All right, folks. Welcome to the first day of the Cantor Healthcare Conference. My name's Yanni Souroutzidis. I'm an analyst here with the team, and today I have with me Entrada Therapeutics. I have Nate Dowden, President and COO, and Natarajan Sethuraman, if I got that right, President of R&D. Today, we'd love to just jump into a bit of the story of the company, what's been going on over the last six months, what are we looking forward to over the next 12 to 18, certainly dive into a bit of the platform and ongoing clinical program.
I'll turn it over to you guys for a few opening remarks.
Okay, great. First of all, thanks very much for having us. It's been a great conference so far, and we love working with you and we really appreciate the coverage and everything that you guys do. Very quickly, I can start with some highlights. Entrada Therapeutics, we're a clinical stage biotech company. The company is based around our Endosomal Escape Vehicle platform, and we'll describe that in a little bit more detail in the coming half hour. We have multiple programs in the clinic in neuromuscular disease. We have two solely owned programs, our ENTR-601-44 and our ENTR-601-45 programs. These are for two submutations in Duchenne muscular dystrophy. We also have a partnership with Vertex Pharmaceuticals, and they are developing a molecule called VX-670 for myotonic dystrophy Type 1, DM1, all based around the same Endosomal Escape Vehicle.
Very briefly, what that Endosomal Escape Vehicle does is when we conjugate it to, in the case of our neuromuscular programs, an oligonucleotide, or in the case of other programs, maybe a protein, peptide, et cetera, what it does is it enables remarkable levels of endosomal escape. What does that really mean? What it means is when you're trying to get biological material into a cell, it's very difficult to get it into the cell. The cell is built to keep biological material out that it doesn't want. When it gets into the cell, it goes into a little structure called an endosome, a little soap bubble of a structure called an endosome. Normally, what happens is almost nothing gets out of that endosome. The cell doesn't want it to. It gets broken down, it gets kicked back out of the cell.
What our technology allows is 50% of that material gets out of the cell and then gets to the target in the cell where it can do its work, and that's compared to the standard, which is 1%. Our differentiator is really simple arithmetic at the end of the day when it comes to that. Where we are with the programs. 601-44 and 601-45, we'll talk about them in great detail going forward. But we are beginning to read data out on these programs, and you will see a cadence of clinical data coming now over the coming months. Very briefly, in 2026, we read out our first data, our multiple-ascending dose data for 601-44, earlier this year, where we saw wonderful safety. We were very excited about that. And we saw some early functional benefit, which was a surprise, but a great surprise.
Coming now, we will have the Cohort 1 multiple-ascending dose data for our 601-45 program, our second clinical program, and that should be coming in October. We are very excited about that. We expect that to continue to show safety, and we will see what the PK/PD looks like going forward. Following that, we will then be showing our open label data from our Cohort 1 for 601-44, going back to 601-44. The reason that data is really important, and why we are really excited about that data is because not only do we hope to see ongoing safety, but we also hope to see an ongoing maintenance of the functional benefit that we saw in our early data. The question we got around our early data was, it was a six/two design, so six patients on therapy, two placebo.
The signal was incredibly strong, time to rise how quickly the children can get off the floor. It looked like they improved, in significant fashion versus placebo. But it is a small trial. You never know, right? If we continue to see this benefit over the course of the year, on six additional doses, we think that will be a remarkable signal that early functional benefit is real. That is a real drug effect. In particular, if we see our placebo patients who got worse start to flatline and get better, well, then that is even more impressive, especially because these patients should be getting a lot worse over the course of the year.
That is why that readout is really exciting and really important. The next two pieces of data will be our Cohort 2 data. We are dosing our 44 patients at 12 mg/kg right now, so double the dose that we saw in our Cohort 1 data, and our 45 patients at 10 mg/kg , so double the dose in our Cohort 1 data. What we hope to show there is, of course, ongoing safety, but also a dose-dependent response with respect to key biomarkers like exon skipping and dystrophin, and potentially also function. Really exciting several months coming up.
Yeah, understood. No, appreciate the walk-through, and maybe just starting a little bit, diving deeper on the EEV platform. Obviously, you mentioned some of the key differentiation elements there, specifically around endosomal escape. Maybe talk us a little bit through in terms of its construct and its unique cyclic structure. It seems like that is pretty key. But also as that relates to its agnostic ability to penetrate different cell and tissue types. Specifically, obviously it seems like there is an interest there in getting into satellite cells in DMD patients as well.
I'll turn it over to our Chief Scientific Officer.
Yeah, thank you. When we look at EEVs, our Endosomal Escape Vehicles, there's a library of peptides, and as Nate said, they're conjugated to the cargo. In the case of DMD, it is PMO. It solves several problems. One, when you take a PMO, which is about 10,000 in molecular weight below the cutoff for kidney clearance and no charge. When you infuse a patient with PMO, most of the drug ends up in the urine very quickly. Whatever gets into the cell gets stuck in the endosome. When you take the same PMO and conjugate to our EEV, then you see that 90% of the drug is still in the body even one week after infusion. The cellular entry process is greatly enhanced by the EEV. The second part is what Nate talked about, endosomal escape is also very, very robust.
You could get 25 to 50-fold more into the cytosol when you conjugate cargo into the EEV. For programs like for exon skipping, et cetera, we also had nuclear localization signal, and that takes the cargo to the nucleus where it needs to be for exon skipping. When you look at distribution of these EEV conjugated PMOs, you're right. I think apart from getting into the muscle fibers, we have shown that we get uniform restoration of dystrophin across the muscle fiber in animal models. Apart from that, it also is very, very good at taking the cargo into quiescent satellite cells. Quiescent satellite cells are very important in the whole biology of DMD because when a muscle is damaged, the satellite cells get more activated, and they're mobilized to the site of injury to repair them.
For them to do this process, you need dystrophin. If you have PMO in a quiescent satellite cell, then as soon as it gets activated, then the exon skipping happens, dystrophin is produced, so it can move the replication into a symmetric division, which is what is required to repair the muscle. Asymmetric division will just lead to more satellite cells being produced. That's what is very exciting about our technology, it solves several problems. Apart from that, duration of effect is also quite impressive. We can dose patients once in six weeks compared to once in a week for a naked PMO. There are several advantages here.
Yeah. No, understood. I think it's part of DMD that we haven't seen too many folks address. It's been much more just muscle focus versus a regeneration element. Maybe also on the platform itself, historically, cell-penetrating peptides have carried some baggage with renal tox. So far you guys have been exceptional and clean across the board. Maybe just speak a little to that and how we might be able to read through, even from these early data sets, how that's de-risking for the platform more broadly.
Yeah, that's a very good question. Again, the characteristics of this peptide makes that possible. We have shown in normal human volunteer study, even at 6 mg/kg , not only did the kidney parameters did not move, but even early biomarkers of kidney proximal tubule damage did not move. Similarly for the Cohort 1 for 44, we have shown data that eGFR, cystatin C, magnesium levels, all of them have been very within normal range. That's because of the fact that these cyclic peptides have all natural amino acids. So when it goes to the kidney and then it gets completely processed, then what is excreted out is predominantly PMO. PMO has less affinity for receptors like cubilin, megalin, so less is getting absorbed back into the proximal tubule, which is what causes the toxicity.
The cyclic nature protects it from exopeptidases in the circulation, but natural amino acid enables us to be totally digested inside the cell so that only PMO comes out, and that is why we get the safety profile that we get.
Understood. Lastly, just as relates to the dosing regimens and the PK of the mechanics here, it seems like initially there was a lot of work done pre-clinically to look at renal saturation and even in the healthy volunteers to understand where that happens, because that leads to an uptick in muscle uptake. Maybe just walk us through that and also dovetailing off the safety element. In my mind, that's a pretty strong marker of if you are already saturating renal clearance and still having safety, that future doses should also be relatively safe. Maybe touch on those two points.
Yeah, that's a very good point. What happens with these oligonucleotides is that when you infuse your patient with low doses, then it goes a lot into the kidney. It is the first organ to get the oligo. Once it is saturated, then you get into the muscle and the tissue. That happens in a very low concentration. Even in healthy volunteers within 3 mg/ kg, you would see exposures in the muscle. As we dose up, then the exposure in the kidney is less than dose proportional and more than dose proportional in the muscle, which is what you want to see. That's one aspect of it in terms of kidney safety.
The second aspect is that excretion into the urine is more than dose proportional. For every 100% increase in dose, you would see more than 100% excretion, which tells me that we have saturated the receptors like cubilin, megalin, which retro transport the oligo back into the proximal tubule from the urine. Because of these two mechanisms, we believe that early on you get to a steady state. After that, more drug goes into the muscle without causing kidney toxicity.
Understood. Now let's start connecting that to what we've seen clinically, because we saw the initial 6 mg/kg data earlier this year. We'll get the open label extension, like you mentioned, and starting to go into higher doses. Obviously, there maybe was a little bit of surprise on the PK, but I think it was informative in terms of at least on a go-forward basis, how to tie into these things of renal clearance when we should be seeing an acceleration of dystrophin expression. Yeah, maybe just briefly recap on what we saw, how that ties into these mechanisms here, and what that means for the upcoming OLE and 12 mg/kg data.
Sure. I can start and jump in. Effectively what we saw in the first cohort of data in the pediatric patients as opposed to the healthy normal volunteers was plasma exposure that was roughly half of what we had expected. That is simply because you have different organ distribution with the pediatrics. You have much larger kidneys, much larger liver. You have a sink effect. You do not see the exposure in the muscle that you hope to see with those pediatric patients. That mirrored effectively what we saw in juvenile NHPs. Unfortunately, we were not able to predict that forward because we got the juvenile NHP data about the same time we got the pediatric data. It did inform the go forward, which is what is really important and what is helpful.
Effectively, where you are now is as we move towards the Cohort 2 data, we saw about half the plasma exposure in Cohort 1 that we expected to, and we have now doubled the dose. The expectation is that we will see the exposures that we originally had hoped to see. Importantly, when we look at the non-human primate data, there is no difference in terms of the biology. The exon skipping as you dose up looks as we would expect. Net-net, we do expect to see the double digit dystrophin coming from that Cohort 2 data for the exon 44 skipping modality. We are excited about that. I do not know if you want to add anything else to that.
No, just that, as we stated before, we expect the kidney to be saturated even at that dose. Incremental increase in dose will only result in exon skipping without causing concomitant kidney toxicity.
Yeah. Again, we'll have to see the data, but the really exciting hypothesis we've had for a long time now is as you dose up, there is this window where you should see an increasing therapeutic index, which is something you almost never see.
Got it. No, that's helpful and I think makes a lot of sense. In effect, it seems like this is a pretty big milestone for you guys in the sense that it is de-risking the broader platform. I think all the current clinical programs are using the same EEV construct in that sense.
Yep.
Hopefully if we clear this well, that bodes well for the higher doses that we might go to as well. Maybe just speaking a little bit about the functional element as well and tying that into the biomarkers and the satellite cell component. You mentioned obviously functional trends we're seeing very early on and statistically significant, although not necessarily designed for that outcome. That's a little bit atypical for perhaps the dystrophin levels that we saw, but muscle biopsies can be noisy and the like. Just walk us through how you view the data holistically, how to think about what we might do if we do see continued effect on function, whereas dystrophin might be increasing but not necessarily proportional as we see some of the Cohort 2 data.
Yeah. It is really interesting. You're right, so it was very early data. It was a post hoc analysis because we didn't look for it originally. We didn't expect to see this. I think a couple of things. Number one, I don't think anybody really understands what the relationship is between dystrophin and functional improvement yet. I think we're learning as we and other constructs are able to push the dystrophin levels higher as we run longer trials, et cetera. But we don't know what that looks like yet. However, what we do know is that we saw this improvement in function, with an improvement in dystrophin of only about 2.3%. That said, those 44 patients that we read out on, ultimately they had dystrophin levels of about 6.3%. That's not insignificant in and of itself. That's really important.
I think what we expect to see going forward with Cohort 2, as we said before, is an increase in these biomarkers. So an increase in exon skipping, an increase in dystrophin, and that's going to be most important when we think about the path forward from a regulatory perspective. As you know, accelerated approval is really contingent upon showing a statistically significant difference in dystrophin production. It's not what you're going to be using for your phase III trial, and realistically, it's not what you're going to be judged on in the clinic going forward once you launch your drug. What's going to be most important for those physicians, for those patients, is going to be that functional data.
Yeah.
If we see continuation of this functional improvement with Cohort 1, if we see a dose-dependent response in dystrophin, and then if we see a dose-dependent response and a continuation of functional benefit, in Cohorts 2 and maybe even in Cohort 3, if and when we go there, then I think that's going to put us in a really strong position to, A, file for accelerated approval, and then B, get a strong phase III readout, and then C, position ourselves very well in the marketplace over time.
Got it. Maybe just briefly double-clicking on that filing. Do you think that the current ELEVATE studies would lend themselves to that? Would it be a separate effort? Would it be an expansion to the current program?
No, that's a really good question. The way we've designed these, is with accelerated approval in mind. Right now we have Cohort 1 done for 44, about to read out for 45, and the designs are the same between 44 and 45. So we have Cohort 1 done. Cohort 2, obviously we've said we're going to read those out soon. Then, we'll end up going to probably a DMC where they will hopefully give us the opportunity to dose up again, in the case of 44, up to 18 mgs per kg, in the case of 45, up to 15 mg/kg . So that'll be one set of data, the multiple-ascending dose data. Then to build out a safety database, because even those are all six/two designs, you'll only have 24 patients at most coming out of Cohorts 1, 2, 3.
We intend to run an expansion cohort, so similar design to Dyne, similar design to Avidity. They have both filed BLAs, wherein we will make up the patient numbers. The thought is you are probably around 40 patients overall. Whatever we do not do in Cohort 1, 2, 3, goes into the expansion cohort that runs parallel to Cohort 3, and then we file for accelerated approval, that full data package.
Understood. Okay. Maybe talking a little bit about the exon 45 program. Obviously, it is earlier, you said we will be getting the first data in October. These different exon-minable mutations, some are easier, some are more difficult to see increases in dystrophin. Just walk us through here, where does 45 fall in that spectrum? Maybe begin to tie it a little bit to the competition out there and the commercial opportunity, and what really is the bar here clinically for patients to see benefit?
You want to take the first part?
Yeah. 45 is on the spectrum of various exon skipping opportunities, it is more difficult to skip. You can see from the baseline levels that AMONDYS, for example, reported less than 1%. It is difficult to skip. Right now, we are ahead of the pack in terms of modified oligonucleotides or conjugates, oligoconjugates in that field. With having the phase Cohort 1 data for 44, it is clear our exposures will be lower in 45 as well. Because of that, we consider this particular Cohort 1 a safety readout, and in Cohort 2 is where we expect to see substantial increase in dystrophin. Go ahead.
Yeah, for the second part of your question, from the perspective of where the competition is today, I think we really benefit from being second to market here. We will be the first to market conjugate oligonucleotide.
As Natarajan said, AMONDYS is out in the marketplace. But they only improved exon skipping by less than 1%, and they are dosed weekly. That is obviously challenging. Even if we were to have roughly the same level of dystrophin production, and we think we will be much better than that, we will be dosing every six weeks. That alone is a huge benefit to patients and physicians and the patients' families. People are quite excited about that when we talk to them about the profile of the product. That is number one. Number two, I think, a benefit to being second to market here is there is already a built-in patient base. One of the challenges you always have with ultra-rare disease, and the DMD community is very strong, and you now finally have genetic testing for the patients, but it is often finding the patients.
Here we have a built-in patient base that we can go talk to the physicians, and they can talk to the families about the benefits of moving to dosing every six weeks, and hopefully much higher levels of dystrophin, and hopefully much better functional responses as we move through phase III and then into the marketplace. It is really a unique opportunity, actually, to move very quickly to a very significant level of uptake.
Understood. Maybe shifting gears a little bit, and coming back to the Vertex partnership. Obviously, there's been some, I think, pretty topical DM1 updates from Novartis this week. Maybe just remind us of the partnership structure, what's been disclosed. It obviously was very, I think, value creating for yourselves a s a company. Then how that ties into what we're hoping to see, especially now in context of the recent updates and how this mechanism is quite a bit different than what's already been seen by Dyne and Avidity.
Yeah. So great question. First and foremost, Vertex has been a fantastic partner. They licensed the drug when we were still in chronic tox. They've taken it forward through regulatory and then into the clinic, and they own all the commercial rights to the product. We actually have, I should preface it with a fairly significant firewall. They're a 130 billion company today. We are not yet a $130 billion company.
Yeah.
What's material to us isn't necessarily material to them. We have to be careful in terms of information exchange, so that we're not in a position to disclose something that they don't yet want disclosed. Net-net, while we are really excited about the partnership, it's been a true collaboration. They've shepherded this molecule into and through the clinic really, really well, and as you pointed out, they continue to voice a lot of excitement about the product. Certainly about the safety, I think they've talked about that already. We haven't seen any data, but it's a nice validation of the safety we've seen on the platform. Beyond that, we don't necessarily have any more insight into what that data's going to look like.
We are very hopeful, and we're very hopeful because, to your point about contrasting with some of the other programs, our approach is a CUG repeat steric block. It's very specific to the pathogenic CUG repeats that result in the downstream mis-splicing, that result in the symptoms of disease these patients suffer. As opposed to the DMPK knockdown, which is more of a, for lack of a better term, a bit more of a brute force approach that the antibody-based therapies take. Not saying one's right, one's wrong. I think the clinical data will ultimately show at the end of the day which one is more effective.
We're very hopeful based on the preclinical data we have and based on the enthusiasm that Vertex has, but also based on another CUG repeat block that's already in the clinic that has shown very significant levels of splice correction, albeit perhaps with a dose ceiling, a tox-driven dose ceiling. It's a very nice clinical validation of the mechanism. We think that's in part why we're differentiated. Yes, I knew you were going to ask us about the Novartis data. Everybody today has asked us about the Novartis data. It's understandable because we have a partner with a program in the clinic, in the same indication. Number one, we have to be very mindful of the fact that Vertex should speak to the program, and we really shouldn't speak to the program.
Also, Novartis hasn't really released much information on what happened. All they've said is that they didn't hit their primary endpoint. There are a number of reasons why that might have happened. Could be target, could be mechanism, could be endpoints, could be trial design. Nobody really knows. We really can't speculate publicly. But what we can say is we do think we fundamentally have a differentiated mechanism. We do believe in that mechanism, and everything that we've certainly seen preclinically would tell us that there's really an opportunity to do something a little bit special for patients.
Yeah, understood. And I guess, in terms of what's been disclosed, if you can you remind us, inevitably, I would imagine this is in Vertex's domain to decide whether to take forward or not. Is there any sort of, kind of clock that's built into the agreement on when that decision has to be made or what are the immediate next steps we can generally expect?
Sure. So no, there's no specific clock associated with a go forward there. So the structure of the agreement was, it was what? $250 million up front, I think, which was great, which really helped us build out our portfolio of DMD and our ophthalmology indications that are a little bit deeper in the pipeline, along with a lot of other discovery research. So that was number one. And then at time of signing, it was $485 million in milestones, and then, mid to high single-digit royalty. So really substantial, and most of that is still to come, as long as the program continues to be successful, which we hope it will be. There's still a lot of value to unlock from that partnership economically, and we don't include any of that in our runway. I don't think our auditors would like that.
Again, there's really a lot of upside there from both the perspective of potential cash in the door, but also probability of success as associated with those milestones, which should translate directly into value.
Understood. Again, I know it will be their decision, but looking across Dyne and Avidity, broadly, it seems like around a 17%-25% splicing, maybe a three-second improvement on vHOT were some of the more translatable and comparable benchmarks.
Yep.
Are those still the main things that you guys are looking at? Are there other functional things? What would be a successful outcome in your mind, appreciating that they might have a different view?
Yeah, I guess I have to be careful what I say there. What have they said? They are going to report splice correction. They are going to report some functional outcomes like QMT, et cetera, as well as vHOT, obviously, and I think those are going to be really important. My guess is what they will say is, what is probably most important at the end of the day are some of those functional benchmarks, because that is what is important to the patients, right?
Yeah.
In fact, we have even seen Dyne come forward in their phase III program with a novel endpoint that they aligned with the FDA on that they believe is more indicative of showing a functional benefit from the perspective of activities of daily living strength, and that makes some sense. My guess is what Vertex would probably say is those are going to be the things that are going to be most important in their upcoming clinical trials as they decide when and how to move forward with additional clinical trials, because that is what is most important for the patients. Ultimately, that is what will result in uptake of the drug going forward.
Understood. Well, I know we're coming up on time, but maybe just touching on, again, kind of cash runway, walking through the upcoming milestones, and really touching on any other messages you guys are hoping to broadcast here at the conference.
Sure. Cash runway, we're still into Q3 2027. I'll look at our CFO in the audience, $223 million on the balance sheet. He's nodding, so that's good. I got that right. The point there is, I'll sort of finish where I started. We have a number of really important dispositive readouts that are coming in the next month, next couple of months, next quarter, et cetera, that will really transform this company, and we have cash on the balance sheet to make that happen. In terms of parting thoughts, the easiest way to think about all these upcoming catalysts is, I think, really in three buckets. The first bucket is, coming from 45, for instance, we expect to see additional safety readouts to build on the safety we've already demonstrated with the 44 program and the healthy normal volunteer trial that we ran.
Safety, number one. Number two, I think with the open label data readout for 44 that we should see by the end of the year, that I think should be definitive support for the biology behind the functional benefit that we saw in that very early multiple-ascending dose trial, right? Very early, very small, but if we see that mature over a year, if we see the placebo patients start to flatline as opposed to drop, it's very hard to say that that's not real biology. Safety, biology, and then finally, next year, in the first quarter and first half, what we should see from Cohort 2 will be safety again, but also dose-dependent responses, from a biomarker perspective and perhaps even a functional perspective. So safety, biology, dose-dependent response. That's what we're looking for.
Understood. All right, well, thank you so much.
Thank you for having us.
Of course.