My name is Paul Choi, and I cover the biotechnology sector here at the firm. It is my pleasure to welcome Entrada for our first session to kick off the conference. Before we begin, I am required to make certain disclosures regarding Goldman Sachs' relationships with certain companies that may be attending or presenting here at the conference. Those relationships include investment banking, 1% or more ownership of the stock, and other relationships. These disclosures and relationships are available to you as customers of the firm through our research portal. I am prepared to read them aloud, but they are available to you publicly through our research portal website. With that, we will kick it off. Please have Entrada here, and I will let Nate introduce himself and his role and a little bit about the company.
Maybe for our first question, for investors who may be new or unfamiliar with Entrada, can you maybe just give us a little bit of background on the company and the EEV platform and what data you have so far that sort of made you excited about its potential application, starting with DMD and potentially other diseases?
Sure. First of all, Paul, thank you very much. It's great to be here. Thank you to the Goldman Sachs team. I'll do a quick introduction of myself and then the company and the platform. I'm Nate Dowden. I'm the President and Chief Operating Officer at Entrada Therapeutics. I've been with the firm since about 2019, and I've had the opportunity to see this amazing platform and the DMD and DM1 programs that we have really go from whiteboard to patient, which is a remarkable opportunity. Very, very briefly, Entrada Therapeutics was founded in 2016. The basic technology that we've been leveraging since then and have been building and improving upon and changing quite substantially, actually, is a library of small cyclic peptides, about 8-10 kD, very, very small, but with remarkable properties.
I'll describe those in a second, and then I'll talk about what we're doing with those. These cyclic peptides, they bind to the cell surface, relatively low affinity, any cell in the body, but just enough to trigger a process called endocytosis. Basically, what this means is the cell takes it up, and it captures the cyclic peptide and whatever that peptide is conjugated to. It could be a protein, small peptide, enzyme, oligonucleotide, what have you. It takes it up into this small vesicle called an endosome, which is what cells do with any biological material that they bring in. What happens is the binding affinity of the peptide goes up several thousandfold. When it does, it drives a process that we call budding. You can see this actually in the microscope, where this endosome buds off these little vesicles.
The endosome reforms, sort of like a soap bubble pinching off of another soap bubble. These vesicles then simply collapse. There is nothing holding them together. They release whatever is in the vesicle into the cytosol. Whatever we have as associated with the cyclic peptide can migrate to the nucleus, proteasome, et cetera, wherever it needs to go. What we have been able to show over many, many years now is that we can conjugate, as I said, virtually anything to these peptides and deliver remarkable amounts of drug to target. To give you an example and where the differentiation in this platform really is, on average, you will see about 1%-2% of biological material escape the endosome. When you think about that, you are pouring a lot of drug into the body.
Some of the drug is getting into the cell that you need it to get into. Only 1% is getting out of that cell and to the intracellular target. We get 50% out. It is simple arithmetic when you think about therapeutic index. You do not have to put as much drug in to get so much drug to target. Now, with respect to the DMD programs, we will carry that forward. What we have put together is an incredibly robust preclinical package at this point, multiple models, very difficult models, disease models that we have worked with. For instance, you think about our ENTR-601-44 program that we are now in patients, going into patients this year with. We have got clearance in the European Union, United Kingdom, the United States to move forward with clinical trials with that program.
We were able to show remarkable exon skipping and dystrophin production. I'll talk about that in just a sec for people who aren't familiar with it, and dystrophin production in a knockout mouse model, which is really important if you want to be able to test your drug and have any sense of what that's going to look like. Similarly, we did the same with our second program, ENTR-601-45, also for Duchenne Muscular Dystrophy patients, but a different submutation. We've done the same for 50, and we've done the same for 51. That gives us a lot of confidence that if we get our drug into the cell and address the mRNA that we need to address, we're going to generate the protein that we need to generate. That protein is stable, useful.
Not only do we see that protein in healthy muscle cells, we see that protein in stem cells, so muscle stem cells, and at 100% uptake. That is something I do not think anybody's ever really quantified in some of these models before. We are really excited about that too, because you are creating this pool of healthy muscle cells, basically, that can then regenerate over time. Now, when we think about the rest of the preclinical package going forward, we have the knockout mouse models, and then we have, obviously, our NHP models.
In our NHP models, what we were able to demonstrate was that the pharmacokinetics, basically how long this circulates and how much of an increase you see in terms of concentration in the blood, as well as exon skipping and the relationship between those two things, what we were able to show there is that goes up exponentially as we dose up at clinically relevant doses. That is very exciting, and we've been able to replicate that. Finally, last year, we ran a healthy normal volunteer trial in the United Kingdom with ENTR-601-44. There we were able to demonstrate safety up to our top dose, no movement in any clinically relevant biomarkers whatsoever, which, as you know, for this class, is pretty remarkable. Also, again, very, very strong pharmacokinetic profile associated with the drug.
Actually, every time we doubled the dose, we saw a corresponding increase in exposure in the plasma and the muscle, and we saw exon skipping, and that we all expected to see. What we did not see, which was fascinating, is we did not see a corresponding increase in the amount of drug that is excreted out. Effectively, I think what we have seen, what we believe we have seen, is there is a maximum amount of drug that you can possibly saturate the kidney with. After that, everything else is flowing out of the body.
Because we have safety at that dose in humans, as well as in our non-clinical tox models, we are very, very confident that as we move into our patient trials, ENTR-601-44, ENTR-601-45, most recently cleared in the U.K. and the EU , and then we are filing 50 later on this year and then 51 next year, as we move in these patient trials and as we dose up in these patients, we should be able to get a significant amount of exposure, exon skipping, and dystrophin production, we hope, without a concomitant increase in any potential tox liability.
OK. Great. Thank you for that, Nate. Maybe to help us contextualize what you've just said versus some of the existing or clinical stage DMD assets, can you maybe help us fill in the gaps, thinking about, in your mind, what solidifies your company's leadership potentially in the space? Just thinking about there are commercially available exon skippers. There's a gene therapy on the market. There are some gene therapies in the clinic, as well as other modalities. Maybe just help us think about how the pieces fit on the board and how Entrada might fit on the board as well.
Sure. Absolutely. When we first started this journey, there were very, very few options for patients. Five years ago, you had a few approved exon skippers. This is just the oligonucleotide, not conjugated to anything that enhances delivery. They have been able to show a little bit of exon skipping, a little bit of dystrophin production. For a patient population that is facing a very challenging disease, obviously, that is helpful, and that is great. I think everybody really believed that we could do better. Over the past five years, we have now seen a proliferation of not only exon skippers conjugated to a variety of different delivery enhancement conjugates, but also gene therapy and a number of other complementary technologies. We can talk about that in just a bit.
I mean, ultimately, when we go and we talk to patients and we talk to patient advocacy groups, the one thing we always talk about is we are very, very far from the finish line, but the future has never looked brighter for these patients. That is wonderful. Now, to put this in context, what you're really trying to do for these patients is you're trying to help the body produce this protein called dystrophin, which ultimately will protect the muscle, prevent the muscle from breaking down, and also, if you can get it into the muscle stem cell, to help the body regenerate properly and appropriately. That is core to care. Everything else is then built around that.
When we look at our program, simplistically, if we can drive more dystrophin in those muscle cells and in those satellite cells, those muscle stem cells, than anyone else, we've got a better product, and we've got something that we believe will be best in class. In some cases, for instance, our 45 program, as far as conjugates go, should be first in class. Now, how do we think about gene therapy? How do we think about some of these other modalities? For patients who have nothing else, and sadly, that's still the majority of patients, having a discussion with their physician, the families have a discussion with their physician, and for the older patients with their families, it's an option. It's something to consider. We still believe that ultimately, that's going to be a limited modality.
If for no other reason, it is one and done, but you're really done. We know that especially the younger patients are just going to grow out of it over time. It's going to dilute out as you build muscle and muscle turns over over time. It may be a nice addition to a true dystrophin-producing therapy. Again, for those patients where there are no exon skippers, it might be something that's quite useful. There are many other things. There are HDAC inhibitors now that present additional transcripts that then can be skipped to produce more dystrophin. Very complementary. There are drugs that protect the muscle, which should be helpful to buy people time as you produce more dystrophin.
There are drugs that potentially drive the proliferation of satellite cells, of stem cells, which, again, if you're using that with our exon skipper and you have dystrophin in those satellite cells, should be incredibly useful from a regenerative perspective. We see ourselves as central to care, but ultimately, we all believe that polypharmacy will be the way to go in this devastating disease.
OK. As with all early stage programs, we often focus on things like PKPD as well as safety. Can you maybe talk a little bit about the safety data you've seen so far, both preclinically and clinically in the healthy volunteers? I think one of the questions on the modality is just what it does. You talked a lot about renal clearance earlier, but just liver clearance maybe would be helpful to understand. In terms of the PK and PD, just what you've seen through the dosing so far in healthy volunteers.
Sure. First of all, non-clinical, the easy answer on that one is when we ran our non-clinical studies, our NOAEL, so No Observed Adverse Effect Level, was at the highest dose we tested.
Great. OK.
We went into the healthy normal volunteer study last year. Again, we dosed up to 6 mg per kg with the ENTR-601-44. As I said before, we had no clinically relevant safety signals at all. We had no treatment-related adverse events at all, which was phenomenal. That became our starting dose for our patient studies, as augmented, obviously, by the non-clinical tox. Now, to your question regarding liver tox, that has not really been an issue for the chemistry that we are leveraging. That is an issue for different chemistries, for PS backbone chemistries, et cetera, ASOs. For the PMO-based chemistry that we use, liver really is not a concern. That is great. One concern that people have brought up in the past because of therapeutic index challenges that others may have faced has been things like hypomagnesemia, et cetera.
We have never seen any of that. We did not see it in the patients. We have not seen it in the non-clinical models. We believe, and we hope, and we have to dose all of these patients up, and we intend to dose up as aggressively as we can to protect the skeletal muscle and to protect the heart. We believe and we are hopeful that we will not see that. Time will tell.
OK. Great. You talked a little bit about trialing patients in England. I just want to maybe help us understand how the geographic split and just kind of what's happening with your U.S. clinical trial development versus ex-U.S.
Yep. Yep. When we submitted regulatory applications around the world for the healthy normal volunteer trial, the British were extremely excited and aggressive, and we moved that program forward. From that program, the idea was let's go straight into patients' multi-ascending dose trials. For 44, 45, 50, and 51, the structure will effectively be the same. You start with your starting dose, second dose, third dose as you go up. Three doses, 24 patients, 6 / 2 placebo-controlled trial design. Fairly rigorous and good patient numbers there. As we think about going forward and the difference between our ex-U.S. trials and our recently approved to go forward ENTR-601-44- 101 trial, sorry, 102 trial in the United States, we wanted to think a little bit creatively.
One population that is remarkably underserved, even in the clinical trial environment, let alone in the marketplace, are those adult patients. It's roughly, we think, 40%-50% of the market as it stands today. Yet they're understudied and underserved. When we went back to the FDA, we had a discussion with them about taking something a little bit more creative forward to both serve this patient population, hopefully, as the trials move forward, and then ultimately do something very useful from a lifecycle management perspective for the drug itself. Now this trial design is a little bit different. It's four cohorts. We're starting at lower doses. We're starting at lower doses because these patients, as you might imagine, have a lot of comorbidities. As they get a little bit older, they can become quite frail.
We wanted to be extremely conservative with this patient population. We'll be adaptive. We'll see how, because these trials are going to run on top of each other for the most part. We'll see how the therapeutic index is shaping up in our 201 trials globally. We'll have a look at what 45 is doing at the same time. The toxicokinetics of these drugs are extraordinarily similar: 44, 45, 50, even the VX-670 program that Vertex is running. I can talk about that in a second. We'll see how those are going, and we'll see if there are any adjustments to be made to the U.S. trial. We're very excited to be able to initiate that trial next year. We know that the patient groups can't wait to see that hit the clinic.
OK. You talked about serving and including an underserved population, the adults. I guess maybe just at a high level, how do you think about sort of the clinical metrics or clinical bar for the adult population versus what historically, I guess, in the DMD clinical space has been more focused on the younger boys, even preteen boys? Maybe just how does the range of outcomes perhaps vary in your mind for these two diverse populations?
Yep. Yep. We think of it in terms of a continuum. As the patients progress throughout their lifecycle, and there is quite a lot of variability, actually, in disease progression, which is why comparing to natural history studies can be challenging for some folks. With the younger boys, obviously, what you're trying to do, first and foremost, is preserve ambulation, their ability to run, walk, play with their friends, et cetera. As the patients progress, they will obviously slowly lose that ability. They will lose upper arm, upper shoulder, upper body function. They have challenges with the diaphragm, which ultimately results in challenges with breathing. There are the cardiac issues, which are the most unfortunate symptom of the disease. As we think about the two different populations, obviously, this older population will probably, as we enroll it, be primarily non-ambulatory.
What we'll be looking at there is not only dystrophin production, but we'll be looking at functional metrics that are associated with upper body strength, basically the ability to do things that will impact quality of daily living, as well as diaphragm, as well as cardiac measures. It's not different per se, but it's where you emphasize. We will be looking at some of those things with the younger boys too. We would expect to see different outcomes.
OK. Just maybe to go back to the geographic differences for a moment, just in terms of the U.K. versus the U.S. trial endpoints or focus, anything you would call out there?
No. Not right now. I would not call out any differences. As we begin enrolling the trial, we will be giving, I think, a little bit more specific guidance in terms of things like data readouts, which everybody is interested in. Until we have started announcing first patient, first dose, we have got everything rolling. We do not want to put something out there that we might have to alter in some way, shape, or form. Everything is going quite well so far in terms of site activation, site enrollment, et cetera. In fact, going ahead of schedule, so that is great.
Our 45 program has actually caught up and is basically right on top of our 44 program, which is also something that we are really excited about, particularly since that one will be probably a first in class as well as a best in class and as a slightly bigger patient population. I would not call out any major differences U.S. versus EU, U.K., et cetera right now. We will be trying to slowly over time harmonize everything so that we have kind of the full package both across multiple exons as well as for multiple age groups as well as incoming functional status over time.
OK. Great. As you advance into clinic, it's probably fair to say that the landscape is evolving in real time, both in the clinic as well as the commercial stage. As Entrada advances in the clinic, can you maybe tell us how you see the DMD market evolving over the next couple of years? There's often some discussion about how much of the prevalent pool will be available for clinical stage companies such as yours to treat down the road as some get treated with gene therapy. Some drugs are being pulled from the market in other geographies, like in Europe and so forth. Just maybe. Other companies like Edgewise are advancing their subsystem program as well. Just maybe how do you see the landscape evolving?
How much of the prevalent pool, I guess in your mind, will be potentially available for your products to treat if they come to market?
Yep. Yeah. We have thought about that since day one, and we continue to think about how to creatively move forward in what will ultimately be a polypharmacy world, you're right. I think it goes back to something I was talking about earlier, which is that the highest level of dystrophin production possible, and not just high numbers, 50%, 60%, 100%, whatever it ends up being, but also the quality of the dystrophin is really critical when it comes to functional outcomes. That's been demonstrated. There was a presentation just a couple of months ago at ASGCT where they talked about that. They showed the example of two different patients. These were BMD patients. You could actually look at this from a natural history perspective. One patient had tremendously high levels of dystrophin production, but very low molecular weight.
They had lost ambulation in their 20s. Another patient had very, very low levels of dystrophin production, but very high molecular weight. They were still walking around in their 70s. They showed the example of another young boy who had very, very low levels of dystrophin production, 3.5%-ish, I want to say, something like that, but very high quality, very high molecular weight, still playing baseball at 16 years old. That does make an enormous difference. That is something that probably does not get enough discussion, really, when talking about the exon skippers versus the gene therapies because microdystrophin is obviously quite small. As I mentioned before, if you do not have an exon skipper available, the thoughtful discussion needs to be had around that. You mentioned the Edgewise program. Yeah.
The Edgewise program, the Satellos program, the Italfarmaco program, these are all complementary technologies. If you put those on top of an exon skipper like ours, where you've generated significant levels of dystrophin production, that should do nothing but help. We are very hopeful that over time, we'll all be able to work together and with the physician and with the patient community to make those things happen. When we talk to physicians out there, we hear that these natural experiments are already happening. People are looking closely at how they can optimize care for the patients.
Great. I guess in your mind, if you had to look in your crystal ball or something like that, just how would you perhaps characterize the sequencing 5-10 years from now of these various different classes of drugs, whether it's exon skippers, gene therapies, or other modalities?
Yep. I think what we've heard from physicians and what we think makes sense from the perspective of the biology is if you have an exon skipper like ours where you can generate significant levels of dystrophin and ultimately you can demonstrate that there's functional improvement associated with those significant levels of dystrophin, that's your core therapy. That's your first, middle, and last option every time. You should be thinking about how to build around that. For instance, one reason might be, OK, so I'm crystal balling. I've got significant levels of dystrophin production. I've seen a functional improvement in a patient. What I'm looking at right now is I'm looking at skeletal muscle. I can see whether or not this person has improved on their 10-meter walk test.
Maybe I'm running MRIs over time, but there's going to be a lag associated with what I'm seeing in terms of cardiac degradation as well as cardiac improvement. What I don't know yet is how well I'm protecting the heart. Anything I can do from both my core therapy, one, two, three, and then anything you can build around that to protect that patient's heart, which may be at this point still a subclinical issue, is nothing but the best standard of care possible.
OK. Great. Maybe just in broad strokes, now that you are enrolling patients in the clinic and both for 44 and sort of 45, and as you sort of think about rough timelines and just thinking about what level of de-risking you might have, can you maybe provide a rough framework for us just in terms of timelines, what you think should be the key metrics in your mind, how much you will potentially de-risk your lead programs?
Yeah. It's going to be a big year, big two years for us, I think. As you pointed out, we're heads down execution on getting these clinical trials up and running and getting the patients dosed. As de-risking goes, obviously, it starts with the nonclinical, right? You pull together the tox package. You're looking at the dystrophin production and the functional metrics you can get from the mice and the full correction we saw with our 45 program, which was amazing. You're looking for correlations across the different programs. What we've seen really is this EEV that I talked about at the outset of this conversation, it really does control the toxic kinetics of the drug.
Regardless of the oligonucleotide that we conjugated to, when we look preclinically and we map these curves, one, two, three, four, it might as well be the same drug. They overlap completely. Every step that we take now in the clinic is a really exciting de-risking event for us. The 44 program that we ran last year with the healthy normal volunteers, I mean, that was better than expected. We did not expect to see no adverse events at all at our highest dose. That was really remarkable and very, very exciting. Similarly, I should step back. We have very little insight into the VX-670 program. That is by design. Vertex is running that program. We have a pretty significant firewall. What is very material to us that we would have to report on is not material to them.
We are not yet a $130 billion biopharmaceutical company. However, we know that they're running this SAD-MAD globally. 26 sites globally have been announced. We know that they've made it through the SAD portion. We know that they've accelerated into the MAD portion. We presume, based on everything that they are telling the public, things are going quite well. We think that they are going quite well. It's been a really, really nice collaboration. The simple fact that they have been obviously successfully dosing through a patient cohort, we've successfully dosed patients with the 44 program, and we've got the nonclinical tox package. That gives us a lot of confidence that not only do we have here but there will be a lot of translation. 44 and 45, I'd like to say 44 will de-risk 45.
45, the data will probably come in so close to 44, they'll be right on top of each other. As those programs come forward, yes, I expect a significant de-risking then for 50 as well as fifty-one and anything else we develop down the road.
OK. Great. We have a few minutes left, and I wanted to touch a little bit on the Vertex program since you brought it up, which is just maybe mechanistically, can you explain the similarities or key differences between the DMD and the AET programs?
Mechanistically, they are both oligonucleotides, both conjugated to the same EEV. I should have mentioned that in terms of de-risking. All the neuromuscular programs, it's the same EEV. With the DMD programs, it's an exon skipper, traditional exon skipper. With the DM1 program, this is a steric block. You're blocking a protein that would otherwise aggregate on these long extended CUG repeat hairpin loops that occur in these patients. Because of that aggregation, you do not have appropriate downstream splicing. What we have been able to show with the 670 program is that we have been able to block that aggregation and simply enable appropriate downstream splicing. We were able to do that across a 22-gene panel nonclinically.
I think it was some of that data as well as some of the rest of the data that they saw in our early DMD programs that got them excited about our DM1 program. Ultimately, when they came to us, we talked a little bit about—we talked a lot, actually, about a shared vision for that disease, the opportunity for, as they will put it, functional cure, and the differentiation of the program based on that data package and based on the approach. They got quite excited. That deal that we did, $250 million upfront, including some equity as well as significant milestones and then royalties on the back end, has really allowed us to invest heavily in the acceleration of the DMD program as well as some of the earlier stage work that we've been doing.
I don't want to leave our ocular programs behind either because those are starting to look quite good. We hope we'll be able to announce a candidate later this year for that.
Great. Speaking of which, do you think about partnering that, or is that something you'd want to keep internal? You obviously have attracted a large high-quality biopharma interest in the form of Vertex, but ophthalmology is also a very large space. How do you think about partnering there potentially?
The way we think about partnering, and ophthalmology would fall into this category, but it's really anything, is it needs to be somebody like a Vertex, right? Somebody needs to bring something to the table that will quite obviously add value, whether it's an ability to expand the platform and to work in things where we have no capabilities, but there's clear opportunity and interest and the biology makes sense, whether it's to accelerate a program that's already being developed today, or whether it's to basically package up a group of programs and be able to say, listen, we've worked in this space. We have a franchise in this space. We can do this and do that in an incredible way. When we talked to Vertex, not only did we have a shared vision for the program, but we also saw a company that has done this before.
They basically invented an entire category of drugs. They've made remarkable, remarkable advances for a group of patients, a very large group of patients who up until that point had very few options and would die quite young. They transformed that space. We saw that opportunity in DM1. It's a pretty high bar, but that's the sort of thing that we look for when we have partnering discussions.
OK. Great. Maybe just on the last note, since we're almost out of time here, just in terms of the Vertex program, are any milestones potentially triggered this calendar year, or is it just still TBD, whether it's 2025 or 2026?
Yeah. We do not bake any milestones into our cash runway. That would be, I think, presumptive and presumptuous. As far as the milestones go, there are additional milestones to go in the clinic and commercial. We do not guide against those. We will see how the clinical trial runs out.
OK. Great. Thank you very much, Nate.
Very nice to talk to you. Thank you very much.