Entrada Therapeutics, Inc. (TRDA) Earnings Call Transcript & Summary

Goldman Sachs Global Healthcare Conference. My name is Paul Choi, and I cover the biotechnology sector here at the firm. And it's my pleasure to welcome Entrada for our first session to kick off the conference. Before we begin, I'm required to make certain disclosures regarding Goldman Sachs relationship 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 through 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. And with that, we'll kick it off. We're pleased to have Entrada here. And I'll let Nate introduce himself and his role and a little bit about the company. And then 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 how -- what data you have so far that sort of made you excited about its potential application, starting with DMD and potentially other disease.

Sure. So first of all, Paul, thank you very much. It's great to be here. Thank you to the Goldman Sachs team. So I'll do a quick introduction of myself and then the company and the platform. So I'm Nate Dowden, I'm President and Chief Operating Officer at Entrada Therapeutics. I've been with the firm since about 2019. And so 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. So very, very briefly. So Entrada Therapeutics was founded in 2016 and 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 810 kD, very, very small, but with remarkable properties. And so I'll describe those in a second, and then I'll talk about what we're doing with those. So 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. So basically, what this means is the cell takes it up and it captures the cyclic peptide and whatever that peptide is conjugated to, so it could be a protein, small peptide enzyme, oligonucleotide, what have you. And it takes it up into this small vesicle called an endosome, which is what cells do with any biological material that they bring in. Then what happens is the binding affinity of the peptide goes up several thousand folds. And when it does, it drives a process that we call budding. And 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's nothing holding them together, and they release whatever is in the vesicle into the cytosol. And then whatever we have as associated with the cyclic peptide can migrate to the nucleus, proteasome, et cetera, wherever it needs to go. So what we've 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. And so to give you an example and where the differentiation in this platform really is, on average, you'll see about 1% to 2% of biological material escape the endosome. So when you think about that, you're pouring a lot of drug into the body. Some of the drug is getting into the cell that you need it to get into. And then only 1% is getting out of that cell and to the intracellular target. We get 50% out. So it's simple arithmetic when you think about therapeutic index. You don't have to put as much drug in to get so much drug to target. Now with respect to the DMD programs, and so we'll carry that forward. What we've put together is an incredibly robust preclinical package at this point, multiple models, very difficult models, disease models that we've worked with. So for instance, you think about our ENTR-601-44 program that we are now in patients -- going into patients this year with. We've 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 second 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. So 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, and that protein is stable, useful. And not only do we see that protein in healthy muscle cells. We see that protein in stem cells -- the muscle stem cells and at 100% uptake. And that's something I don't think anybody has ever really quantified in some of these models before. So we're really excited about that, too, because you're 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, so we have the knockout mouse models and then we have, obviously, our NHP models. And 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, the relationship between those 2 things. What we were able to show there is that goes up exponentially as we dose up at clinically relevant doses. So that's very exciting, and we've been able to replicate that. And then finally, last year, we ran a healthy normal volunteer trial in the United Kingdom with ENTR-601-44. And 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. And also, again, very, very strong pharmacokinetic profile associated with the drug. So strong actually that 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. But what we didn't see, which was fascinating as we didn't see a corresponding increase in the amount of drug that's excreted out. So effectively, I think what we've seen, what we believe we've seen is there is a maximum amount of drug that you can possibly saturate the kidney with. And after that, everything else is flowing out of the body. And because we have safety at that dose in humans as well as in our nonclinical 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're 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.

Okay. Great. Thank you fopr 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? And just thinking about there are commercially available exon skippers. There's a gene therapy on the market. There's some gene therapies in the clinic as well as other modalities. So 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, right, 5 years ago. You had a few approved exon skippers. So this is just oligonucleotide, not conjugated to anything that enhances delivery. And they've been able to show a little bit of exon skipping, a little bit of dystrophin production. And for a patient population that's facing a very challenging disease, obviously, that's helpful, and that's great. But I think everybody really believed that we can do better. And so over the past 5 years, we've now seen a proliferation of not only exon skippers conjugated to a variety of different delivering enhancements conjugates, but also the gene therapy and also a number of other complementary technologies. And we can talk about that in just a bit. But 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, and that's 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, right? That is core to care. Everything else is then built around that. So 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. And 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 the physician and for the older patients with their families, it's an option, right? And it's something that to consider. But we still believe ultimately, that's going to be a limited modality, if for no other reason, it is one and done, but you're really done. And we know that especially the younger patients are just going to grow out of it over time, right? It's going to dilute out as you build muscle and muscle turns over, over time. So it may be a nice addition to a true dystrophin-producing therapy. And again, for those patients where there are no exon skippers that, it might be something that's quite useful. But there are many other things. There are HDAC inhibitors now that present additional transcripts that then can be skipped to produce more dystrophin. So very complementary. There are drugs that protect the muscle, which should be helpful to buy people time as you produce more dystrophin. And so we're -- 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. So we see ourselves as central to care. And -- but ultimately, we all believe that polypharmacy will be the way to go in this devastating disease.

Okay. As with all early-stage programs, we often focus on things like PK/PD 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. And just I think one of the questions on the modalities is just what it does -- you talked a lot about renal clearance earlier, but just liver clearance maybe would be helpful to understand. And then just in terms of the PK and PD, just what you've seen through the dosing so far in healthy volunteers?

Sure. So first of all, so nonclinical, the easy answer on that one is when we ran our nonclinical studies, our NOAEL, so no adverse effect level was at the highest dose we tested. Great. Okay. So that's -- so then we went into the healthy normal volunteer study last year. And again, we dosed up to 6 milligrams per kilogram with the ENTR-601-44. And 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. And so -- and that became our starting dose then for our patient studies as augmented, obviously, by the nonclinical tox. Now to your question regarding liver tox, that hasn't really been an issue for the chemistry that we're leveraging. So that is an issue for different chemistries for PS backbone chemistries, et cetera, ASOs, but for the PMO-based chemistry that we use, liver really isn't a concern. So that's great. One concern that people have brought up in the past because of therapeutic index challenges that others may have faced have been things like hypomagnesemia, et cetera, but we've never seen any of that. We didn't see it in the patients. We haven't seen it in the nonclinical models. And 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. But we believe and we're hopeful that we won't see that, but time will tell.

Okay. Great. You talked a little bit about trialing patients in England. And 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.?

Yes. Yes. So 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. And then from that program, the idea was let's go straight into patients, multi-ascending dose trials. So 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. So 3 doses, 24 patients, 62 placebo-controlled trial design. So fairly rigorous and good patient numbers there. So as we think about going forward and the difference between our ex U.S. trials and our recently approved to go forward 601-44-101 trial, sorry, 601-44-102 trial in the United States. We wanted to think a little bit creatively. And 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% to 50% of the market as it stands today. And yet they're understudied and underserved. So 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 life cycle management perspective for the drug itself. So now this trial design is a little bit different. It's 4 cohorts. We're starting at lower doses. And 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. So we wanted to be extremely conservative with this patient population. But we'll be adaptive, right? So we'll see how -- because these trials are going to run on top of each other for the most part. So 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. And the toxicokinetics of these drugs are extraordinarily similar, 44, 45, 50, even the VX-670 program that Vertex is running, and I can talk about that in a second. So we'll see how those are going, and we'll see if there are any adjustments to be made to the U.S. trial. But we're very excited to be able to initiate that trial next year. And we know that the patient groups can't wait to see that hit the clinic.

Okay. You talked about serving an under -- including an underserved population of the adults. But 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. So just maybe just how does the range of outcomes perhaps vary in your mind for these 2 diverse populations?

Yes. So we think of it in terms of a continuum, right? So as the patients progress throughout their life cycle, 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. But 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. Then they'll lose upper arm, upper shoulder, upper body function. And then they have challenges with the diaphragm, which ultimately results in challenges with breathing and then there are the cardiac issues, which are the most unfortunate symptom of the disease. So as we think about the 2 different populations, obviously, this older population will probably, as we enroll it, be primarily non-ambulatory. So 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 impact quality of daily living as well as diaphragm as well as cardiac measures. So it's not different per se, but it's where you emphasize, right? So we will be looking at some of those things with the younger boys, too, but we would expect to see different outcomes.

Okay. And 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 I guess, focus, anything you would call out there?

No, not right now. I don't -- I wouldn't call out any differences. We will -- as we begin enrolling the trial, we'll be giving, I think, a little bit more specific guidance in terms of things like data readouts, which everybody is interested in. We just -- until we've started announcing first patient first dose, we've got everything rolling. We don't want to put something out there that we might have to alter in some way, shape or form. But everything is going quite well so far in terms of site activation, site enrollment, et cetera. So in fact, we're going ahead of schedule. So that's great. Our 45 program is actually caught up and it's basically right on top of our 44 program, which is also something that we're really excited about, particularly since that one will be probably a first-in-class as well as a best-in-class and is a slightly bigger patient population. So I wouldn't call out any major differences, U.S. versus EU, U.K., et cetera, right now. We'll 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.

Okay. Great. As you advance the 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. And so 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. So just maybe -- and other companies like Edgewise are advancing their substance program as well. So 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?

Yes. We have thought about that since day 1, and we continue to think about how to creatively move forward in what will ultimately be a polypharmacy world, you're right. And 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, right, 50%, 60%, 100%, whatever it ends up being, but also the quality of the dystrophin is really critical when it comes to functional outcomes. And that's been demonstrated. There was a presentation just a couple of months ago at ASGCT, where they talked about that. And they showed the example, 2 different patients. These were BMD patients. So 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, and they had lost ambulation in their 20s. Another patient had very, very low levels of dystrophin production, but very high molecular weight, and 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. So that does make an enormous difference, and that's something that probably doesn't get enough discussion really when talking about the exon skippers versus the gene therapies because microdystrophin is obviously quite small. But as I mentioned before, if you don't have an exon skipper available, a thoughtful discussion needs to be had around that. And then you mentioned the Edgewise program. Yes, the Edgewise program, the [indiscernible] program, the Telepharmaco 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. So we're 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. And when we talk to physicians out there, we hear that these natural experiments are already happening. And so people are looking closely at how they can optimize care for the patients.

Great. I guess in your mind, if you have to look in your crystal ball or something like that, just how would you like 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?

Yes. So 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. But then you should be thinking about how to build around that. And for instance, one reason might be, okay, so I'm crystal balling. I've got significant levels of dystrophin production. I've seen a functional improvement in a patient. But what I'm looking at right now is I'm looking at skeletal muscle, right? I can see whether or not this person is 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. So what I don't know yet is how well I'm protecting the heart. So anything I can do from both my core therapy, 1, 2, 3 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.

Okay. 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 we sort of think about rough time lines and just thinking about what level of derisking you might have. Can you maybe provide a rough framework for us just in terms of time lines, what you think should be the key metrics? And in your mind, how much you will like potentially derisk your lead programs?

Yes. This is -- it's going to be a big year, big 2 years for us, I think. So as you pointed out, we're heads down execution on getting these clinical trials up and running and getting the patients dosed. As derisking goes, obviously, it starts with the nonclinical, right, and you pull together the tox package and 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. And then you're looking for correlations across the different programs. So what we've seen really is this EEV that I talked about at the outset of this conversation, it really does control the toxicokinetics of the drug. So regardless of the oligonucleotide that we conjugated to, when we look preclinically and we map these curves, 1, 2, 3, 4 it might as well be the same drug. They overlap completely. And so every step that we take now in the clinic is a really exciting derisking event for us. So the 44 program that we ran last year with the healthy normal volunteers, I mean, that was better than expected. We didn't expect to see no adverse events at all at our highest dose. That was really remarkable and very, very exciting. And similarly, I should step back. We have very little insight into the VX-670 program. And that's by design. That's Vertex is running that program. We have a pretty significant firewall. What's 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. And we presume based on everything that they are telling the public, things are going quite well, and we think that they are going quite well. And it's been a really, really nice collaboration. So the simple fact that they've been obviously successfully dosing through a patient cohort. We've successfully dosed patients with a 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 -- I'd like to say 44 will derisk 45, but 45 will -- the data will probably come in so close to 44, they'll be right on top of each other. But as those programs come forward, yes, I expect a significant derisking then for 50 as well as 51 and anything else we develop down the road.

Okay. Great. We have a few minutes left, and I want 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 AAT programs?

So mechanistically, they are quite [indiscernible] oligonucleotides, both conjugated to the same EEV. I should have mentioned that in terms of derisking. All the neuromuscular programs, it's the same EEV. So with the DMD programs, it's an exon skipper, traditional exon skipper. With the DM1 program, this is a steric block. So you're blocking a protein that would otherwise aggregate on these long extended CUG repeat hairpin loops that occur in these patients. And because of that aggregation, you don't have appropriate downstream splicing. And what we've been able to show with the 670 program is that we've been able to block that aggregation and simply enable appropriate downstream splicing. And we were able to do that across a 22-gene panel nonclinically. And 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. And 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. And 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 then 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, and 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 a partnering there potentially?

So 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 in 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 the 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 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 and they transform that space. And we saw that opportunity in DM1. And that's -- it's a pretty high bar, but that's the sort of thing that we look for when we have partnering discussions.

Okay. Great. And 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 '25 or '26?

Yes. We don't bake any milestones into our cash runway. That would be, I think, presumptive and presumptuous. But as far as the milestones go, there are additional milestones to go in the clinic and commercial, but we don't guide against those, and we'll see how the clinical trial runs out.

Okay. Great. Thank you very much, Nate.

Very nice to talk to you. Thank you very much.