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

Welcome. We're really pleased to have, as our next company, participating in the Goldman Sachs Healthcare Conference, Entrada Therapeutics. My name is Chris Shibutani, and along with my esteemed cum logical, well-organized associate colleague, Stephen Sloan. We are very pleased to be having a discussion with the management team, CEO, Dipal Doshi; as well as Natarajan Sethuraman, the Chief Scientific Officer. Welcome and thank you so much for making this trip. We would really appreciate this opportunity and look forward to really creating more content and substance to help people familiarize with the company, the platform, the scope of opportunities and really be thoughtful about developing that further here so that people can understand. So perhaps a quick overview Dipal.

And thank you, Chris. Thank you, Steve. Thanks for the Goldman team for having us here. It's always nice to be kind of in person. In fact, we just had a Board meeting a couple of weeks ago, where we were in person for the first time and the dialogue was so substantial, and it's just different than being on Zoom.

Yes.

So Entrada is a biotech company focused on intracellular biologics, right? And so the name of the game for us is the ability to deliver drugs into the cell itself. And we use a proprietary platform called endosomal escape vehicles or EEVs. And these EEVs are a family of cyclic cell-penetrating peptides have these remarkably unique characteristics, including the ability to get into the cell, the ability to get out of the early endosome, which we will spend some time talking about, I'm sure, and then ultimately, to be able to get delivered into the cytosol of the organelles with specificity, which is really important. Today, we're focused on a variety of diseases based upon the modularity of the platform, but we're laser-focused on our Duchenne muscular dystrophy program, and that's specifically for an exon called exon 44 and our myotonic dystrophy Type 1 program or DM1, both are rare monogenic diseases with a profound unmet clinical need.

Talk a little bit about, given the potential range of opportunities that your core technology platform can go, the decision that you made to go after Duchennes and DM1. What made those the logical lead programs?

Yes. And so I think thematically at Entrada, we really do follow the science. And what we have seen with this science, early, early days of the company is that ability to get to the muscle. The ability to use these EEVs and conjugate them, so chemically conjugate them and watch and see how they can get to these difficult-to-reach muscles, including the cardiac tissue. And when we saw that, and we saw that in a mouse model, we said, "Hey, this is a profound opportunity." And when you look at DMD from an overall perspective and when you look at DM1, there is a remarkable unmet clinical need. And so DMD has approved programs, but their ability to really transform the disease for the patients is quite limited. And DM1 does not have any approved therapeutics. So we thought that based upon the merit of the diseases -- I'm sorry. Okay. Based upon the merit of the approach in that we knew we could target difficult-to-reach muscles. And then, of course, coupled with the scientific and clinical need within those diseases, these were 2 diseases that we prioritized at the onset.

This was actually a very fortuitous thing, to have your booming voice in the darkness next to a curtain is actually extremely impactful. So I'm confident we should continue to carry on. And which we'll do so. And with my exit line here, I'll turn it over to Stephen. And he -- let's dive into some of the specific programs and the indications and the assets and the program. So off you go Dr. Sloan?

And maybe just before we get into the program, we'd love to maybe hear from Natarajan about your EEV platform in particular and how this differentiates. I know there are a few other companies going after self-penetrating peptides, and I'd love to hear how you're just differentiated and are expecting to achieve superior efficacy compared to some of these competitors?

Yes, yes. So let me talk a little bit about the history. Peter Kim, who used to be the Head of MRL, he saw Dehua Pei from Ohio State University present about this EEV technology. And Peter Kim himself because his work on HIV, was very familiar with cell-penetrating peptides. And he was very excited about this platform for 2 reasons: one, the endosomal escape rate was extraordinary; and two, they also knew the mechanism by which they were working. And so that got us very excited about it. And then I joined earlier on and then shepherded it through seed financing. So the -- what differentiates this EEV technology is that, one, it's a library of cyclic peptides. So we can screen them for what exactly Dipal was talking about were tissue tropism. Secondly, they increased the circulating half-life of cargo. This becomes extremely important when it comes to oligonucleotides, which gets cleared very, very quickly through the kidney. And so when you take the same oligonucleotide and attach it to the EEV, then 90% of the cargo remains in the body even days after infusion. So you get huge bioavailability. And second, as Dipal said, endosomal escape, over 50% of the cargo exits the endosome and then by using nuclear localization signal, for example, we can get this cargo into the nucleus if you wanted. So that's -- we increased the drug concentration in the target tissue and the target organ extraordinarily. And that leads to very robust target engagement and the pharmacology follows. And that really differentiates us from all the existing technologies which either are very unstable themselves in the circulation, so they get rapidly cleared and cause kidney toxicity, and thus require higher dose. So with a lower dose, we can get very good concentration inside the cell with the result we get very high therapeutic index.

And clearly, there are many potential indications where this EEV platform would be very useful. Can you just explain your thought process, why you chose DMD, in particular, as the lead program for this? And what data has gotten you're really excited about the opportunity here.

Yes. So we -- a lot of focus has been on monogenic diseases. For example, DMD is passed by genetic mutation deletion in the gene itself, where you can restore the reading frame by skipping an exon. So that way, the translation between animal model and the human becomes very simple because we are not talking about complicated diseases. That is one thing. And that's -- and secondly, coupled with the fact that we can get to the muscle and especially cardiomyocytes in the GFP mouse model, that is really thinking here is a monogenic disease, which could translate quite well the existing medications that are approved have 1% to 6% dystrophin even in the skeletal muscle, nothing in the cardiomyocytes. If we really have a robust technology like ours, which can increase the dystrophin level quite substantially, then that could differentiate in the marketplace. And that was the thought process that helped us land on DMD.

I think just adding a little bit to that, Stephen. These young boys then who become young men, ultimately succumb to a cardio event with a cardiomyopathy as a cause of death. And so the ability to really target the heart with the therapeutic becomes really important here. And I think some of those data that we have presented and have studied aggressively are one of the reasons why we get very excited about our approach within DMD. And so I'll add to that a little bit in terms of we've done extensive research, right? And so as Natarajan said, this is a rare monogenic disease with high translation, right? So we've started with a canonical model that we've gone to a very, very high bar model and the nonhuman primates then ultimately, of course, we'll go into humans. And all of the models that we've used have translated quite, quite well, both from an exon skipping perspective and then, of course, from a dystrophin production perspective. And importantly, the duration of activity that we've been able to demonstrate has been quite, quite high. So we hope that we see a dosing advantage here as well, too, for the patient. So all of the information -- all the data that we've collected, all the preclinical data that we've collected have led us to this level of enthusiasm to be able to bring this program into the clinic.

Yes, we think you've shown some pretty exciting results in those various models showing exon skipping, dystrophin production in multiple different tissues. And I want to touch on that point, you talked about the durability. I think recently you published some data nonhuman primates showing exon skipping out to a certain time period. We love for you to maybe discuss those results and how that will inform your clinical strategy going forward.

Sure. Do you want to?

Yes. So what we are seeing in nonhuman primate is quite extraordinary. After a single dose of EEV conjugated PMO we see exon skipping in -- going out to 12 weeks. It starts off at very, very high levels of 85% of exon skipping and then continues to be quite high, even at 12-week period. So that could translate potentially into very convenient dosing schedules for patients. Right now, we are guiding towards at the minimum of 6 weeks between 2 doses. And when you compare to the existing approved therapies, which are weekly infusions, this could be a great advantage for the patients, and we are quite excited about that.

And so thinking about it from an NHP perspective now with what Natarajan said, with the durability here and duration, it certainly informs our clinical strategy. And our clinical strategy will first start with a single ascending dose study within healthy normal volunteers. And then based upon the learnings from that study, we will then progress to patients and use a multiple ascending dose study. So it's a very calculated way of being able to get to patients relatively quickly. And I think importantly, there's been precedence here as well, too. So we can follow some of the path from other companies that have gone down this path before.

Yes, definitely. And I guess I'd love to dig into some of the upcoming clinical studies. But first, I guess, on the other end, we've seen companies developing gene therapies for Duchenne muscular dystrophy and that would potentially be a onetime dose "cure" would love to hear your thoughts there and why you think exon skipping is really the right approach for these patients.

Yes. Maybe I can start and then Natarajan, you can support this. Look, at the end of the day, what we care about is a treatment for these patients. That ultimately, from an industry perspective, from a company perspective and certainly from a personal perspective, watching these families and these young boys suffer through this disease is certainly heart wrenching. So the more competition in some respects, the merrier because we know that hopefully one of them will stick. Now gene therapy, and I'm going to use your air quotes, right, from a curative perspective is a great aspirational goal to hit. However, based upon the data that we have seen, especially within DMD, there's a lot of challenges along the way, right? So the rigidity of going with a gene therapy approach to a disease in young boys who are growing, there's a disconnect there, right? And so far, we've seen some issues around toxicity, we've seen issues around duration. And remember, as you said, like gene therapy is one and done, so you can't redose it, right? So I think there's more questions that are out there than answers right now when it comes to gene therapy. And so when we view that and we view our approach with our exon skipping approach, we look at the inverse of that, right? So we've been able to -- we can control the dose, we can start and stop the dose. We can titrate up, we can titrate down. We -- as Natarajan mentioned, we have a duration of effect that so far is quite long and would hopefully provide a nice course of treatment for these patients. And we've seen a safety profile that's quite attractive as well, too. So I think the flexibility of the EEV platform, as we marry the programs up to our approach is something that's super advantageous. Because obviously, we're dealing with a lot of sick people. Anything to add, there?

Yes. Only thing to add is, in gene therapy it is microdystrophin, whereas when we exon skip, it is closer to dystrophin. So I think that is also a big differentiation.

And this program is approaching the clinic. You've announced an IND is expected in the fourth quarter. Can you just talk about gating factors to IND, what, if any, new data we might see before then? And then I would love to know just what clinical questions you're looking to answer with your initial study, which is in healthy volunteers.

Sure. I think between now and the submission of our regulatory package for our exon 44 program, the only step that's really left between now and submission is just the completion of GLP tox. And so -- and that's a normal process, right? And so once we get that, then we'll package everything together and submit it to the agency. Questions that we're trying to get answered from our initial study. So remember, our initial studies within healthy normal volunteers, single ascending dose study. What we would like to understand, first and foremost, is safety, right? So we want to make sure that this is safety -- there's -- the safety profile is certainly acceptable for the healthy -- for the HNBs before we get into patients. So that is the primary. There's been a lot of questions around exon skipping in healthy, normal volunteers as well, too. It's something that we will assess. But let's just remember that these are healthy normal volunteers, right? So they have a fundamentally different physiology than a patient that has DMD, but nevertheless, it is something that we will also measure.

And to the extent you can speak to dosing interval, any doses, the key endpoints. I know you just talked about some of the PD effects possibly exon skipping, but we would love to just know a little more detail, if you could.

If you want to take that one?

Yes. So the dosing interval that we are guiding to is minimum of once in 6 weeks. And apart from looking at exon skipping we will also look at distribution, see how much do we get to the muscle in the biopsies. And we see very, very good correlation between the amount of drug that we get in a muscle biopsy versus what we get in the part, so monkey. And similarly, there's a one-to-one correlation between the drug disposition in a mouse versus nonhuman primate. So that will give us also a good idea based on PK/PD modeling, how much we can expect in terms of exon skipping and dystrophin production ultimately in patients.

Yes. And there is -- there are approved exon skipping therapies and I know many of our conversations have focused on the translatability of this preclinical data of the humans. So I would just love to know your level of conviction that the data you're seeing in these nonhuman primate D2.mdx models will translate to humans.

I have a very high level of confidence. But I think the rigorous nature of how we approach science and the experiments that we run and the questions that we ask. And then, of course, the questions that we -- or the answers that we receive back give us confidence, right? So once again, we started with the canonical MDX-mouse model, that's kind of like the entry-level model. Those data looked really good. The D2.mdx mouse model, which we're one of a few companies that actually run that model and that have shared our results is a very, very high bar model, right? That is the model that really closely represents the phenotype of a patient. And those data, not only the biochemical data, but also the functional data, i.e., like grip strength and things like that were remarkable, right? And so when we got those data that was another big check in a box in terms of our level of conviction. And then finally, the NHP data, right? So the NHP data is really going to measure toxicity, safety, biodistribution and ultimately, just like levels of exon skipping, right? You can't measure dystrophin since the nonhuman primates don't have any mutations that are relevant to DMD. So you take all of that together and you realize also that there's a one-to-one correlation and the data has been very, very consistent. And then you compare it. You compare it to the approved programs and the paths that they have taken as well too, and it's consistent, right. The difference is that we're just consistently better based upon the package that we have now. And so that's what gives us the high level of conviction for DMD 44 as a starting exon and then hopefully, we'll address the others in due time as well.

Thinking ahead, obviously, once you get past the healthy volunteer study, we're going into patients. And looking at the approved therapies, all the exon skipping therapies have been approved through an accelerated approval pathway based on dystrophin production. Would love to know your thoughts there on how you're thinking about potential approval of your programs for exon 44 and beyond? And if you think that similar pathway would be available to Entrada?

Yes. And so it's a good question. And I think the way that we kind of approach it is that we -- everything gets informed by our interactions with the regulatory agencies, right? And so the collaborative nature of our discussions with FDA will hopefully allow us to find a path that's right for the patients. But our current thinking is exactly that, Stephen. It's the accelerated approval pathway. Once again, there's precedence here, there's a lot of precedence here for -- to follow that pathway. And so we will continue to do that as well, too.

And maybe one more, and then, Chris, if you have any on DMD before we shift over to DM1. So obviously, our initial program in DMD is focused on patients that are amenable to exon 44 skipping. Could you talk about that opportunity relative to the overall population? And then your thinking about the additional mutation population.

Sure. So there's over 30,000 patients that have DMD. And there are 4 primary exons, which comprise 40% of those patients. That's exon 44, 45, 51 and 53. Exon 44 itself has several thousand patients that are afflicted with DMD. And so that in itself is a wonderful opportunity for us to pursue first. There are no approved treatments for exon 44, and the clinical competition is quite limited when it comes to exon 44. So our strategy would be to, of course, progress as fast as we can and as focused as we are to be able to get data within that population, but then, of course, also expand our offerings to the other exons as well too. So once again, profound on that clinical need based upon dystrophin levels that currently are only between 1% and 6%. So there's a lot of need here. There's a lot of room for improvement. There's a lot of patients. And so we feel as though we have a good shot at addressing certainly exon 44.

And on that topic, the regulatory, we've touched on this a little bit in terms of what's happening now, possibilities in terms of how the pathways from a regulatory standpoint could evolve. For going through -- immediately, right now, this process with the next PDUFA accelerated approval pathways outside of oncology are being widely discussed and sorted through and figured out, particularly for a company like yours with a platform in the context of DMD, where you think about the different exon skipping, where you have some base of experiencing data, essence of proof that you could go through. Talk to us a little bit about what the potential might be for the subsequent exon skipping opportunities to perhaps unfurl in its own accelerated way?

Sure. Yes. It's a good question, and I've enjoyed our discussions about this. The caveat is we have to work with the agencies to figure out obviously the right strategy. But -- if we are able to achieve what we hope we are able to achieve with our exon 44 program and show safety and show dystrophin production, sure that -- also show the dosing frequency that Natarajan had mentioned as well, too. We feel as though those learnings and those data will certainly be applicable -- highly applicable to other exons as well too. And so it would be our strategy, of course, to work with FDA to figure out how to expedite even more our work within the other exons. So i.e., could there be an opportunity to leverage data across, right, which then, of course, helps us get to patients faster. If the healthy normal volunteer study continues to -- or reads out correctly, can we take those learnings and go straight into patients for the next exon? Is there an opportunity for a basket trial, things like that, right? And so we'll work with, of course, the agency, but importantly, we're also going to work very directly and continue to work very directly with the patient groups as well, who obviously understand the disease very, very intimately as well, too. So all those are on the table for us as we think through because I think thematically, we're in a rush as well too, as a company because there's just so much need for these patients.

Right. The urgency certainly seems under question. If we think about what's available to investors, though, currently, literally in this realm, this whole idea of applying novel technologies towards achieving some sort of transformational ultimate therapeutics. There are several companies that are out there that are relatively making progress in the same sort of arena in tandem with you somewhat. Can you identify for us what you think is the distinguishing characteristic about the philosophy of how you are developing these things? There's an element of needing to be patient here, but maybe you can emphasize what the importance of that is because there's urgency. We're talking about accelerated paths. People are waiting for data, et cetera. But I think we've discussed previously how there's a very foundational thinking that goes into your approach of what needs to happen when?

Yes. And look, I think every company is in a rush, right? And so I think they're in a rush for the patients, they're in a rush for their investors. For us, it really starts 5.5, 6 years ago when Natarajan and I first came to this company, him before me. It's really following the science. Where is the science going to take you, right? What questions do you need to ask? What questions do you need to have answer, especially with the novel technologies as well, like this one is? And so for us, is we have to stay very disciplined. We have to stay very focused. But don't get us wrong. It's like the old analogy of a duck in water, right. Above they're very calm. But underneath, they're churning and they're continuously moving, continuously thinking, continuously trying to be creative. And so we have that. But we will remain focused -- we will remain laser-focused on getting our programs into the clinic, and we will continue to follow the science in that way. So I think a lot of that is disciplined. I think there's a lot of things that we can't talk about, of course. But -- and at the end of the day, we're working as fast as we can to get these treatments to the patients, and we will not jeopardize the time lines or things like that. Because at the end of the day, that's not what we're about.

Sure. That makes sense. Stephen, leave me 2 minutes at the end, to do some wrap up, but perhaps you'd like to take it into DM1.

Yes. Myotonic dystrophy type 1, a development candidate was recently announced -- and we'll be going into IND shortly. You can talk about time lines. But yes, what preclinical data got us to this point. And again, this is a field where there is high unmet need, no approved therapies, but there are competitors. And how do you see your EEV approach and general mechanistic rationale competing and differentiating your landscape?

Yes, let me set the stage and then Natarajan, of course, you can walk through the science a little bit. So as you said, DM1 profound on that clinical need, over 50,000 patients have DM1. And there are no approved treatments. There's one program, I believe, in the clinic as well, too. So a fair amount of space here to kind of navigate. What we've seen in that disease, which, once again, is a rare monogenic disease, but the largest neuromuscular one is the formation of like 2 camps, right? So you have one camp that's going after the knockdown of DMPK, and Natarajan will get into that, into more detail. And then you have another camp, which is really focused on what we're trying to do, which is the -- it's focused on CUG repeats and the steric blocking of those repeats as well, too. We feel as though our approach is a little bit more personalized, right, and a little bit more specific, right, as we understand, as we continue to understand the pathway for these -- for this specific disease. But I'll turn it over to Natarajan and he could talk specifically.

Yes. So our approach compared to others is a little specific. So you have normal allele, which doesn't have a large number of CUG repeats. And then you have alleles with a large number of CUG repeats. So when we look at the mRNA, our approach is to block the mRNAs that have CUG repeat so that we can relieve MBNL1 and correct the splicing. The other approach, as Dipal said, is to degrade all DMPK mRNA. So that's one huge differentiation. Ultimately, we think that DMPK has a normal function, and it will be an advantage not to disturb that. So what we are finding, however, is that not only are we correcting, by our approach, the splicing abnormalities and myotonia, we are actually reducing the level of CUG containing mRNA for DMPK while leaving the normal level of the normal mRNA alone. So that's a huge differentiation for our technology. Secondly, when we think about a multisystemic disease like DMPK, DM1, where you need to get to tissues rather than muscles as well technology like EEV technology where we get the broad distribution across the body, will have a huge advantage. And then the PMO chemistry itself is a lot more safer than the other chemistries that probably ultimately will be safer for a disease like DM1.

And here, given there really hasn't been much in the clinic, tell us about how you're thinking about the translatability of the preclinical data you've seen reduction in nuclear foci, correction of splicing and correction of myotonia in some of these DM1 mouse models.

Do you want to take…

Yes. So ultimately, when we look at the pathology of the disease, right, the muscle function is altered because important proteins are mis-spliced and you have new splice forms alternate splice forms of P proteins. So correcting the spliceopathy as it is called is critical. And we show that the models that we use really reproduce both the spliceopathy as well as the myotonia. So we're able to robustly correct that in animal models. So we have also done patient derived cells with different lengths of CUG repeats in the mRNA and we are able to correct both the nuclear foci as well as the spliceopathy in these cell lines. So that gives us a lot of confidence as it's very translatable.

Maybe one last question we're nearing end time. Do you have internal expectations about the level of splicing that you need to see to achieve these functional benefits?

Yes. So that's currently -- we had a good meeting of KOLs, the experts in the field. And there is no consensus, there are a number thrown around like 20%, 30% by others. But I don't think as a field, we know what percentage of splicing correction we can do. So in our assays we are getting very, very good splicing. So that needs to be determined, see where we are working with natural history study that is currently undergoing, to look at patients with different extensive CUG repeats correlating them with the phenotype that they get so that we can -- and looking at the splice abnormalities to get to that answer. But I don't think that the answer exists yet.

Okay. No, we'll definitely look forward to advancing say clinical -- additional preclinical data.

Yes, I just add one more thing there. I think there's an advantage here to watch the company that's in the clinic and observe their learnings from a market perspective and then integrate those learnings into kind of like a second mover advantage here as well, too. And I do think that Natarajan did mention the natural history study that is key, right, to understand the progression of this disease. It's a classic rare disease kind of model that we're looking at here, too. So -- but so far, the data looks fantastic from our side and the KOLs so as well.

Then perhaps to close on 2 things. One, perhaps related to some intangibles, which nonetheless embedded within that is always tremendous intrinsic value. And then just something that's more a matter of fact and classic to fluctuate from a numeric standpoint. On the intangible side, we're seeing this paradox, companies that are pursuing innovative science, the robustness and the level of activity has everyone articulates how tremendous that is. On top of which, you guys are located in the Boston, Cambridge Seaport area, which is literally this marsh pit, the scrum of talent and energy. What is it that you are doing to be able to retain, attract talent and keep that energy eyes off of the ticker and really just on the mission and the purpose?

Yes. Thank you, Chris, for that. It is a highly competitive market. I mean we are fortunate that we have a very, very, very low turnover compared to the [ VOS ] market. I really think it really starts with kind of like the thematics. What's important to us? We're trying to build a company that we want to build that we want to work for. And there's values that are associated with that, right, including collaboration, honesty, work hard, help your teammates out, be real, be accessible, be present and things like that, right? So I think that resonates really well, right? And we also -- once again, we follow that science, right? And our labs comprise 80% of the employees, right, of the company. And we're all in this together. And I think that's that common journey really to provide some treatments to patient populations that really need it. And we live that. And I think that's what keeps people motivated for sure.

And this is the Goldman Sachs Healthcare Conference. So I'll close and punctuate with something that's just sort of classic, the communication about cash runway…

Sure.

Into the second half of 2024. Talk about what we should anticipate in terms of proof of concept with the progress points that you can be able to generate that's embedded within that guidance?

Yes. We're in a fortunate position, as you know, to have 2 years of cash right now on the balance sheet. And so our cash, as you said, runs into the second half of 2024. That was carefully constructed during our IPO in that we want to be able to get through inflection points. We want to be able to submit the IND for 44. We want to be able to get into the clinic into healthy normal volunteers, showcase some of that data in 2023. And then proceed with exon 45 as well, too. And then get DM1 through an IND as well, too. We think it sets us up really well over the next couple of years to be able to achieve those goals.

Terrific. Eyes on the prize, the journey continues. Thank you, gentlemen, for joining us.

Thank you, Chris. Thank you, Steve.

Thank you.