping based on adult human normal volunteer study because that was the only human data available at the time of Cohort 1 dose selection. Data from juvenile NHP study did not become available until the end of the first quarter of 2026. at the time of Cohort 1 design, the adult normal human volunteer study and adult NHP data were the best available anchors for human PK projection, and this is not unique to Entrada. Now that we have both Cohort 1 patient PK data and Juvenile NHP data, we have right shifted our projections. The Juvenile NHP data reinforces the lower initial AUC set point in subjects and suggests that we will see dose-dependent increase in AUC.

More importantly, Juvenile NHP data also shows a steep nonlinear exon skipping response at higher AUC levels, suggesting Cohort 2 will see a disproportionate increase in exon skipping to the dose increase. This gives us much more relevant basis for Cohort 2 and Cohort 3 projections than the other data provided for Copart 1. Our updated PK analysis projects higher levels of plasma concentration, exon skipping and dystrophin in Cohort 2 and Cohort 3, supporting our path to accelerated approval and eventually full approval.

The DMD community at large continues to learn about the biology of Duchenne and the relationship between dystrophin and functional benefit. Despite lower plasma exposure and dystrophin level, we obtained earlier-than-expected functional response that was statistically significant, which we will go through in the following slides. As I mentioned, the ultimate goal of any therapy is functional benefit, and that is why we are so encouraged to see earlier-than-expected functional response that were both statistically significant and clinically meaningful.

Let me give some background on time to rise functional assessment. TTR is a measure which carries the largest absolute and proportional annual signal and is used as an early prognostic factor for disease progression and loss of ambulation. It is generally the first functional metric to respond to therapy and has good statistical properties for evaluating motor function in individuals with DMD. Duchenne from the floor engages most of the proximal muscle groups that fail earliest and most dramatically. TTR velocity is expressed as rises per second and is designed to reduce the impact of outlight.

With that background, in Cohort 1, we have shown statistically significant improvement in treated patients time to rise velocity versus placebo. The mean change of TTR velocity was 0.08, 3.5x higher than minimal clinically important difference or MCID threshold of 0.023, suggesting that ENTR-601-44 is potentially changing the trajectory of the disease. Positive change in TTR velocity was seen across majority of the participants, irrespective of the severity of their disease or age, which likely suggests that Cohort 1's functional benefit is drug-related effect.

Further, the end of Cohort 1 dystrophin level correlated with the end of Cohort 1 TTR velocity, suggesting that dystrophin production may have crossed a critical threshold for functional improvement. Additionally, we have also seen a positive trend in 10-meter walk run assessment, another metric used to evaluate motor function in DMD. It is important to note that TTR velocity is recognized as an approval Phase III endpoint in DMD clinical studies that has been and is currently being used by companies.

We are already generating clinically meaningful functional benefit at the lowest dose tested in the study and the TTR velocity we saw in Cohort 1 data is unprecedented. TTR velocity treatment difference of 0.115 dices per second is nearly 2x or to be at 1.7x compared to what was seen with pamelione signal that FDA accepted as a registrational primary endpoint at 0.06 per second in their VISION-DMD study. The fact that we achieved statistical significance with just eight participants at the lowest planned dose leads us to feel confident that we will see further functional benefits as we dose up in Cohort 2 and 3.

Let's now drive into why we believe the highly differentiated delivery mechanism with ENTR-601-50 to ENTR-601-44 could lead to these differences. DMD progression is driven by both aggressive muscle breakdown and impaired muscle regeneration. The therapy can therefore be protective, regenerative or both. An ideal therapy shifts the balance back towards regeneration to parent protection. One potential path to establishing a functional cure is by assessing quite and satellite cells, which are the stem cells the body relays upon to repair and regenerate damaged muscles.

These critical drivers of muscle repair are emerging as potential significant competitive differentiator by addressing the dystrophin double-head problem. We believe we have highly differentiated delivery mechanism, including ability to access quiet and satellite cells, suggesting a potential not only to protect existing muscles from further damage, but to provide basis for regeneration of new healthy muscles.

One potential driver of functional benefit that we saw in Cohort 1 could be due to our ability to access quiet and satellite cells, the target cell population that transfer into receptor targeted antibody conjugates and other platforms do not reach, driving muscle repair and regeneration that manifest as improvements in muscle function before it fully manifests at dystrophin levels in a western blot from a muscle biopsy.

Now I'll turn it back to Dipal.

Thank you, Natarajan. We'll now shift gears and take a look at our 2026 inflection points. We have significant clinical momentum and are well positioned to continue to advance our pipeline through multiple near-term clinical milestones. All eight study participants in Cohort 1 of ELEVATE-44-201 have now progressed to the open-label period, where they are receiving six doses of ENTR-601-44 at the 6 mg per kg dose. We expect to see a continued benefit of functional response over time, and we look forward to sharing data from the open-label period by the end of this year.

Additional study participants are now being dosed in Cohort 2, in which they will receive placebo or three doses of 12 mg per kg of ENTR-601-44. We anticipate we'll see an increase in exon skipping and dystrophin expression in Cohort 2 with continued functional benefit. We plan to share data from Cohort 2 by the end of this year as well. Our ELEVATE-45-201 study is now fully enrolled with a data readout expected in the middle of 2026. Because the design of Cohort 1 is based on previous modeling, we expect plasma exposures to be similar to those seen in ELEVATE-44-201 Cohort 1.

This implies the potential for lower-than-expected exon skipping in dystrophin, but the potential for functional improvement at the 5 mg per kg dose. I'd like to take a moment to emphasize how incredibly grateful we are to those living with Duchenne, their care partners and the study investigators and personnel who are taking part in our clinical study. Advancing potential therapies is not possible without the participation of the community, and we're inspired every day by their commitment to make progress for those living with Duchenne.

To wrap up today, we have established significant clinical momentum with our top line results from ELEVATE-44 Cohort 1. Importantly, we believe that we have achieved a drug treatment response that has pushed the dystrophin levels above a certain threshold required for functional benefit.

We continue to remain on track towards multiple near-term value drivers, including our ELEVATE 44 data readouts for the Cohort 1 open-label period and Cohort 2 by the end of the year and the ELEVATE 45 Cohort 1 data readout planned for the middle of 2026. We are executing well against the goal to have four clinical stage programs in our DMD franchise in 2026, and our partners at Vertex are on track to complete enrollment and dosing in that study and share results in the second half of 2026.

Beyond neuromuscular, we expanded our pipeline late last year to include ENTR-801, our first IRD clinical candidate targeting Usher Syndrome Type 2A, and we plan to nominate our second IRD candidate this year. We are confident that our efforts to establish a new class of genetic medicines will unlock new disease targets, all within our proven efficient development framework. With cash runway into the third quarter of 2027, we have the team, the pipeline and the financing to deliver on our bold mission for both patients and investors alike.

With that, we're happy to take your questions.

[Operator Instructions] Our first question comes from Konstantinos Biliouris from Oppenheimer.

Congrats on the update here. Maybe a two fold question from us. Could you share what dystrophin levels does your updated model predict for 12 mg per kg and 18 mg per kg as investors are trying to compare your dystrophin levels with -- against the competitor Avidity? And the second question is, is there a way you can demonstrate that your clinical benefit or functional benefit is superior to competitors even with lower dystrophin levels? And maybe how physicians will be thinking about that in the commercial setting if you have lower dystrophin levels than competitors, but your functional benefit is superior to others. Any thoughts around that would be helpful.

Great. Thanks, Kostas. Appreciate the question. First and foremost, I really do believe that today is an important day as it's a win-win for patients. Not only we have established safety at the 6 mg per kg dose, but as you just called out, we also have very strong functional benefit at a low dose. And that's a big deal because that's what it's really about safety plus functional benefit -- to your direct question, on the dystrophin levels for Cohort 2 and Cohort 3, what we're essentially doing is we're right shifting everything by cohort. So we expect to see double-digit dystrophin levels in Cohort 2 and then a linear or nonlinear increase above that for Cohort 3.

So we fundamentally and fully believe that based upon this updated modeling on the juvenile NHP model that we will be very competitive when it comes to dystrophin levels alone as we look towards Cohort 2 and certainly Cohort 3. To your second question, in terms of benefit and how we kind of match up, I think we've already shared a lot of functional benefit today. The time to rise velocity metric is a very rigorous non-biased, non-noise generated functional measurement. And what we've shown today is not only statistically significant, but also clinically meaningful benefits within that TTRV measurement.

We do also have good trends within the 10-meter walk as well. But these data are early, right? This is at day 127, hence, our surprise that we already received functional benefits. And those are probably because of some mechanistic differentials between our approach versus other companies as well, too. But as it stands today, our functional benefit is better than others as well. And it's also very clean. We represented the data as the data showed. It was based upon six patients and then, of course, 2 on placebo.

Other companies that you had mentioned, look at this from a pooled response. So it's kind of very difficult to do an apples-to-apples comparison between ENTR-601-44 and other companies. But what we can say for TTRV, as it stands today, we are in very, very good shape when it comes to functional benefit.

Our next question comes from Jonathan Miller from Evercore ISI.

I'd like to start with the AUC, which seems to be driving the delta in dystrophin from what we expected. And I'd love to get more color on why you think it didn't translate so neatly from healthy volunteers. It seems like there's a really substantial drop in the realized exposure here that I'm not sure we can say other programs in this space have seen, at least when we think about the doses they've gone forward with in patients versus healthy volunteers. So why would your program here have a bigger difference between healthy volunteers and patients and others have observed?

And then maybe secondly, when we think about the functional benefit -- can you give us a little bit more granularity on the baseline TTR for both the placebo and treatment arms and maybe the range of changes, the variability in TTRV for the treatment arm? How variable is that on a patient-to-patient basis?

Great. Thanks, Jonathan. I'm going to ask Natarajan to address the AUC question, and then we'll go to the second question after that.

Yes. Thanks, Jon. One, it is a new modality. So it's difficult to kind of predict what the adults and the pediatric population will do. Secondly, there's not much data on the plasma exposures for other platforms. So I think it is very difficult to conclude that they had similar exposures between pediatric population and adult population. I think we do see similar trends in the NHPs. So from a mechanistic point of view, that kind of makes sense that we saw lower exposures in pediatric patients, and we saw lower exposures in pediatric juvenile NHP as well.

Okay. And the second question, Jon, was more around TTR. I think it was a two part question. One was -- and correct me if I'm wrong, one was the baseline TTR and what we observed. And then second was the variability around the TTRV as a measurement. I think I'll ask Natarajan to jump in, but why don't you take it first?

I think the TTR velocities, initial velocities are going to vary between patients, and we have only six patients. But what is great about our results is that regardless of where they start or regardless of the severity of the disease or the age of the disease, we saw trends towards improvement in TTR velocity after treatment. I think that's probably the most important thing to remember is that regardless of where they started, they ended up improving the TTR velocity.

And I think the variability question I think the variability question between TTR and TTRV is answered by the calculation around TTRV. I think TTR has some bias associated with it and the calculation to get to TTRV, which is essentially one over TTR takes out a lot of that bias, takes out the outliers, takes out some of the noise that's associated with it. And I think that's why most companies, not only us, but other companies as well, too, are looking at this as an endpoint today.

Sure. But the range of values in TTRV among the six patients in the experimental arm, like how variable is it in your cohort?

It is variable. We have TTR across the spectrum.

As would be expected, right, because the severity of the disease is different amongst the six patients that were on treatment. So there is variability around what the TTRs look like. Everyone is going to be a little bit different from that measurement. But what we did see, Jon, I think the point that we did see was that the results were very consistent. They were clinically meaningful and they were statistically significant.

Our next question comes from Joseph Thome from TD Cowen.

Maybe just one, I guess, still trying to understand a little bit in the recently completed juvenile NHP study that you completed, I guess, mechanistically, why exposures would be lower in juvenile NHPs versus adults? If you can kind of help us with that? And are you anticipating presenting that data going forward? And then second, when we look to the second cohort as well, should we also be expecting more than a dose proportional increase in exposure in the satellite cells? I guess that's kind of a way of getting it, what do you expect for the functional outpoints endpoints in the second cohort?

Great. Thanks, Joe. Thanks for questions. Natarajan, do you want to talk about the juvenile?

Yes. I think we still are understanding the mechanism why the exposures would be low in the juvenile patients. But the consistency that we see with the NHP data between the adults and juvenile explains some of the differences. It could be because of the differences in lead mass muscle differences between the two populations. When it comes to what we expect in terms of Cohort 2, we are expecting a linear increase in exposure in Cohort 2. So -- and based on the modeling from NHP data, I think that should give robust exon skipping and dystrophin. As Dipal mentioned, we have right shifted it. What we expected from Cohort 1 is now probably what we would get in Cohort 2 and double-digit.

And to build on that, Joe, just from a functional benefit perspective, our expectation is the functional benefit will continue when we go to the second cohort. And that alone would be a big win to sustainability of that functional benefit over a significant period of time.

Great. And maybe one more, if I can. It looks like the age of the placebo patients is just a little bit higher than the age of the active arm. I guess, do you think that played in at all to the results here? I guess we can't see the individual agents. So I guess, what should we read into that?

Yes, it's a good question. I think though the average age in the placebo looks to be higher than the treatment, but we have all age groups represented in the treatment group as well.

And just to note on top of that, just recall that all the patients were ambulatory and all were on steroids as well. So there was a consistency around that -- around those parameters, too.

Our next question comes from Paul Choi from Goldman Sachs.

My first question is with regard to PK. And if you could elaborate a little bit more on that. Specifically, do you think this is the evidence that you've seen to date is more sign of protection or potential evidence of improvement in the patients given the dystrophin data. If you could help us triangulate that, that would be great. And my second question is, with the 45 readout coming up here in the near term as well, can you clarify if your learnings from your PK and AUC modeling here for the 44 program has implications for 45? And just any changes in assumptions we should make for that program?

Thanks, Paul. Natarajan, why don't answer the first question? I'll take the second, please.

That's a good question. With this change in dystrophin modest change in dystrophin, we didn't see statistically significant changes in PK, and that is understandable because we are not probably addressing the muscle fiber issue, but we are addressing the regeneration issue by satellite cells. And that's why there is this between the functional improvement we see and the dystrophin levels that we see. In terms of your second question on 45, we do expect the exposures to be lower in 45 as well. But again, the bar for 45 is not very high. The competitor is 1% or so dystrophin. And so I think from that point of view, 45 is a different.

I think that's an important point, especially around the second question, Paul. The numbers are very different. The dystrophin baseline numbers are very different since, as Natarajan said that they're lower. We've also been guiding to single digits when it comes to a dystrophin production perspective. And we also believe that, that will still stay intact. We'll see how it goes with Cohort 1, but I think that's still intact in terms of our expectations. But like what we said with Cohort 1 for 44, we have this dose escalation, and that becomes very, very important.

And it's always been an important part of the Entrada strategy, the ability to go in at a low dose but then escalate beyond that. So we have many shots on goal here, and this is a long game, of course. To your first question, just to go back a little bit, I think that's a it's a very good question in terms of what is the role of dystrophin. And I'd definitely like to ask Dr. Servais to get his viewpoint on this because we feel as though there's a dual role in dystrophin.

And I'll pause there and maybe Dr. Servais, if you can hear us, maybe you can answer part of Paul Choi's question.

[Operator Instructions]

One second, operator. Dr. Servais, can you hear us?

Yes. I think -- sorry, guys. I think we're having a tough time. Dr. Servais is traveling through Europe right now, and it was very generous with this time. But let me ask Dr. Servais one more time. Dr. Servais, if you can hear us, perhaps you can address the question around the dual role of dystrophin and the importance of regeneration, if you can hear us. Okay. We'll pass on that. But Paul, to get that answer...

Yes, sorry. I was on mute. So actually, dystrophin is the absorber of the muscle cell, but also it fixes several proteins. And I wanted to emphasize that muscle biopsy is just a snapshot at a very specific moment in time and at a very specific place. if you look at all programs of Duchenne muscular dystrophy, obviously, in very early biopsy that has been performed, the level of dystrophin is actually much lower, right? If you look at the first data from DND from Wave, the very early dystrophin level was also much lower than anticipated. So there is really a time sensitive issue here in the questions of the amount of dystrophin that is expressed.

Our next question comes from Myles Minter from William Blair.

I was just wondering whether you could comment on the actual tissue concentration of the 44 Skipper that you're treating with here. We did have some questions going into the data whether you were going to achieve adequate amounts here with this dose. And then maybe just from your preclinical data, just the idea of the split percentage of where the 44 skipper is going to the actual muscle tissue versus the satellite cells, that would be helpful.

Yes. Thank you, Myles. So when we looked at the muscle -- the muscle biopsy was taken six weeks post the dose and the Cmax for muscle exposure is less than 24 hours. So we did expect low muscle concentration. We saw single-digit nanomolar at the time of biopsy on an average, that was outliers on both sides. But on an average, I would say, single-digit nanomolar. But the good news is that we do have good exposure as we would have expected based on plasma exposures, corresponding exposures in the muscles. In terms of your second question, what proportion goes to the myofiber versus satellite cells, I don't think we have done that experiment yet in preclinical studies.

Our next question comes from Ioannis Souroutzidis from Cantor.

Just a couple of questions. I mean, one, I think it's pretty remarkable that the safety was so clean. And so with that in mind, as you kind of shift things to the right in terms of the dosing cohorts, is there any opportunity to kind of assess and open the 18 mg per kg cohort in advance to start running some of these in parallel? And then secondarily, a lot of the dystrophin skipping and kind of tissue uptake seems to be dependent on kind of clearing or stat rate and clearance. Just kind of curious if there's any signals of that early on, if that's some of the excretion data that you previously reported, if you could use some of those metrics here to kind of gauge how close you are to that threshold to really start seeing the exon skipping component begin to accelerate?

Thanks, Ioannis. Natarajan?

Yes. So we have not looked at urinary excretion in the Cohort 1. We would add those things as we go to the other cohorts. So we don't have excretion data. But the general principle is true. I think as a first pass organ, kidney does receive the first gold of the oligos. And then when it gets saturated, then you get a lot more to the muscle. So based on the exposures that we have gotten in the plasma, I would say, I think that is why we have a little good confidence that the exposure in the muscle should at least linearly increase to get to probably about 50 to 200 range in the 12 milligrams per kg that should give very robust exon skipping dystrophin.

Got it. And -- sorry I thought you guys [indiscernible]. Yes, just a follow-up to that. With regards to kind of opening updated cohorts in parallel, is there any flexibility to do that to assess kind of safety as the 12 is progressing to then kind of accelerate things?

Yes, it's a good question, Ioannis. I think it will be pretty difficult based upon the protocol that we have to be able to run both in parallel. I think one builds off of the other, right? So even our 6 mg per kg going to 12 mg per kg was predicated on what the 6 mg per kg look like from -- mostly from a safety perspective. I think that's for these first-in-human trials in Europe. That's what they're looking for. And they're going to look for the same thing when we go to 12 mg per kg and then if and when we go to 18 mg per kg as well.

So I think it's pretty difficult to find those efficiencies. But the good thing here is that the 12 mg per kg data is expected before year-end. And then on top of that, we also expect to have the 6 mg per kg cohort 1 open-label data before year-end as well, too. And that's -- so in the next six, seven months, we should have clarity on both of those, too.

Our next question comes from [indiscernible] from Guggenheim.

We just have two quick questions around what prompted you to do the juvenile nonhuman primate study in the first place? And second, going to satellite cells, what's your hypothesis about whether the drug target the satellite cells preferentially -- or is it just that this slow -- this little low dystrophin increase is sufficient to kind of achieve a threshold where you start getting productive asymmetric cell divisions.

Perfect. Thank you for the question. Natarajan?

Yes, the juvenile study is part of the preclinical package that we do in terms of long-term studies in juvenile monkeys to enable treatment of Juvenile population. To the second question, I do believe that there is a threshold level. And what is the threshold level for producing dystrophin level that shows up in the Western blot may be very different from the threshold level that is required to activate satellite cells.

So some of the preclinical experiments that we have done where we treat animals for three doses and give 12 weeks of washout, we still see majority of the satellite cells to stay for PMO. So it may be because of proximity to the blood vessels, et cetera, it may be a physiological thing that satellite cells do get more. We still have to figure that out. We are doing experiments to do that. But the results do indicate that we probably have more regeneration than repair at this point.

And I think it's a good question. And I think also just to provide context, right? So we're still learning. We, meaning Entrada, but also, I would say, other pharmaceutical sponsors, patient groups, KOLs, et cetera, we're still learning about what the role is of dystrophin and how it correlates to functional benefit. And so to your point about the threshold, that becomes a very, very important belief, and we feel as though we have the preclinical data that shows the ability to get into these stem cells.

And I think that's a very unique characteristic and the ability to regenerate quickly may be the driver that's allowing us to get to that threshold that then allows us to show functional benefit, albeit at a lower dystrophin level. But at the end of the day, what's really important here is the establishment of safety and, of course, the functional benefit for these patients. Dystrophin is important, but the role of dystrophin is something that I think is still being informed. And Entrada's unique ability to get to the satellite cells is a great effect, but more analysis will be done by the company to answer some critical questions to the point of a clinical study.

Our next question comes from Raghuram Selvaraju from H.C. Wainwright.

This is sitting [ Yonzu ] filling in for Ram. So my first question relates to ENTR-801. What remaining IND-enabling work and regulatory interactions need to be completed before clinical entry? And could first human dosing be viewed as a possible '26 or something that's more likely as a '27 one?

It's a great question. Thank you. So ENTR-801 is our first development candidate that's going into inherited retinal diseases that we're very, very excited about. These programs are still, as you said, they're pre-IND. So I think they just need to continue to go through the normal course of tox studies and whatnot as we prepare to submit a formal IND -- in terms of timing as to when we will begin that study, we haven't guided to that. We have to get through some of these preclinical analyses, but it's likely a 2027 start for that program.

I would also like to point out that we also will be nominating a second development candidate in the second half of this year, too. So by the end of this year, we'll have two development two candidates with IND soon thereafter within inherited retinal diseases.

Got it.. And beyond the ENTR-601-45 Cohort 1 readout that's expected in mid-'26, what are the gating items for 601-50 and 601-51? And when do you think we can -- when could initial clinical data from those programs realistically follow up?

Yes. Another good question, right? And so we purposely staggered our DMD programs to one to learn from each other. So we learned from 44, we apply that to 45, so forth and so on. For 50 and 51, 50 has approval to move forward in the U.K. But what we're going to do is we're going to -- what we want to be able to do is we want to be able to learn more about these data that we just generated today from Cohort 1 for 44, see what the applications are to the 50 and 51 programs and the 45 program for that matter as well and then decide how best to proceed from a regulatory perspective.

We have a lot of different opportunities here, the satellite cell information and perhaps changing the course of the disease via the entry into the satellite cells puts us into a very unique situation to have discussions with regulatory agencies about the role of dystrophin and the role of satellite cells. So we'll come back to the community later on this year with more specificity around how these data positively, and I want to make sure that, that word is understood, how these data positively affect the 50 and 51 programs.

Fantastic. And if I may, just a quick follow-up. Given that Cohort 1 functional signal and the updated PK modeling, what would determine whether the 12 mg per kg is sufficient to carry forward versus needing Cohort 3 before selecting a registrational dose? And how do you think we can think about regulators...

Yes. I think it's a good question. I'll start, and Natarajan should certainly jump in. I think first and foremost, safety needs to be established again, right? So we have that at 6 mg per kg. There was no renal signals. I mean, safety in this oligonucleotide class of therapeutics alone as a stand-alone is a big accomplishment in our opinion, looking at a lot of the other approaches that have come and gone over the years. We want to reestablish that, of course, as we dose escalate by 100% and go to 12 mg per kg. So I think that's the first.

The second really becomes the maintenance or continuation of functional benefit. We want to be able to see the functional benefit continue at the 12 mg per kg. I think that becomes really important as well. I will say the third factor, and it's always been the third factor is -- but an important one. But once again, it depends upon the relationship between dystrophin and functional benefit. The third becomes how much does dystrophin increase in the second cohort and what is our belief system as to how that affects functional benefit, right?

So I think those are the three things that we'd be looking for in the second cohort. And I think those answers will then determine how we evaluate the third cohort. If we -- I'll be a little bit more clear here. If we maintain a strong safety signal plus we maintain and continue the functional benefit, we may be done. And that may be enough because functional benefit at the end of the day, plus safety is what drives the regulatory process when it comes to these types of drugs.

Thank you. That concludes the Q&A session. I will now turn it over to management for closing remarks.

Thank you, everyone. We appreciate you joining us this morning. As you can see, we're very excited about the positive top line results from Cohort 1 and importantly, the clinical path ahead for our DMD franchise, which really has the potential to transform the lives of people living with DMD. We look forward to keeping you updated on our progress and wish you all a great day. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Good afternoon, everyone. My name is Susmita Roy. I'm an associate on the health care investment banking team here at JPMorgan. On behalf of JPMorgan, first of all, welcome. Thank you so much for taking the time to attend the conference. It's been a great conference so far. And to continue the festivities rolling, I'm thrilled to introduce Entrada Therapeutics for their company presentation today.

A little bit about Entrada before we get started. Entrada is focused on treating devastating diseases with intracellular targets. Last week, Entrada highlighted an important progress across its EEV portfolio for neuromuscular and ocular diseases. The company is advancing multiple clinical programs in people living with Duchenne muscular dystrophy in the U.K., EU and the U.S. In 2026, Entrada expects to have 4 clinical stage programs in its DMD franchise, complementing the ongoing clinical programs, progress of its myotonic dystrophy type 1 partnership, VX-670 with Vertex. The year is shaping up to have several value-driving catalysts.

I'm pleased to welcome on stage next to me, Entrada's Chief Executive Officer, Dipal Doshi, who can share more about Entrada's year ahead. And also on stage, we'll have Natarajan as well. Thank you for joining us this afternoon. I'm really pleased to hand it off to the team.

Great. Thank you. Thanks for the kind introduction and to the JPMorgan team for inviting us here to present. I look forward to talking more about the work that we're doing at Entrada.

Before I go too far, it's the normal disclaimer about making forward-looking statements. So just refer to our SEC filings and whatnot that could impact our business.

So I think I did this last year as well. First and foremost, we have a mission at Entrada. I think a lot of companies have missions. Ours has been intact for the past 9 years, and it's to treat devastating diseases with intracellular therapeutics. And at the end of the day, these boys here on this slide here all have DMD. They've all been to our offices. We have pictures of them and their stories. And I think that's one of the most important things for me, and I'm very fortunate to be able to interact with not only these patients, but also their families and understanding their journey and sharing with them, along with Natarajan and my colleagues from Entrada, sharing with them the progress that we're making to hopefully help themselves as patients and their families as well.

So Entrada, today, has an expanding portfolio of intracellular therapeutics. We'll spend the most amount of time today talking about our Duchenne muscular dystrophy programs or franchise, and we'll also spend a little bit of time talking about myotonic dystrophy type 1 or DM1, that's our partnered program with Vertex. And then last but not least, we did announce the -- on Sunday, an expansion of our focus into ocular diseases, which is really exciting for the team as well, too. We're excited to expand beyond neuromuscular to really show the full strength of what Entrada can bring to the table. But this is one of those pipelines that can continue to expand. And as such, 75% of all disease targets are intracellular in nature. So you can start to imagine all the different opportunities and diseases that the Entrada team can go after.

So I'll start -- it's a busy slide, but when I stood up at JPMorgan last year, I said that 2025 would be a year where we are heads down as a company, executing to be able to put ourselves in a position to have multiple clinical stage programs by the end of 2025. So now I stand here a year later saying we achieved that. And we're advancing these 4 clinical stage programs to the point where we're going to have inflection -- clinical inflection points with our ENTR-601-44 program, our ENTR-601-45 program and our partner program with Vertex, which we call VX-670 in 2026.

So going left to right, the momentum and the excitement around Entrada is building because we're getting close to that data. So in the second cohort -- sorry, in the second quarter of this year, our ENTR-601-44 program -- we'll share those data, that top line data from the first cohort. I'm pleased to announce that, that dosing is complete. The open-label dosing has been initiated. And so we expect that first cohort of data in Q2. And then we expect the second cohort of data in Q4 or by year-end 2026.

Our ENTR-601-45 program, we expect the first cohort of data in mid-2026. So therefore, you could see in Q2, we expect data, mid-2026, we expect data. And by the end of the year, we expect data for our DMD franchise.

And we have a stepwise progress when we start to think about the diseases we're going after. Our ENTR-601-50 program is a little bit behind that, and that's staggered by design. And -- but we have received authorization by the U.K. regulatory agencies to go forward, and we expect to file our EU regulatory applications this year as well. So lots going on, on DMD.

Our 670 program with Vertex for DM1, Vertex has completed the single ascending dose portion of the global Phase I/II study. The multiple ascending dose portion to evaluate safety and efficacy is ongoing. And I'm pleased to announce for their announcement that they've completed -- they plan to complete enrollment and dosing of this very important trial midyear. That partnership is a very robust partnership for us. Not only did it include a very sizable upfront, but there's a significant amount of milestone payments and royalties that are associated with that very important disease.

From a pipeline perspective, based upon what I said about intracellular targets, we continue to advance this preclinical pipeline. We are pleased to announce, as I said earlier, our expansion into, inherited retinal diseases, or IRDs. And we nominated our first candidate, clinical candidate, which we call ENTR-801 for a disease called Usher syndrome type 2A, which we'll talk about in a little bit. We also have a second program that's in lead optimization that we plan on announcing a candidate for in 2026. There are additional discovery efforts kind of like the tip of the spear for us where we will continue to expand in neuromuscular and ocular, but we will also look at a range of undisclosed modalities and diseases as well as we continue to build Entrada into a leading intracellular therapeutics company.

From a financial perspective, we ended 2025 with about $296 million on the balance sheet, and we have a healthy cash position that takes us into Q3 of 2027.

So let's start with our neuromuscular diseases and specifically with Duchenne muscular dystrophy. So our story and our strategy really is predicated on 3 pillars: differentiation, derisking and speed to global approvals. As many of you know on the audience and online, this is a devastating disease, which leads to -- ultimately leads to a cause of death, which is attributed to some type of cardiomyopathy. What we have in Entrada is a differentiated, what we call endosomal escape vehicle platform and also a novel PMO conjugate. And what we've been able to see, I'm not going to read the entire slide, but what we've been able to see is a 25-fold improvement in endosomal escape, which resulted in nonclinical best-in-class efficacy. The novel PMO sequences that my colleague, Natarajan, and his team have developed are superior to the marketed PMOs even without conjugating them to the EEVs. Our nonclinical data has translated into very compelling healthy normal volunteer PK data and safety data supporting the potential for even a more robust differentiation.

Importantly, what we have learned is that there are -- there is an uptake that we can facilitate into the satellite cells, and we have a slide on that, that we'll talk about. But that's really important when we start to think of how functional improvement will be affected by our EEV conjugated therapies. And that is a distinct differentiation between us and some of the antibody-based therapies.

Importantly, when we start to think of these young boys that become young men, the amount of dose or the amount of drug that goes into their system is something that we are very careful about. Obviously, we want low dose with high concentration. And what we've been able to see when we compare ourselves to other companies is a drug load that is substantially less than the antibody-based therapies, which, therefore, then increases or decreases the risk of exposure and antibody response. It also -- when we start to think forward, it also decreases our manufacturing burden as well.

So when we start to think of, okay, great, great profile, but what comes next? We are running all of these DMD studies outside of the U.S. That's a very calculated strategy. And so what we plan on doing is running these studies outside of the U.S., collecting those data and bringing those data back to U.S. to share with the FDA and then, of course, enter the U.S. market. It's a very efficient and it's a very fulsome strategy that has worked well for our 44 program, and we'll continue with the other exons.

When we start to think of these endosomal escape vehicles, they are very specific for neuromuscular diseases. And what we're excited about is the same EEV that we're using for our DMD programs is the one that Vertex is using for the 670 program. So a lot of synergies between the diseases as well.

When we start to think of what our expectations are, and we spent the entire day talking about this with investors, from the first cohort of data for our 44 program, we expect to see double-digit dystrophin production, which is really important, right? So we want it to be safe, and we want it to be efficacious. Efficacy, in this case, is measured by dystrophin. We feel as though that, that is the first domino to fall, right, in a good way. If we get both safety, which we expect to, and double-digit dystrophin production, which we expect to as well, we feel though that sets up a translation to the other DMD exons, 45, 50 and 51. And that positive data in 1 EMV-enabled candidate immediately derisks the clinical profile. So really exciting, right, when you start to generate these data.

Ultimately, our goal at Entrada is to get these drugs on the market and to get them to the patients. And so the ex-U.S. strategy really kind of enables a rapid acceleration of getting clinical data. And then, of course, helps us initiate discussions with FDA to discuss accelerated approval. That pathway is open in the U.S., that pathway is not open ex U.S. So accelerated approval in the U.S. is something that we believe, one, is open and, two, is something that we are going to strive for with all of our exons. This is fundamentally based on the opportunity to develop a best-in-class PMO across our portfolio. So when we think about a time line, the accelerated approval pathway would be expected to coincide with a confirmatory trial outside of the U.S. So the team is really gearing up for a very, very busy 2026, not only from an execution perspective, but also from a regulatory perspective as well.

So let's talk about the EEVs, right? Because when we start to think about these EEVs, they are distinct from some of the other approaches, including antibody-derived therapeutics. So what are EEVs? They're a family of cyclic cell penetrating peptides that have 3 unique characteristics: one, a very unique chemistry, which allows for an improved uptake into the cell and then escape from the endosome. The second, which is a cyclic structure in nature, allows us to increase the stability and also extend the half-life, which becomes important. And then the binding to the phospholipid allows us to enable a broad biodistribution to a plethora of cells.

What this has also shown to us in our studies, now once again, this is across DMD and DM1, is both consistent and predictable pharmacokinetics, or PK. So the character on the right exactly shows what we're able to do. So from an endosomal escape perspective, you don't want to get stuck in the endosome, you want to get out of the endosome, so you can actually get to the muscle that you're trying to get to. We're able to do that at a 25-fold increase compared to other programs.

So if you're able to do that, that means you have a bolus of material that's getting into the cell and getting into at a 90% uptake and then you're able to get out of it. So the more that gets in and the more that gets out translates the more that, that gets to the muscle. And that's kind of like what the secret sauce is with Entrada when it comes to neuromuscular diseases. This is what allows us to get to the muscle in high concentrations at a very, very low dose.

And we show this here, too. It's not only about the EEVs. It's also about optimizing the active conjugate. So it's a 2-part thing. So on the left part of the slide, this is a comparison against the R6-PMO, which is a competitor program. And what you can see here is the EEV optimization is profoundly different when it comes to us versus this R6-PMO. But also the optimization of the PMO itself or the conjugate is something that the team has worked on extensively. So now you have this double effect. You got a remarkable delivery vehicle, plus you also have an optimized PMO that, put together, allows us to generate the data that we've generated to date and also prospectively looking at what the clinical data may look like.

And I mentioned the satellite cells. So let's spend a minute on this. So the satellite cell uptake is something that is highly differentiated for Entrada. And what that allows us to do, at the end of the day, it really doesn't matter how much dystrophin you can make. If it does not translate to functional benefit, then it doesn't benefit the child or the young man. And so at the end of the day, the ability to get into the satellite cells which essentially are a cause for regeneration will allow us to help with -- will allow us to utilize the satellite cell data to regenerate muscle fibers that will then ultimately help with functional benefit. And this is something that we've proven not only in this slide here, but we're also starting to see in preclinical models as well, too. So a very, very exciting differentiating characteristic between us and the other approaches.

We conducted a healthy normal volunteer study in the U.K. and this study was not only compelling, but it resulted in exactly what we wanted it to do. We wanted to run this study in healthy normal volunteers to derisk the program. We had a lot of preclinical data, not only within different mouse models, but also with the nonhuman primates. But we wanted to -- before we inject it into a child or a young man, we wanted to make sure that the PK and the safety characteristics read out the way that we wanted them to. And I'm pleased to say that this was a very important study that allowed us to achieve a couple of things.

First and foremost, safety. You could see by the purple box on the bottom that there was absolutely 0 treatment-related adverse events. That's super important, of course, right? Safety is paramount. What we were also able to show within these 32 adults was target engagement, right? The ability to not only generate exon skipping, but more importantly, the ability to get to the muscle, showing concentrations in the muscle. So it's the right recipe before you go into patients. It's safe, it gets to the muscle, and it promotes exon skipping, which happens in the nucleus. And that was really what an aha moment for us to say, all right, let's go all in here and let's go straight into patients, which is what we are doing right now.

Importantly, this was -- this safety and this study showed strong clinical safety up to 6 mg per kg, which is the starting dose of the patient study that I'll talk you through in a few minutes. And so the translation ultimately of nonclinical data to the Phase I healthy normal volunteer data establishes the potential of our DMD therapy.

So on this slide, what you see here within the healthy normal volunteer study is a dose -- go left to right, is a dose response from a plasma concentration perspective. You could see as the dose goes up, so does the plasma concentration. In the middle, you also see the same thing between 3 mg per kg and 6 mg per kg, a dose response where the skeletal muscle concentration also increases. And then, of course, from an exon skipping perspective. There is no dystrophin production, of course, because these are healthy normal volunteers who already have dystrophin. But these were 3 very, very important factors. The dose response becomes extremely important when we start to think of what the therapeutic index looks like.

We spent some time -- DMD is a very competitive space as is neuromuscular. And so we spent some time putting together a slide that essentially says what are the differences between Entrada and some of the other approaches here. And what you can see here, I'm not going to read all this, but this trends well based upon everything that we've been able to see, right? So from the design, from the dose and from the uptake in the target engagement, what we've been able to see is that not only does the 25-fold improvement in endosomal escape lead to better data, but it leads to a lower whole drug requirement when we compare it to these antibody delivered therapeutics.

So there's a lot on the slide. But what we wanted to do is put this together. This is preclinical and clinical data. So on the left, we decided to do a study to compare ourselves to the published data that Avidity presented regarding their del-zota 44 program. And what we were able to see on the left side of the first chart was 2 weeks post dose, green is Entrada, the gray is del-zota. You could see the profound difference between the skeletal muscle and then, of course, the difference between us and the heart. Then you go 4 weeks and you see a similar thing. What's important here is, at the end of the day, this is 6 mg per kg for Entrada, okay? So 5 mg per kg is the oligonucleotide, 1 mg per kg is the EEV. When you compare that to del-zota's 5 mg per kg, that's 5 mg per kg for the oligo, not including the antibody. So the whole drug size, when you want to do an apples-to-apples comparison between the 2 companies, we are 1/6 of their dose. 1/6 of their dose leads to this type of data. This is why we get excited about these data. This is why we get excited about Entrada, right? The ability to deliver higher concentrations at lower doses, right? And so that's what gets us really excited.

The middle slide or the middle chart shows a nonlinear dose response. So this is from 10 mg per kg to 40 mg per kg. What you can see is at 10 mg per kg to 20 mg per kg, you see a difference of doubling from 5% to 10%, but this is the hockey stick-like type of advance, right? So you see a 3x greater muscle concentration ultimately. And so this is what we expect. Our first dose in our 44 program is at 6 mg per kg. The second is at 12 mg per kg. The third is at 18 mg per kg. We expect to see this hockey stick type of reaction to dystrophin production.

The third part of this slide oligonucleotides, neuromuscular-focused oligonucleotides have had -- their liability has been to the kidney, right? The ability to get to the muscle is great, but not at the cost of the kidney. And what we have been able to see here on this analysis here is that for every doubling of our dose, we've been able to see a more than doubling of the metabolite excretion, which means that we double the dose, more stuff up "gets out." So we are limiting the liability to the kidney. What this may imply is the potential to increase efficacy without a proportional risk of increasing toxicity. That is a very, very important point here, and it's a very compelling point for Entrada. The ability to get out of the kidney, the ability to not cause damage to the kidney is something we've seen not only in our preclinical models, but we've also seen that in our healthy normal volunteer study, no effect to the kidney. That's a big, big takeaway for oligos and a big advancement within DMD and DM1.

So this is a study. This is our ELEVATE-44-201 clinical study. It's designed to support a U.S. accelerated approval and form the basis of a global registrational program. So if you look at this, there are 3 cohorts, as I said. The first cohort is 6 mg per kg, the second is up to 12, and the third is up to 18, a very wide therapeutic window. There are 8 patients in this, 6 on drug, 2 on placebo. And I'm pleased to report, if you look at the middle, there was this double-blind period, that is concluded for all the patients. So each patient has been dosed 3 doses, and they've all entered the open-label period. So now we're at that point where we are waiting for the data, which we will then present in Q2 of this year.

This will be very similar. It's a very similar design for the 44 program as is the 45 program. So it's a little bit of a rinse and repeat. The 45 program has a little bit of a lower dose, right? So it's 5, 10 and 15. But what I will say is the 44 program goes straight up against del-zota, right? And that's our plan is to beat those data. The 45 program goes straight up against casimersen. Casimersen has roughly 1% dystrophin production. We think we can comfortably beat 1% dystrophin. Now that allows us to say we can go after these 2 exons. Oh boy, we can go after 50, 51 and 53 as well. So it's the basis for Entrada to be a leader within the DMD space.

And so this slide shows our time lines and our regulatory. I'm not going to focus on that because we've already shared it. I'll focus on the left side. So when we think about the 44, 45, 50 and 51 exons, that's over 14,000 patients in the U.S. and Europe. That's a substantial opportunity. That's a substantial amount of patients who do not have an adequate therapeutic option when it comes to treating their disease. We also believe that if this data that we believe will translate to more than positive, we feel as though that the conversion or the adoption will be heavily weighted towards Entrada. So this supports, in our belief, based upon really high-quality data, the ability to be the leader with -- not a leader, but the leader within DMD.

Let's move over to myotonic dystrophy type 1, our partner program with Vertex. So there's a pretty significant materiality wall between the 2 companies. We did this program, we established this partnership 2 years ago -- actually, sorry, 3 years ago now and try to receive for a preclinical asset, $224 million upfront and a $26 million equity investment by Vertex, and then there was $485 million of milestone. So a very significant single asset preclinical deal.

We feel as though the DM1 space is getting, of course, a lot of interest. And we feel as though there's a significant differentiation for our VX-670 program compared to the antibody-based approaches. And specifically, what that distinction is, is a very unique, and I'll use specific again, blocking of the pathogenic CUG repeats. This targeted approach to be able to block the mutant DMPK is very different than our competitors' views as to how they block essentially indiscriminately DMPK. We think that this targeted approach will lead to a better outcome, and we're starting to see that. I think the other differentiating characteristic is what I was talking about with satellite cells. The satellite cell uptake may also increase the differentiation when we start to think of functional data as well.

Vertex is advancing this program. They -- as I said earlier, they are planning on finishing up this MAD from a dosing and enrollment perspective in mid-2026. They have over 25 global sites initiated. The open-label extension is enrolling. I feel as though they are going all in here. They've been spending a lot of time on this, and they highlighted it during their presentation as well, too. So this is a, once again, a disease that has over 110,000 patients. So it's a big one. And I think we have a really, really good opportunity here led by our colleagues at Vertex.

I'll move over to inherited retinal diseases, which we announced this weekend. So once again, this takes a similar strategy that we took with DMD. We looked at this from a top-down perspective, what are diseases that have a profound unmet clinical need? And then from a bottom-up perspective, what are we good at, right? And the link here is that we're going after Usher syndrome type A (sic) [ type 2A ], which has mutations in the exon 13 -- in exon 13. So it's an exon skipping type of approach. We've already proven that or proving that within our DMD and DM1 programs, and now we're moving that over to Usher.

What I like about this as well, too, is that this is a large disease, right? We're talking about 15,000 patients across the U.S. and Europe and probably even more that we can potentially address who do not have any therapeutic options. And so for us, when we start to think about where else is Entrada going to grow besides DMD and perhaps DM1, this is our next big pillar. And so we're really excited about this. We'll share more about our clinical plans and whatnot as the year progresses. But this is our first one, right? So we announced this one. We're going to announce another clinical candidate in 2026 for inherited retinal diseases as well, too. So we put our flag, so to speak, in the ground here when it comes to ocular. I'll reemphasize that there's no disease-modifying treatments for Usher syndrome type A (sic) [ type 2A ]. So we're really excited about the ability to go after this on behalf of the patients.

The data here -- we'll share a little bit of data here, but what we've shown in this slide is a single IVT dose of ENTR-801 reaches the exon skipping target that we hear from KOLs is clinically relevant. We've also been able to generate a protein that's measurable for at least 90 days, which shares the potential for a dosing of 1 to every 2 to 3 months. So we're excited about the fact that at this early stage in this program, we've been able to achieve that clinically relevant exon skipping of above 25%, but at the same time, have a potential dosing regimen, which will be advantageous to the patients. So more to come here, but a very exciting start to our ocular programs.

I think that's that. And then pipeline expansion. So as I said in the beginning of this presentation, when you go after these intracellular targets, there are plenty of them to go after. We can't go after all of them, of course, but the flexibility and modularity of our approaches lends well to exploring other therapeutic areas as well, too.

So what we are working on back in our Boston labs is more complementary modalities to go after diseases of interest, including next-generation EEVs to continue to advance the TI and also increase efficacy; continuing to optimize oligonucleotides so that we can develop proprietary sequences, not only from an IP perspective, but also from an enhanced safety and efficacy perspective with and without EEVs. Also a protein engineering group, which is just probably the best -- the best out there that is working on improving not only potency, but efficacy and bioavailability. So what we see specifically is we will continue to expand in neuromuscular. That is something that is dear to us and something that we're good at. And so we will continue to seek out and share news about other diseases we're going after.

As I said in the previous slides, we will also continue to expand our ocular franchise. We're starting with Usher, and we will expand out of that into other inherited retinal diseases and perhaps diseases that are larger and broader within the ocular. And then, of course, there's a whole host of undisclosed diseases that are looking at -- they're looking at metabolic diseases, we're looking at CNS, we're looking at a bunch of others as well, too.

So in summary, 2026 has a lot of catalysts, right? We've talked about our ENTR-601-44 program, first catalyst, first clinical data will be Q2. Second clinical data will be end of year. Our 45 program continues to go well. That data, first cohort will be shared in the middle of this year. Our 50 program is going through the regulatory process, and we'll start to initiate that by the end of the year -- before the end of the year, then 51 as well. VX-670, that's under great leadership with the Vertex team, and they expect to finish enrollment and dosing in the middle of this year and hopefully sharing data soon thereafter. Our newest entry into ocular, where we've initiated -- we've announced a candidate for our Usher program, and we'll continue to expand about that and then also a significant round of pipeline expansion.

Entrada is being -- Entrada is here to build the next best stand-alone intracellular therapeutics company. We're excited to -- we still have a lot of cash and -- to achieve all these goals. But obviously, we're going to have to invest more into the company, but the current cash runway goes into Q3 of 2027, so well capitalized for now to achieve a lot of these milestones.

With that said, please go to our website to learn more, but open to Q&A, and Natarajan is up here as well, too, as our President of R&D, to answer any questions that anybody may have. I think we have about 10 minutes.

All right. You have a question? Go ahead.

Is this on? It is. So to kick off the Q&A, could you talk a bit more about how this first cohort from the ENTR-601-44 study will derisk your other Duchenne programs?

Yes. So as I said, it's -- first and foremost, it's the same EEV across all the DMD programs, right? So that's half of it. So you got the EEV and then you got the oligonucleotide or the proprietary oligonucleotide. And so we feel as though that this first -- the approaches are all the same. We feel as this first cohort of data sets up that positive domino effect, right? So 44 data should translate well to 45 data to 50 data to 51 data.

I will caveat that by saying that these are all under the DMD landscape. We view these as individual diseases, but they have a tight correlation between them. But I think the similar EEV or the same EEV, coupled with a PK that we understand really, really well is how we view derisking future -- not only future cohorts, but future programs for DMD.

Thank you. Any other questions from the audience? Okay. Any last remarks?

No. Thank you for hanging out with us, and please do reach out to us if you have any questions.

Thank you all.

Thanks, everyone.

My name is Raghuram Selvaraju. I'm a Managing Director and Senior Health Care Equity Research Analyst here within the Equity Research Department at H.C. Wainwright & Company. I'm joined today by Dipal Doshi, Chief Executive Officer of Entrada Therapeutics. Entrada is traded on the NASDAQ under the ticker symbol TRDA, and we cover Entrada with a buy rating and 12-month price target of $20 per share. Dipal, it's a pleasure to have you with us today.

Ram, I appreciate the opportunity and look forward to the discussion.

So perhaps we could start by having you give our audience a brief overview of Entrada Therapeutics and in particular, the Endosomal Escape Vehicle technology platform.

Yes, happy to do that. So Entrada is a clinical stage biotech company that is aiming to transform patients' lives. We have a proprietary application or technology called Endosomal Escape Vehicles that we also call EEVs. We'll use that interchangeably, which we really believe enhances the value proposition, especially for our two lead indications, which are in Duchenne Muscular Dystrophy or DMD, and Myotonic Dystrophy Type 1, otherwise known as DM1.

What is so unique about this platform of EEVs is that it fundamentally enables us to access intracellular targets. And as you know, this is super important because most disease targets are actually intracellular in nature, something like 75% or so. So what's unique about the platform and what's unique about our approach is that these EEVs have a very unique chemistry, which facilitate an improved uptake into the cell and escape from the endosome and they are cyclic cell-penetrating peptides in nature that essentially extend the half-life of the program and increase the stability. And so essentially, the unique budding mechanism that allows us to get out of the endosome conserves the integrity of the endosome.

Why this is important is because these EEV conjugates release approximately 50% of the drug from the endosome resulting in remarkable levels of target exposure and engagement. And why that is important once again is because the ability to get out of the endosome at 50x what current therapeutics are able to do allows us to increase that target exposure and engagement within the muscle, which is obviously very important for both DMD and DM1.

We've leveraged this technology across our neuromuscular franchise. The same EEV is being used across our DMD programs as well as our partner DM1 program with Vertex. And so it's an exciting, exciting application that allows us to really essentially get a proposed product to patients that at low doses with high efficacy, which we feel is always important.

I'll pause right there, though.

So obviously, for those in our audience who may not be familiar, Duchenne Muscular Dystrophy is a very well-known, progressive, relentlessly degenerative muscular disease that is genetically driven, and that has been associated with various exon specific mutations. So perhaps you could talk a little bit about the kind of etiology of Duchenne Muscular Dystrophy and in particular, how the exon skipping concept applies therapeutically in this condition?

Yes. It's a great point. So taking a step back, as you said, DMD is a muscle disease. And there are specific exons where there is a mutation in those exons. And so specifically, we'll talk interchangeably about our DMD programs. We're going after -- our primary focus is to go after exons 44, 45, 50 and 51. And the whole point of these exon skippers is to skip an exon so that this train can continue to move forward.

And what it's moving forward to do is to be able to produce a protein called dystrophin. Dystrophin is extremely important in the stability and the integrity of muscles. So when we say it's a muscular disease, it's a multi muscular disease. It can be your upper limbs, it could be your lower limbs. And eventually, these boys who become young men ultimately succumb to a cardiovascular event.

So when Entrada says that we're going after DMD, it's really going after four different exons that comprise roughly about 40% of the -- 38% of the DMD population. So we consider our 44 program to be distinct from the 45, 50 and 51 because the etiology is a little bit different in each.

Got it. So maybe give us a bit more background on the nature of the therapeutic need and the size of this market. You were talking earlier about how the exon-skipping approaches that Entrada is pursuing would effectively encompass close to 40% of that market. But just give us a sense of how large it is in size? My understanding is that while DMD is clearly classified as an orphan condition, it is certainly far from being an ultra-orphan condition and afflicts tens of thousands of people.

So I think it would be helpful for our audience to be a little bit more educated about the total addressable market opportunity here as well as the extent to which you expect with these four discrete candidates to position Entrada as a one-stop shop as it were for treatment of DMD in the context of providing exon skipping capability.

No, it's great. So to characterize the disease from an epidemiology perspective, there's roughly about 40,000 people in the U.S. and Europe that are living with Duchenne. So a very, very significant amount of patients that puts it in that rare disease category, and as you said, not in that ultra-rare disease.

If you break it down by exon, right? So our 44 exon roughly has about close to 3,000 patients in the EU and the U.S., 45 has a little bit over 3,000, 50 is a pretty small but highly unmet clinical need with about 1,200 to 1,300 patients. And then 51 has about 5,000 patients, right? So you start adding up the math, and that gets to roughly 35%, 40% of the population.

What's important about DMD though, is that there are no current therapeutics that are approved that fundamentally addressed to the disease. And so there's first-generation products that have been approved.

But what they do not do is they do not effectively produce dystrophin, which is what's missing for these boys, right, because it's a male-dominated disease. So if you don't produce dystrophin, then you're not going to have the muscle integrity. You're not going to have the muscle strength, which then ultimately will lead regrettably to a cause of death, which is usually ascribed to a cardiovascular event.

So what's different from Entrada goes really back to this EEV technology when it comes to neuromuscular diseases. We have to get the drug to the muscle. And nobody has been able to effectively do that within the exon skipping environment. There are other programs we're going after, but there's limitations as well, too. What we've been able to show essentially within our clinical programs, and I'll start with a healthy normal volunteer study that we did in England was the ability to provide a safe medicine to patients -- to healthy normal volunteers, but also to engage the target that we're trying to go after, which is the muscle.

So we were able to show significant muscle concentration within this healthy normal volunteer study, which means that we're getting to where we need to go, and we're hoping that within our current clinical trials within patients that we'll be able to do the same.

So maybe you can kind of compare and contrast the EEV technology platforms, capabilities and performance to date against those of other, for example, RNA platforms, in particular, as this pertains to potency considerations, say what you would project in terms of safety and tolerability in the context of what you saw in the healthy volunteer data as well as potentially also on the ease of manufacturing front?

Yes, great question. So what I will say is that in today's market, the need for better and more flexible treatments is paramount and exists. The patient groups will say this. We partner with the global patient groups to be able to design clinical studies that are highly correlated to what the patient need is and what any patient group in DMD. And frankly, in DM1, will say is that we need better and more flexible treatments, and we'll come to that in a second.

So as we said, there are approved exon therapies in the market today, but the dystrophin levels produced by these programs or approved products have yet to result in a demonstrated clinical benefit. And we believe that, that's due to a lack of adequate target engagement, which is kind of where we come into the play -- we come into play.

So the extensive preclinical data that we've generated across a variety of mouse models and of course, monkey models and then, of course, our healthy normal volunteer study for the Phase I program have indicated that our EEVs have the potential for best-in-class in these neuromuscular diseases. Now specifically, let's talk about other approaches, right? So Avidity with their 44 program is an antibody drug conjugate approach, right?

So there's an antibody conjugated to the oligonucleotide. And it's certainly a promising and a good first step, but there are limits to those data in a few specific areas. And let me cap those at a very high level. First of all, there's a lack of dose response, which has capped the potential efficacy within RNA-44, right? And what we have been able to juxtapose is consistently demonstrate a dose response. That dose response is very important because you want to have the flexibility of going after small or low doses up to high doses, which essentially means you have a significant therapeutic window.

So once again, you can match your treatment to the specific patient themselves. So what we've been able to show is a consistent dose response, both in clinical and nonclinical settings, which RNA-44 has not been able to do. I would also say the long-term impact of administering very large doses of antibodies are unknown. And these are very significant doses, right? There's a lot of drug that's going into the system. And so we are kind of a little concerned about that. And I think the market is a little concerned about that as well, too.

What we've been able to see is our EEVs do not appear to have a meaningful impact on immunogenicity, which is an issue with RNA-44. The ability to integrate what we believe will become an increasingly more cost-sensitive polypharmacy environment is really important when it comes to cost of goods. And that takes you to the manufacturing question, right? So the ability to produce that much antibody plus oligonucleotide, which is what RNA-44 is going to need to do, creates perhaps a challenge.

Now I'm not obviously in the weeds there, but what we've been able to show is a very, very low cost of goods because of the very, very extreme nature of being able to get to target engagement at low doses, which once again goes right back to the ability to escape the endosome. So I think there's a lot of merit here.

And the data for RNA-44 is good, but there's limitations around that as well, too. And that's our 44 program, but we're going head-to-head with 44. Our 45 program is different, right? Our 45 program is well ahead in our belief around the marketplace. So RNA-44 may be first-in-class, but we're hoping to be best-in-class. Our 45 program, hopefully, is both first and best-in-class.

I think the last point that I'll say here is Entrada is the first company that can demonstrate evidence of delivery into the satellite cells. And the satellite cells is a compelling finding that we've discovered because generating dystrophin and protecting these skeletal muscle progenitor cells may enhance the ability to regenerate damaged muscle fibers and hopefully contribute to a rapid deeper and more durable clinical response.

To the best of our knowledge, we're the first company that's been able to show that. So I will say some of the pros for us, besides the translation of preclinical data into clinical data is a dose response is the ability to get there at really, really low cost of goods to be able to get there with low doses, but have a high therapeutic window and frankly, the ability to get to the satellite cells. So there's a lot of good things going on for Entrada that may not be known as well, but also juxtapose us to some of the competitive programs.

So I think just in summation, you effectively touched upon high levels of target engagement, the ability to deliver low doses, the clear demonstration of a dose response curve, the low cost of manufacturing because you're able to achieve therapeutic impact with said low doses, the ability to provide a flexible therapeutic opportunity to DMD patients, whether they're suffering with mutations in one exon versus another exon as well as the fact that across the exon skipping portfolio that Entrada has, there's differential levels of competition, whereas in exon 44, there are noteworthy competitors.

In exon 45, you're kind of in a class by yourselves. But pretty much wherever you look, because of the unique attributes of the EEV platform, you're able to offer solution that really stands on its own two feet and clearly demonstrates an edge versus the other competing technologies that are out there.

So I think here, we can maybe turn a little to what you're looking to do next with the exon skipping portfolio, and in particular, talk about the proof-of-concept clinical studies that are currently ongoing, particularly with the exon 44 and exon 45 programs. And I think it would maybe be helpful for our audience to better understand the regulatory experience that Entrada has had moving the exon 44 program forward because, hopefully, that has important read-through and risk mitigation for the broader exon skipping portfolio as well.

Yes. First and foremost, I'd like to thank you for that summary that you provided. I think you could not have said it any better, and you certainly said it better than me. So I appreciate that.

All eyes today at Entrada are on these initial patient studies. So we are -- as you said, we're running studies in Europe for both our 44 and 45 program. So the 44 program we announced, the first patient was dosed in the summer, and we're well on our way there. We plan on sharing more data in the first half of 2026. Our 45 program is right on the heels of our 44 program and is about, call it, a couple of months to a quarter behind.

But this has really been the setup for Entrada. We wanted to be able to create a one-stop shop for DMD, and we're able to do that. So 2025 has really been spent on setting up our clinical operations in Europe, getting the sites initiated, getting the patient groups going, getting, of course, the trials enrolled and then executing so that we could start to release data in 2026 around our 44 and 45 studies. So that's -- we're super excited about this. These are double-blinded studies, so we're not privy to the studies themselves, but enrollment has been going quite well.

I think the message around the importance of Endosomal Escape in the context of other therapies that are going after these exons has resonated extremely well because of that translation and because of the summary -- the summation that you just provided with high target engagement, low cost of good, great therapeutic window, a safety profile that's compelling and ease of dose, low manufacturing. And once again, the word flexibility has to continue to be emphasized.

So what are we looking for, right? So each of these 44 and 45 programs have essentially the same clinical trial structure from -- they're a little bit different in dosing. So let me start with 44. 44 has three different doses. The low dose is 6 mgs per kg, then it can go to 12 mgs per kg, and then all the way up to 18 mgs per kg.

Remember, our healthy normal volunteer study started at 6 mgs per kg. So we're getting off at a really good start already. Each cohort, there's three cohorts. Each cohort will have six -- eight total patients randomized 6 to 2, right? So we'll have six that have DMD and then two to a placebo.

Our first cohort of data, which is for our 6 mgs per kg will read out in the first half. And what are we looking for first half of 2026? And what are we looking for? We're looking for a couple of things. Of course, we're looking for safety, right? We want to make sure that the safety profile is as good as we believe it should be based upon all the translational work that we've done.

The second is dystrophin production. At the end of the day, it really comes down to dystrophin production. And we ultimately believe that we'll be in the double digits within that first cohort. We feel as though cohort 2, the dystrophin production will increase as well. And we feel as though there's this hockey curve type of reaction or response between 6 mgs per kg and 12 mgs per kg. Cohort 2 and cohort 3, we'll see, right? But we feel as the momentum that we'll have with cohort 1 and hopefully, some positive data will certainly help drive the enrollment for the rest of 44.

Our 45 program has a little bit of a different dosing. It's 5 mgs per kg, 10 mgs per kg and up to 15 mgs per kg. It's more of a technicality more than anything, but it's the same exact structure, right? Six patients, six on drug, two placebo, three cohorts. And those data, we believe, will -- we're projecting public guidance as we'll get that in mid-2026 as well. So 2026 is being set up to be a very inflective year for us when it comes to 44 and 45.

And just to confirm, as you may have, I think, mentioned at the beginning, the EEV chassis regardless of which exon-skipping candidate we're talking about remains the same, right?

Yes, it's a great point, and it's a good point to reiterate, Ram. So it's the same EEV that we're using for 44, 45, 50, 51 and importantly, our DM1 program that's partnered with Vertex. So the chassis is sound and it's foundational.

And as I alluded to earlier, because now the exon 44 -- exon skipping program has been subjected to extensive regulatory review on both sides of the Atlantic, I would think that it's a fair statement to make that dispositions the rest of the exon skipping portfolio very favorably from the regulatory standpoint because regulators at this juncture are very, very familiar with the EEV platform and with the EEV approach that you're using specifically in each of these exon skipping cases.

Truer words cannot have been spoken, right? And so what we -- what I will say is that we're running these trials and let me hit this point because you did ask about this. We're running these trials, these preliminary studies ex U.S. And why are we doing that, right?

One is because we're only running one healthy normal volunteer study, and that was for 44. It was a derisking study to make sure that the next step goes into patients, whether it's 44, 50, 51, et cetera. That is a check in the box. Every other study will go straight to patients. But the familiarity of not only U.K. MHRA but the EMA with the platform and the data is super high. And so we feel as though we have a very collaborative relationship with the regulatory agencies in Europe across the EU and the U.K. And so we'll just rinse and repeat there, right? But let's not forget the U.S. is obviously extremely important as well.

So a couple of things that we've done in the U.S. One, the feedback that we've received, because FDA has seen the protocol for 44. The feedback that we've received from FDA has been incorporated into the protocols that we are currently executing on in Europe. So they are as harmonized or as homogenized as possibly as we could do.

What we plan on doing is taking this initial data set, let me just specifically say 44 because the others are exactly on the same strategy. We'll take this cohort -- Phase I/II cohort data, plus an open-label extension data, we'll take this bolus of data, quantum of data, bring it back to the U.S. at the appropriate time and use that as the basis to have a discussion, pending data, of course, and how well the data looks or how well the package looks, we'll use that as the basis to have a discussion with the FDA on the merits of accelerated approval, right?

So our belief is that since we've incorporated a lot of what FDA wants into these protocols, that's one. Plus we're talking about high regulatory bar countries that we are in and running these trials in U.K., et cetera, plus a DMD patient in Europe is essentially the same phenotype as a DMD patient in the U.S.

So we feel that we have a really good collaborative discussion that may happen with the FDA pending data. At the end of the day, it's all about data. It's all about the package. It's all about -- within DMD, it's all about being able to balance out an adequate safety profile with the efficacy and hopefully functional benefit that we can provide to these patients. And we're confident so far that we'll be able to do that.

Obviously, it would be remiss of me not to focus since we're talking about DMD on two specific things given the regulatory and commercial precedent here. I'd remind our audience that multiple other drugs that have gotten regulatory approval particularly in the U.S. in DMD have benefited from the accelerated approval pathway and indeed were approved, if memory serves me correctly, on the basis of single-arm open-label data, whereas as you pointed out, your proof-of-concept studies being run in DMD patients are, in fact, randomized and controlled.

So maybe talk a little bit about the regulatory precedent there, and perhaps we could also touch upon recent commercial developments, for example, pertaining to the gene therapy ELEVIDYS and safety concerns around adeno-associated viral vector-based technologies, particularly with regard to the incidence of acute liver failure that can result in death and how this potentially positions Entrada for the ability to deliver to patients a truly safe and well-tolerated option.

Yes. So two really good questions there and two really good topics. So I think on the first one. The regulatory precedent has been set, right? Sarepta set this up with the approval of their first generation, naked oligo linear -- naked oligo approaches. The high -- as we've said repeatedly during this conversation, there is a remarkably high unmet clinical need, unfortunately, that still exists within DMD. The first generation programs didn't cut it. I'll come to gene therapy in a second.

We don't plan on recreating the wheel here when it comes to regulatory approval. But what we do plan on doing is providing that high regulatory caliber worth of data. The ability to compare this to placebo, the ability to look at a whole host of biomarkers, of primary and secondary endpoints to bring the most robust package because the way that we view clinical development and to an extent, regulatory processes is we put ourselves in the patient's life as much as we possibly can.

And how do we do that? We do that by partnering with the patient advocacy groups. So we plan on submitting the highest bar. We are looking for questions. We're looking for answers. If you go back to the beginning of how Entrada was founded and what runs through our veins it's scientific curiosity that will lead to drug development. And so if you look at our preclinical data for DMD alone and frankly, for DM1, you will see that it's the most rigorous set of data out there because we are trying to answer every question that we possibly can before we go to a regulator to approve a drug, right?

And so I don't want to put the cart before the horse here, but the amount of discipline that the company has, we are a long-only company here. We are just looking to get drugs approved so we can change patients' lives. And of course, shareholder value will improve and increase after that. But from a regulatory perspective, we're bringing all of our data with us, right?

And the story is already known. We already know that there's high unmet clinical need, but there's no shortcuts here. And so I think that's really, really important. And that's why this year has been a very foundational executional year to set up the data that will start to come next year, and we're super excited about that.

In the background, though, and I've said this to our Board since 2022, yes, about 2022, we've said that there would be a clearinghouse between 2025 and 2026. And we're starting to see that, right? Some companies have fallen out of the DMD space based upon risk-benefit analysis that includes part of Sarepta with their SRP-5051 program that includes PepGen in their DMD study. But all eyes were on ELEVIDYS, all eyes were on gene therapy. And we were very -- as much as we would love to have seen a 1 shot that can cure a patient or functionally cure a patient because that's the right thing to do as human beings, to be able to hold that there's a cure out there. That did not happen. And why did that not happen? And I've publicly said this as well, too.

Gene therapy for DMD and for these highly compromised neuromuscular diseases is more of a hammer approach when you need the flexibility, right? And so what we have seen then is exactly what you're just getting at, right? We have seen the flip side of gene therapy where you can't control the dosing, where you can't control starting and stopping a dose, where you can't control the variability or the external factors of how to treat a patient because once it's in, it's in and there's no take-backs, and you can't redose.

And what we've seen here is that hammer approach, unfortunately. We've also seen a lot of pain, right, within the patient groups have put a lot of emphasis and a lot of support behind gene therapy. Maybe it will come one day, but do you really need it, right? That -- it will be a good thing to have.

But if you can find a drug that balances out, it's a safe and efficacious drug, plus it provides not only dystrophin production, but functional benefit in a dosing regimen that is very long, standard of care right now with naked oligo once a week. Well, right now in our clinical trials, we're once every 6 weeks, that may even extend to longer, right? That is something that can potentially get and move the dial when it comes to the therapeutic need in a big, big, big way, and we continue to build upon this. What does Entrada 2.0 look like? What does Entrada 3.0 look like? How do we make even better EEVs to conjugate with better oligonucleotides to go after these diseases.

So I feel as though both from a regulatory perspective and the high bar that we've set internally, but not recreating the wheel here and using the precedents, coupled with the fact that we are in a backdrop where you need a flexible drug to go after these really difficult diseases and gene therapy has unfortunately run into several issues with the acute liver failure, death, et cetera, that there's a remarkable opportunity that still exists here for a game-changing and perhaps best-in-class approach, and I think that's where we play in.

Yes, and I think the prospect of being able to apply personalized medicine in the truest sense of the term to the DMD population is certainly not something that historically DMD patients have been able to avail themselves of. And certainly, in the context of a world in which the gene therapy, as you put it to a hammer, everything looks like a nail, right?

It's no longer being considered sort of one size fits all for DMD patients because of the safety issues that have been seen so far may potentially pave the way for something that is more personalized, more tailored to the individual patients' needs and less likely to result in safety issues, which I think, frankly, should be considered more than they have been historically because what you ultimately want is to provide the best possible risk benefit profile to the population. Even though this is a debilitating so far, inevitably fatal disease. At the end of the day, these are still patients who have pretty long life spans. It's not a disease that results in infant mortality per se. And certainly, if you have the ability to extend patients' lives, you want to do it in a manner that does not compromise the functioning of vital organ systems.

You're 100% correct. And I think that's why it's really important not only to get to the skeletal muscle, but the cardiac, right, to be able to get to the heart, which ultimately becomes extremely compromised within the whole subset of DMD patients, that's something that's not talked about enough within the -- not only the current standard of care because it doesn't really do much for the heart, but also with these next-generation opportunities, right? And so that's something that we plan on highlighting even more as the weeks turn into months because we feel as though we have a differentiated cardiac phenotype when it comes to the data as well.

So maybe we can talk a little bit about sort of what you consider to be the principal efficacy readouts, the ways in which you want to try to quantify and demonstrate clinically meaningful effectiveness in each of the exon skipping context that you're going after. And if there's any kind of distinction to be drawn when you look at exon 44 versus 45, 50 or 51 or if essentially the efficacy outcomes that you're looking at are essentially analogous across all of these approaches.

Yes, it's a good question. And I think in the beginning, I did mention that, we view all 4 of these exons as different diseases because they have different -- there's a different biology associated with them. There's a different patient journey that's associated with them, right? So for the 44 patient population, there's already dystrophin that's being produced in the background, right?

We do expect to have double-digit dystrophin production above background, right? And so we feel as though -- and I'll be very candid here that we -- Avidity has set a dystrophin bar that we plan on meeting. And our data so far, based upon our own models show that we have a very, very good opportunity to be beating that benchmark.

Remember, they're at 5 mgs per kg. The other thing that I will say about Avidity is that, that's 5 mgs per kg that correlates. We're at 6 mgs per kg, but 5 mgs per kg is roughly 6x the total drug size as what we have because that's the antibody plus the oligonucleotide. Our peptide is essentially 1 mg per kg and then it's 5 mgs per kg for the oligo. So we're talking about 1/6 of the dose from apples to apples when we look at cohort 1.

But I think at the end of the day, we plan on hopefully showing a remarkable dystrophin production. And I'm going to come back to functional benefit in a second, but let me talk about 45. 45 is a little bit different, right? So 45 will go up against casimersen, right? Casimersen has about 1% dystrophin production, right? I think the biology is a little bit different here.

I won't say that because we get double digits, high double digits or whatever it is within 44, that that's going to be a rinse and repeat for 45. I think each exon has its own distinct measurements of success, right? And so when we look at 45, one, of course, we need to beat casimersen, but how much we beat casimersen by, is something that we're holding close to the company's chest, so to speak. But we expect to hopefully beat the standard of care there but we're not going to project out by how much.

I think at the end of the day, Ram, it really comes down to -- ultimately it comes down to you can make all the dystrophin you want, right? But if it doesn't translate to a functional benefit, that is a very significantly missed opportunity. And I think that's where we start to think about things like, wow, we get to the satellite cells. Well, in our preclinical models, we've been able to show functional restoration, things like that.

At the end of the day, we want to be able to see a patient whether they are 44, 45, 50, 51. We want to be able to see an Entrada-derive therapeutic being able to fundamentally help them from a functional perspective as well, too, whether that's better upper limb movement, things like that, right? Because then we know that the drug is actually really, really working. That's something that we continue to investigate as well too, when we look at -- when we look at what -- how we define success.

So I think each -- so just to recap, each exon will be different when it comes to dystrophin production. Safety is, of course, paramount as we talked about many, many times for any drug, but also for us, of course, as well, too. But at the end of the day, we also want this to translate the functional benefit as well. And we'll start -- we're measuring a lot of that within the OLEs and things like that as well.

Super helpful. So maybe we can just talk a little bit about the preclinical data that's been generated with the 45, 50 and 51 exon skipping candidates. You mentioned a lot about what's been shown in early proof of concept with the exon 44 candidate. But maybe talk a little bit about the preclinical data that's been generated with the other exon skippers and how this potentially reinforces your level of confidence in generating meaningful clinical evidence of therapeutic impact with those programs?

Yes. Let me start with 44 for a second because it's the same type of high-caliber scientific investigation, right? So it starts with the mouse models, right? So the canonical mdx mouse model. But with -- what we did with 44 is we started there. That's great. That's kind of like the entry-level car into a market. And then we got more and more complicated, the D2-mdx mouse model, the human dystrophin mouse model, right?

So the del45 mouse model. So all these different mouse models that represent the disease in a different way, but mostly from the human phenotype perspective. We're using that same rigor for 44 as we did for 45. And then, of course, getting to nonhuman primates, right? From a nonhuman primate perspective, you don't measure dystrophin, right, because it's a wild-type nonhuman primate as we know. But looking at them from a safety perspective, looking at it from a target engagement, exon skipping perspective as well, leveraging the 44 data and the experiences in the clinic that we will likely have for 45.

So as you know, as we've discussed in the past, the Venn diagram of treaters for 44 and 45 is very, very tightly correlated. So we are leveraging a lot of the 44 preclinical data and the 45 preclinical data to be able to help with this enrollment. I think the healthy normal volunteer study for 44, even though it's a clinical study, not a preclinical study, certainly derisks this program in a significantly meaningful way as there were no safety observations whatsoever from an adverse event perspective.

So clean as a whistle as what I call it, but not technically a term. Plus at the same time, that robust target engagement that we saw as measured by exon skipping, but also muscle concentration. So I think what we've been able to see is this translation within the preclinical, from the mouse to the monkey. And then, of course, to the healthy normal volunteer in 44, we're banking on that for 45 as well, and there's no reason not to believe any of that.

And I think as a reminder to our audience, you probably mentioned this very early on in the discussion. The total number of DMD patients estimated to have exon 45 mutations, exon 45 deletions is around 9%, right?

That's right. So it's around 9% so a little over 3,000 patients. And I think that's really important because all lines seem to be on Entrada for the 44 study. I think it's the wrong way to look at it. I think the right way to look at it is the 44 and 45 study because it's a different backdrop, right? 44 is being compared to a drug or a potential therapeutic with Avidity that has not even been approved yet, right?

45 is going up against a drug that has been approved, right? And from the best of our knowledge, we are well ahead of the other competitors in the market for 45. 45 also has a larger patient population as well, too. So the ability to have two distinct but very, very inflective shots on goal from a data perspective in the first half or mid-ish 2026 is very, very important. We feel as though the company in nine months' time will be fundamentally different than where we sit today on September 25.

Very, very helpful also. And I think it would just be important to kind of clarify whether you see differential needs across these different populations targetable with the various exon-skipping candidates that you have. So the two questions I would ask at this juncture are: a, do you see kind of a differential therapeutic need when you look at exon 44 patients versus exon 45 patients? And also, if you look at, more broadly speaking, all of the potential areas where a theoretical exon skipping approach might be applicable, do you anticipate ultimately that Entrada would seek to advance the candidate across all of those arenas, like, for example, going all the way up to exon 55 or do you expect Entrada to effectively stop at 44, 45, 50 and 51?

If you don't mind, let me answer that question in reverse. So let me answer the question around, are we going to stick with these four exons? Or are we going to go even further? I would like to go is -- I would like to solve every single exon. I think that's the name of the game. The challenge with that is that the 4 to 5 major exons represent 40% of the DMD population. The rest of the 60 are comprised of very, very, very many mutations. And so we have to look at it from a -- will there be regulatory flexibility that's afforded to the company to be able to look at creative structures so that we can get drug to patient, right, or hopefully, a functional benefit to the patient.

And so I think at the end of the day, as we look at very standard rare disease clinical trial enrollment and then protocols there would have to be flexibility around that because there's not a lot of patients that have exon X or exon Y, right? And so you're not going to be able to run these robust clinical trials.

And FDA, and Vinay Prasad has said this, the end of 1 -- and let's just call it NF1, NF2, NF3, whatever you want to call it, is a pathway that FDA is willing to explore. That's something that we want to prosecute more because we really believe if we have the right approach that works the best for a patient that has exon 44, exon 45, exon 50, exon 51, well, it would be a shame not to afford that same type of potential treatment to a patient that does not have that because of the difficulties around the regulatory environment, the commercial environment. That's not good enough for us. That's not a good enough reason. However, we need to be able to see an agency, we need to be able to see a clinical trial that can be executed with the flexibility that can be afforded to us for these patient populations that are a lot smaller. So that's something we will continue to work on as the data comes out. I think good data makes that conversation easier because you have something to back it with.

I think from a differential product approach, look, at the end of the day, I view this, and I think Natarajan Sethuraman, who is President of R&D, who you know well, too, he'd say it the same way. The more dystrophin, the better, right? So what we're trying to do is create programs that can essentially provide as much dystrophin to a patient as possible, right? With the caveat that we have to figure out functional benefit as well, right?

And so I think that at the end of the day, is really the goal here, right? So our bars for dystrophin production are also, of course, they have to be tied to the exon, the specific biology around the exon, the specific patient need around an exon, what their journey looks like, how they're doing ambulatory, nonambulatory, all the different factors that go into the patient journey. But at the end of the day, a differentiated product or has to -- the way we view it has to have, first and foremost, a very strong safety profile that can actually work with the risk benefit, right, and that risk is safety, that benefit ultimately is the highest amount of dystrophin production you can get and then ultimately translating into functional benefit. So that's kind of how we view it. We don't try to complicate it too much because the science itself is complicated. But from a TPP perspective, that's how we kind of view it.

Yes. No, that makes a lot of sense. Just in terms of the treatment paradigm here to kind of contextualize it for the audience who may be more familiar with the whole gene therapy concept, it's 1 shot and you're done pretty much for life. There's no question of retreatment or redosing. How does the exon skipping therapy kind of treatment paradigm look like in the context of the fact that DMD is clearly a lifelong disease and you're not providing a one-stop curative regimen. Although clearly, nobody else has ever been able to do that in DMD, and it's doubtful perhaps that this will ever take place. But just give us a sense of how the exon skipping candidates are likely to be deployable in a real-world setting.

Yes. So I think, first and foremost, the earliest intervention is where we're trying to get into, right? To be able to affect the disease as early in a young boy's life is something that we need to be able to do before time becomes something that is not on their side, right? So that's something that we will continue to look towards as these data become available. So that's one.

Two, I think the dosing regimen of one -- dystrophin is a long-lasting protein as we've talked about as well, too. But the dosing regimen that we're viewing right now is once every six weeks, right? So it's an infusion once every six weeks. We have to see how that applies within a real world. Is it once every six weeks? Is it once every eight weeks? The good thing once again -- and I'm taking out any reimbursement, any commercial stuff right now, I'm just thinking practically. The good thing is that since we have a very flexible approach here, whether it's a young boy or a young man, we could probably customize it accordingly, right?

But I think if it's once every six weeks, great, it beats once a week, if it's once every eight weeks, good as well, too, right? So I think that becomes very important, like from a not only a quality of life perspective, but how a patient lives their life, right? And so it becomes obviously, very -- and this is what we talked about with the patient groups. It becomes part of their routine, right? And so we have to incorporate that in the correct way.

What I don't like about nomenclature is that the word cure can cut very, very many different ways, right? And so is it a cure, which is what gene therapy tried to push across? Or is it a functional cure, right? Is it something you can live with chronically, but you can live with, right, and you increase the quality of life compared against what the standard of care was at one point, right?

Are you moving the proverbial needle for a patient enough that they actually regain or gain certain aspects of their life that they would not have necessarily had if that product was not made available to them, right?

So I think there's a lot -- there's a big delta here that we can continue to look at when we start to think about what the life of a patient who has DMD may look like, right? That's where the hope is, right? That's where the hope of -- perhaps and hopefully, a differentiated treatment that allows us to get dystrophin production up to the point where it can catalyze into functional benefit with a safety profile that allows you to continue to live the life to the best that you possibly can, incorporating the dosing frequency into a life without -- with incorporating it into a life where the patterns then become predictable.

I think there's so much that we can do here that can really affect what the real-world experience could be for a disease like this, that's what gets us going in the morning, right? That's what -- that we feel as though we're on to something really good here. We have the data to prove it. More data will come out as we look at 2026, but we feel as though we have the ability here and the opportunity, and we're blessed with this opportunity to be able to hopefully put forth an alternative to patients and to their families that could be better and as we were supposed to do, which is advancing science.

Exactly, exactly. And one thing I did want to get some kind of commentary from you on is with respect to the pricing paradigm here. When you look at, for example, historically where DMD therapies have been priced, the gene therapy priced at over $3 million per patient. You look at some of the other exon specific modalities like EXONDYS 51, price at over $1 million per patient. You certainly don't see any DMD therapies, even the nongenetic medicine ones priced at less than around a few hundred thousand dollars per patient annually.

So clearly, you mentioned earlier the very low cost of goods, the low manufacturing cost applicable across the Entrada Therapeutics exon skipping portfolio. So that obviously provides a great deal of flexibility when it comes to thinking about pricing. But maybe give us some of your thoughts around potential pricing approaches, particularly in the context not only of applying an exon skipping portfolio broadly across significant swath of DMD patients, but also making this deployable equivalently across both sides of the Atlantic and multiple U.S. and ex U.S. markets.

Yes. So I'll start very high level. It's interesting when people ask me why do I want to be -- why have I been the CEO of Entrada for the past eight years. It's to have conversations like this, which means that you're getting close, right? You're getting close, right? We still have data that needs to come out, and we're not -- we don't drink our own Kool-Aid, so to speak. But to start to have conversations where you talk about -- I don't talk about pricing. I talk about accessibility, right? I'll pivot for one second.

I was in India a couple of years ago, meeting with DMD patients and the community there. That they can't afford a $3 million product or $800,000 product, right? The cost there is -- does not marry up to what the infrastructure looks like there, right, when it comes to how do you get accessibility. I think theoretically, and we will put this into motion. And I think we have some ability here because of the cost of goods sold.

We want to get this drug if it gets approved, if the data support is getting approved in the years to come, we want to get it to as many patients as we possibly can. We do not want accessibility to be an issue. I think that's really important.

And I think that really comes back down to why I'm the CEO of a really cool company right now. It's because we have the opportunity to do a lot of good. I think people price the hell out of drugs, one, because it costs a lot, obviously, to make that drug. And we all know that R&D is extremely expensive. But at the same time, certain advantages that afforded to very novel approaches to drugs like we have with this endosomal escape capture or endosomal escapability allows us to look at margin in a different way, right? And so I think that's something that we will continue to look at as we have to spend more time on this.

I think the other way is the SG&A for a rare monogenic disease that has a lot of -- that people know a lot about also decreases as well, too, right? And so the infrastructure that you need is a lot less globally than what you need for some other type of product, right? So I think what's going for us besides a therapeutic product profile and efficacy and safety that we hope translates when we start to see these data is a cost of goods sold that is advantageous to a company and a cost structure from an SG&A perspective that will hopefully be advantageous to the company that then will allow us to be able to create a mechanism around accessibility that will allow us to be able to get to as many patients as we possibly can, irrespective of what pricing pressures exist.

Yes. So I think the key takeaway for our audience is, given the manufacturing cost considerations here, given the flexibility, broadly speaking of the EEV platform, you have the advantage of being able to contemplate pricing models that maximize patient accessibility and patient impact regardless of what the region is, regardless of what the specific exon mutation is. And that really affords you a unique position as it were in the context of DMD therapeutics development.

That's exactly right, Ram. And like without getting into specifics about that, of course, but that's the theory, right? And it's not only the theory. It's what we've seen from a man -- we just had a Board meeting, we showed this to the Board as well, too, in terms of like why we have so much comfort within manufacturing as well? It's because we've proven it, right? Because we've been able to scale this up. We've been able to find those efficiencies. We have a rock star manufacturing group as well, too. And so that has all shown.

From an SG&A perspective, we can just look at other companies and use those as comps and realize that we might have a therapeutic offering that might be better than that, right? And so I think we have all -- I look at this from a recipe perspective, we have all the right components here as we anticipate data.

Okay. I know that we're running short on time, but I did want to touch upon a very important aspect of the Entrada story, which clearly, just as much, if not even more so than your DMD programs is being overlooked by the market. And that is the activities in myotonic dystrophy type 1, that is the DM1. So maybe talk a little bit about the history of Entrada's collaboration with the Vertex, that capital that's been committed by Vertex, what you've already received and what you are potentially eligible to receive under the scope of that collaboration and specifically about the VX-670 candidate, which used to be called ENTR-701, which is currently in clinical development for treatment of DM1.

Yes. So I'm glad you brought that up. And there's a lot of news around DM1, especially with some of the data that came out after hours yesterday with PepGen. So a good point to talk about this. So DM1 is a partner program. It's called VX-670, as you said. Vertex paid $224 million for rights that -- a preclinical asset at that time.

Once again, same EEV being used across the entire neuromuscular franchise. So you can imagine the amount of diligence they did before they wrote a very, very, very sizable check. And they also put a little bit of equity into the company as well, too. So that was good.

So I cannot emphasize enough, but I believe my colleagues at Vertex would say the same thing, that this has been an amazing collaboration between the two companies. We have been able to do a lot of great work together. The communication has been fantastic as well, too. Let us remind ourselves that DM1 has approximately 110,000 patients in the U.S. and Europe. So it's huge, right? It's a big disease that has no therapeutic approved products today. It's a life altering life-shortening disease as well to muscle weakness, wasting, myotonia, things that we've talked about.

And so what VX-670 is designed to do is to enable essentially the intracellular delivery of an oligonucleotide to engage -- it's getting a little technical -- to engage the CUG repeat and liberate splicing factors. Essentially, it's a very specialized specific way of looking at the CUG repeat, right?

And I think what we're -- this approach is very differentiated against some of like once again, Avidity and Dyne, which is more of a nondiscriminate DMPK knockdown. And some of those data from PepGen that were shared yesterday by the company are relevant to Entrada because it's a similar approach, albeit a highly differentiated mechanism since we are an EEV and they are not. But what they were able to show is one, a dose response; and two, data that from a single dose seems to be pretty good, right? But they also have some safety liabilities as well, too, which is not surprising, considering their approach.

So what we're excited about here is we have a partner in Vertex that is not only leading clinical development, but they have the wherewithal to go at this in a speed and an execution that a smaller company may not be able to do. And they are proving that time and time again.

So what we have announced -- we haven't announced specifically what milestones. We don't include the milestones in our runway, which is important for the audience to know as well, too. But what we have achieved a fair amount of milestones with Vertex, but there's a lot that's left there. I will say from a public guidance perspective because we are privy to what the public knows.

There is a firewall up between the two companies based upon materiality thresholds. What's material to us is certainly not material to them, right, considering the scale of the company. But they've accelerated this study, and they have initiated the multiple ascending dose portion of the study, which will -- which they have said we will have dosing and enrollment completed in 2026. So they're well within the execution range. So we look forward to seeing the data just like everyone sees it, but another huge catalyst another huge opportunity for the company, both from another validation perspective, but also because of the amount of milestones and royalties that we are contractually obligated to...

So I don't know if you want to touch upon the other competing DM1 programs that have received some degree of visibility. I think there's one from a privately held company called Juvena Therapeutics. Arrowhead is active in this area as well. But one of the things that should be apparent to our audience is that DM1 is every bit as intriguing a commercial opportunity as, frankly, DMD. And while still comparatively underserved, there is a lot of competing activity in the space. But what you and Vertex are doing clearly looks differentiated. And if anything, one should take away from the recently released data with-- I think it's PGN-EDODM1. Effectively, that should give people more confidence in Entrada's approach because...

100%. And I think really, once again, just to lay this out, a more specific CUG repeat approach is what we think is a better approach than full DMP knockdown. And that's the difference between us and like Avidity and Dyne. I also think from an Avidity and Dyne perspective, the transfer and receptor-based programs, which is what they are, have been dose limited. They've shown that, right? They can't really scale that up because of the saturation of the receptor.

When you look at companies, you mentioned this, when you look at like companies like Arrowhead and Juvena, Arrowhead's program is pretty early. So we'll look to their clinical readout there. Their nonclinical data did not appear as robust as the VX-670 package, but I know they're exploring infrequent dosing. So we'll see.

PepGen's data looks good. I mean, once again, it's a balance. But on the efficacy side, it looks good. Safety, there's still questions. But once again, they've shown the specificity of the CUG knockdown or the specific approach as being advantageous, right? And they showed a dose response, right? Hence, they're probably doing pretty well today in the market. I think what you are saying -- and once again, I know we're up to time, same EEV across DM1 and the DMD exons as well. So another very, very big shot on goal for Entrada that we're not counting into our own valuation nor are we counting into our own budget and runway.

So to touch upon runway before we close here, maybe you can just briefly recapitulate for our audience Entrada's most recently reported cash position, your stated guidance in terms of the length of the operational runway and which clinical data catalysts you expect to report within the scope of that runway window?

Yes. So we reported $354 million of cash. That runway gets us into Q2 of 2027, which is important because of your third question in terms of the catalyst of data, right? So let me start with DMD. So exon 44, the first cohort will be in the first half of 2026. Exon 45, the first cohort will be in mid-2026. We haven't provided guidance around the second and third cohorts, but those will also be in relative short order behind the first cohort.

And then DM1, we don't know what Vertex's disclosure strategy is going to be, but they plan on enrolling and completing dosing of the MAD portion of that study in 2026 as well, too. So if you look at 2026, there's a lot of shots on goal for the company, and we expect, hopefully, the investor interest. So we're starting to see it now, the investor interest to start to increase as we get out of this execution year and into a data release year.

Yes. So just before we close, I wanted to touch upon one last thing, which is a little known aspect of the Entrada story. You effectively out-licensed the candidate previously known as ENTR-501 to a privately held company called Pierrepont Therapeutics. This is effectively a proprietary enzyme replacement therapy for mitochondrial neurogastrointestinal encephalomyopathy or colloquially called MNGIE.

And I wanted to just ask you to sort of briefly recapitulate this for our audience in terms of what the potential future long-term upside to Entrada could be incremental though it might be in this context as well as maybe gives the audience a sense of how this could provide some insight into how Entrada may look to optimize the value of the EEV platform outside the core areas of focus in DMD and DM1.

Great question. Happy to talk about MNGIE. MNGIE is a clear example of the modularity of the platform, right? So what we have been able to show is we've been able to show data across neuromuscular, ocular, which we haven't talked about, and hopefully, we will soon, and metabolic diseases, which MNGIE falls under, right? So we can go after a lot of different things, and we've generated great data across three very, very big disease areas.

MNGIE is an ultra-rare progressive ultimately fatal genetic disorder that affects the digestive and nervous systems, it's truly a horrific disease, and we're excited to partner with Pierrepont on this as well, too. They're the right partner. They know the disease. They know the market. They continue to progress the program. But importantly, from what Entrada can do, a lot of attention is, of course, being paid on DMD and as you just said, the DM1. Those are great. Ocular is right behind that as well, too, from an Entrada 2.0 perspective, but also we can do a lot within metabolic diseases as we've shown within MNGIE and some data that we also have not presented. So a lot of shots on goal for the company based upon the modularity of the platform, too.

So unfortunately, I think that's all we have time for today, but Dipal really want to express my appreciation and our audience's appreciation for you taking the time to walk us through the Entrada Therapeutics story. I think the key takeaways for the audience are very straightforward here.

Entrada is clearly undervalued, one might say, massively overlooked entrant in the DMD and DM1 spaces. You have a lot going for you with multiple clinical data readouts coming up in the next several months. Along with a very committed large-cap collaborator in Vertex.

Clearly, there is corroborative evidence across the competitive landscape that, in effect, only serves to validate and strengthen what should be conviction in the exon skipping approach and the use of the EEV platform. And of course, from a regulatory standpoint, your team has done a massive amount of foundational work both last year and this year in effectively mitigating the risk from a regulatory perspective, from a regulatory acceptability perspective with regard to the Endosomal Escape Vehicles technology and its myriad applications.

So really appreciate you taking the time to walk us through the Entrada Therapeutics story. We look forward to continuing to follow the company's progress in the coming months. And thank you to our audience for their attention.

Appreciate it, Ram. Thanks, everyone, for paying attention too. We'll talk soon.

Thank you.

Take care.

Okay. We are all clear.

Thank you so much. Appreciate it.

Dipal, I will see you next week in Boston.

Absolutely. I will be there.

Bye. Thank you. Bye-bye.

Goldman Sachs Global Healthcare Conference. My name is Paul Choi, and I cover the biotechnology sector here at the firm. And it's my pleasure to welcome Entrada for our first session to kick off the conference. Before we begin, I'm required to make certain disclosures regarding Goldman Sachs relationship with certain companies that may be attending or presenting here at the conference. Those relationships include investment banking, 1% or more ownership of the stock and other relationships.

These disclosures and relationships are available through to you as customers of the firm through our research portal. I am prepared to read them aloud, but they are available to you publicly through our research portal website. And with that, we'll kick it off. We're pleased to have Entrada here. And I'll let Nate introduce himself and his role and a little bit about the company. And then maybe for our first question, for investors who may be new or unfamiliar with Entrada. Can you maybe just give us a little bit of background on the company and the EEV platform and how -- what data you have so far that sort of made you excited about its potential application, starting with DMD and potentially other disease.

Sure. So first of all, Paul, thank you very much. It's great to be here. Thank you to the Goldman Sachs team. So I'll do a quick introduction of myself and then the company and the platform. So I'm Nate Dowden, I'm President and Chief Operating Officer at Entrada Therapeutics. I've been with the firm since about 2019. And so I've had the opportunity to see this amazing platform and the DMD and DM1 programs that we have really go from whiteboard to patient, which is a remarkable opportunity.

So very, very briefly. So Entrada Therapeutics was founded in 2016 and the basic technology that we've been leveraging since then and have been building and improving upon and changing quite substantially actually, is a library of small cyclic peptides about 810 kD, very, very small, but with remarkable properties. And so I'll describe those in a second, and then I'll talk about what we're doing with those. So these cyclic peptides, they bind to the cell surface, relatively low affinity, any cell in the body, but just enough to trigger a process called endocytosis.

So basically, what this means is the cell takes it up and it captures the cyclic peptide and whatever that peptide is conjugated to, so it could be a protein, small peptide enzyme, oligonucleotide, what have you. And it takes it up into this small vesicle called an endosome, which is what cells do with any biological material that they bring in. Then what happens is the binding affinity of the peptide goes up several thousand folds.

And when it does, it drives a process that we call budding. And you can see this actually in the microscope, where this endosome buds off these little vesicles, the endosome reforms sort of like a soap bubble pinching off of another soap bubble, these vesicles then simply collapse. There's nothing holding them together, and they release whatever is in the vesicle into the cytosol. And then whatever we have as associated with the cyclic peptide can migrate to the nucleus, proteasome, et cetera, wherever it needs to go.

So what we've been able to show over many, many years now is that we can conjugate, as I said, virtually anything to these peptides and deliver remarkable amounts of drug to target. And so to give you an example and where the differentiation in this platform really is, on average, you'll see about 1% to 2% of biological material escape the endosome. So when you think about that, you're pouring a lot of drug into the body. Some of the drug is getting into the cell that you need it to get into. And then only 1% is getting out of that cell and to the intracellular target.

We get 50% out. So it's simple arithmetic when you think about therapeutic index. You don't have to put as much drug in to get so much drug to target. Now with respect to the DMD programs, and so we'll carry that forward. What we've put together is an incredibly robust preclinical package at this point, multiple models, very difficult models, disease models that we've worked with. So for instance, you think about our ENTR-601-44 program that we are now in patients -- going into patients this year with. We've got clearance in the European Union, United Kingdom, the United States, to move forward with clinical trials with that program.

We were able to show remarkable exon skipping and dystrophin production. I'll talk about that in just a second for people who aren't familiar with it, and dystrophin production in a knockout mouse model, which is really important if you want to be able to test your drug and have any sense of what that's going to look like. Similarly, we did the same with our second program, ENTR-601-45, also for Duchenne muscular dystrophy patients but a different submutation. We've done the same for 50, and we've done the same for 51.

So that gives us a lot of confidence that if we get our drug into the cell and address the mRNA that we need to address, we're going to generate the protein that we need to generate, and that protein is stable, useful. And not only do we see that protein in healthy muscle cells. We see that protein in stem cells -- the muscle stem cells and at 100% uptake. And that's something I don't think anybody has ever really quantified in some of these models before. So we're really excited about that, too, because you're creating this pool of healthy muscle cells basically that can then regenerate over time.

Now when we think about the rest of the preclinical package going forward, so we have the knockout mouse models and then we have, obviously, our NHP models. And in our NHP models, what we were able to demonstrate was that the pharmacokinetics, basically how long this circulates and how much of an increase you see in terms of concentration in the blood as well as exon skipping, the relationship between those 2 things. What we were able to show there is that goes up exponentially as we dose up at clinically relevant doses. So that's very exciting, and we've been able to replicate that. And then finally, last year, we ran a healthy normal volunteer trial in the United Kingdom with ENTR-601-44.

And there, we were able to demonstrate safety up to our top dose, no movement in any clinically relevant biomarkers whatsoever, which, as you know, for this class is pretty remarkable. And also, again, very, very strong pharmacokinetic profile associated with the drug. So strong actually that every time we doubled the dose, we saw a corresponding increase in exposure in the plasma and the muscle, and we saw exon skipping and that we all expected to see. But what we didn't see, which was fascinating as we didn't see a corresponding increase in the amount of drug that's excreted out.

So effectively, I think what we've seen, what we believe we've seen is there is a maximum amount of drug that you can possibly saturate the kidney with. And after that, everything else is flowing out of the body. And because we have safety at that dose in humans as well as in our nonclinical tox models, we are very, very confident that as we move into our patient trials, ENTR-601-44, ENTR-601-45, most recently cleared in the U.K. and the EU, and then we're filing 50 later on this year and then 51 next year. As we move in these patient trials and as we dose up in these patients, we should be able to get a significant amount of exposure, exon skipping and dystrophin production, we hope, without a concomitant increase in any potential tox liability.

Okay. Great. Thank you fopr that, Nate. Maybe to help us contextualize what you've just said versus some of the existing or clinical stage DMD assets. Can you maybe help us fill in the gaps thinking about, in your mind, what solidifies your company's leadership potentially in the space? And just thinking about there are commercially available exon skippers. There's a gene therapy on the market. There's some gene therapies in the clinic as well as other modalities. So maybe just help us think about how the pieces fit on the board and how Entrada might fit on the board as well.

Sure, absolutely. When we first started this journey, there were very, very few options for patients, right, 5 years ago. You had a few approved exon skippers. So this is just oligonucleotide, not conjugated to anything that enhances delivery. And they've been able to show a little bit of exon skipping, a little bit of dystrophin production. And for a patient population that's facing a very challenging disease, obviously, that's helpful, and that's great.

But I think everybody really believed that we can do better. And so over the past 5 years, we've now seen a proliferation of not only exon skippers conjugated to a variety of different delivering enhancements conjugates, but also the gene therapy and also a number of other complementary technologies. And we can talk about that in just a bit. But I mean, ultimately, when we go and we talk to patients and we talk to patient advocacy groups, the one thing we always talk about is we are very, very far from the finish line, but the future has never looked brighter for these patients, and that's wonderful.

Now to put this in context, what you're really trying to do for these patients is you're trying to help the body produce this protein called dystrophin, which ultimately will protect the muscle, prevent the muscle from breaking down. And also if you can get it into the muscle stem cell to help the body regenerate properly and appropriately, right? That is core to care. Everything else is then built around that. So when we look at our program, simplistically, if we can drive more dystrophin in those muscle cells and in those satellite cells, those muscle stem cells than anyone else, we've got a better product, and we've got something that we believe will be best-in-class.

And in some cases, for instance, our 45 program, as far as conjugates go, should be first-in-class. Now how do we think about gene therapy? How do we think about some of these other modalities? For patients who have nothing else and sadly, that's still the majority of patients, having a discussion with their physician, the families have a discussion with the physician and for the older patients with their families, it's an option, right? And it's something that to consider.

But we still believe ultimately, that's going to be a limited modality, if for no other reason, it is one and done, but you're really done. And we know that especially the younger patients are just going to grow out of it over time, right? It's going to dilute out as you build muscle and muscle turns over, over time. So it may be a nice addition to a true dystrophin-producing therapy. And again, for those patients where there are no exon skippers that, it might be something that's quite useful. But there are many other things. There are HDAC inhibitors now that present additional transcripts that then can be skipped to produce more dystrophin.

So very complementary. There are drugs that protect the muscle, which should be helpful to buy people time as you produce more dystrophin. And so we're -- there are drugs that potentially drive the proliferation of satellite cells of stem cells, which, again, if you're using that with our exon skipper and you have dystrophin in those satellite cells should be incredibly useful from a regenerative perspective.

So we see ourselves as central to care. And -- but ultimately, we all believe that polypharmacy will be the way to go in this devastating disease.

Okay. As with all early-stage programs, we often focus on things like PK/PD as well as safety. Can you maybe talk a little bit about the safety data you've seen so far, both preclinically and clinically in the healthy volunteers. And just I think one of the questions on the modalities is just what it does -- you talked a lot about renal clearance earlier, but just liver clearance maybe would be helpful to understand. And then just in terms of the PK and PD, just what you've seen through the dosing so far in healthy volunteers?

Sure. So first of all, so nonclinical, the easy answer on that one is when we ran our nonclinical studies, our NOAEL, so no adverse effect level was at the highest dose we tested. Great. Okay. So that's -- so then we went into the healthy normal volunteer study last year. And again, we dosed up to 6 milligrams per kilogram with the ENTR-601-44. And as I said before, we had no clinically relevant safety signals at all. We had no treatment-related adverse events at all, which was phenomenal. And so -- and that became our starting dose then for our patient studies as augmented, obviously, by the nonclinical tox.

Now to your question regarding liver tox, that hasn't really been an issue for the chemistry that we're leveraging. So that is an issue for different chemistries for PS backbone chemistries, et cetera, ASOs, but for the PMO-based chemistry that we use, liver really isn't a concern. So that's great. One concern that people have brought up in the past because of therapeutic index challenges that others may have faced have been things like hypomagnesemia, et cetera, but we've never seen any of that.

We didn't see it in the patients. We haven't seen it in the nonclinical models. And we believe and we hope and we have to dose all of these patients up, and we intend to dose up as aggressively as we can to protect the skeletal muscle and to protect the heart. But we believe and we're hopeful that we won't see that, but time will tell.

Okay. Great. You talked a little bit about trialing patients in England. And I just want to maybe help us understand how the geographic split and just kind of what's happening with your U.S. clinical trial development versus ex U.S.?

Yes. Yes. So when we submitted regulatory applications around the world for the healthy normal volunteer trial, the British were extremely excited and aggressive, and we moved that program forward. And then from that program, the idea was let's go straight into patients, multi-ascending dose trials. So for 44, 45, 50 and 51, the structure will effectively be the same. You start with your starting dose, second dose, third dose as you go up. So 3 doses, 24 patients, 62 placebo-controlled trial design. So fairly rigorous and good patient numbers there.

So as we think about going forward and the difference between our ex U.S. trials and our recently approved to go forward 601-44-101 trial, sorry, 601-44-102 trial in the United States. We wanted to think a little bit creatively. And one population that is remarkably underserved even in the clinical trial environment, let alone in the marketplace are those adult patients. It's roughly, we think, 40% to 50% of the market as it stands today. And yet they're understudied and underserved.

So when we went back to the FDA. We had a discussion with them about taking something a little bit more creative forward to both serve this patient population, hopefully, as the trials move forward and then ultimately do something very useful from a life cycle management perspective for the drug itself. So now this trial design is a little bit different. It's 4 cohorts. We're starting at lower doses. And we're starting at lower doses because these patients, as you might imagine, have a lot of comorbidities. As they get a little bit older, they can become quite frail.

So we wanted to be extremely conservative with this patient population. But we'll be adaptive, right? So we'll see how -- because these trials are going to run on top of each other for the most part. So we'll see how the therapeutic index is shaping up in our 201 trials globally. We'll have a look at what 45 is doing at the same time. And the toxicokinetics of these drugs are extraordinarily similar, 44, 45, 50, even the VX-670 program that Vertex is running, and I can talk about that in a second.

So we'll see how those are going, and we'll see if there are any adjustments to be made to the U.S. trial. But we're very excited to be able to initiate that trial next year. And we know that the patient groups can't wait to see that hit the clinic.

Okay. You talked about serving an under -- including an underserved population of the adults. But I guess, maybe just at a high level, how do you think about sort of the clinical metrics or clinical bar for the adult population versus what historically, I guess, in the DMD clinical space has been more focused on the younger boys even preteen boys. So just maybe just how does the range of outcomes perhaps vary in your mind for these 2 diverse populations?

Yes. So we think of it in terms of a continuum, right? So as the patients progress throughout their life cycle, and there is quite a lot of variability actually in disease progression, which is why comparing to natural history studies can be challenging for some folks. But with the younger boys, obviously, what you're trying to do, first and foremost, is preserve ambulation, their ability to run, walk, play with their friends, et cetera. As the patients progress, they will obviously slowly lose that ability. Then they'll lose upper arm, upper shoulder, upper body function. And then they have challenges with the diaphragm, which ultimately results in challenges with breathing and then there are the cardiac issues, which are the most unfortunate symptom of the disease.

So as we think about the 2 different populations, obviously, this older population will probably, as we enroll it, be primarily non-ambulatory. So what we'll be looking at there is not only dystrophin production, but we'll be looking at functional metrics that are associated with upper body strength, basically the ability to do things that impact quality of daily living as well as diaphragm as well as cardiac measures. So it's not different per se, but it's where you emphasize, right? So we will be looking at some of those things with the younger boys, too, but we would expect to see different outcomes.

Okay. And just maybe to go back to the geographic differences for a moment, just in terms of the U.K. versus the U.S. trial endpoints or I guess, focus, anything you would call out there?

No, not right now. I don't -- I wouldn't call out any differences. We will -- as we begin enrolling the trial, we'll be giving, I think, a little bit more specific guidance in terms of things like data readouts, which everybody is interested in. We just -- until we've started announcing first patient first dose, we've got everything rolling. We don't want to put something out there that we might have to alter in some way, shape or form. But everything is going quite well so far in terms of site activation, site enrollment, et cetera. So in fact, we're going ahead of schedule. So that's great.

Our 45 program is actually caught up and it's basically right on top of our 44 program, which is also something that we're really excited about, particularly since that one will be probably a first-in-class as well as a best-in-class and is a slightly bigger patient population. So I wouldn't call out any major differences, U.S. versus EU, U.K., et cetera, right now. We'll be trying to slowly over time, harmonize everything so that we have kind of the full package, both across multiple exons as well as for multiple age groups as well as incoming functional status over time.

Okay. Great. As you advance the clinic, it's probably fair to say that the landscape is evolving in real time, both in the clinic as well as the commercial stage. And so as Entrada advances in the clinic, can you maybe tell us how you see the DMD market evolving over the next couple of years? There's often some discussion about how much of the prevalent pool will be available for clinical stage companies such as yours to treat down the road as some get treated with gene therapy. Some drugs are being pulled from the market in other geographies like in Europe and so forth. So just maybe -- and other companies like Edgewise are advancing their substance program as well. So just maybe how do you see the landscape evolving? How much of the prevalent pool, I guess, in your mind will be potentially available for your products to treat if they come to market?

Yes. We have thought about that since day 1, and we continue to think about how to creatively move forward in what will ultimately be a polypharmacy world, you're right. And I think it goes back to something I was talking about earlier, which is that the highest level of dystrophin production possible and not just high numbers, right, 50%, 60%, 100%, whatever it ends up being, but also the quality of the dystrophin is really critical when it comes to functional outcomes. And that's been demonstrated.

There was a presentation just a couple of months ago at ASGCT, where they talked about that. And they showed the example, 2 different patients. These were BMD patients. So you could actually look at this from a natural history perspective. One patient had tremendously high levels of dystrophin production, but very low molecular weight, and they had lost ambulation in their 20s. Another patient had very, very low levels of dystrophin production, but very high molecular weight, and they were still walking around in their 70s.

They showed the example of another young boy who had very, very low levels of dystrophin production, 3.5%-ish, I want to say, something like that, but very high quality, very high molecular weight still playing baseball at 16 years old. So that does make an enormous difference, and that's something that probably doesn't get enough discussion really when talking about the exon skippers versus the gene therapies because microdystrophin is obviously quite small. But as I mentioned before, if you don't have an exon skipper available, a thoughtful discussion needs to be had around that.

And then you mentioned the Edgewise program. Yes, the Edgewise program, the [indiscernible] program, the Telepharmaco program, these are all complementary technologies. If you put those on top of an exon skipper like ours, where you've generated significant levels of dystrophin production, that should do nothing but help. So we're very hopeful that over time, we'll all be able to work together and with the physician and with the patient community to make those things happen. And when we talk to physicians out there, we hear that these natural experiments are already happening. And so people are looking closely at how they can optimize care for the patients.

Great. I guess in your mind, if you have to look in your crystal ball or something like that, just how would you like perhaps characterize the sequencing 5, 10 years from now of these various different classes of drugs, whether it's exon skippers, gene therapies or other modalities?

Yes. So I think what we've heard from physicians and what we think makes sense from the perspective of the biology is if you have an exon skipper like ours, where you can generate significant levels of dystrophin and ultimately, you can demonstrate that there's functional improvement associated with those significant levels of dystrophin, that's your core therapy. That's your first middle and last option every time. But then you should be thinking about how to build around that. And for instance, one reason might be, okay, so I'm crystal balling.

I've got significant levels of dystrophin production. I've seen a functional improvement in a patient. But what I'm looking at right now is I'm looking at skeletal muscle, right? I can see whether or not this person is improved on their 10-meter walk test. Maybe I'm running MRIs over time, but there's going to be a lag associated with what I'm seeing in terms of cardiac degradation as well as cardiac improvement. So what I don't know yet is how well I'm protecting the heart. So anything I can do from both my core therapy, 1, 2, 3 and then anything you can build around that to protect that patient's heart which may be at this point, still a subclinical issue is nothing but the best standard of care possible.

Okay. Great. Maybe just in broad strokes now that you are enrolling patients in the clinic and both for 44 and sort of 45 and as we sort of think about rough time lines and just thinking about what level of derisking you might have. Can you maybe provide a rough framework for us just in terms of time lines, what you think should be the key metrics? And in your mind, how much you will like potentially derisk your lead programs?

Yes. This is -- it's going to be a big year, big 2 years for us, I think. So as you pointed out, we're heads down execution on getting these clinical trials up and running and getting the patients dosed. As derisking goes, obviously, it starts with the nonclinical, right, and you pull together the tox package and you're looking at the dystrophin production and the functional metrics you can get from the mice and the full correction we saw with our 45 program, which was amazing. And then you're looking for correlations across the different programs.

So what we've seen really is this EEV that I talked about at the outset of this conversation, it really does control the toxicokinetics of the drug. So regardless of the oligonucleotide that we conjugated to, when we look preclinically and we map these curves, 1, 2, 3, 4 it might as well be the same drug. They overlap completely. And so every step that we take now in the clinic is a really exciting derisking event for us. So the 44 program that we ran last year with the healthy normal volunteers, I mean, that was better than expected.

We didn't expect to see no adverse events at all at our highest dose. That was really remarkable and very, very exciting. And similarly, I should step back. We have very little insight into the VX-670 program. And that's by design. That's Vertex is running that program. We have a pretty significant firewall. What's very material to us that we would have to report on is not material to them. We are not yet a $130 billion biopharmaceutical company.

However, we know that they're running this SAD/MAD globally, 26 sites globally have been announced. We know that they've made it through the SAD portion. We know that they've accelerated into the MAD portion. And we presume based on everything that they are telling the public, things are going quite well, and we think that they are going quite well. And it's been a really, really nice collaboration.

So the simple fact that they've been obviously successfully dosing through a patient cohort. We've successfully dosed patients with a 44 program, and we've got the nonclinical tox package. That gives us a lot of confidence that not only do we have here, but there will be a lot of translation. 44 and -- I'd like to say 44 will derisk 45, but 45 will -- the data will probably come in so close to 44, they'll be right on top of each other. But as those programs come forward, yes, I expect a significant derisking then for 50 as well as 51 and anything else we develop down the road.

Okay. Great. We have a few minutes left, and I want to touch a little bit on the Vertex program since you brought it up, which is just maybe mechanistically, can you explain the similarities or key differences between the DMD and the AAT programs?

So mechanistically, they are quite [indiscernible] oligonucleotides, both conjugated to the same EEV. I should have mentioned that in terms of derisking. All the neuromuscular programs, it's the same EEV. So with the DMD programs, it's an exon skipper, traditional exon skipper. With the DM1 program, this is a steric block. So you're blocking a protein that would otherwise aggregate on these long extended CUG repeat hairpin loops that occur in these patients. And because of that aggregation, you don't have appropriate downstream splicing. And what we've been able to show with the 670 program is that we've been able to block that aggregation and simply enable appropriate downstream splicing. And we were able to do that across a 22-gene panel nonclinically.

And I think it was some of that data as well as some of the rest of the data that they saw in our early DMD programs that got them excited about our DM1 program. And ultimately, when they came to us, we talked a little bit about -- we talked a lot actually about a shared vision for that disease, the opportunity for, as they will put it, functional cure and the differentiation of the program based on that data package and based on the approach, they got quite excited. And that deal that we did, $250 million upfront, including some equity as well as significant milestones and then royalties on the back end has really allowed us to invest heavily in the acceleration of the DMD program as well as then some of the earlier stage work that we've been doing.

I don't want to leave our ocular programs behind either because those are starting to look quite good, and we hope we'll be able to announce a candidate later this year for that.

Great. Speaking of which, do you think about partnering that? Or is that something you'd want to keep internal? You obviously have attracted a large high-quality biopharma interest in the form of Vertex, but ophthalmology is also a very large space. How do you think about a partnering there potentially?

So the way we think about partnering and ophthalmology would fall into this category, but it's really anything is it needs to be somebody like a Vertex, right? Somebody needs to bring something to the table that will quite obviously add value, whether it's an ability to expand the platform and to work in things where we have no capabilities, but there's clear opportunity and interest in the biology makes sense, whether it's to accelerate a program that's already being developed today or whether it's to basically package up a group of programs and be able to say, listen, we've worked in this space. We have a franchise in the space, we can do this, and do that in an incredible way.

When we talked to Vertex, not only did we have a shared vision for the program, but we also saw a company that has done this before. They basically invented an entire category of drugs. They've made remarkable advances for a group of patients, a very large group of patients who up until that point had very few options and would die quite young and they transform that space. And we saw that opportunity in DM1. And that's -- it's a pretty high bar, but that's the sort of thing that we look for when we have partnering discussions.

Okay. Great. And maybe just on the last note, since we're almost out of time here. Just in terms of the Vertex program, are any milestones potentially triggered this calendar year? Or is it just still TBD, whether it's '25 or '26?

Yes. We don't bake any milestones into our cash runway. That would be, I think, presumptive and presumptuous. But as far as the milestones go, there are additional milestones to go in the clinic and commercial, but we don't guide against those, and we'll see how the clinical trial runs out.

Okay. Great. Thank you very much, Nate.

Very nice to talk to you. Thank you very much.