Let's get underway. Welcome. We're really pleased to have, as our next company participating at the Goldman Sachs Global Healthcare Conference, Entrada Therapeutics. My name is Chris Shibutani, and along with my esteemed, calm, logical, well-organized associate colleague, Steven Sloan, we are very pleased to be having a discussion with management team, CEO Dipal Doshi, as well as Natarajan Sethuraman, the Chief Scientific Officer. Both of you, 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, you know, developing that further here so that people can understand. Perhaps a quick overview, Dipal.
Sure. Yeah, no.
Just to make sure everybody levels in.
Thank you, Chris. Thank you, Steve. Thanks to 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 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.
Yeah.
Entrada is a biotech company focused on intracellular biologics, right? The name of the game for us is the ability to deliver drugs into the cell itself. We use a proprietary platform called Endosomal Escape Vehicles, or EEVs. These EEVs are a family of cyclic cell-penetrating peptides that 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 or 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 Duchenne's and DM1, what made those the logical lead programs?
Yeah. I think thematically at Entrada, we really do follow the science. What we have seen with this science, 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. When we saw that in a mouse model, we said, "Hey, this is a profound opportunity." When you look at DMD from an overall perspective, and when you look at DM1, there is a remarkable unmet clinical need. DMD has approved programs, but their ability to really transform the disease for the patients is quite limited. DM1 does not have any approved therapeutics.
We thought that based upon the merit of the diseases. I'm sorry.
Are we still on? I think so. Try it again.
Oh, 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 two 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 that we should continue to carry on.
Oh.
In which we'll do so. With my exit line here, I'll turn it over to Steven. Maybe let's dive into some of these specific programs and indications and the assets in the program. Off you go, Dr. Sloan.
Sure. Great. Thanks, Chris. Maybe just before we get into the programs, 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 cell-penetrating peptides, and I'd love to hear how you're differentiated and are expecting to achieve superior efficacy compared to some of these competitors.
Let me talk a little bit about the history. Peter S. Kim, who used to be the head of MRL, he saw Dehua Pei from The Ohio State University present about this EEV technology. Peter S. Kim himself, because his work on HIV, was very familiar with cell-penetrating peptides. He was very excited about this platform for two reasons. One, the endosomal escape rate was extraordinary. Two, they also knew the mechanism by which they were working. That got us very excited about it. I joined earlier on and shepherded it through seed financing. What differentiates this EEV technology is that one, it's a library of cyclic peptides. We can screen them for what exactly Dipal was talking about, with tissue tropism.
Secondly, they increase the circulating half-life of cargo. This becomes extremely important when it comes to oligonucleotides, which get cleared very, very quickly, through the kidney. 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. You get huge bioavailability gained there. Second, as Dipal said, endosomal escape. Over 50% of the cargo exits the endosome. By using nuclear localization signal, for example, we can get this cargo into the nucleus if you wanted. Thus we increase the drug concentration in the target tissue, in the target organelle extraordinarily. That leads to very robust target engagement, and the pharmacology follows.
That really differentiates us from all the existing tech, technologies which either are very unstable themselves in the circulation, so they get rapidly cleared and cause kidney toxicity, and thus require higher dose. With a low dose, we can get very good concentration inside the cell. With the result, we get very high therapeutic index.
Great. Clearly, there are many potential indications where this EEV platform would be very useful. Could you just explain your thought process why you chose DMD in particular as the lead program for this? And what data has gotten you really excited about the opportunity here?
A lot of focus has been on monogenic diseases. For example, DMD is caused by genetic mutation deletions in the gene itself, where you can restore the reading frame by skipping an exon. That way the translation between animal model and human becomes very simple because we are not talking about complicated disease. That is one thing. Secondly, coupled with the fact that we can get to the muscle and especially cardiomyocytes in the GFP mouse model. That is really thinking, you know, here is a monogenic disease which could translate quite well. The existing medications that are approved have 1%-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. That was the thought process that helped us land on DMD.
Mm-hmm.
I think just adding a little bit to that, Steven. These young boys then who become young men ultimately succumb to a cardio event, whether it's cardiomyopathy as a cause of death. The ability to really target the heart with a therapeutic becomes really important here. I think some of those data that we have, you know, presented and have studied, you know, aggressively are one of the reasons why we get very excited about our approach within DMD. I'll add to that a little bit in terms of we've done extensive research, right? As Natarajan said, it's this is a rare monogenic disease with high translation, right? We've started with a canonical model, then we've gone to a very high bar model, and then non-human primates.
Ultimately, of course, you know, we'll go into humans. All of the models that we've used have translated quite well, both from an exon skipping perspective and then, of course, from a dystrophin production perspective. Importantly, the duration of activity that we've been able to demonstrate has been quite high. We hope that we see a dosing advantage here as well too, for the patient. 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.
Yeah, we think you've shown some pretty exciting results in those various models showing exon skipping dystrophin production in multiple different tissues. I wanna touch on that point. You talked about the durability. I think recently you published some data in non-human primates showing exon skipping out to a certain time period. We'd love for you to maybe discuss those results and how that will inform your clinical strategy going forward.
Sure. Do you wanna-
Yeah.
Okay.
Yeah. What we are seeing in non-human primate is quite extraordinary. After a single dose of lyo reconstituted PMO, we see exon skipping going out to 12 weeks. It starts off at very, very high levels of 85% exon skipping and then continues to be quite high even at 12-week period. That could translate potentially into very convenient dosing schedules for patients. Right now we are guiding towards at a minimum of six weeks between two doses. 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.
Thinking about it from an NHP perspective now, with what Natarajan said, with the durability here and duration, it certainly informs our clinical strategy. You know, our clinical strategy will first start with a single ascending dose study within healthy normal volunteers. Then based upon the learnings from that study, we will progress to patients and use a multiple ascending dose study. It's a very calculated way of being able to get to patients relatively quickly. I think importantly, there's been precedents here as well too. We can follow some of the path from other companies that have gone down this path before.
Yeah, definitely. I guess I'd love to dig into some of the upcoming clinical studies. First, I guess on the other end, we've seen companies developing gene therapies for Duchenne muscular dystrophy, and that would potentially be a one-time dose, quote-unquote, cure. Would love to hear your thoughts there and why you think exon skipping is really the right approach for these patients.
Yeah, 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, you know, 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, you know, hopefully, one of these stick. Now, gene therapy and I'm gonna 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?
The rigidity of going with a gene therapy approach to a disease in young, you know, young boys who are growing, there's a disconnect there, right? So far, we've seen, you know, some issues around toxicity. We've seen issues around duration. Remember, as you said, like, gene therapy is one and done, so you can't redose it, right? I think there's more questions that are out there than answers right now when it comes to gene therapy. When we view that, and we view our approach with our exon skipping approach, we look at the inverse of that, right? 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. You know, would hopefully provide a nice course of treatment for these patients. We've seen a safety profile that's you know, quite attractive as well too. 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?
Yeah. One thing to add is, in gene therapy it is microdystrophin, whereas when we exon skip it is closer to dystrophin. I think that is also a big differentiation.
Yeah, definitely. Okay. This program is approaching the clinic. You've announced an IND is expected in the fourth quarter. Can you just talk about gaining factors to IND, what, if any, new data we might see before then? Then, I'd 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, you know, we're. The only step that's really left between now and submission is just the completion of GLP tox. That that's a normal process, right? Once we get that, then, you know, we'll package everything together and submit it to the agency. Questions that we're trying to get answered from our initial study. Remember, our initial study is within healthy normal volunteers, single ascending dose study. What we would like to understand first and foremost is safety, right? We wanna make sure that this is safety.
The safety profile is certainly acceptable for the HNVs before we get into patients. 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, you know, remember that, you know, these are healthy normal volunteers, right? They have a fundamentally different physiology than a patient that has DMD. But it nevertheless is something that we will also measure.
Okay. To the extent you can, could you 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'd love to just know a little more detail, if you could.
Do you wanna take that one?
Yeah. The dosing interval that we are guiding to is a minimum of once in 6 weeks. Apart from looking at exon skipping, we will also look at distribution, see how much do we get to the muscle in the biopsies. We see very, very good correlation between the amount of drug that we get in a muscle biopsy versus what we get in the, so in a monkey. Similarly, there's 1-to-1 correlation between the drug disposition in a mouse versus non-human primate. That'll 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.
Yeah. There are approved exon skipping therapies, and I know many of our conversations have focused on the translatability of this preclinical data to humans. Would just love to know your level of conviction that the data you're seeing in these non-human primate D2-mdx models will translate to humans.
I mean, I have a very high level of confidence. You know, 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? Once again, we started with a canonical mdx mouse model. It's kind of like the entry-level model. Those data looked really good. The D2-mdx mouse model, which, you know, 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.
Those data, not only the biochemical data, but also the functional data, i.e., like, you know, grip strength and things like that, were remarkable, right? When we got those data, that was another big check in the box in terms of our level of conviction. Finally, the NHP data, right? The NHP data is really gonna measure, you know, toxicity, safety, biodistribution, and ultimately just like levels of exon skipping, right? You know, you can't measure dystrophin since the non-human primates don't have any mutations that are relevant to DMD. You take all that together, and you realize also that there's a one-to-one correlation and the data has been very, very consistent.
Then 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. That's what gives us the high level of conviction for DMD 44 as a starting exon, and then hopefully, you know, 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 Program 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?
It's a good question, and I think the way that we kind of approach it is that, you know, everything gets informed by our interactions with the regulatory agencies, right? The collaborative nature of our discussions with FDA will hopefully, you know, allow us to find a path that's right for the patients. Our current thinking is exactly that, Steven. It's the accelerated, you know, approval pathway. Once again, there's precedent here. There's a lot of precedent here for to follow that pathway, and so we will continue to do that as well too.
Maybe one more, and then Chris, if you have any on DMD before we shift over to DM1. Obviously, your 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 how you're thinking about the additional mutation populations?
Sure. You know, there's over 30,000 patients that have DMD, and there are four primary exons which comprise 40% of those patients. That's Exons 44, 45, 51, and 53. Exon 44 itself has, you know, several thousand patients that are afflicted with DMD. That in itself is a wonderful opportunity for us to pursue first. There are no approved treatments for Exon 44 and the quote-unquote competition is quite limited when it comes to Exon 44. Our strategy would be to, of course, you know, progress as fast as we can and as focused as we are to be able to get data within that population. Of course, also expand our offerings to the other exons as well too.
Once again, profound unmet clinical need based upon dystrophin levels that currently are only between 1% and 6%. There's a lot of need here. There's a lot of room for improvement. There's a lot of patients. We feel as though we have a good shot at addressing, you know, certainly Exon 44.
Okay, perfect.
On that topic of the regulatory, we've touched on this.
Yeah.
A little bit in terms of what's happening now, possibilities in terms of how the pathways from a regulatory standpoint could evolve. We're 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 experience and 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. Yeah. It's a good question, and I've enjoyed our discussions about this. The caveat is, you know, we have to work with the agencies to figure out obviously the right strategy. 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, and 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. It'd be our strategy, of course, to work with the FDA to figure out how to expedite even more our work within the other exons.
i.e., you know, could there be an opportunity to leverage data across, right? Which then of course helps us, you know, 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?
Mm-hmm.
We'll work with, of course, the agency, but importantly, we're also gonna work very directly and continue to work very directly with the patient groups as well, who obviously understand the disease, you know, very, very intimately as well too. All those are on the table.
Mm-hmm.
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.
Mm-hmm.
for these patients.
Right. The urgency certainly seems unquestioned.
Yes.
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're 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, you know, very foundational, thinking that goes into your approach of what needs to happen when.
Yeah. Look, I think every company is in a rush, right? I think they're in a rush for the patients, they're in a rush for their investors. For us, it really starts, you know, 5.5-6 years ago, when Natarajan and I first, you know, came to this company, him before me. It's really following the science. Where is the science gonna take you, right? What questions do you need to ask? What questions do you need to have answered? Especially with the novel technologies as well.
Mm-hmm.
Like this one is. For us, we have to stay very disciplined. We have to stay very focused. Don't get us wrong, it's like the old analogy of a duck in water right above. They're, you know, very calm, but underneath they're churning and they're continuously moving, continuously thinking, continuously trying to be creative. We have that. 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. I think a lot of that's discipline. You know, I think there's a lot of things that we can't talk about, of course.
Mm-hmm.
at the end of the day, you know, we're working as fast as we can to get these treatments, you know, to the patients. We will not jeopardize the timelines or things like that. Because at the end of the day, that's not what we're about.
Sure. No, that makes sense. Steven, leave me two 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 timelines, but yeah, what preclinical data got us to this point? Again, this is a field where there is high unmet need, no approved therapies, but there are competitors. How do you see your EEV approach and general, mechanistic rationale, competing and differentiating-
Sure.
In the landscape?
Let me set the stage and then, you know, Natarajan, of course you can walk through the science a little bit. As you said, DM1, profound unmet 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. You know, 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, you know, the formation of like two camps, right? You have one camp that's going after the knockdown of DMPK, and Natarajan will get into that into more detail.
You have another camp, which is really focused on what we're trying to do, which is, you know, 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. You could talk specifically.
Yeah. Our approach compared to others is allele-specific. You have a normal allele which doesn't have a large number of CTG repeats, and then you have alleles with a large number of CTG repeats. When we look at the mRNA, our approach is to block the mRNAs that have CUG repeats, so that we can relieve MBNL1 and correct the splicing. The other approaches people said is to degrade all DMPK mRNA. That's one huge differentiation. Ultimately we think that DMPK has a normal function and it'll be an advantage not to disturb that.
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. That's a huge differentiation for our technology. Secondly, when we think about a multisystemic disease like DMPK, DM one, where you need to get to tissues other than muscles as well, a technology like EEV technology where you get a broad distribution across the body will have a huge advantage. The PMO chemistry itself is a lot more safer than the other chemistries that probably ultimately will be safer for a disease like DM one.
Mm-hmm. Here, given that 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.
Yeah. 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, alternative splice forms of key proteins. Correcting the spliceopathy, as it is called, is critical. We show that, you know, the models that we use really reproduce both spliceopathy as well as the myotonia. We're able to robustly correct that in animal models. 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. That gives us a lot of confidence this is very translatable.
Okay, maybe one last question. We're nearing the end of time. Do you have internal expectations about the level of splicing that you need to see, to achieve these functional benefits?
Yeah. That's currently, you know, we had a good meeting of KOLs, you know, the experts in the field. There is no consensus. There are a number thrown around like 20%, 30% by others. I don't think, as a field we know what percentage of splicing correction we need to do. In our assays, we are getting very, very good splicing. That needs to be determined. Yeah, we are working with natural history study that is currently undergoing to look at patients with different extents of CUG repeats, correlating them with the phenotype that we get so that we can, and looking at the splicing isoforms to get to that answer. I don't think that the answer exists yet.
Okay. No, we'll definitely look forward to advancing to the clinic additional preclinical data.
Yeah. Just to 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.
Mm-hmm
From a market perspective and then, you know, integrate those learnings into kind of like a second mover advantage here as well too. 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. But so far, the data looks fantastic from our side and the KOLs believe so as well.
Okay, great.
Perhaps to close on two things. One, perhaps related to some intangibles, which nonetheless embedded within that is always tremendous, intrinsic value. Just something that's very more matter of fact and classic to punctuate from a numeric standpoint. On the intangible side, you know, we're seeing this paradox. Companies that are pursuing innovative science, the robustness and the level of activity has, you know, everyone articulates how tremendous that is. On top of which, you guys are located in the Boston-Cambridge Seaport area, which is literally this mosh pit, this 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?
Thank you, Chris, for that. It is a highly competitive market. I mean, we are fortunate that we have a very low turnover compared to the Boston market. I really think it 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. There's values that are associated with that, right? Including collaboration, honesty, work hard, you know, help your teammates out, be real, be accessible, be present, and things like that, right? I think that resonates really well, right? We also, once again, you know, we follow that science, right? Our labs comprise 80% of the employees, right? Of the company.
We're all in this together, and I think that's the common journey really to provide some treatments to patient populations that really need it. We live that. I think that's what, you know, keeps people motivated for sure.
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, you know, proof of concept.
Yep
The progress points that you can be able to generate that's embedded within that item.
Yeah. We're in a fortunate position, as you know, to have 2 years of cash right now on the balance sheet. Our cash, as you said, runs into the second half of 2024. That was carefully constructed during our IPO in that we wanna be able to get through inflection points. We wanna be able to submit the IND for 44. We wanna be able to get into the clinic, into healthy normal volunteers, showcase some of that data in 2023. Proceed with Exon 44, 45 as well too, and then get DM1 through, you know, an IND as well too. We think it sets us up really well over the next couple years to be able to achieve those goals.
Perfect. Eyes on the prize. The journey continues. Thank you, gentlemen, for joining us.
Thank you, Chris.
Thank you.