Entrada Therapeutics, Inc. (TRDA) Earnings Call Transcript & Summary

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 Vehicles 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 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 it's -- 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 [indiscernible] 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 at the --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 -- 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 50, 51 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 four 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?

Let me -- 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 end of 1, end of 2, end of 3, 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. 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 more -- 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, it's 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%. 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, right, 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.

Thanks-- 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.