Thank you. Good morning. Thank you for joining us. I'm Paul Choi, and I cover this mid-cap biotech sector here at Goldman Sachs. Joining us here at the Goldman Sachs Global Healthcare Conference is Entrada. Before we begin, I'm required to make some certain disclosures. These disclosures pertain to investment banking and other relationships that we may have with companies discussed here at the conference. For anyone listening or who are clients at the firm attending, these disclosures are available to you on our research portal. We are prepared to read them aloud, but they are available for you through your Goldman Sachs Research. With that, it's our pleasure to have Entrada here. Maybe what we'll do is start it at a high level with Dipal here and maybe talk about for those who are new to the Entrada story and/or maybe the DMD space. Can you maybe walk us through what is the EEV platform, and what, I guess, in the early or preclinical data has made you excited about its potential? Sure. Yeah, thanks, Paul, and thanks to the Goldman team for asking us to participate. The Entrada Therapeutics story starts back in 2016. When we start to think about what is so special about this company, it starts with the Endosomal Escape Vehicles or EEVs, which are essentially a family of cyclic cell-penetrating peptides that have these remarkable and unique properties that allow us not only to get into the cell but to get out of the early endosome with efficiencies that have not been seen before. Why is that important? These EEVs can be conjugated to a lot of different things. In this case, and in our DMD and DM1, we're talking specifically about oligonucleotides. Conjugating the two together, or chemically synthesizing the two together, allow us to get out of the early endosome with efficiencies that are much, much, much greater than conventional biologics or conventional other therapeutics, upwards of 50%. What that allows us to do then is to get to the muscle in a much more efficient, concentrated way that allows us to hopefully affect change to the disease. In this case, with DMD, it allows us to affect the dystrophin levels. It allows us to affect the function of those muscles for those children as well, too. It starts with DMD. It goes into myotonic dystrophy type 1, which is DM1, partnered with Vertex. Then there's a whole plethora of other diseases that we can also address via EEVs and also other modalities. Okay, great. Maybe starting with the DMD space, you talked a little bit about oligonucleotides. We know obviously there are certain exon skippers that are already approved and commercially available in the space. Can you maybe talk about what, in your view, solidifies the EEV and using the cyclic peptides to deliver these medicines as potentially differentiating or what could be potentially best in class in this category? Yeah, it's a great question. If you take a step back and look at DMD, in the U.S., it's a $5 billion market by itself. Ex-U.S., you multiply that by at least two. It's a huge market with a profoundly unmet clinical need. There are companies that are going after DMD with a variety of different approaches, whether it's naked oligonucleotides, conjugated oligonucleotides, gene therapy, et cetera. What makes it interesting and what makes our approach even interesting is the preclinical data that has translated remarkably to clinical data. First and foremost, when you go after a pediatric disease, or mostly a pediatric disease like DMD, where there's a deficiency within the dystrophin protein, you want to establish safety. Safety is the most important thing to be able to establish for these patients, especially the younger ones. Safety plus functional benefit. Functional benefit, in this case, is measured by an increase in dystrophin initially. That's what conventional thought always was. For us, what we're happy to see is that within our preclinical data, we've been able to translate from the canonical mouse models all the way through NHP to a healthy normal volunteer adult study into our recently released Cohort 44 patient data. We've seen this consistent translation around safety. What we're starting to understand is that the dystrophin relationship, the functional benefit, is pretty complicated. I think other approaches would also say the same thing. What becomes really important is changing the lives of these patients with an established and safe medicine, and I think that's what's exciting about Entrada's EEV approach. Can you maybe just remind us where you are in terms of overall clinical development versus some of the other modalities that are in the clinic and just maybe before we go on to the next question- Yeah. Just to level set? DMD is a cascade of different mutations in a variety of exons. There's five major mutations, but then there's a lot of different mutations below that. We're going after exons 44, 45, 50, and 51. Our 44 program just released its first multiple ascending dose patients data. We're going to continue with our cohort 2, then we'll go to a cohort 3. We're a little bit behind the competition, so to speak there. Once again, at the end of the day, what a patient will choose and what a PI will choose is a drug that has both the safety and the functional benefit. Our cohort 145 data for our exon 45 program is likely the first in class and hopefully best in class when it comes to that exon as well too. Those data for the first cohort will read out the middle part of this year. 50 and 51. We're right in the middle of this right now and going against a lot of other really interesting companies and really interesting approaches. At the end of the day, Paul, we've talked about this extensively. The more approaches, the merrier, right? Because at the end of the day, I think all of us are aligned on the same exact thing, to bring treatments and a variety of treatments to these patients that have these diseases. Okay, great. You mentioned something earlier, which is key in development of DMD drugs, which is safety. Notably, there's always been sort of this historical concern with exon skippers with regard to liver toxicity and just what comes and what you can discover with dose escalation. Can you maybe remind us what you've seen so far? Natarajan, if you want to turn it over to you, and just how you think about escalation here and what the safety data to date show. Yeah. The safety data has been very clean for us. We haven't seen any SAEs, we have not seen any AEs that lead to patients dropping from the trial. When we look at PMO as a class of drugs, the main toxicity is kidney, and we have looked at all the kidney parameters like GFR, magnesium levels, cystatin C. You cannot even differentiate between placebo and treated. It's that clean. When it comes to liver toxicity, it is more for the PS chemistry rather than for the PMO chemistry. Of course, we didn't see any liver toxicity, and we didn't expect any. Similarly, AAV has liver toxicity, but the modality that we are using, we didn't expect any liver toxicity, and we didn't see any liver toxicity. Right. Just given the difference between a vectorial approach and. Yeah. What you guys are doing. Yeah. I think that's a really interesting point, right? When you start to think about diseases that have such a profound unmet clinical need, it becomes an analysis for the PIs and of course the families around risk versus benefit. I think the risk part usually comes up with safety, right? In our first Cohort 44 data, which was eight patients, as Natarajan said, we saw no safety concerns whatsoever. When you start to think of some of the other programs that are out there, they've all had safety concerns. That's a huge differentiation right now at this early stage in development, so we're really pleased with that. Once again, going back to one of your original questions, we saw all this solid safety within preclinical models, and so we're happy, and this is what gives us a level of confidence that it will continue to translate as we get further and further into the clinic. Okay. You mentioned for your Exon 44 program, you recently top-lined cohort 1 data. Can you maybe summarize for us what you saw in terms of your PK/PD and sort of early efficacy signals and just how you're thinking about the biomarker results to date? Yeah. I think Natarajan and I will both take this. I think when we looked at these data, there were three components of data, frankly in this order, right? Safety, which I think we've already mentioned a bunch of times. That's been confirmed. The second really was dystrophin production, and let me come back to that. The third was functional benefit. We believe that we would see dystrophin production in the double digits. We did not see that. We know why we didn't see it, and we're confident as to when we will see it as we get into cohort 2. Natarajan will speak a little bit more about why we didn't see the dystrophin levels. What was interesting was the functional benefit. We did not expect to see functional benefit this early at day 127 within these patients. What we saw was statistically significant functional benefit as measured by two factors. One called time to rise, and the other called time to rise velocity, which are robust and clinically relevant endpoints that regulators have all approved. We also saw meaningful trends within 10-meter walk. The question becomes, well, how did we see functional benefit with low dystrophin levels? I think that's what the market is grappling with right now. I think it comes back down to the importance of the relationship between dystrophin and functional benefit. Perhaps it's not a one-to-one correlation. Perhaps it's actually more complicated than that. I think what becomes interesting from the Entrada perspective is our preclinical data that shows the ability to get into these quiescent satellite cells and activate those satellite cells to be able to regenerate muscle. Right now, preclinically, we've proven it. Clinically, we're looking into that as to perhaps that's the reason why we were able to see functional benefit earlier. At the end of the day, Paul, PIs, patients, the reasons why are not the important ones. That's for us, right? That's for us, for you, for our investors to understand. From a product perspective, a potential therapeutic perspective, what they are seeing is safety and early functional benefit. They don't care as much as to whether or not it's double-digit dystrophin. You can have 25% dystrophin, but if you have mediocre functional benefit, then what's the point, right? For us, we have to explain that a little bit better. We have to learn about that a little bit better. I think in time and with data, we'll be able to understand that better. DMD is a complicated disease, but let's talk about the dystrophin levels and our projections and why we think that we're going to get back to where we need to be. Yeah. Maybe Natarajan, you could walk us through before you went into the clinic, how you modeled it, and then just kind of how that differed actually in the clinic with regard to PK/PD. We had a robust data set to model what we were going to get in DMD patients. We had non-clinical studies. We had NHP, adult NHP subchronic tox, and we had other NHP studies, and then we had normal human volunteer study. We could get a correlation between plasma exposure, muscle exposure, exon skipping, and then we used that to project what exposures we would get in patients and how that could translate into muscle exposure and exon skipping, and eventually dystrophin. What we saw in the cohort 1 is that the exposures that we got was half of what we expected based on our normal human volunteer study and NHP study. Of course, the dystrophin level went from 4 point some percent to 6 point some percent, about 2% increase or 50% increase from baseline. The reason for that turns out that when we went back and looked at pediatric or juvenile NHP, there was again low exposures in the pediatric population. Probably the differences in the kidney volume versus total volume contributes to low exposure in younger subjects compared to older subjects. Essentially what has happened is that we have right shifted our projections based on our new model using pediatric or juvenile NHP, where what we expected in cohort 1, we would now get in cohort 2, because we just need a linear increase in exposure, which is when double our dose should happen, and that should result in eventually having the double-digit dystrophin that we had projected for cohort 1. Great. I actually just thought of a question. You talked about the descriptive statistics showing functional benefit, I'm just sort of curious on things like time to rise and the velocity of the time to rise. I'm just sort of curious if you actually took a look at the sort of completeness and length and sort of quality of the dystrophin that was produced. Any comments there that might potentially explain the delta between the level of increase versus the functional outcomes? In terms of quality of dystrophin, we do expect for majority of the patients, we do expect the quality of the dystrophin to be good. This is based on lot of analysis that we have done from BMD, which is a related disease where there is in-frame deletions where when you have 44 amenable patients, majority of them produce a protein that is robust. I think the difference here, I think, is more exposure into the satellite cells because DMD is a two-hit disease, where the first hit is to the mature fibers, which causes muscle breakdown and fat cells and necrosis occupying that space because of lack of regeneration, which is due to inactivation of the satellite cells activation. I think the ability to get to satellite cells and activate them, I think is playing more of an important role here. Okay. I think the interesting thing, Paul, because we spent a lot of time on this as well with you, your team, and the company, is there's no biology risk here, which is what gives us confidence, right? At the end of the day, we do believe the dystrophin levels will come up. That is important, and we'll get there with the second cohort. This was a projection miss more than anything. Now that we have the right data, this juvenile NHP data that Natarajan's referring to is a 55-week study. We got those data right about the same time we needed to share the data as well too. Since they sit right on top of each other based upon the concentrations, we feel as though that will allow us to be able to. That's what's giving us the confidence around cohort 2. What's interesting, once again, going right back to what Natarajan said was, when we start to think of cohort 2 success for 44, which will come by the end of this year, we think of it in three ways. One, we want the maintenance of a favorable safety profile, and that's no small feat considering we're doubling the dose to 12 mgs per kg. If we do that's huge, once again, from the risk-benefit perspective. The second becomes getting those dystrophin numbers into those double digit range. I think Natarajan explained that with the right shifting. The third is the maintenance of functional benefit. If we can maintain functional benefit, that is a big deal, right? Because these patients, especially the patients that we are observing, once again, in this first cohort, the patients that we had a baseline dystrophin that was much lower than what Avidity and what NS Pharma saw. We had 4% versus their 7%-10%. If we can maintain that functional benefit, that's a big deal, right? We'll know that in the next several months. We're excited about this. Great. Maybe just to clarify, both in terms of timing and. Yeah. Potential magnitude of changes. You talked about a right shift in your data expectations based on what you've learned from cohort 1 and your updated NHP modeling. Can you maybe, again, not to necessarily put you in a corner, but just help us think through what the 12 mg and the 18 mg dose might look like based on your updated information? Yeah, I could start. I think for the second cohort, for the 12 mg/kg, it really depends upon what the baseline looks like, right? Because we don't want to be cute with these numbers. If you really want to look at this, if we had baseline dystrophin levels of what Avidity or NS Pharma had, then we would have double digits. There's a cuteness there that we're not trying to go for. When we say double digits, we mean double digits, right? We think we're going to get there at 12 mg/kg. At 18 mg/kg, if we have to go to 18 mg/kg, I think that's a big if, right? Based upon what the safety and functional benefit look like at 12 mg/kg. That's where you get to the 25%+. It might not be necessary because the important thing here is are we getting into the satellite cells? Is that what's affecting the functional benefit in a positive way? We know that the antibody approaches can't get into the satellite cells, it's not expressed on the antibody itself, right? It's not expressed on The surface. The surface, right? Yeah. We already know that that's a differential, right? For us, if at 12 mgs per kg, we achieve what I laid out, which is a favorable safety profile, double-digit dystrophin production, so above 10%, and then a maintenance of functional benefit with the types of cost of goods sold that we have, with the types of efficiencies around manufacturing that seem to be delaying the BLA for Delzota, that's a big win for us. If we have to go to 18 mgs per kg, we can go to 18 mgs per kg. We just don't know if we need to do that, but we're prepared to. Okay. Can I just play devil's advocate here? Sure. Yeah. Let's say you go to 18 mgs, and you have no safety events or DLTs keeping you from theoretically going higher. What's the rationale for stopping there versus, It's a great question. A 24 mg dose or 28 mg dose or whatever the. It's a very fair question. You could, theoretically, if the curve is linear or logarithmic. Can you keep on pushing it? Can you keep on pushing it to get to almost a wild type level of expression here? There is a possibility to do that. The tox data and the cohort 3 data will determine that, whether we can go, and we have probably good confidence that we could go there. The question is, do we have to go there? Based on the revised model that we have, even at 12 milligrams per kg, we should hit both the aspects of it, addressing the dystrophin level in the fibers, and addressing the dystrophin levels in satellite cells, which we already seem to be doing. Yes, we can probably move based on safety in cohort 3, but [I think,] most likely we don't have to go beyond 18. The other thing is, if we continue to show what we've shown, right? Safety, dystrophin getting there, functional benefit, early but sustainable functional benefit, there will be a fair amount of pressure from the patient groups as well too, to say, "Can we get access to drug?" We're already seeing that. A lot of rare disease companies see compassionate use requests, expanded access requests, things like that. If we continue the momentum that we have here, albeit the setback last month, but we catch up to that, there's going to be a lot of good pressure on us to say, "Let's get this out to the patients as soon as we can." Maybe just to wrap on the Cohort 44 program, can you remind us what, if any, updated longer term follow-up you will present on cohort 1, and when that will be, and when cohort 2 data might come? That's a great point. We're excited. We will have our open-label at 6 mgs per kg data readout before the end of this year. That's going to be a very important readout because it's going to be roughly one year on drug, multiple doses, of course. That will be interesting to see. That data point, when we share that data, we will also share a more robust analysis of the functional measures, right? In our corporate presentation, there's a whole list of functional measures that we're looking at that we will be able to read out on. It will give a much more fulsome view. The cohort 1 data was supposed to be more of a snippet, but the open-label will explain a lot more. Remember, open-label only, and all eight patients have converted to the open-label. Open-label will only measure really two things. It's going to measure safety and functional benefit. There's no dystrophin level that's being measured in the open-label. That'll come out before the end of the year. Cohort 2 data at 12 mg/kg is coming out at the end of this year as well too. We're continuing to monitor it. I think it's an exciting data set. Those two data sets by the end of this year are going to be very telling for 44. Okay. Does it make sense to present them simultaneously? It's something that we're working on now internally. Okay. The question becomes, and just I think all company cases, is that when you're running these studies, you're getting into the winter. You're getting into the holiday period. You just want to make sure that you can present that correctly. We're keeping an eye on it in terms of how best to present it and where to present it, things like that. Okay. You referenced some competitors earlier, including Avidity and Enzast. The space is obviously very actively invested in right by the industry. How do you think about the market, especially given the context of what's happened with some of the Sarepta products, specifically with ELEVIDYS, and just I guess upon market entry for yourselves and other companies, how do you think about positioning and just sort of timing to market? Data wins, right, at the end of the day. I think unfortunately, what we've seen over the past year, well, more than the past year, over the past 5 years really, is DMD is difficult. It's a difficult disease that was not fully explained by the first generation movers like Sarepta, that's okay, right? We're learning a lot more about it, right? Delzota comes in and shows us remarkable dystrophin production, let's call it what it is. It was remarkable dystrophin production, albeit at a safety, at a 5 mg and a 10 mg per kg dose that is kind of difficult to understand because you don't know what's 5 mg per kg or what's 10 mg per kg. They pooled a lot of their data. They had safety concerns. It's an antibody. How do you manufacture that much of antibody? There's pluses and minuses. ELEVIDYS set gene therapy back, right? I think that hurt the patient groups a lot as well too. They're trying to come back. Years ago, people would ask us, "Do you think that an exon skipper can be added on top of gene therapy?" I think it's the other way around now. I think it's, can a gene therapy be added on top of an exon skipper? I think 5 years ago, if you look at some of the stuff that I've said and Natarajan has said, the flexibility of this approach, the ability to start, stop, increase, decrease dose, things like that, becomes really important to be able to match up to a patient's own journey. What hasn't stopped is the fact that it's a $5 billion market in the U.S. that is under-penetrated, that patients are clawing and desperate for a drug that not only works, also has that flexibility and those characteristics that marketing teams usually put out, sometimes they're not supported by data. I think we have the opportunity to be in that mix. I think for us, yeah, competition's good. That doesn't mean that I'll give an example of my former company with Amicus Therapeutics. With Fabry disease and Pompe disease, they certainly weren't the first to market. In some, they weren't the second to market. They were able to carve out a very lucrative and meaningful business because of the data profile. I think for us, I think that's what's going to drive this safety plus functional benefit when it comes to 44 and 45, ultimately. That's what's going to drive utility of the drug in the years to come. We're seeing that within our clinical trials. We're seeing a tremendous amount of excitement. We released last week a press release around a Data Monitoring Committee for our Exon 45 Program, which is a very difficult exon. The Data Monitoring Committee essentially said, "Go to 10 mg/kg." It's a 5 mg/kg study, as you know, but go to 10 mg/kg. There's an influx of emails. The patients, the PIs, I think even with a competitive landscape around, still the bar has not been fully met. I think that's where we can come in here. Since you mentioned the 45 Program, I want to ask, the construct is fundamentally the same with the 44 Program. Can you maybe talk about the translatability? Yeah. Maybe what you learned from your early PK work on the 44 Program in the clinic? You also referenced that your Data Monitoring Committee recommended dose escalation here to the next dose. Are there any particular learnings that you would communicate from the 44 Program about the 45 Program to investors? Yeah. I think I'll start. Natarajan, please jump in as well, too. We've always said that the 45 program. We didn't expect to see, and we still don't expect to see the levels of dystrophin that you would see in 44. First, why is that? First, the baselines are usually much lower. Yeah. When I say much lower, I mean like just above zero. The caveat is that in 44, we had 4% where we thought we'd have 7%-10%. It moves. I still think that that would be consistent with 45. If you have baseline of less than 1% of dystrophin, we've also said that our expectation, ultimately, not with the first cohort, but ultimately would be to get into the single-digit dystrophin above, which would be huge. [Because] casimersen, AMONDYS 45, barely shows any dystrophin production because it's a difficult disease. Yeah. For us in this first cohort, we want to establish this as safety. Safety is no small feat here. I think the DMC result from last week puts us on a path where we believe that we are establishing safety here, and we're excited about that. Dystrophin functional benefit, that will come in time. It may not come in that first cohort. That's okay. For us, if we establish full safety, that in itself, plus, which cannot be, I have to emphasize this as much as I can, the dosing around our 45 drug is once every six weeks. The dosing around casimersen is once a week. That dosing difference, that regimen is huge. If we start to think about quality of life, we start thinking about you don't have to go and get infused every week. Yeah. For a six-year-old kid, seven-year-old kid. I think there's so many characteristics around this 45 program that if we establish consistent safety in that first cohort, safety plus a dosing regimen, which is every six weeks, that alone is a huge win. In cohort 2 and in maybe cohort 3, we'll start to see some of that functional benefit and dystrophin start to move in a more meaningful way. Great. In our remaining time, I want to talk about some of your other programs, including VX-670, which you've partnered with Vertex. Can you maybe just remind us of what are Entrada's obligations under this partnership? Yeah. We entered this partnership a few years back, and our job was really to take the preclinical work up to an IND. That's all been completed. Our obligations essentially to date have been completed. We are now waiting, of course, for the study to read out, this MAD study to read out, which Vertex has publicly declared that that will come out the second half of this year. Our obligations are done. We think we partnered a really good drug here, that 110,000 patients in the world have DM1, and we are eagerly awaiting those results in the second half of this year. Okay, great. With regard to the DM1 program, to help maybe guide investors who are following it maybe from the Vertex side as well as for your side, can you talk about the translatability of the 44 or 45 program data you've seen to date internally and how that may read across to DM1? Do you want to take that one? When we think about it uses the same EEV. The safety should translate across the platform, and we have seen that in pre-clinical studies. We have established safety at 6 milligrams per kg, I think, in both normal human volunteers and in patients. That should translate. The second thing is that this is a different disease. I think DM1 is a very different disease compared to DMD, and the patients are not pediatric patients, they're adult patients. We don't expect the exposure differences that we have seen in pediatrics to translate that. I think between safety and exposure, we are expecting good splice correction. I think we had the most robust pre-clinical data with a panel of over 20 genes that we have shown splice correction. I think it should, in our opinion, translate in the clinic as well. Okay. I think what becomes important in DM1, and it's probably a better question for Vertex, but taking a step back is also safety plus functional benefit ultimately, right? Spliceopathy, it's still kind of difficult to understand what that means. I think as they return those results or present those results, we'll be very interested to see how this pans out within an increasing competitive dynamic as well. Great. With all small and mid-cap biotechs, cash runway is always the classic question. Can you remind us if, assuming the DM1 MAD data are positive, how that potentially helps your cash position down the road there? Is there milestones, Yeah. Tied to this particular readout? We haven't disclosed what the milestones are in terms of the individual milestones, but the aggregate is pretty significant. What I can say is that our cash runway goes into Q3 of 2027, and it does not include any milestones per the DM1 collaboration. Anything above and beyond would, and it's significant in terms of the milestones, would just add to that cash runway. Okay. Maybe in our last minute or two here, you talked about other applications. Yeah. You've started for your EEV platform, started talking a little in the past about ophthalmology and other things like that. Can you maybe just walk us through what sort of early development you have there and just in terms of other areas? Yeah. kind of what you might disclose to the street in the coming call it year or year and a half? Yeah. We're super excited about the ophthalmology franchise. I'm going to let Natarajan talk about the inherited retinal diseases, specifically Usher syndrome type 2A. Yeah. We had already nominated a candidate for USH2A, with significant patient population, and the pre-clinical data that we have seen is quite good. First of all, it's intravitreal injection, and there may be a possibility of once in a quarter injection. It is looking very attractive from that. We are about to, this year, to nominate candidate for another inherited retinal disease as well. It just talks about the platform and our ability to work on this exon skipping and steric blocker space, where we are able to get deep tissue penetration and get very robust target engagement. I think that is enabling us to do this. In the back of the eye. Yeah. Yeah. Indeed. I think we'll share more as the year goes by. Neither one of those programs will enter the clinic this year, but we do expect them to start to robustly move into clinical development. We're figuring out the plan. We have to talk to the regulators. There's a global approach here as well, so we're looking for those efficiencies because once again, 10 - 15,000 patients, but with a remarkable unmet clinical need as well. We're excited about that as it leverages not only core expertise within exon skipping, but it also allows us to obviously branch out and show the applications of the Entrada capabilities to other diseases. Yeah, I think, just given the frequency of how often patients get VEGF injections for AMD or DME, it doesn't even have to be a quarterly, right? Right. Necessarily. That's exactly right. Yeah. Okay. We're out of time, so my thanks to the Entrada team for joining us today. I appreciate it, Paul. Thank you. Thank you.