Afternoon, and thank you for joining us at Guggenheim's 2026 Emerging Outlook Biotech Summit. I'm Debjit, one of the therapeutic analysts, and next presenting company is Entrada Therapeutics. Joining us from Entrada is the CEO, Dipal Doshi. Thank you so much for making time for us.
Thanks, Debjit. Happy to be here.
Given that this is our first in-person conference, I do remember hosting you back in 2021, but that was virtual in the COVID days. It'll be great to get a refresh introduction to the company, and then we'll take it on from there.
Sure, yeah, happy to do it. So Entrada Therapeutics is a company that's really focused on the development of intracellular therapeutics. And so today we are led by programs in Duchenne muscular dystrophy and myotonic dystrophy type 1. We are leveraging a proprietary delivery mechanism that we call endosomal escape vehicles to deliver therapeutics to a wide variety of diseases, first and foremost led by those two. We also recently announced our entry into ocular diseases, where we're focused on inherited retinal diseases. And that first disease that we announced is Usher syndrome type 1A. So a company's based in Boston, 150-160 employees, very, very significant mandate going into 2026, where we have several inflection clinical data inflection points along the way.
So let's start with the data inflection points. You'll have one update in the Q2 , and then a different exon in probably the middle of the year. End of the year, you get the 12 mg/kg dose from exon 44. You might also get Vertex data this year in the DM1 program. So there's a lot happening for the company.
Yes, yes. You know, we spent 2025 progressing into where we feel as though 2026 is going to be a data-rich year. And so to break that down a little bit for our DMD programs, as Debjit said, our first data our first clinical data set within patients will be announced in Q2 of this year. And that's a 6-mg/kg dose for our ENTR-601-44 program. I'll stay with that for a second. We expect to have double-digit dystrophin levels within that. So the real key of this first data set is, once again, to reestablish safety, because our non-clinical plus our healthy normal volunteer data within that 44 program established a very robust safety database. We want to reestablish that, of course, now within patients as well. So that's the really big key takeaway, that plus dystrophin production.
The second cohort of data, which is up to 12 mg/kg, as Debjit said, will be released before the end of the year. And so we'll talk, I'm sure, more about that as well. Our second exon is ENTR-601-45, which is, of course, focused on the 45 patient population. We expect that first cohort of data to come out the middle of this year. So right then and there, within our 44 and 45 programs, we expect three clinical inflection points this year. Our partner program, which is named VX-670, which is our DM1 partner program with Vertex, should complete their dosing and enrollment by the middle of this year. We don't control how they decide on disclosing the data or whether they disclose those data, but we do know that that's obviously a very important data set for Vertex and for Entrada.
Let's start with the exon 44, double-digit dystrophin expression at the starting dose. Are you setting yourself a hurdle which is too high, or you guys are really confident that you should be able to hit double?
Yeah, it's a great question. We are very confident. Entrada has developed probably the most comprehensive non-clinical data set within companies that are focused on DMD, everything from the canonical MDX mouse model to more advanced human dystrophin mouse models through NHPs or non-human primates, and then, of course, a healthy normal volunteer study. All of this has translated into dystrophin levels, which we feel as though are remarkable. So for this first cohort of data, which is 6 mg/kg and just to break that down a little bit, that is 5 mg/kg of the conjugate and then 1 mg/kg of the delivery vehicle or EEV, which adds up to 6 mg/kg. We do readily expect to see double-digit dystrophin levels.
I will say, ultimately, that benchmark of data needs to be compared against Avidity's del-zota data, which did establish roughly 25% dystrophin levels above background. We expect to beat those data in our second cohort. I think that is something that we are also very confident about, because our non-clinical data shows the translational effect of what this endosomal escape vehicle-driven PMO can actually do.
How much does, say, peer data from PepGen, which also sort of leverages direct blocking endosomal escape in DM1, where we are seeing very significant splicing correction in the single ascending dose study, help you with your confidence in your programs in DMD?
Yeah, I mean, I think it's—I will say that PepGen, if you recall, PepGen was in DMD but then had to—they decided to exit DMD mostly because of the risk-benefit that wasn't really established there, because there were safety liabilities, unfortunately, with their approach. Now, recall that PepGen has a linear peptide approach. It's a technology that's been leveraged before. Of course, Sarepta has leveraged it as well, too. There's a fundamental, almost apples to kangaroos difference between what Sarepta and what PepGen have done versus what Entrada is doing in DMD. And I just made up the kangaroo thing for a second. And I think that's really important. The cyclic cell-penetrating peptide chemical structure that we are utilizing to be able to deliver the PMO into the muscles is very, very different, right? It has characteristics that are very, very unique.
You could see that within the data set, right? You could see the safety that's been established within non-human primates, of course, mice, and then healthy normal volunteers, which is very, very, very different. When we start to think about DM1, it's a little bit different, right? And so their data within DM1 looks pretty good, right? And they're 5, I think it's 5 mg/kg. Their 5 mg/kg data, from a splicing perspective, looks potentially better than what Dyne and Avidity have. The difference, of course, is that we expect, unfortunately, that they're going to probably fall back on some of the same concerns, right? And I think a lot of that comes down to the delivery vehicle. And I think that's where the EEVs for neuromuscular diseases really have this competitive differential, right? So we've established safety.
The regulators have allowed us to go up to 12 mg/kg, up to 18 mg/kg. So this ability to dose escalate, and we've also shown dose response, is something where the therapeutic index of Entrada is very, very different than what PepGen has shown in DM1, in DMD, what Avidity, which obviously has just been taken out by Novartis, what they've been able to show as well. And I think that is really important when we start to think about diseases that are going after young children or young men, where that ability to be flexible with your dose becomes very, very important.
I'm assuming it's going to be Western blot data that you plan to share for dystrophin, along with exon skipping and dystrophin expression. Is there functional data that you plan to disclose as well?
Great question. So the market has moved to functional data, right? So I've publicly said, you can make all the dystrophin in the world that you want, but if it doesn't translate to a functional benefit, then what's the point? And I think that's very clear here. But what I will say is that for this first cohort of data for 44 and for 45, the most important two factors are safety and dystrophin production. Exon skipping kind of goes away, right? Because exon skipping is supposed to yield to dystrophin production, right? And muscle concentration goes away because that also becomes dystrophin production becomes important. So if I had to say the most important thing besides safety, it's dystrophin production. So that's one. Functional benefit is something that we are measuring. We will not see. We do not plan on seeing functional benefit in the first cohort.
The reason why is because the time is too short. It's going to take some time to develop functional benefit, especially in the 44 patient population, partially because they have background dystrophin already. They have roughly between 6%-10%, 6%-9% background dystrophin. So it's going to take time to be able to show whether it's time to rise or some of these other factors or these other assessments. It's going to take some time. But that is something that we plan on establishing. I think Entrada is in a unique position in that we have non-clinical data. These are in mice that have been able to show functional benefit and functional change. I think that's one. I think the second thing is we have this ability within these EEV PMOs to get into the satellite cells.
The satellite cells are a very important compartment to be able to access because they help with regeneration of muscle fibers. The ability to regenerate or refresh that muscle becomes really important and an important factor when you're looking at functional data. We've been able to establish both. Ultimately, functional benefit is the most important thing. We plan on getting that, of course, but not in this first cohort of data.
Got it. So when you do provide the 12 mg per kg data from the 44, will you have a long enough follow-up with these patients to have functional measures, say SV95C?
Sure. Ultimately, yeah, because what happens is that there's a 19-week study, which is 3 doses. Then the patients have the ability to transfer into an open-label study as well, which is you probably know better than I because you just did the initiation, which is 39 weeks or so. And so the important thing is that by the time, at about 1 year, these patients will have several doses. And I think that's probably a better time to actually assess functional benefit. And so we will ultimately get there, of course. But within 44, I think it's going to take a little bit longer. Within 45, I will juxtapose that because the amount of background dystrophin is a lot smaller level. So we could potentially get to 45 functional data faster than we get to 44. But let's see.
Got it. The timing of the biopsies, was that yours slightly different than everybody else's?
Yeah, yeah.
What was the specific reason behind picking that?
Yeah, I think each of these companies, whether it's an antibody-based company, which has a longer circulating half-life than what we have, are relatively in the same spot. So our timelines for biopsies are, of course, right before dosing. And then we biopsy six weeks after the third dose, so roughly a day, I think it's 127. Avidity, with their del-zota program, biopsy four weeks after their third dose. So that's roughly about the same. I think what we expect to see, the most important thing is that we're trying to optimize this so that we can actually see what the dystrophin levels look like within real-life practices for these patients who hopefully get access to a drug like this. So they're not so far off of each other.
What you will see is you'll see differences, of course, within, I think, secondary parameters like exon skipping and muscle concentration. And that is primarily because you have an antibody-based drug that has a larger circulating half-life than an EEV that has a very short circulating half-life, right? It's in and out of the system pretty quickly. And so I think those two will be different. But the true measure really will be dystrophin production. I think that's the important measure to be looking for.
Got it. So in terms of conducting study in the U.S. versus ex-U.S., when do we start to see the move into or enrolling U.S. patients?
Into the U.S.?
Yeah.
Yeah, it's a great question. So currently, we have the FDA approval to be able to enroll an adult study in the U.S. Our current guidance says that we will enroll that study in the second half of this year, which we are able to do. I will caveat that, though. We get this 6 mg/kg data in the Q2 of this year, as I've mentioned repeatedly. I think it's going to be important for the company to assess those data and see how those data look and then have a discussion with FDA to see if we can increase the dose within the U.S. Right now, the U.S. study, which was agreed upon a fair amount of time ago, is the doses are they cap out at 1.28 mg/kg or around there, which we do believe we'll see some therapeutic activity there.
But that's a pretty significant difference between 1.28 and 6 mg/kg or 12 mg/kg. And what we want to be able to do is do what's in the best interest of these patients. And these adult patients that have the 44 mutation have oftentimes been overlooked. And so the ability to provide a therapeutic to an overlooked patient segment that does not have any current access to treatment is something that's very important to us. So our plan really is to assess those data, talk to the FDA, see how to best provide a potential treatment to these adult patients, and then come back and obviously disclose those data. So right now, we have two options. We can run the study, the adult study in the U.S., or we can pause, and we can wait for FDA feedback and then reassess how best to approach it.
Right now, internally, we're still thinking about how best to do that when we wait for these data.
What's the FDA's position as to limiting the dose to sub 2 megs?
Yeah, I don't think the FDA did not have in the FDA's defense, they did not have the 6 mg/kg healthy normal volunteer data, right? So they were really basing it upon a level of conservatism that has been seen within FDA, within Neurology One under CDER. And I think that has been a challenge for many companies, right? And so for us, that level of conservatism allowed us, or frankly, kind of said, maybe we'll come back to the U.S. Let's run this at 6 mg/kg, which we think is a therapeutically relevant dose. Present those data back to the FDA. And the one thing that I will say is that we've had very active discussions with FDA. And the protocol that's being run ex-U.S. was also shared with the FDA. And that feedback that the FDA provided was incorporated into that protocol.
It's what companies say that when they try to harmonize these studies, right? And that's the best way that we can harmonize it. So we'll come back to the FDA, right? I think they had the data that they present that they thought was the best data to go after. Now we have more advanced data. And so I think when the 6 mg/kg data comes out and hopefully shows that safety and double-digit dystrophin production, I think it's a very healthy discussion and collaboration to have with FDA.
What does it mean for, let's say, everything looks clean? What does it mean for 45 or any other future exons, 50, 51?
It's a great question. So first of all, the same EEV that we're using for 44, we're using for 45, 50, and 51. We're also using that same EEV for the DM1 collaboration with Vertex. So we know that the EEV dictates or controls PK/PD. So that becomes a very, very important de-risking event. And so we feel as though if the data presents itself in Q2 of this year for 44 in the way that we have provided our guidance, that is a tremendous de-risking event for 45, 50, and 51. I think it's going to not only give regulatory agencies the comfort that this is a safe and efficacious program, but it's also going to send a signal to the patient groups as well, too, which we take very seriously as well, too, that there is another alternative here.
Because as we all know, and we've gone through a series of we read your report, and you've talked to a lot of neurologists as well. The DMD space is somewhat confusing right now. We feel as though it's an opportunity for us to show the fact that there is a potential therapeutic here, not only for 44, but also for the other major exons as well. And I think we will see that come through in the Q2 of this year.
So with the NHP data that you talked about before, exon skipping was almost nonlinear with respect to the dose. Is that a function of EEVs? Is that the function of the potency of the PMO? And how do you contrast that with the current benchmark?
Yeah, it's a good question. So I think, one, I think it's both. I think it's the EEV plus it's the design of the PMO. So the PMO itself is also engineered by Entrada as well. So not only are we changing the EEV structure, we're changing or the EEV, we're also looking at this from a PMO characterization perspective.
What we were able to see within the NHP data was essentially we compared it to the human data, and we saw a 3x increase in muscle concentration, which is what gives us a lot of confidence in this almost hockey-shaped curve that or maybe even a linear curve, well, a linear line or a hockey-shaped curve where we think that from 6 mg/kg to 12 mg/kg, we're going to see this tremendous increase within dystrophin production because we've seen this with muscle concentration between NHPs and humans at 20 mg/kg to 40 mg/kg. So I think that is something that is a true testament to not only the EEV but also the scientists who are behind a lot of this drug discovery and drug development, but also how they've changed the PMO as well.
Now, exon 44 patients obviously have relatively high background levels of dystrophin. So I'm assuming they also have less fibrosis, et cetera. So when you start thinking about the more complex or faster progressing exons, how do you think this is going to translate in, say, a 50, 51 patient?
It's a good question. I think first and foremost, I think the key is to get to these patients as soon as you possibly can. We want to insert this intervention as early as possible within the young boy's life. I think that's important, right? Early intervention becomes really important. I think the second thing is you are correct. Some of these and I hesitate using this word, but some of the patient populations that are sicker, right? And there are certain phenotypes of this disease that are more advanced than others. I don't think we will see the 40%-50% exon skipping or dystrophin production that we may see within our 44 patient population. But that's not necessary either. So I'll draw a comparison to Casimersen, which is Amondys 45, so Sarepta's approved product, the only approved product for exon 45 patients.
The dystrophin production there is somewhere between 0.8%-1.2%. We should handily beat that within our first cohort of data. Our second cohort of data for 45, we should even be better than that, right? But we're not going to see dystrophin production that will match what we will see within 44. We expect it to be tempered more because of the severity of that phenotype. But that's not really the right question to answer. The right question to answer is, will you beat standard of care, right? And will you be able to capture a significant part of that $5 billion U.S. market that we think exists for DMD? And the answer is yes, because we have a better mousetrap here, right?
So for our 45, we have to beat 0.8%-1.2%, and we think we'll handily beat that within a dosing regimen that is even more advantageous than what standard of care looks like today.
Is there any consensus in the field of what a threshold dystrophin expression needs to be, which will translate into clinical benefit if you do a long enough study?
Long enough study for 44 and 45?
Or 45 and 51.
Yeah, it's a good question. I think what we've heard from the PIs is just the more dystrophin, the better. And I think what it comes down to is dystrophin is a long-acting, a long-lasting protein as well. I think if we're able in 45, I'll just put an example there. In 45, if we're able to sustain that mid to high single digits from a dystrophin production, we're going to see functional benefit. I think that's the belief within the community as well, especially from the treating physician community.
In your discussions with the FDA, has there been any movement on migrating from North Star Ambulatory Assessment to SV95C, which is now the primary endpoint in Europe, or even Rise Time from Floor, something like that?
Yeah, I think that's evolved over time as well, too. And I think not only talking to regulators, but also talking to patient advocacy groups and some of the key KOLs in the field, some of those the movement to Time to Rise and other endpoints where it's going to be a composite. We're going to not a composite, but we're going to be measuring a bunch of these different endpoints. But I think at the end of the day, we've talked to FDA, we've talked to the European agencies. We've talked to the patient groups as well, too. We'll have a bunch of different functional endpoints that we look at.
Let's talk about the platform a little bit, because one of the interesting differentiations for us when we were looking at Entrada was you've been able to now expand the scope of the pipeline to the other exons while you're still waiting for data from the first. We haven't seen that with the other companies, maybe because it's COGS. So maybe help us understand commercially or even your clinical timelines. How can you expedite if you can any further?
Yeah, it's a good question, something that we wrestle with every day. Faster, faster, faster, right? Because the patients are rightfully so needing a therapy, and it's our job to get it to them. I think there's a couple of things there. One, we decided a few years ago to put a heavy investment within DMD, not only to go after 44, but also to begin 45, 50, and 51. And why is that? It's because of the aforementioned non-clinical data and the volume of non-clinical data, the depth of those data, the translation of those data that gave us a lot of confidence to put a significant amount of capital behind DMD alone. So I think that's one. I think the second part really becomes how do we leverage those to get to data timelines that are faster.
There's only so much you can do there. But I think the other thing is it's a key advantage of the company that you rightfully bring up. From a capital-intensive perspective, the cost of goods sold for these EEV conjugated therapeutics is very, very low. And why is that, right? I think it all comes down to the thesis of the company that's been proven time and time again. It comes down to efficient endosomal escape. So the ability to get out of the early endosome and to get to where you need to go and I'll put that in air quotes since people can't see me. I think that becomes really important. And what we've been able to show is this efficient ability at 6 mg/kg . Once again, 6 mg/kg is about roughly 1/6 the total drug size of del-zota's 5 mg/kg , right?
That's a big difference, right? And so part of that is because of the efficiency around the ability to get into the muscle at very, very low therapeutic sorry, get to the muscle at very high therapeutic levels at very low doses. And I think it all starts with the endosomal escape within the EEVs.
Unfortunately, I could go on a lot, but we are literally running out of time at this point. Appreciate you joining us and looking forward to a very productive, interesting year ahead.
Thanks, Debjit. We appreciate it.
Thank you so much.
Thanks, man.