Hello and welcome to the latest in this series of fireside chats here at the H.C. Wainwright BioConnect Conference. Thank you very much all for joining us. My name is Ram Selvaraju, and I'm a Managing Director and Senior Healthcare Equity Research Analyst within Wainwright's Equity Research Department. I'm joined here today by the next in our series of presenting companies, Entrada Therapeutics, represented by Nathan Dowden, President and Chief Operating Officer. Nathan, it's a pleasure to have you with us.
It's a pleasure to be here. Thanks, Ram. Thank you to Ram, and thank you to Wainwright for putting on such a great conference. It's been a wonderful day.
I just wanted to remind everyone that Entrada Therapeutics is publicly traded on the Nasdaq under the ticker symbol TRDA, and we at Wainwright cover Entrada with a buy rating and 12-month price target of $20 per share. Nathan, perhaps you could start by giving us a description of Entrada's core proprietary technology platform, the endosomal escape vehicle, and some of its unique attributes.
Sure, happy to. The endosomal escape vehicle platform is a cyclic peptide that we chemically conjugate to an active moiety. That can be an oligonucleotide in the case of our Duchenne muscular dystrophy programs or the partnered program we have with Vertex in myotonic dystrophy type 1. It can be a protein, it can be an enzyme, etc. Effectively, what it does is it binds to the phospholipid bilayer of the cell directly, relatively low affinity, but this triggers the process of endocytosis, which in simple English just means the cell takes the cyclic peptide and whatever it is conjugated to up into the cell.
That goes into a structure called the endosome. The endosome can be thought of as a simple soap bubble, which is an oversimplification, but it is an easy visual metaphor. What happens then is, in a pH-dependent manner, the affinity of the conjugate increases by several thousandfold. That actually then creates a process of budding, wherein a piece of the endosome, a bud, another soap bubble basically, buds off of the endosome and drifts off into the cytosol.
The endosome itself isn't damaged, but as this bud drifts off, there's really nothing holding it together. It's not a natural structure. It collapses. As it collapses, it releases everything in that bud into the cytosol. That's what gives us our remarkable target exposure. To put it in context, it's very, very difficult to get biological material into a cell. Cells are kind of designed to be very choosy with respect to what actually gets into the cell and even more so what gets to critical structures like the nucleus.
Historically, the holy grail of drug delivery has been, can you get more than 1% of that biological material out of the endosome to the target, say the nucleus, to engage in something like exon skipping? We get 50% target exposure. Obviously, it's a simple arithmetic differentiation that we have. Where we are today with respect to the platform modality is we're using the same endosomal escape vehicle, which has been optimized for uptake in muscle specifically for all four of our DMD programs, as well as the Vertex myotonic dystrophy type 1 program.
We've generated a significant amount of safety in humans in our Healthy Normal Volunteer trial last year. That allowed us to identify a starting dose for our first patient trial, our exon 44 skipping trial, which we've got authorization for now in the U.K., the European Union, the United States. It has also de-risked the rest of our portfolio to a great extent because, again, same endosomal escape vehicle, that endosomal escape vehicle controlled by distribution as well as toxicokinetics. We are very excited to be able to then move our 45 program forward across Europe, as well as our 50 program a little bit later in the year, and then 51 program coming roughly a year later.
Thanks very much for that. Maybe give us a sense of how Entrada came to arrive at indication selection in Duchenne muscular dystrophy and myotonic dystrophy type 1, and why these two areas are perhaps uniquely suited to applicability of the EEV platform?
Yeah, that's a great question. It's really a convergence of serendipity and strategy at the end of the day. As with probably most valuable things in biotech over the years, the uptake that we saw with this platform in muscle came as a surprise. I remember the first day I was sitting in our CSO's office and the data came across the desk, and we were looking at it, and we were looking at biodistribution in a number of tissues. Muscle in particular stood out, and we thought, that's remarkable.
We went to talk to people who are experts in the field, and effectively they said, you have no idea what you're sitting on. We had been doing broad landscape assessments because obviously this platform is quite flexible and modular, and thinking carefully about what would make sense from the perspective of our initial indication selection, because this is a critical strategic decision that any biotech company makes. At the end of the day, DMD made a lot of sense because the biology was well understood.
The correlation between dystrophin production, the quality of dystrophin, and then ultimately patient outcomes was well understood, well accepted, and dystrophin was accepted as a biomarker from an accelerated approval perspective. That was very helpful. That was number one. Number two, we knew that obviously there were multiple sub-mutations associated with this disease, each one of which represents a patient population that we have an opportunity to serve.
from a synergy perspective, it's effectively the same EEV, a similar process in terms of sequence identification, the same sort of toxicology, the same sort of regulatory pathway, same clinical sites, and ultimately same commercial sites. That gave us not a pipeline in a pill per se, but certainly a pipeline and a platform when it came to addressing that disease. Now, as far as myotonic dystrophy type 1 goes, again, a neuromuscular disease, very different mechanism, very different oligonucleotide sequence, but also relying on the same EEV, also relying on uptake in muscle.
That one was a little bit more challenging early on from a theoretical perspective because there was, as of yet, no regulatory pathway that had been defined, and there was some uncertainty with respect to the correlation between splice correction and functional outcomes. That is in part why, even though we were progressing that program very aggressively when we were approached by Vertex and we started talking about a collaboration, we were more than happy to work with them.
They had the same vision for the disease. They had the same vision for the platform. More importantly, they were a company that had already created an entire space to a great degree with respect to cystic fibrosis. We saw the opportunity, but also the challenges very similar for DM1. That is how that partnership came to be.
Specifically within DMD, maybe you can just explain to us how the principle of exon skipping works in this disease and why Entrada chose to prioritize exon 44 and exon 45 skipping candidates relative to the 50 and 51 candidates that you also have in your pipeline.
Great question again. I'll explain it the same way I try and explain it to my kids, although they're getting older now and I think they know more biology than I do. When we administer an exon 44 or an exon 45 or an exon 50 skipping candidate, what we're looking to do is bring the exon back into the reading frame. You can basically translate the protein. What does that really mean? Think of the mRNA as computer code.
There's a genetic mutation that's left out, that is deleted, an important piece of the code that's necessary to generate the protein, or at least a functional protein. What we do with the exon skipping therapy is we ensure that as the pre-mRNA to mRNA splicing occurs, that that deleted frame is skipped. Instead of as the ribosome reads through the mRNA, instead of just stopping and resulting in a non-functional protein, it actually reads all the way through.
You have a very large, slightly truncated, but fully functional protein that will ultimately then, we hope, work as an effective shock absorber for the muscle, which will then result in functional outcomes for these patients. In terms of how we decided to go from 44 to 45 to 50 to 51, I'd like to say it was just in numerical order, but that's not exactly the case. With 44, we saw an opportunity at the time to address a patient population for which there was nothing in market, and there were very few products in the pipeline.
When we talked to the patient groups and the KOLs extensively, because not only of the limited number of options associated with this patient population, but also because there's a fairly sizable population as DMD goes here, they thought this was a great opportunity to bring something forward that would be really meaningful and impactful. That is where we started with 44. There was another reason to go after 44 as well, which is these patients tend to have a little bit more background dystrophin than some of the others, 45, 50, 51.
The expectation was that we would be able to do something relatively significant, relatively quickly for these patients, prove out the efficacy of the therapy, and then that would enable more rapid accrual over time across some of the rest of the portfolio. 45 then made a lot of sense because it's a slightly larger patient population. Exon skipping has been proven as a modality in that population, and we were able to leverage those two. Our 45 program is virtually on top of our forty-four program at this point because we've invested heavily to really move that forward as quickly as we can.
That program, I believe, is now the most advanced conjugate exon skipping program in the clinic today. When we looked at 50, 50 is a population where there's no development at all right now, as far as we know from anybody. Yet these patients still suffer in the same way that the other subsegments do. Our preclinical data there was actually quite remarkable. We moved forward with 50. A lot of companies initially moved forward with the exon 51 skipping population.
In the very, very early days, we looked at that and we said, that looks fairly crowded. Let's prove this platform out. Let's show what we can do from a dystrophin perspective and a functional perspective. That, we think, would enable clinical accrual. I think as this marketplace has shaken out now over time a little bit, as people have read out data, it is becoming more and more clear that based on our own non-clinical data, the hurdle that we need to clear is very, very achievable.
We actually went back and we reinvested and we accelerated that program. That is why that one is now right on the heels of our 50 program, roughly a year hence. We are excited about the entire portfolio, and we think there is a lot of synergy across it, but that is a long answer to a short question.
Very much appreciated. Maybe you can also give us some context around the current state of the DMD treatment landscape, as well as what hypothetically could be offered by Entrada if all four of these exon skipping candidates were to successfully make it across the finish line.
In other words, would that ultimately culminate in Entrada being able to offer a comprehensive sort of one-stop shop, as it were, therapeutic solution for the entire DMD population, or would there still remain pockets of that population that would not be treatable with one or another of these candidates? Maybe you can comment in the context of all of this on kind of the current status of gene therapy utilization in DMD.
We've probably, many of us in the audience have become familiar with the well-documented emergent safety concerns with Elevidys from Sarepta Therapeutics and why that might potentially open up even more of a market opportunity for exon skipping modalities.
Sure. I think if you're thinking about this as a patient, as a parent, as a provider, or a patient advocacy group, to a certain extent, the future has really never looked brighter. When we started this journey roughly five years ago, there were almost no options available for these patients, for any of the patients, let alone the exon skipping amenable patients. As we look forward now, we are obviously very excited about what we believe will be our best-in-class data that we think is going to make a tremendous amount of difference to these patients.
We fully expect to be the center of the care paradigm when it comes to treating these patients because obviously you're talking about high-quality dystrophin that you're producing that will make a tremendous difference from a functional perspective, we believe, and I think everybody that we talk to believes. On the other hand, there are a wide range of supportive care options that these patients will have as well that should work in theory synergistically. If you think about an HDAC inhibitor that's going to present more transcript, more transcript to be translated with an exon skipper should result in not only high-quality dystrophin, but more dystrophin.
That's great. There are programs that protect the muscle while we're helping to shore the muscle up. There are programs that prefer to ensure more satellite cell proliferation. As far as we know, we're the only company that's convincingly demonstrated in a quantifiable way, significant, in fact, 100% uptake in satellite cells of our exon skipper, which in quiescent satellite cells, I should say, creates a pool of progenitor cells that then differentiate into mature muscle cells with exon skipper already on board producing dystrophin.
These things should all work synergistically. Now, how the gene therapy story plays out, I think, is still a book to be written. I think we're in the very early days of this. There was the Pfizer program. There's now the Sarepta program. There are challenges associated with gene therapies generally that have played out. It's quite possible that for some patients, and I'll get to the last part of your question, that have nothing else, that that risk-benefit decision might make sense, at least from the perspective of the patient, the family, and the physician. It's a difficult decision to have to make.
I wish we could treat all the different sub-mutations, but we can't right now. As you all know, after you get past exon 50 skipping amenable patient populations, those individual populations get very, very small, very, very fast. I think that's why there's such a big push now to look at the regulatory frameworks to figure out how we can effectively move N of 1, N of 10, N of 50 programs forward in a way that's meaningful and bring therapies to patients. There's no technical reason why we shouldn't be able to out of the nonsense mutation, which is a slightly different subpopulation, but the regulatory framework isn't there yet.
With respect to the difference between ambulatory and non-ambulatory patients, as well as what you currently see as the paradigm vis-à-vis accelerated approval, and clearly there have been some noteworthy changes at the FDA recently, maybe give us a sense of how you see the ambulatory versus non-ambulatory patient population opportunity within the context of DMD, what potential unique challenges each population presents from a clinical development perspective.
A nd also what you see as a potential path to accelerated approval if there remains one in DMD, clearly a severe unmet medical need, debilitating, life-threatening condition. It would seem, at least on the face, that DMD represents still one of the, if not the best case to be made for continued viability of the accelerated approval pathway.
I wouldn't disagree with any of that. Working backwards, in terms of accelerated approval, we certainly haven't heard anything negative with respect to taking that pathway away, whether it's our competitors noting at their own presentations that they've been having conversations with the agency about the accelerated approval pathway. If anything, some of them have become more aggressive in terms of how they believe they're going to be able to get to an approval with the data sets that they're generating.
We see that as a positive. We think it's because there's such a clear correlation between dystrophin and, again, functional outcomes. This is a validated biomarker without question. As we look at that and we think about bringing these programs forward, we are nothing but optimistic, quite frankly.
Maybe talk a little bit about how Entrada is thinking about this from a strategic perspective. Clearly, Sarepta demonstrated the ability to successfully self-commercialize within the DMD space. Just give us a sense of how you're thinking about DMD self-commercialization versus partnership, strategic optionality, and whether you're thinking about DMD as being a very different sort of situation to DM1.
Yeah, that's a good question. I think in the United States, you're talking about roughly 150 treatment centers across the country. It's a well-defined, well-organized, highly communicative, excuse me, group of physicians, treatment centers, patient advocacy groups, et cetera. If we start to think about the challenges associated with commercialization, we see a very straight path to commercialization. Now, as a company, we will always maintain as much optionality as possible.
From a commercialization perspective, it's very clear and very straightforward. There's definitely synergy across DM1 as well. Again, that's a larger patient population. It's also a more heterogeneous patient population. It's also a more slowly progressing disease. There are different challenges associated with that. No, there's a lot of synergy across the exons, across the treatment centers that translates directly into a commercial opportunity.
Maybe if we can shift now to DM1 for a second, just give us a sense of what you expect the next value inflection point to be for the VX-670 program, which, as mentioned, is in partnership with Vertex. Also maybe benchmark this for us relative to rival programs at companies like Dyne Therapeutics and Avidity Biosciences.
Sure. I mean, I think the reason Vertex was so interested in this program was because of the quality of the preclinical data we generated, right? Especially basically reverting to wild type across a 22-gene panel, which was just extraordinary data. Obviously, we've got a lot of safety data that we've built in across the platform, which is now translated from the DMD program to, we assume, because the trial is still ongoing and they're in the multi-ascending dose portion of that trial now, to the DM1 program.
We expect it to translate further. That program is in phase one two. Twenty-six sites are open if you look at clinicaltrials.gov. Our understanding is they couldn't be more thrilled. We have a pretty significant firewall because they are a $130 billion pharmaceutical company. We are not a $130 billion pharmaceutical company. What is material to us is not necessarily material to them. They obviously want to manage how that data is presented. They have been a fantastic partner from word go. We are just completely excited to have them as a collaborator.
Now, when you think about the upcoming value inflection points and this relative to your operational runway, I think there are three aspects that are worth highlighting here. Firstly, Entrada is not just about DMD and DM1, but you did announce sort of strategic focalization, if you will.
A nd maybe give us a sense of beyond DMD and DM1, what remaining pipeline programs you expect to be advancing in the near and medium term, as well as give us a sense of the length of your operational runway, which I understand is considerable still, and what value inflection points beyond the DM1 program you expect to accrue over the course of the next 12 to 18 months.
Sure. For a context-setting perspective, you're right. We've got cash into Q2 2027, which makes us fairly unusual with respect to our peer set. We've been very thoughtful about capital formation, and we expect to be able to generate clinical catalysts before we have to think a little bit more about that. With respect to the rest of the pipeline, you're right. We're quite excited. Obviously, we've got a large DMD portfolio moving forward in the clinic now, but we've got a couple of ocular programs, so completely different therapeutic category looking at the retina. We hope to be able to announce a candidate somewhere around the end of the year.
Then there's considerable, obviously, exploratory research beyond that. When we think about where this platform could go, it is extraordinarily modular. You're right. Over the last couple of weeks, really, we made some difficult, but I think capital responsible decisions to focus a lot of our investment in ensuring timely execution of the clinical trials. There is still a robust research framework in place at Entrada. As we've chatted about internally, it's still much larger than the group that discovered the original DMD applications and moved those forward. We are still quite excited about the work that they're doing.
Just in terms of the ocular program, and I think this is probably the last question we'll have time for today, maybe contextualize this with respect to whether or not you would categorize it as kind of analogous to what historically has been done at companies like Spark and Nightstar, or if you're setting your sights on broader spectrum ocular conditions.
That is a great question. We are focused on genetically defined retinal diseases. Much as with the rest of our pipeline, we are really focused in those areas where there is significant unmet need, where there is very little of interest in the pipeline today, unfortunately, for the patients, and where we think we can make a significant difference in a devastating disease. We have two programs that are vying for lead right now. One will probably come before the other, but I cannot even say which. They both look quite good.
Do you anticipate being able to disclose more about those programs before the end of this year?
Yeah, that's the intent.
Fantastic. Thank you again so much for participating in our conference and for taking the time to walk us through the salient points of Entrada. I hope our audience will agree that this represents a very interesting time at which to consider Entrada as an investment opportunity. Thank you so much.
Thank you very much.