All righty. I think we're gonna go ahead and get started. Thank you everyone in the room and online for joining us at the 46th Annual TD Cowen Healthcare Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen. It is my pleasure to have with us today the team from Entrada. Dipal Doshi, the CEO, is gonna be doing a brief presentation, and then we're gonna jump in with some Q&A.
Awesome. Thanks, Joe. All right. Foremost, thank you to the TD Cowen team for having us. We're excited to be here. I'll just go through a couple quick slides here on Entrada. It starts with kind of a disclaimer. We'll be making forward-looking statements, so just take that into account. You know, 2026 is turning out to be a transformational year for the company. We purposely set up 2025 as a year of operational excellence to lead to a year like we're gonna have this year. Fundamentally what we're looking for is, in this year, is we're gonna have from our DMD and DM1 programs, we're gonna have four potential clinical readouts. Let me go through that a little bit from our pipeline perspective.
We will have in our DMD franchise, we plan on having readouts within our exon 44 and exon 45 studies. The first one in the second quarter of this year, and then another readout by the end of the year, and then in our 45 program, a readout in the middle of the year. We're excited about these. We're also excited about our DM1 partnership with Vertex, and they plan on having, you know, fulfilled their guidance of their enrollment and the dosing of their phase II MAD study in the middle of this year as well too. There's potentially four readouts from a clinical perspective within two diseases that have a profound unmet clinical need.
Importantly, late last year and at a different conference, we also shared our expansion into the ocular disease franchise as well too, led by our Usher syndrome program as well. These programs, albeit early, are once again, they follow the same makeup as what we've pursued with DMD and DM1. Profound unmet clinical need, a very high commercial opportunity, and an ability to really profoundly change the lives of patients. If we break that down a little bit, let's start with DMD. The DMD market in the U.S. alone is roughly $5 billion. There's limited competitive penetration, and outside the U.S., it's an untapped global market.
That's a remarkable opportunity for Entrada and we are aggressively pursuing not only our clinical studies, but also an Accelerated Approval, you know, pathway that's open in the U.S. so that we can get these drugs to the patients as quickly as we possibly can. It's important that our therapeutics are not only proprietary, but they're differentiated from not only approved therapeutics, but also those in the pipeline, and we can talk about that more as well. At the end of the day, what we're looking for is best in class, right? We already have best in class preclinical data, but we need to expand that to best in class clinical data. From a value inflection point, you know, our cash runs into Q3 of 2027 with roughly $296 million on the balance sheet.
It's important for us to be able to get through, get through some very important clinical catalysts, and we have the cash to be able to do that. Our DM1 partnership with Vertex also allows us access to up to $485 million in DM1 milestones, importantly, none of which are included in today's current cash runway. If we start to break this down a little bit, you know, left to right on this slide, there's multiple clinical milestones as we discussed. Importantly, our ENTR-601-44 program, the first cohort of dosing is complete. Open label dosing is ongoing. Our second cohort was cleared to initiate at 12 mgs per kg. This happened via a data monitoring committee meeting, you know, earlier this year, so we're excited about that.
Once again, that first cohort of data at 6 mgs per kg is expected in Q2. The second cohort, which is 12 mgs per kg, is expected by the year-end. Once again, two clinical milestones there. Our 45 data or 45 program continues to enroll well, and that first cohort of data is expected in middle of 2026, and then so forth and so on with our 50 and 51 programs. As you see, a staggered approach here, and we will continue to monitor and share progress with those programs as well. Highlight there is, you know, four clinical stage programs in DMD with multiple data points along this year. As I mentioned previously, Vertex continues to advance what they're calling VX-670 for the treatment of DM1.
This continues to move forward with the MAD portion to evaluate safety and efficacy, you know, hopefully reading out in the middle of this year. Importantly, we are building Entrada to be a next generation company. We start with our DMD and DM1 programs, but a very active pipeline led by our inherited retinal diseases. I mentioned Usher syndrome type 2A, but then we will also announce a second clinical candidate later on this year. The labs at Entrada continue to operate at a high efficiency, and we look forward to expanding our neuromuscular and ocular franchises by leveraging next generation EEVs or endosomal escape vehicles. A lot going on.
From a pipeline perspective, you know, this is a very, you know, illustrative graph here, but, you know, it starts with DMD, gets into myotonic dystrophy type 1, inherited retinal diseases, and then the pipeline expansion. It's a nice makeup in terms of, of how the company is staggering its approach. A, a critical focus on DMD, but also a heightened focus on other areas as well too. Importantly, we will be advancing five clinical stage programs by the end of this year, and the phase I/II data from the ex-U.S. studies that we're running in DMD should hopefully support an Accelerated Approval pathway in the U.S. Let's break into DMD a little bit more. Our strategy in DMD is really founded on three strategic pillars: differentiation, de-risking in best-in-class opportunities.
That starts with the EEV or endosomal escape platform, which we combined with novel PMO conjugates. Not only are we optimizing the delivery vehicle to get into the muscle, but we're also optimizing the drug or the conjugate, or the PMO itself. What that has allowed us to do is not only create novel EEV and PMO sequences, but it's really allowed us to drive best-in-class non-clinical data, which has translated importantly into compelling human muscle uptake and safety. Importantly, when we start to think of DMD and the issues that patients have with dystrophin, it's important to be able to point out that we also have the access into satellite cells, which can be used to help regenerate muscle via dystrophin.
When we start to think of these young boys that are becoming men, the amount of drug that goes into the system is also something to be very mindful of. In our lower whole drug exposure compared to some of the competitive approaches, decrease the risk of, you know, anti-drug antibody, you know, responses, and importantly, as we look forward, a lower cost of goods sold. We're trying to de-risk and rapidly clinically develop these programs. It starts with our clean, healthy, normal volunteer data that we shared, a couple years ago for our ENTR-601-44 data, which essentially was set up to just firmly establish safety and target engagement. It did that with ease.
What we expect out of our 601-44 study for the first cohort is double-digit dystrophin production. Ultimately, we expect to surpass Avidity's or Novartis' Del-zota program by the end of the year with our second cohort of data. All of our neuromuscular programs utilize the same EEV. Our DMD 44, 45, 50, 51, and our partner program with Vertex VX-670 all use the same EEV. That's really important because a PK/PD has become very predictive. We fundamentally believe that when we obtain our data for our first cohort in the second quarter of this year for our 44 program, that that will de-risk the rest of our franchise. It's a very, very important milestone for the company.
We feel as though that these programs allow us for a potential best-in-class commercial opportunity. As I said before, these studies are being run ex-U.S., but we'll bring those data back to the U.S., and those data will help support hopefully a U.S. Accelerated Approval. We feel as though we're, you know, we continue to strive to create these best-in-class therapeutics across all of the DMD programs as well. When we start to think of what a commercial opportunity looks like, so we start to fast-forward a little bit, let me back up. 30,000 patients in the U.S. and Europe have DMD. We have the opportunity to go after roughly a third of these patients. What that comprises in the U.S. alone is a $5 billion market.
Ex U.S., it's much, much more. What we feel and why we get excited about this is because there are unfortunately a few available treatment options for these patients, but there is a very, very understood market. Out of the 5,000 U.S. patients and the 6,500 European patients, we feel as though the commercial opportunity is significant because there is such an unmet clinical need, and these markets have been untapped, right? You know, we look forward to hopefully servicing a lot of these patients in the geographies that we are focusing on. I'm not gonna read this slide, but the key takeaway for this slide is that we have an unprecedented PD profile, and that's been demonstrated across the mouse, the non-human primate, and human studies.
We call this the seven, seven, seven slide. The first seven, if you go left to right, is that we've been able to establish within a mouse model a four- to seven-fold increase in dystrophin compared to Del-zota, Avidity's program. If you go to the middle, there's a seven-fold greater exon skipping with a less frequent dosing than Del-zota and the NHP. If you go to the final, the final graph, what we see is a seven-fold greater exon skipping in healthy volunteer muscle than Del-zota. So seven, seven, seven . This is the makeup of a potential program that could be extremely differentiated against a program that has established a really good profile. Our clinical study is on this slide here. It's really designed to support a U.S. Accelerated Approval.
If you go left to right, screening, we obviously do a very good job of screening. The double-blinded period is a 19-week study where we give three doses, and you can see at 6 mgs per kg, 12 mgs per kg, and up to 18 mgs per kg. Then we transfer these patients over into an open label period of 31 weeks, and then we follow up with them. The whole point really here is to amass data, both from a safety perspective and from a dystrophin production perspective, and then ultimately from a functional benefit, which will take time, but that is the key, to be able to establish functional benefit and demonstrate functional benefit for these patients. It starts working backwards. Functional benefit is predicated on dystrophin levels, which is also predicated on a safety profile as well.
We feel as though the robustness of this clinical study will demonstrate that. Importantly, the same study is being used for our 45 program. It's a bit of a copy and paste, which increases the efficiencies for the program and the company. If we switch over to DM1, this is a transformational partnership with Vertex, which we established in Q1 of 2023, a significant upfront payment, but more importantly at this point, up to $485 million in achievable milestones with a tiered royalty system. VX-670 is very different than the competition in that it is a very targeted and specific blocking of pathogenic CUG repeats. That's important because it's a non-discriminate knockdown to DMPK. I'm sorry, it's a discriminate and selective knockdown to DMPK versus some other approaches as well.
We also believe that the satellite cell uptake, which I mentioned before, could also help with outcomes too. Vertex is advancing this as the CEO discussed this morning in a placebo-controlled phase I/II program at over 25 global sites. The MAD portion of the clinical study is on track and expected to complete dosing in mid-2026. We look forward to seeing how the results look. Once again, it's the same EEV that's being used in VX-670, as is being used in our DMD programs. I'll close off with our inherited retinal diseases. We're addressing another area of a profound high unmet clinical need within these IRDs. These are new and novel oligo-based, oligonucleotide-based therapies.
Our first program is called ENTR-801, which targets Usher syndrome type 2A. The addressable population is somewhere around 15,000 patients in the U.S. and Europe. Importantly, there's no approved therapeutics. The approach here is that we're going after a sub-subtype of population here. In some patients, mutations in exon 13 prevent production of the usherin protein, which then ultimately leads to a gradual decline in vision. We feel as though we have an approach here that can help reestablish this. Today, there's no disease-modifying treatments available for this disease that can slow or stop the progression, and that's where we kinda fall into this mix.
You can see on the, on the right side of this, on the, on the right side of the slide, the graph shows an expression of truncated Usher protein, low doses correlating to high doses as well. Our 801 program is a proprietary exon 13 skipping therapy. We've demonstrated, as I said, robust exon skipping in usherin protein, usher protein production. There's a potential for quarterly dosing, and this is IVT. We feel as though this year will be critical for this program as we enter IND-enabling studies. Once again, the patient population is quite robust at over 15,000 patients. Across our entire franchise, DMD, DM1, and then, of course, our inherited retinal diseases, 2026 is a very, very important year, inflective year for us.
We'll start off with our 44 program again, to round that out, you know, once again, data is expected in cohort one in the second quarter. The second cohort of data is expected by the end of the year. Our 45 program continues to progress with the first cohort of data expected middle of this year. Our 50 and 51 programs are going through the regulatory processes, you know, ready to engage as well too. Our partners at Vertex are doing a remarkable job as expected with VX-670, that portion of the MAD study should read out in the middle of this year. We move our focus to ENTR-801, which is our entry into inherited retinal diseases.
Pipeline expansion continues to be a robust activity as we not only create next generation, oligonucleotides, but also next generation EEVs to go after a bunch of other diseases of high unmet clinical need. Cash runway goes into Q3 of 2027. That is Entrada.
Awesome. Well, I think we're gonna do some Q&A. Wanna come over here?
Yeah.
G reat. Thank you for the presentation. I guess, for the upcoming data for exon 44, obviously you set the bar at the double-digit dystrophin production. I guess maybe first just how did you get to double-digit dystrophin at this first dose? Maybe elaborating a little bit more on maybe the preclinical data that got you there to select this dose? What else are you gonna be looking for in this first data set, either on efficacy or safety to potentially be differentiated?
Yeah. It's a good question. I knocked out my microphone, so excuse me.
Should I do yours?
Yeah. First and foremost, our science groups have done a great job of evaluating and prosecuting a lot of different species. We started with the canonical mdx mouse model, and then we elevated that all the way to a human dystrophin mouse model. We've understood the parameters of not only safety, but dystrophin production within these models. We progressed to non-human primates, where we studied safety and exon skipping. These are, you know, normal human primates, so we can't really evaluate dystrophin. That also allowed us to be able to continue modeling from a PK/PD perspective.
The healthy normal volunteer study, which we ran in the U.K., is also critical to that 'cause that was run at 6 mg/kg, and that 6 mg/kg showed exactly what we wanted it to show, which was clear safety and targeting engagement. If you take all that together, the non-clinical data plus the clinical healthy normal volunteer data, that allows us to project what dystrophin production will look like. That's why we're saying, you know, double digits because we've seen this non-clinically, and we've also seen, you know, the stability and the repeatability of these results. This is a phase I/II study. Importantly, what we're trying to establish within the ENTR-601-44 study is safety, right? We wanna show and prove safety in patients.
We've kinda done that with our data monitoring committee readout, which show that 6 mg/kg is quite safe. Thank you. We're half of the way there. The other half becomes dystrophin production, that's where we get to the double digits. If we continue to show safety and we show double-digit dystrophin production within the patients, I think that's a home run.
Great. When we look at the second cohort, what's the bar there? Obviously, you said you'd like to be, you know, best in class. Is that then above that 25% dystrophin? Obviously some of the competition has seen a ceiling effect where they stop kinda going up. Do you expect that to happen at some point or not anywhere near the doses that you're doing right now?
Yeah, it's a good question. I think one of the key advantages of Entrada is that we have a very, very wide therapeutic index. So we do not expect to see a ceiling effect. If anything, we expect to be able to continue to dose escalate, and get dystrophin levels that are above and beyond what the competition has shown. If you take a step back, right, we have three shots on goal here. We have 6 mgs per kg, which we think is therapeutically relevant. We have 12 mgs per kg, and then we have up to 18 mgs per kg. At that 12 mgs per kg. Actually, between the 6 mgs per kg and 12 mgs per kg, we almost see a nonlinear response. Part of that is from the PK/PD modeling that our team has done.
Our expectations, and to be clear, our expectations and projections at the 12 mgs per kg by the end of this year is to beat the competition. That will surpass the 25% dystrophin production that the competitor has established.
Great. Can you go a little bit more into your projected filing strategy? Obviously, it'll depend on kind of what doses you need to go to, but what are you thinking in terms of a potential timeline for when you would be in a place to submit a regulatory application for Accelerated Approval? I guess, has anything with the FDA over the past year, either in the landscape or in their interactions with your team, changed your expectations for Accelerated Approval?
Yeah. I mean, we purposely designed these studies to initiate ex U.S. Part of that was a higher risk tolerance that we saw within the DMD and the oligonucleotide space, ex U.S. versus in the U.S. Now that we've not only established safety, but we're on the cusp of establishing efficacy or dystrophin production within patients, you know, we feel as though the time will be right soon meaning in Q2 or Q3, to come back to the FDA to share the data. The one thing we did do, or one of the things that we did do before we initiated these studies ex U.S. was that we had a discussion, a very productive discussion with FDA, where we shared with them a prospective protocol that we would run ex U.S.
We solicited and we incorporated a lot of their feedback. You know, a lot of companies do that to harmonize these clinical studies as best they can. The structure of the study should not be a surprise to FDA. What I think is gonna be really interesting about that conversation, or that, hopefully, that conversation or that dialogue, will be that, you know, this is proven safety at 6 mgs per kg, and hopefully there's dystrophin production. We want to bring this program back to the U.S. because there's such a .profound unmet clinical need in DMD for the thousands of patients that have not only our 44 mutation, but 45, 50, and 51. We'll see how those discussions go. They are fact-based. They're gonna be data-based as, of course, as well.
The establishment of safety alone is a big deal. We feel as though we have a high level of confidence that, you know, that the FDA will support, you know, the clinical study, you know, post conversations.
When you think about the eventual therapeutic use profile of skippers and gene therapy for those that they're allowed to, you know, kinda use those treatments, I guess, do you see a world where if there's a couple exon skippers approved for a specific exon or a gene therapy and an exon skipper, like, how does combination therapy work here? Do you think that's an opportunity or payer's gonna make people kinda pick one, you think?
You know, it's interesting. I mean, unfortunately, gene therapy, at least in DMD, has obviously had a bit of a setback. I mean, I think some of the marketing messages got ahead of the data, so to speak, right? That's unfortunate. What we say at Entrada is that all we care about is designing a drug that works for the patients, right? It doesn't need to be a glamorous drug. Doesn't need to be, you know, this next-generation technologies. It just needs to work. It needs to work, and it needs to be flexible to the growth of a young boy into a young man. You know, people had always asked us a few years ago, you know, could we be used in combination with gene therapy as a second-line?
I think that calculus has now changed, right? Can gene therapy be used as a second line to these skippers that are much more flexible and, you know, much more potent in some regards as well too. I think there might be a world of combination use. I think the payer community is going to have a difficult time being able to justify the cost of gene therapy. But maybe a skipper makes it better. I think only time will tell. Right now, we are really focused on the fact that, the best shot on goal from a clinical perspective for these, you know, young boys and young men are skippers.
The advancements in technology have been so profound that these skippers, you know, hopefully will be used, you know, across all the exons if, you know, if the data continues to read out correctly.
In these initial studies, you know, either for 44 or across all of them, I guess, will you be following patients long enough that you think you could potentially see some changes in, you know, functional measures or some others? How are you thinking about the time of when is right to disclose some of those?
Yeah. I mean, we've said it today, and we've said it a bunch of times. You know, you can make all the dystrophin in the world that you want, but if it doesn't convert or translate to functional benefit, then what's the point, right? So for us, at the end of the day, a true success rests within the ability for a patient to establish or reestablish some type of functional benefit, within their quality or within their life to increase their quality of life. You know, I think at the end of the day, it takes time, though, right? It takes time to show these functional benefits. For 44, for exon 44, there is, you know, background dystrophin production, which also makes it a little bit harder and a little bit longer to establish functional benefit.
I think this is where Entrada differentiates itself, right? It's one of the only companies, if not the only company, that has proven the ability to get into the satellite cells, which are really important for the regeneration of. Hopefully the reestablishment of functional, you know, functional use of hands or whatnot. It's gonna take time. We feel as though it's something that we're keeping an eye on. In the U.S., Accelerated Approval needs to be followed by functional benefit. Ex-U.S., you have to show functional benefit. There's no biomarker strategy there. All of our studies are being designed to establish functional benefit. That's the name of the game, to increase and improve the quality of life for a patient.
We think it's gonna take some time. We think we also have a very good shot of showing it. We've shown it non-clinically. Now we just need to show it clinically. That'll take time.
Obviously the 45 initial data are coming not too long after the initial readout. I guess you laid out the plan for 44 in terms of what you wanna see in cohort one and cohort two. Is it as clear in 45 or what are you hoping to see in that first cohort for that as well?
Yeah. It's a great question, Joe. Thanks. For 45, you know, there is a competitor, it's Sarepta's casimersen, that product has shown roughly 1% dystrophin production, so it's a different bar, right? For us, we, in our first cohort, which is mid 26 at 5 mgs per kg, you know, we wanna have single-digit dystrophin production. In our second cohort, you know, we wanna have more than that, right? It's not gonna be at the numbers, or the dystrophin levels that the 44 program has. Part of that is because it's a harder exon to skip, and two, there's much more dystrophin in the background for the 44 patients. A clear win in 45 would be the establishment, once again, of safety, and then also double-digit dystrophin production.
We are confident that we'll be able to... I'm sorry, single-digit dystrophin production, but more than what casimersen has shown. We are confident that we'll be able to show that, you know, mid-year. I think that the strategy post that is very similar to the strategy that we just talked about for 44.
Maybe on the Vertex partnership, just 'cause to kinda get a flavor of, you know, if you do these more going forward, if the opportunity arises. Can you just kinda walk us through how that originated kind of, you know, the level of interest? Was it the target? Was it the profile, the platform? Maybe how Vertex is as a partner, and how you share responsibilities there?
Yeah. It's all of the above. I mean, when we model ourselves into what type of company we want to be, you know, there's an N of one. What, you know, Jeff Leiden and then of course Reshma have done with that company has been phenomenal. The way that we interacted with them was, you know, they were interested in DM1. They had taken a look at the delivery mechanism of EEVs, found it to be compelling. It started a conversation around, you know, what are the opportunities that the two companies can collaborate on. DM1 was a disease, you know, three years ago, which is still today, where there's ambiguity in the disease.
For us to take it forward would've been fine, but a company with the background and characteristics of Vertex and their success that they've had in diseases like CF, where they changed the treatment paradigm, was super compelling to us, right? Could you do the one plus one equals three math? We quickly formed, you know, a partnership agreement, and they obviously, you know, invested a tremendous amount of money into the upfront and the milestones. I will say that the delineation of responsibilities between the two companies were very, very clear, which also is a, is a recipe for success.
We have a Joint Steering Committee, which our president of R&D and our president and COOs sit on. There's constant communication between the two companies. There's materiality thresholds between the two companies. We're doing everything correctly, and I will say This has been one of the best collaborations that I would think that they would say the same thing, that both companies have seen. We look forward to that data, you know, hopefully this year as they wrap up, you know, the MAD portion in the middle of this year.
Maybe jumping over to the earlier platform. I guess what sort of jump, if any, was there to take the EEV platform from, you know, more of a muscle-based disease like DMD into some of these IRDs and then the retinal diseases?
It wasn't really a jump because I think over the past several years we've developed a really remarkable bench of not only chemists, but protein engineers. The CMC Group is the unsung heroes. We have a phenomenal clinical group. What we did was really kind of did a landscape analysis like most companies do. Inherited retinal diseases are an area that we are all familiar with from a management team perspective, but we also started to do a deeper dive and realized that no one's really figured it out, and why haven't they figured it out? Once again, it comes down to the characteristics of the disease and matching up a matching up an approach.
I think importantly for Usher syndrome type 2A, you know, it's an exon-skipping approach, and we are very, very familiar with, you know, those types of approaches. This, from a landscape analysis, the IRDs fulfilled the requirements that Entrada has. One, profound unmet clinical need. Two, an ability to, quote-unquote, "win for the patient" here because our approach is differentiated and unique. Ultimately, a clinical design and a regulatory landscape that is well understood. You know, we're super excited about our IRDs, and we're super excited about what comes after that as well.
Maybe just last question, you know, kind of looping back to obviously the Vertex deal was very, a great setup for the company and a good source of non-dilutive capital. I guess how much of a focus is that going forward, sort of these additional BD deals to kind of go forward into other areas that maybe you don't wanna do internally or?
I mean, I think like any company, you know, we are very careful with our capital, and you could see that from our balance sheet perspective. I mean, we went public at the end of 2021, and we've raised $100 million since that IPO. In five years we've raised, you know, $100 million besides the Vertex, you know, upfront payment. I think we can't go after it all. We know that we can't go it after all, after all these diseases. If we have a formula that's very similar to Vertex, where we have a partner that is as committed to a disease as we are, then we are open to, you know, any discussion around that. Economics aside, right? I think it's really going after these diseases for the patients.
Awesome. Well, thank you very much. We look forward to the data next quarter.
Thanks, Joe.