Entrada Therapeutics, Inc. ($TRDA)

Thank you. Good morning. Thank you for joining us. I'm Paul Choi, and I cover the mid-cap biotech sector here at Goldman Sachs, joining us here at the Goldman Sachs Global conference is Entrada. Before we begin, I'm required to make some certain disclosures. These disclosures pertain to investment banking and other relationships that we may have with companies discussed here at the conference for anyone listening or who are clients at the firm attending. These disclosures are available to you on our research portal. We are prepared to read them allowed, but they are available for you through our Goldman Sachs research. And with that, it's our pleasure to have it and try to hear -- and maybe what we'll do is started at a high level with Dipal here and maybe talk about for those who are new to the Entrada story or maybe the DMD space.

Can you maybe walk us through what is the EV platform -- and what, I guess, in the earlier preclinical data has made you excited about its potential?

Sure. Yes. Thanks, Paul, and thanks to the Goldman team for ask us to participate. So the Entrada Therapeutic story starts back in 2016. But when we start to think about what is so special about this company, it starts with the endosomal Escape vehicle or EVs, which are essentially a family of cyclic cell-penetrating peptides that have these remarkable and unique properties that allow us not only to get into the cell, but to get out of the early enorm with efficiencies that have not been seen before. So why is that important? These EVs can be conjugated to a lot of different things. So in this case and in our DMD and DM1, we're talking specifically about oligonucleotides. So conjugating the 2 together or chemically synthesized into 2 together allow us to get out of the early endosome with efficiencies that are much, much, much greater than conventional biologics or conventional other therapeutics, upwards of 50%. And what that allows us to do then is to get to the muscle in a much more efficient, concentrated way that allows us to hopefully affect change to the disease. And in this case, with DMD, it allows us to affect the dystrophin levels -- it allows us to affect the function of those muscles for those children as well, too. So it starts with DMD. It goes into myotonic dystrophy type 1, which is DM1 partnered with Vertex and then there's a whole plethora of other diseases that we can also address via EUVs and also other modalities.

Okay. Great. Maybe starting with the DMD space. You talked a little bit about oligonucleotide, and we know obviously exon skippers that are already approved and commercially available in the space. So can you maybe talk about what, in your view, solidifies the EV and using the cyclic peptides to deliver these medicines as potentially differentiating or what could be potentially best-in-class in this category?

Yes, it's a great question. I mean if you take a step back and look at DMD, in the U.S., it's a $5 billion market by itself. Ex-U.S., you multiply that by at least at least 2. And so it's a huge market with a profoundly unmet clinical need. And there are companies that are going after DMD with a variety of different approaches, whether it's nacodoligonucleotide, conjugated oligonucleotide gene therapy, et cetera. What makes it interesting and what makes our approach even interesting is the preclinical data that is translated remarkably to clinical data. So first and foremost, when you go after a pediatric disease or mostly pediatric disease like DMD, where there's a deficiency within the dystrophin protein, you want to establish safety. Safety is the most important thing to be able to establish for these patients, especially the younger ones. [indiscernible]. That within our preclinical data, we've been able to translate from the canonical mouse models all the way through NHP to normal healthy normal volunteer adult study into our recently released Cohort 44 patient data, we see this consistent translation around safety. What we're starting to understand is that the dystrophin relationship, the functional benefit is pretty complicated. And I think other approaches would also say the same thing. But what becomes really important is changing the lives of these patients with an established and safe medicine. And I think that's what's exciting about Entrada's EEV approach.

Can you maybe just remind us where you are in terms of overall clinical development versus some of the other modalities that are in the clinic and just maybe bid before we go on to the next question to level that?

So do is a cascade of different mutations that in a variety of exons. There's 5 major mutations, but then there's a lot of different mutations below that. We're going after exon 44, 50 and 51. Our 44 program just released its first multiple ascending dose patient data. That is we're going to continue with our cohort 2, and then we'll go to a cohort 3. We're a little bit behind the competition, so to speak, there. But once again, at the end of the day, what a patient will choose and what a PI will choose is a drug that has both the safety and the functional benefit. Our cohort 145 data for our exon 45 program is likely the first-in-class and hopefully, best-in-class when it comes to that exon as well, too. And those data for the first cohort will read out the middle part of this year. And then [ 1551 ]. So we're right in the middle now and going against a lot of other really interesting companies and really interesting approaches. At the end of the day, Paul, we've talked about this extensively. The more approach is the barrier, right? Because at the end of the day, I think all of us are aligned on the same exact thing to bring treatment in a variety of treatments to these patients that have these diseases.

Okay. Great. You mentioned something earlier, which is key in development of DMD drugs, which is safety. And it's always been sort of the historical concern with exon skippers with regard to liver toxicity and just what comes and what you can discover with dose escalation. Can you maybe remind us what you've seen so far, Natarajan, if you want to turn it over to you and just how you think about escalation here and what the safety data to date show?

Yes. So the safety data has been very clear -- so we haven't seen any SAEs. We have not seen any AEs that lead to patients dropping from the trial. When we look at PMO as a class of drugs, the main toxicity is kidney -- and we have looked at all the kidney parameters like GFR, magnesium levels, cystatin C, you cannot even differentiate between placebo and treated. So it's that claim. When it comes to liver toxicity, it is more for the PS chemistry rather than for the PMO chemistry. And of course, we didn't see any liver toxicity and we didn't expect any. Similarly, AB has liver toxicity -- but the modality that we are using, we didn't expect any liver toxicity and we didn't see any liver toxity.

Right. Just given the difference between a vector approach and what you guys are doing?

And I think that's a really interesting point, right? So when you start to think about diseases and have such a profound unmet clinical need, it becomes an analysis for the PIs and of course, the families around risk versus benefit. And I think the risk part usually comes up with safety, right? And so in our first cohort 44 data, which was 8 patients, as Natarajan said, we saw no safety concerns whatsoever. When you start to think of some of the other programs that are out there, they've all had safety concerns. And so that's a huge differentiation right now. at this early stage in development. And so we're really pleased with that. And once again, going back to 1 of your original questions, we saw all this solid safety within preclinical models. And so we're happy and -- this is what gives us a level of confidence that it will continue to translate as we get further and further into the clinic.

Okay. You mentioned for your exon 44 program, you recently top line cohort 1 data. Can you maybe Sunrise for us what you saw in terms of your PK/PD and sort of early efficacy signals and just how you're thinking about the biomarker results today?

Yes. So I think Nataraj and I will take this. So I think when we looked at these data, there were 3 components of data, frankly, in this order, right, safety, which I think we've already mentioned a bunch of times. So that's been confirmed. The second really was dystrophin production. And let me come back to that. The third was functional benefit. We believe that we would see dystrophin production in the double digits. We did not see that. And we know why we didn't see it, and we're confident as to when we will see as we get into cohort 2. Nataraj will speak a little bit more about why we didn't see the dystrophin levels. But what was interesting was the functional benefit. We did not expect to see functional benefit this early at day 127 within these patients. And what we saw was statistically significant functional benefit as measured by 2 factors, 1 called time to rise and the other called time to rise velocity, which are robust and clinically relevant and endpoints that regulators have all approved. We also saw meaningful trends within 10-meter walk. So the question becomes well, how did we see functional benefit with low dystrophin levels. And I think that's what the market is grappling with right now. And I think it comes back down to the importance of the relationship between dystrophin and functional benefit, but perhaps it's not a one-to-one correlation. Perhaps it's actually more complicated than that. And I think what becomes interesting from the Entrada perspective is our preclinical data that shows the ability to get into these quieten satellite cells and activate those satellite cells to be able to regenerate muscle. And right now, preclinically, we've proven it. Clinically, we're looking into that as perhaps that's the reason why we were able to see functional benefit earlier -- at the end of the day, Paul PIs patients, that's not the reasons why are not the important ones. That's for us, right? That's for us, for you, for our investors to understand. But from a product perspective, a potential therapeutic perspective, what they are seeing is safety and early functional benefit. They don't care as much as to whether or not it's double-digit dystrophin. You can have 25% dystrophin, but if you have mediorfunctional benefit and what's the point, right? So for us, we have to explain that a little bit better. We have to learn about that a little bit better. And I think in time and with data, we'll be able to understand that better. But DMD is a complicated disease. But let's talk about the dystrophin levels and our projections and why we think that we're going to get back to where we need to be.

Maybe Natarajan. Can you walk us through what your -- before you went into the clinic, how you modeled it and then just kind of how that different actually in the clinic with regard to PD?

Yes. So we had a robust data set to model what we were going to get in DMD patients. So we had nonclinical studies. We had NHP, how does the NHP sub-chronic toxs and we had other NHP studies, and then we had a normal human volunteer study. So we could get a correlation between plasma exposure, muscle exposure, exams skipping. And then we use that to project what exposures we would get in patients and how that could translate into muscle exposure and exon skipping and eventually dystrophin. What we saw in the Cohort 1 is that the exposures that we got was half of what we expected, based on our normal human volunteer study and an HP study. And of course, the dystrophin level was -- it went from 4-point-some percent to 6-point-some percent. About 2% increase 50% increase from baseline. So the reason for that turns out that when we went back and looked at pediatric or zonal NHP, there was, again, low exposures in the pediatric population. So probably the difference is in the kidney volume versus total volume contributes to low exposure in younger subjects compared to older subjects. So essentially, what has happened is that we have right shifted our projections based on our new model using pediatric juvenile NHP than what we expected in cohort 1, we would now get in Cohort 2 because we just need a linear increase in exposure, which has been double our dose should happen. And that should result in eventually having the double-digit discipline that we had projected for Cohort 1.

I actually just thought of a question. I don't know, you talked about the descriptive statistics showing functional benefit. But I'm just sort of curious on things like time to rise and the velocity of the time to rise. But I'm just sort of curious if you actually took a look at the sort of completeness and length and sort of quality of the dystrophin that was produced, any comments there that might potentially explain the delta between the level of increase versus the functional outcomes?

Yes. In terms of quality of dystrophin, we do expect for majority of the patients, we do expect the quality of the distaphinto be good -- this is based on a lot of analysis that we have done from DMD, which is a related disease, what that is in frame deletions that when you have 44 enable patients, majority of them produce a protein that is robust. But I think the difference here, I think, is more exposure into the satellite cells because DMDs are 2 disease, where the first hit is to the mature fibers, which causes muscle big down and fat cells and necrosis occupying that space because of lack of regeneration, which is due to inactivation of the satellite cells activation, right? So I think the ability to get to satellite cells and activate them, I think it's playing more of an important role here.

I think the interesting thing, Paul, because we spent a lot of time on this as well with you, your team and the company is there's no biology risk here, which is what gives us confidence, right? So at the end of the day, we do believe the dystrophin levels will come up. That is important, and we'll get there with the second cohort. This was a projection miss more than anything. Now that we have the right data, this juvenile NHP data that Natarajan is referring to is a 55-week study. We got those data right about the same time we needed to share the data as well, too. Since they sit right on top of each other based upon the concentrations, we feel as though that will allow us to be able to get -- that's what's giving us the confidence around Cohort 2. But what's interesting, once again, going right back to what Natarajan said was we -- when we start to think of cohort 2 success for 44, which will come by the end of this year, we think of it in 3 ways. One, we want the maintenance of a favorable safety profile and that's no small feat considering we're doubling the dose to 12 mgs per 0. So if we do that, that's huge, once again, from a risk-benefit perspective. The second becomes getting those dystrophin numbers into those double-digit range. And I think Natarajan explained that with the right shifting. And the third is the maintenance and functional benefit. If we can maintain functional benefit, that is a big deal, right? Because these patients, especially the patients that we've are observing once again, in this first cohort, we -- the patients that we had a baseline dystrophin that was much lower than what avidity and what NS Pharma saw. We had 4% versus their 7% to 10%. If we could maintain that functional benefit, that's a big deal, right? And so -- and we'll know that in the next in the next several months. So we're excited about this.

Great. So maybe just to clarify, both in terms of timing and potential magnitude of changes, you talked about a right shift in your data expectations based on what you've learned from Cohort 1 and your updated HP modeling. So can you maybe, again, not to necessarily put you in a corner, but just help us think through what the 12 mg and the 18 mg dose might look like based on your updated information.

Yes. I mean I could start. I mean I think we -- for the second cohort for the 12 mgs per kg, it really depends on what the baseline looks like, right? Because we don't want to be cute with these numbers. But if you really want to look at this, if we had baseline dystrophin levels of what Avidity or NS Pharma had, then we would double digits. So there's acuteness there that we're not trying to go for. When we say double digits, we mean double digits, right? We think we're going to get there at 12 mgs per kg. At 18 mgs per kg, if we have to go to 18 mgs per kg, and I think that's a big in, right, based upon what the safety and functional benefit look like at 12 mgs per kg. That's where you get like to the 25% plus, right? But it might not be necessary because the important thing here is are we getting into the satellite cells? Is that what's affecting the functional benefit in a positive way. We know that the antibody approaches can't get into the satellite cells, just -- it's not expressed on the antibody itself, right? Or it's not expressed on maybe the surface, right? So we already know that, that's a differential, right? And so for us, if at 12 mgs per kg, we achieved what I laid out, which is a favorable safety profile, double-digit dystrophin production, so above 10%. And then a maintenance of functional benefit with the types of cost of goods sold that we have with the types of efficiencies around manufacturing that seems to be delaying the BLA for Delzoda, that's a big win for us. And then if we have to go to 18 mgs per kg, we can go to 18 mgs per kg. We just don't know if we need to do that, but we're prepared to.

Okay. Can I just play devil's appear -- and let's say, you go to 18 mgs and you have no safety events or DLTs like keeping from theoretically going higher. What's the rationale for not -- for stopping there versus 24 mgs dose or 28 mgs, it's a very fair question. So you can theoretically, if the curve is linear logarithmic fishing. Can you keep on pushing it to get to almost a wild-type level of 1 question here.

One, there is the possibility to do that. So the tax data and the Cohort 3 data will determine that. whether we can go and we have probably good confidence that we could do that. The question is, do we have to go that. I think based on the revised model that we have, even at 2 milligrams per gig, we should hit both the aspects of it, the addressing the dystrophin level in the fibers and that's addressing the discipline levels and satellite cells, we already -- which have already seem to be doing. So I think yes, we can probably move based on safety in third cohort. But I think most likely, we don't have to go beyond eating.

I think the other thing is we -- if we continue to show what we've shown, right? So safety, dystrophin getting there, functional benefit, early but sustainable functional benefit. I think there'll be a fair amount of pressure from the patient groups as well, too, to say, can we get access to drug. And we're already seeing that a lot of rare disease companies see compassionate use requests, expanded access requests, things like that. I think if we continue the momentum that we have here, albeit the setback last month, but we catch up to that, then there's going to be a lot of good pressure on us to say, let's get this out to the patients as soon as we can.

Okay. Maybe just to wrap on the 44 program. Can you remind us what, if any, updated longer-term follow-up you'll present on Cohort 1 and when that will be and then when Cohort 2 data might come?

Yes. So that's a great point. So we're excited. I mean we'll have our open label at 6 mgs per gig data readout before the end of this year. So that's going to be a very important readout because it's going to be roughly 1 year on drug multiple doses, of course. And so it will be interesting to see. And that data point, when we share that data, we'll also share a more robust analysis of the functional measures, right? So there's a whole -- in our corporate presentation, there's a whole list of functional measures that we're looking at that we will be able to read out on. So we'll give a much more fulsome view. I mean the cohort 1 data was supposed to be more of a snippet, but the open label will explain a lot more. And remember, open label only -- and all 8 patients have converted to the open label, open-label only measure really 2 things. It's going to measure safety and functional benefit. There's no dystrophin level that's being measured in the open label. And so that will come out before the end of the year. Cohort 2 data at 12 mgs per gig is coming out at the end of this year as well, too. We're continuing to monitor it. I think it's an exciting data set. And so those 2 data sets by the end of this year can be very telling for 44.

Okay. Does that make sense to present them simultaneously I guess?

It's something that we're working on now internally. The question becomes and just I think all companies all company space is that when you're running these studies, you're getting into the winter, so you're getting into the holiday period. And so you just want to make sure that you can present that correctly. And so we're keeping an eye on it in terms of how best to present it and where to present and things like that.

Okay. You referenced some competitors earlier, including Avidity and NS. And so -- the space is obviously very actively invested in right by the industry. But how do you think about the market, especially given the context of what's happened with some of the Sarepta products specifically with levees and just, I guess, upon market entry for yourselves and other companies. How do you think about positioning and just sort of timing to market?

Data wins right? At the end of the day, I think, unfortunately, what we've seen over the past year -- well, more than the past year, over the past 5 years really is DMD is difficult. It's a difficult disease that was not fully explained by the first-generation movers like Sarepta, that's okay, right? We're learning a lot more about it, right? So then DELZODA comes in and shows us remarkable dystrophin production. And let's call it what it is. It was remarkable dystrophin production, albeit at a safety out of 5 mgs and 10 mgs per kg dose that is kind of difficult to understand because you don't know what's 5 mg per kg or what's 10 mg per kg. They pulled a lot of their data. They have safety concerns. It's an antibody, how do you manufacture that much antibody. So there's pluses and minuses. Elavitus levers set gene therapy back, right? And I think that hurt the patient groups a lot as well, too. And they're trying to come back years people had asked us, do you think that an Exxon skipper can be added on top of gene therapy. I think it's the other way around now. I think it's kind of gene therapy to be added on top of an Exxon skipper, I think 5 years ago, if you look at some of the stuff that I've said and Natarajan has said, the flexibility of this approach, the ability to start, stop, increase, decrease those, things like that becomes really important to be able to match up to a patient's own journey. What hasn't stopped is the fact that it's a $5 billion market in the U.S. that is underpenetrated and that patients are clawing and desperate for a drug that not only works but also has that flexibility and those characteristics that marketing teams usually put out, but sometimes they're not supported by data I think we have the opportunity to do that in that mix, right? And so I think for us, yes, competition is good, right? But that doesn't mean that -- like I'll give an example of my former company with Amicus Therapeutics, right? With Fabry disease and Pompe disease, they certainly weren't the first to market. In some, they weren't the second to market, but they were able to carve out a very lucrative and meaningful business because of the data profile, right? And I think for us, I think that's what's going to drive the safety plus functional benefit when it comes to 44 and 45 ultimately, that's what's going to drive utility of the hopeful of the drug in the years to come. And we're seeing that within our clinical trials. We're seeing a tremendous amount of excitement. We released last week our -- a press release around a data monitoring committee for our Exxon 45 program, which is a very difficult Exxon and the data monitoring committee essentially said, go to 10 mgs per kg, it's a 5 mgs per kg study, as you know. But go to 10 mgs per kg and there's an influx of e-mail. So the patients, the PIs I think even with the competitive landscape still -- the bar has not been fully met. And I think that's where we can kind of come in here.

Since you mentioned the 45 program, I want to ask construct is fundamentally the same between with the 44 program, but can you maybe talk about the translation ability and maybe what you learned from your early PK work on the 44 program in the clinic, you also referenced that your data monitoring committee recommended dose escalation here to the next dose. And so are there any particular learnings that you would communicate from the 44 program, about the 45 program to investors?

Yes. I mean, I think I'll start and Natarajan, please jump in as well too. We've always said that the 45 program would be -- we didn't expect to see and we still don't expect to see the levels of dystrophin that you would see in 44. First, and why is that, right? So first, the baselines are usually much lower, right? And when I say much lower, I mean like just above 0, right? Now the caveat is that in 44, we had 4% where we thought we'd have 7% to 10%. So it moves, right? But I still think that, that would be consistent with 45%. So if you have a baseline of less than 1% dystrophin. Then we've also said that our expectation, ultimately, not with the first cohort, but ultimately would be to get into the single-digit dystrophin above, which would be huge, right, because casimersen a minus 45 barely shows any dystrophin production, right, because it's a difficult disease. So for us, in this first cohort, we want to establish is the safety. Safety is no small feat here. And I think the DMC results from last week puts us on a path where we believe that we are establishing safety here. And we're excited about that, right? Dystrophin functional benefit, that will come in time. It may not come in that first cohort, but that's okay, right? For us, if we astonish full safety, that in itself plus which cannot be -- I have to emphasize this as much as I can. The dosing around our 45 drug is once every 6 weeks. The dosing around casimersen is once a week. That dosing difference, that regimen is huge, right? If we start to think about quality of life. We start thinking about, you don't have to go and get infused every week for a 6-year-old kid 7-year-old kid I think there's so many characteristics around this 45 program that if we establish consistent safety in that first cohort, safety plus a dosing regimen, which is every 6 weeks, -- that alone is a huge win. And then in cohort 2 and then maybe Cohort 3, we'll start to see some of that functional benefit and dystrophin start to move in a more meaningful way.

Great. In our remaining time, I want to talk about some of your other programs, including 670, which you've partnered with Vertex. Can you maybe just remind us of what are Entrado obligations under this partnership?

Yes. So we entered this partnership a few years back, and our job is really to take the preclinical work up an IND. So that's all been completed, right? And so our obligations essentially to date have been completed. And so we are now like -- we are now waiting, of course, for the study to read out this MAD study to read out, which Vertex has publicly declared that, that will come out for the second half of this year. So our obligations are done. We think we partnered a really good drug here that 110,000 patients in the world have DM1, and we are eagerly awaiting those results in the second half of this year.

Okay. Great. With regard to the DM1 program to help maybe guide investors who are following it maybe from the Vertex side as well as for your side. Can you talk about the translatability of the 44 or 45 program data you've seen to date internally and how that may read across to DM1.

Do you want to see that?

Yes. So when we think about it reduces the same -- so the safety should translate across the platform, and we have seen that in preclinical studies. So that's -- we have established safety at 6 milligrams per gig, I think, in both normal human volant patients. So that should translate -- the second thing is that this is a difference between -- it's a different disease, right? I think DM1 is a very different disease compared to DMD. And the patients are not pediatric patients, they are adult patients. So we don't expect this the exposure differences that we have seen in pediatrics to translate that. So I think between safety and exposure, we are expecting good supply correction. We have seen -- I think we had the most robust preclinical data with a panel of over 20 genes that we have shown splice correction. So I think it should, in our opinion, translate in the clinic as well.

I think what becomes important in DM1, and it's probably a better question for Vertex, but taking a step back is also safety plus functional benefit ultimately, right? And so slysopathy gets -- it's still kind of difficult to understand what that means. And so I think as they return those results or present those results, we'll be very interested to see how this pans out within an increasing competitive dynamic as well.

With all small and mid-cap biotech cash runway is always a classic question. So can you remind us if -- assuming the DM1 MAD data are positive, how that potentially helps your cash position down the road there. Is there a milestones tied to this particular readout?

So the -- we haven't disclosed what the milestones are in terms of the individual milestones to the aggregate is pretty significant. So what I can say is that our cash runway goes into Q3 of 2027, and it does not include any milestones for the DM1 collaboration. Anything above and beyond would -- and it's significant in terms of the milestones, would just add to that cash runway.

Okay. Maybe in our last minute or 2 here, you talked about other applications. You've started for your EV platform. You started talking a little in the past about ophthalmology and other things like that. Can you maybe just walk us through what sort of early development you have there and just in terms of other areas and just kind of what you might disclose to -- the Street in the coming, call it, year a year on?

Yes, we're super excited about the ophthalmology franchise. I'm going to let Rajan talk about the inherited retinal diseases. -- specifically Usher syndrome, 2 way.

Yes. So we had already nominated the candidate for us Ilera significant patient population. -- and the preclinical data that we have seen is quite good. It is, first of all, it's IVT injection and there may be a possibility of once in a quarter injection. So it is looking very attractive from that. So we are about to this year to nominate candidates for another inherited retinal disease as well. It just talks about the platform and our ability to work on this XAN skipping and aesthetic blocker space that we are able to get deep tissue penetration and get very robust target engagement. So I think that is enabling us to the back behind. Yes, yes, indeed.

And I think we'll share more as the year goes by. Neither 1 of those programs will enter the clinic this year. but we do expect them to start to robustly move into clinical development. We're figuring out the plan. We have to talk to the regulators. There's a global approach here as well. So we're looking for those efficiencies because once again, 15,000 -- 10,000 to 15,000 patients but with a remarkable unmet clinical need as well. So we're excited about that as the leverage is not only core expertise within exon skipping. But it also allows us to increase branch out and show the applications of the Entrada capabilities to other diseases.

Yes. I think just given the frequency of how often patients get VEGF injections for AMD or DME it doesn't even have to be a quarterly, right?

Necessarily, that's correct. Exactly right.

Okay. Well, we're out of time. So my thanks for the Entrada team for joining us.

I appreciate it, Paul. Thank you.

Thank you.