My name is Chris Shibutani. I'm a member of the research effort. All the hard work gets done by Stephen Sloan, who's joined me upstage here. Entrada, ticker TRDA. We've known you guys for a couple of years. We're really pleased to have you join us once again. Dipal Doshi, President and CEO, and Natarajan Sethuraman, Chief Scientific Officer. So a business powerhouse and scientific trust. Entrada, even the name of the company has a meaning in terms of foundationally what you guys do. We're going to get into the details, and Stephen will ask all the relevant, precise questions that think about the model and your pipeline, et cetera. You know, it's almost pejorative to say that you're like a drug delivery company. Within that, there is just really a platform, and there are strategic decisions that you've made about sort of like, where best to apply this platform in terms of scientific probability of success, commercial opportunity. It's very interesting to see how you could leverage that. That's been expressed with different segments where you're aiming, that's been expressed by the potentiality of you doing strategic things, et cetera. Framing that, I think it's very relevant that people get a deeper understanding of that. Maybe you just want to do a little bit of an opening in terms of letting us know who you are and what's important before we go into more details about sort of like, progress points. Well, that's great. That's great. Chris and Stephen, thanks for having us back. It's, you know, as you said, Entrada actually means opening. When we were trying to rename or name the company, we were trying to match that up to what it is that we actually do, and that's probably half the story, right? Opening. What's important is that Entrada is really based upon this family of cyclic cell-penetrating peptides that we have renamed Endosomal Escape Vehicles or EEVs, and you'll hear a lot about today. These little, you know, EEVs are foundational to where we are today. The important aspect of that is the ability to not only get into the cell, but get out of what is called the early endosome. The reason why you want to get out of the early endosome is because you need to get a therapeutic to, in our case, the muscle. The ability to get to the muscle in a profound way with a lot of quote-unquote, "drug," and in low doses, is what makes Entrada really special. These EEVs cut across a plethora of diseases where there's so many different opportunities, right? All these diseases that Entrada is focused on suffer from the same issues in that there is a high unmet clinical need because people just simply can't get to the muscle, or current standard of care can't get to the muscle. For us, our current focus is on Duchenne muscular dystrophy, which is a fatal muscular dystrophy disease that is well-studied, but once again, has a profound, a high unmet clinical need. Our second disease, which is myotonic dystrophy type 1, which is the largest muscular dystrophy disease that we just recently partnered with Vertex on. Once again, the common link between those two diseases is the inability for current standard of care in DMD that is, because in DM1, there is no standard of care yet. The inability to get to the muscle, and that's where these EEVs become really, really important, and that's what the foundation of this company is. There's a lot that's really cool going on scientifically, biologically, from an engineering perspective. Yeah. There are other folks who are trying to deliver all sorts of important stuff, oligos, et cetera. Clarify for us how you would differentiate your platform versus some of the other folks who are, you know, on similar missions. I think, the easiest way to say that is we have probably one of the best protein engineering groups that are out there, led by our Chief Scientific Officer, Natarajan. Maybe I'll ask Natarajan to comment on why we are different in that regard. Yeah. Thank you. When we look at other therapies, the naked oligonucleotide therapies, the issue there is that, you know, after infusion, 90% of the drug within 3 hours is excreted through the urine. Bioavailability is very, very low. You have other versions of that with linear peptides, and linear peptides inherently are very, very unstable, and they get chopped off in circulation. Really, within few minutes, they are no different from naked PMO. You take the same PMO and conjugate it to our EEV, then 90% of the drug remains in the body days after infusion. The amount of the drug in the body is increased tremendously. Add that to more than 50% endosomal escape, now we have, at low doses, very high concentration in the right tissue, and that results in the pharmacology that follows. We have really best-in-class exon skipping data for DMD that we are very excited about, and that's because of the fact that these cyclic peptides are stable. They are very, very good at not only entering into the cell, but more importantly, as people said, getting out of the early endosomes so that they can go to the nucleus and have target engagement. Just to be clear, escape, that's actually a good thing. That's what you're trying to do, right? That's the kind of the final chapter in the journey that's very relevant. Maybe not the final, but a very important part of the chapter there is the release once you get to target destination. Yeah. Right? I think sometimes escape has multiple meanings, but here, to be clear, it's absolutely important. We sit here. A year ago, you were with us. Mid-2023, continued progress. Strategically, talk to us about your strategic priorities, and where things are at this midpoint of the year. Yeah, thanks for that. Yeah, it's been quite a lot of progress in the past year for us. You know, in this market, obviously, cash is something that's very, very important for lots of companies, and, you know, we're pleased that our cash runway lasts into the second half of 2025. A lot of that is fueled not only by disciplined spending, but also a transformative deal with our new partners at Vertex for our DM1 program. It is a preclinical program, Vertex invested $224 million upfront for that and $26 million in equity, and there's a whole host of milestones as well, too. That was a transformational deal, not only for the patients, but also for the validation of the EEV platform. Continuing to move forward with our partnership on DM1 will be a very important strategic priority this year. Continuing to move forward and progress our early DMD franchise to get our 44 program, our ENTR-601-44 program into the clinic is a huge priority this year, followed on by our 45 program, followed on by our 51 and 50 programs. There's a cadence of events that will occur within our DMD franchise. That's another huge priority. I think the final priority is, goes once again back to the versatility and flexibility of these EEV. We started to talk a little bit about. In a recent K, we talked a little bit about our disease focus and modality focus, that is different than oligos and outside of neuromuscular, and we're looking forward to hopefully presenting some ocular data as the year progresses, looking at other modalities, such as gene editing as well, too, which once again, will tie really well to the flexibility and power of these EEV. Expanding outside of neuromuscular is probably the third big priority for this year as well. Right. Again, use platform is often discarded and readily used, but it genuinely is. You have a strategic focus and opportunities to flex beyond that. But let's focus what's front and center, and thinking about that, I'll turn to Stephen now to go through in a disciplined way what your projects are and the status, and take it away, Stephen. Sure. Thanks, Chris, and thank you both for being here today. Let's start with your DMD program, the lead asset, ENTR-601-44, a next-generation exon skipping approach for DMD patients amenable to exon 44 skipping. I think to date, the preclinical data has been very strong. In our view, some of the, that's levels of exon skipping as well as dystrophin production in DMD mouse models, those high levels of exon skipping in non-human primates. Maybe, Dr. Natarajan, can you just walk through incrementally since we were speaking last year, what kind of preclinical data have you put out that gives you more confidence in the platform and this program in particular? Yeah, thanks. Thanks for the question. The, if you look at us, you looked at our non-human primate data, with reasonable doses, we get almost saturating levels of exon skipping in the skeletal muscles. Moreover, we get very robust exon skipping in the heart, and that's one part of it. The second part, which is even more exciting, is that after a single dose, we are seeing exon skipping going up to 3 to 4 months. When we think about patient compliance, use to the patients, et cetera, that's very, very important to have a therapy where we have convenient dosing frequencies. Those are the datas that have been put out for 44, and we have, of course, given data on 45. Looks very exciting from in terms of, the, very first in class data as well. I want to dig a little deeper on the question of dosing. I know other competitors, some of the approved agents for DMD, showed some pretty exciting clinical data at high dose concentrations, but then really had to walk that back when they got into humans due to some tolerability issues. Can you talk about how you're thinking about this? And yeah, you mentioned at low doses, you're seeing these profound effects. So should we expect that the doses you're setting preclinically will kind of translate to what we'll see in humans? When we go back to the platform itself, the EEV bind to phospholipids, which are conserved across animal kingdom. That's why I think our data would translate very well into humans. When we look at our therapeutic index in animal models, we have a very good therapeutic index, and we are very confident that we can get to doses which are very efficacious in humans. I think just to add to that a little bit, Stephen, and it's a very, very good question. It really is all about therapeutic index and the ability to have the flexibility to go higher, to go lower, go somewhere in the middle, but at the end of the day, having that flexibility to be able to customize your dose and your treatment to the specific patient that is suffering from that disease. I think the data over the past 12 months, once again, this is, you know, this is arguably the most, you know, robust data set across multiple mouse models that are, you know, phenotypically representative of the disease, but also the NHPs or non-human primates, that, you know, we show exon skipping, and of course, we show safety in as well, too. Those data in combination give us a lot of confidence because of the therapeutic window and the ability to see a translation at, you know, at arguably very, very low doses when we think about, you know, the patients who hopefully will be taking our 44 program. Obviously, we're anticipating the phase I to initiate, hopefully near term. Can you provide us a range of potential doses that you'd be looking at, both on the lower end and upper end, or is it still early days, well, we have to wait for that data? Just to specify or clarify, you mean in the clinic? Mm-hmm. Yeah. Yeah. Yeah. You know, it's a good question, right? At the end of the day, you know, we have a subchronic study that is subchronic NHP study that is ongoing, which will influence the data or the dosing within patients. When we start to think of the first trial, which is a healthy normal volunteer study, we are gonna be evaluating that in a range of doses, right? The good thing about that range of doses, which I don't think we've specified what they are, but it is exactly that. It is a range of doses that cut across, you know, from the low to the middle to the high. Once again, it goes, it's a testament to the therapeutic index that we've been able to develop with these EEV. Got it. Okay. I know there's been strong data supporting the translation of exon skipping to dystrophin production to clinical benefit. Let's focus on safety, which has been another key aspect. I think some competitors have seen hypomagnesemia. Can you just talk about that adverse event in particular, if you've seen that preclinically, and if that's something you'd expect in clinical studies, if you're designing protocols to mitigate those effects? Yeah. When we look at our animal studies, hypomagnesemia is not something that we have seen. So that we are confident of our data. Again, when we think about human, you know, studies, these are easily monitorable symptoms, and there are mitigations already in place for others. Should we find such an event, we can intervene. We can monitor it, intervene, and that's what is good about these kind of symptoms, which are easily monitorable and treatable. The key there, as Natarajan said, is that we have not seen hypomag. Which is different than what some of the landscape, you know, other companies that are focusing on DMD have seen. Once again, I think that goes right back to, you know, the profile of these EEV and how Natarajan and his team conjugate them to the oligonucleotides. Got it. Okay. maybe addressing the elephant in the room, this program has been on clinical hold since, I think about mid-December. Can you just talk about this hold, and how we should be thinking about next steps? I think more importantly, putting this in the context of development programs from competitors, which I think this field has been riddled with clinical holds, most of them have been overcome. Yeah, no, and it's a very good question. We don't really shy away from the hold. I think at the end of the day, it is unfortunate that a lot of companies in this division of FDA have been placed on hold. As you said, Stephen, you know, they do get off of the hold as well. I think at the end of the day, we are very confident. As every day goes by and we have a little bit more data, our confidence does not stay the same. It increases around how we view this 44 program in terms of how it's gonna work in the clinic. The hold, which seems to... Somebody quoted a rite of passage in this division, is a temporary roadblock for us. However, remember, we're doing a healthy normal volunteer study. The healthy normal volunteer study will be in only one country. At the end of the day, like, we will look at every single disease that we are pursuing, we look at these in a global setting, so we are committed, and we're convinced, and we're optimistic, and frankly, very confident that we will run a trial for our for our 44 program in healthy normal volunteer studies this year, in 2023. We wouldn't be saying that if we were not confident in our ability to do that. Importantly, as we look ahead in terms of other exons or other DMD programs, you know, we plan on going straight to patients with our 45 program, our 51 program, and our 50 program. Our exon 44 program will lay the foundation, and some of that is difficult because we are on hold, and we'll work through that. Once we get through that, it'll hopefully allow us to have our 45, 51, and 50 programs, you know, go straight into patients. I will also say that the 44 program uses the same EEV as our DM1 program that we partnered with Vertex as well. Once again, we are very confident in the ability to, you know, to move these programs into the clinic in short order. Okay. Yeah, you mentioned that there is potential for OUS recruitment for this healthy, normal volunteer phase I study. Yeah, how are your development plans taking into account, okay, like, is there a certain time you're looking at? If we resolve the hold by this time, we'll do it in the U.S. versus after that, we really need to get this initiated outside the U.S. to get. Yeah, no, it's, once again, it's a good question. I think speed is something that's important, of course, right? Especially for our 44 program, in that there are no approved treatments for 44, for those patients who have the 44 mutation. Speed is important. Quality is obviously super important to us as well, too. I think, you know, for the audience that's listening in, I mean, you know, we are very, very patient-focused. We've been working with the patient group since the beginning of the company. A lot of us come from patient advocacy backgrounds as well, too. We will run this trial for 44, whether it's in the U.S. or outside the U.S., we will run this trial. We will run this trial, with the quality that it deserves so that we can get a treatment out there for these patients in short order. We're not, whether it's in the U.S., whether it's outside the U.S., you know, we continuously navigate the timelines between the two. At the end of the day, you know, all that matters is what's the right thing to do for patients, and that's the North Star for us. Got it. Well, we definitely look forward to developments on that front and learning more about this study. Maybe we can move on to the second DMD asset, targeting exon 45, where there are approved assets. Can you just remind us from an epidemiology standpoint, how these two, exon 44 versus exon 45 patient populations differ, and if there are unique considerations when developing a candidate here or running clinical trials in patients? Yeah, I'll address the first part. Natarajan can address the second. epidemiology-wise, you know, our ENTR-601-44 program represents, you know, roughly around 7.5%-8% of those patients that are in the category of 44, 50, 51, 45, 53. that's roughly translates to, you know, 2,000 or so patients in the U.S. and EU. 45 is actually similar in a lot of regards. It's a little bit bigger. It represents roughly around 8% of the population, which translates to roughly 2,700 patients. The difference, the science aside for a second, Natarajan will answer that. The difference is that there is an approved program for 45, and I think that's important, and that there are no approved programs for 44, so it's a little bit, a little bit more open. For 45 specifically, maybe you could talk about, you know, how that data looks and specifically also about how it's looking when we think of it from a landscape perspective. Yeah. When I started the data that we have, in vitro, we have shown very robust exon skipping, and that translates very nicely into dystrophin production and functional data as well in vitro. In human DMD mouse model, we have shown very robust exon skipping, not only in the skeletal muscles, but also in the cardiac tissue. Very, very exciting data. In terms of differences in diseases, each exon is almost like a different disease from that perspective. The intron-exon junctions are different, the amenability for exon skipping is slightly different between each exon. Of course, when you make a protein that is deleted in a few exons, the stability of those proteins are also different. 45 and 44, as Dipal said, are somewhat similar in this category. Okay. I guess digging a little deeper there, is the quality of the dystrophin in either of those patient populations better? Do they have a different clinical phenotype on the whole? From the quality of the protein point of view, you have DMD patients, which have, you know, real evidence that you can skip these exons and get a quality protein that restores enough function for these patients to be different from DMD. BMD really gives us an idea of how whether there will be a functional correction in these patients when you skip these two exons. From that point of view, we are very confident that for both these exons, as well as for 50 and 51, we have a good path forward. Got it. I think the foundation, Stephen, of the 44 data and the amount of work and the amount of analysis that's been done across the canonical mdx mouse model, the D2-mdx mouse model, the human dystrophin, you know, mouse model, then, of course, NHPs, you know, will cut across 45 to 51 to 50 as well, too. Foundation in 44, great exon skipping, really encouraging dystrophin production, long duration, which is really important, and also, you know, low doses. We feel as though those four characteristics will cut across the other exons as well. Thinking about clinical development, as we've talked about, there are approved options for exon 44 amenable, or 45 amenable patients. How do you envision that impacting patient enrollment when you do start patient-based studies? I guess there's the additional consideration now, potentially nearer term, we'll have an approved gene therapy for these patients. Do you expect competition for these patients and, you know, the likelihood or just talk about that in general? Yeah. I think at the end of the day, these are, you know, the DMD patient groups and the patient advocacy efforts around DMD are remarkably sophisticated. You know, the patient groups have been working on supporting treatments for years. I think the parents of the, you know, whether they're young boys or young men, who have this disease, are very cognizant of the different data that's out there for these diseases. I think the data will drive enrollment. All we could say for 44, 'cause there is no real competition there right now, is that those data are compelling. You know, those data will carry over to 45 as well, too. Like a lot of companies, we will work with the patient groups to enroll these studies, diligently, across the, you know, the globe. I think to your question around gene therapy, you know, I think a lot of us watched that AdComm and listened into that AdComm, the, you know, the very closely, eight to six vote. I still think there's a tremendous amount of questions that have remained unanswered around the gene therapy program. You know, we're excited that there might be an option here as well, too. If you really take a step back, the same questions are still there. You know, micro-dystrophin is still something that's not well understood. gene therapy for DMD still has the issues of dosing or redosing and, you know, a waning effect and, you know, the inability to start and stop. Those limitations really kind of lend well to a much more flexible approach, which is what our EEVs are and our EEV-led therapeutics are, in that we are able to, you know, customize dosing to a patient. We are able to have these remarkably long duration of effects. Right now, we're targeting at least, you know, dosing every six weeks, which, you know, standard of care is every week. The profile or the therapeutic product profile, what we're developing here for our DMD programs are, you know, they mirror a lot of the benefits or perceived benefits that these gene therapies have. They just have the flexibility around doing what's, you know, around meeting the patient as to where they are at a certain time period. Got it. Maybe one last question on DMD before we move on to some of your other programs. Related to this point we were just talking about, how do you think about designing clinical enrollment criteria for your DMD studies? If there is an approved gene therapy, and for 45, there will be approved therapies, will you allow patients that have had prior therapies, or are you looking for naive, treatment-naive patients? Yeah, it's a good question. I think only time will tell, right? We don't know what the label is going to look like for gene therapy. I think that's first and foremost, right? You know, we don't know what the exclusion criteria is going to look like in terms of what the label says. I think we have to kind of push pause on that and see how that evolves. You know, for 45, I still think, once again, you know, we'll work with the patient groups, you know, we will work to enroll this study. Whether or not they need to be treatment naive or have, you know, a washout period from a specific, you know, for casimersen or whatnot, I think remains to be seen. What does not remain to be seen is the fact that, you know, exon 45 has a profound unmet clinical need. At the end of the day, the data is what's going to drive, hopefully, you know, the patients to enroll into a specific study. Got it. Okay. That's all very helpful. Let's move on to the DM1 collaboration with Vertex. I'm curious what piqued Vertex interest in your program. Obviously, you do have a strong, preclinical database and interesting results there. There are other programs farther along in development, some with clinical data. What made them choose your program over the others? Yeah, just to use one word, it's just data, right? At the end of the day, the data that they saw, and how that data can frankly convert hopefully into, you know, a clinical drug that helps patients, you know, check the boxes for them, right? They did a tremendous amount of diligence on the asset, and they know the asset extremely well. They know the disease extremely well. I think at the end of the day, and Natarajan can get into the more specifics, but the fact of the matter is that the specificity of this approach is really important when you think of some of the other companies that are going after DM1 from a DMPK knockout perspective, because it could be indiscriminate at times as well, too. The specificity of this allele-specific focus that Entrada has developed for DM1 is probably what piqued, you know, our friends at Vertex, but maybe you can go into a little more. Yeah, I think that's a very important point, right? When we think about allele-specific knockdown of DMPK, that way, you preserve the function of DMPK, and just get rid of the pathogenic part of the mRNA. And also the data, right? When we look at the splice correction and myotonia correction, we have best-in-class data there as well. The duration of effect, again, is very profound. All of that added up. Got it. Can you remind us of Entrada's responsibilities in this collaboration? I believe you're still responsible for some development early on. Just speak to that. Yeah, I mean, it's a pretty stringent delineation of responsibilities. We're responsible for all the preclinical work, and they're, I mean, Vertex are responsible for regulatory, clinical, and commercial. Essentially, anything past the IND is Vertex's responsibility. Got it. Obviously, Vertex, one of the premier larger biotech companies. Can you speak to what learnings you've had? Obviously, Yeah ... working very tightly together, I'm sure the way they look at development is slightly different than the Entrada team does, but yeah, what takeaways have you had there? Yeah, I mean, I think the common vision of the management teams of both companies is really, really important. You know, I think we all, you know, collectively see the world in the same place or in the same way. Our learnings are, you know, they're remarkable. What they've done with CF and what they're continuing to do with other diseases, being a, you know, a trailblazer in terms of, you know, commitment to the patients, commitment to the data, creativity, sense of urgency, is something that is infectious in a lot of regards. I think we frankly, you know, we know we're a lot smaller. We strive to be what they are as the company continues to build. Taking a lot of that knowledge, having our teams work together, allows us to be able to, you know, learn from some of the things that we may not see, you know, and that they have seen. DM1 is a clear example of that, because the story for DM1 is still being teased out. What clinical endpoints are going to look like, what approval endpoints are going to look like, you know, there's ambiguity around that as well, too. Working with the Vertex team that's dealt with this, you know, many times, is something that is really important for us to, you know, to learn from as well. Great. Are you at liberty to discuss kind of the progress of this program, what the next updates will be? We should expect the timelines to be generally similar to how Entrada had laid them out initially. Yeah, I think, you know, unfortunately, you know, I know, I know Reshma presented yesterday, but, you know, they really, you know, control the timelines because most of the updated timelines are going to be regulatory and clinical. The preclinical package looks really, really good, and we're confident in that, but right now we'd have to defer to them in terms of timelines for clinical trial initiation. Okay. No, looking forward to updates on that front. As you had alluded to earlier in the presentation, Entrada is not just about DMD, not just about DM1. You have this very compelling platform that could be applied to multiple new modalities as well as disease areas. Can you just talk about the progress here, what you find most compelling, and then, you're an early-stage biotech company. How do you balance these priorities, given that there's only limited cash to go around? Yeah. I'll start a little bit at a high level, and then Natarajan can hopefully talk a little bit more about, like, what, why we're so excited about our non-neuromuscular programs. At the end of the day, we all have to make choices. Yes, cash is finite. A good thing we don't have to raise, you know, cash in the immediate future in this year. For us, you know, being able to focus on diseases of high unmet clinical need, being able to focus on diseases where we think that the platform will be able to substantially change the course of a disease, is really important. You know, we've shown that with DMD, and we're showing that with DM1. What we don't want to be is a company that's good at a lot of little things, right? Because that doesn't move the needle, right? What we want to do is be able to show our commitment within the neuromuscular diseases, to use that as a launchpad for these other diseases. Have the same type of, you know, critical features in terms of how we prosecute data, how our scientists are curious about, you know, different experiments. The thoroughness of our concentration within looking at those diseases and answering the question, like, what will move the needle for a patient? That's what's gonna drive us. That's what's driven us in neuromuscular, and that's what's gonna drive us in non-neuromuscular. Specifically, maybe we can talk a little bit about, you know, some of those areas. Yeah. I think when we, when we look at the data for DMD, right, and when we look at the expression restoration in a muscle, not only us, but most of the experts in the field are excited how uniformly we can cover a tissue. Mm-hmm. That speaks to the versatility and modularity of the platform. We ask the question, where are the other areas that we could go and where we would be differentiated because of our platform? We had already guided that we are looking at ocular indication. Again, you know, getting to, you know, retina and others is not all that simple for other platforms. We may have a edge there. The other thing that we are looking at, you know, is gene editing, where you have Cas9, you have guide RNA, and they have to be delivered efficiently. AAV has size constraints, when can we look at the whole field without the constraints of a size? Those are things, some of the things that we think about, that are very exciting, in the near term. Got it. Obviously, it's early. Is there any time frame where we should be expecting more updates from those programs? Yeah, I think you guys know as well, and that, you know, we won't unveil a lot of this until we're absolutely ready to share those data. The fact that we're starting to, you know, speak to it, you know, shows our level of confidence. You know, hopefully, we'll have more to share as the months come. Okay. Chris, I'll turn it over to you after this last question. As we sit here, looking forward, say, 12-18 months, maybe this time next year, if we're hosting you again, what will Entrada look like? Yeah, I think it's gonna look very different. I think it's gonna be a step progression, I think we can look at last year to this year as an example for that. You know, for next year, 44 in the clinic, 45 on the verge of an ID or a regulatory submission. Could be an ID, could be something else as well, too. That will go straight into patients. We'll have announced the candidate for our 51 program or 50 program. DM1, of course, will be further along as well, too, and we will have shared, you know, the aforementioned, you know, really compelling non-neuromuscular data. I think at the end of the day, it's just gonna be a progression in the clinic and, you know, starting to see what else, what excited us seven years ago when we started this company, you know, hopefully starts to come even into more fruition. Got it. Perfect. Well, thank you both for joining us and for the insightful comments here. I think that the space that you guys are part of interrogating, particularly from the clinical development side and the scientific innovation, is fascinating to watch. We will look forward to monitoring your progress and exciting second half of the year. Sure. Thank you both. Thanks, guys. Thank you. Great job, Stephen.