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

Welcome to the conference. My name is Chris Shibutani, I'm a member of the research effort. All the hard work gets done by Stephen Sloan, who's joining me up stage here. Entrada, ticker TRDA, we've known you guys for a couple of years. We're really pleased to have you join us once again, Dipal Doshi, President and CEO; and Natarajan Sethuraman, Chief Scientific Officer. So the business powerhouse through scientific trust. Entrada, even the name of the company has a meaning in terms of foundationally what you guys do. And we're going to get into the details, and Stephen Sloan will ask all the relevant precise questions that think about the model and your pipeline, et cetera.

It's almost [ majority ] say that you're like a drug delivery company. But within that, there is just really a platform and there are strategic decisions that you've made about sort of like where best to apply this platform in terms of scientific probability of success, commercial opportunity. It's very interesting to see how you could leverage that. That's been expressed with different segments where you're aiming, that's been expressed by the potentiality of you doing strategic things, et cetera. So framing that, I think it's very relevant that people get a deeper understanding of that. Maybe you just want to do a little bit of an opening in terms of letting us know who you are and what's important before we go into more details about sort of like progress points.

That's great. That's great. And Chris and Stephen, thanks for having us back. It's -- as you said, Entrada, actually means opening. And so when we were trying to rename or name the company, we are trying to match that up to what it is that we actually do. And that's probably half the story, right, opening. But what's important is that Entrada is really based upon this family of cyclic self-penetrating peptides that we have renamed Endosomal Escape Vehicles or EEVs. And you'll hear a lot of that today. And these little EEVs are foundational to where we are today. And the important aspect of that is the ability to not only get into the cell, but get out of what is called the early endosome. And the reason why you want to get out of the early endosome is because you need to get a therapeutic to -- in our case, the muscle. And the ability to get to the muscle in a profound way with a lot of "Drugs" and in low doses, it's what makes Entrada really special. And so these EEVs cut across a plethora of diseases where there's so many different opportunities, right? So all these diseases that Entrada is focused on suffer from the same issues. In that there is a high unmet clinical need because people just simply can't get to the muscle or current standard of care can't get to the muscle. And so for us our current focus is on Duchenne muscular dystrophy, which is a fatal muscular dystrophy disease that is well studied, but once again, has a profound or high unmet clinical need. And our second disease, which is Myotonic dystrophy type 1, which is the largest muscular dystrophy disease that we just recently partnered with Vertex on. But once again, the common link between those 2 diseases is the inability for current standard of care in DMD that is, because in DM1, there is no standard of care yet. The inability to get to the muscle. And that's where these EEVs become really, really important, and that's what the foundation of this company is.

And there's a lot that's really cool going on scientifically, biologically from an engineering perspective. There are other folks who are trying to deliver all sorts of important stuff, oligos, et cetera. Clarify for us how you would differentiate your platform versus some of the other folks who are on similar missions?

Yes. I think the easiest way to say that is we have -- we have probably one of the best protein engineering groups that are out there, led by our Chief Scientific Officer, Natarajan -- and maybe I'll ask Natarajan to comment on why we are different in that regard.

Thank you. So when we look at other therapies, naked oligonucleotide therapies. The issue there is that -- after infusion, 90% of the drug within 3 hours is excreted through the urine. So bioavailability is very, very low. So you have other versions of that with linear peptides. And linear peptides inherently are very, very unstable. And they get chopped off in circulation. So really, within few minutes they are no different from naked PMO. So you take the same PMO and conjugate it to our EEV, then 90% of the drug remains in the body days after infusion. So the amount of the drug in the body is increased tremendously. And add that to more than 50% endosomal escape. Now we have that low doses, very high concentration in the right tissue, and that results in the pharmacology that follows. We have really best-in-class exon skipping data for DMD that we are very excited about. And that's because of the fact that the cyclic peptides are stable, they are very, very good at not only entering to the cell, but more importantly, as people said, getting out of the early endosomals so that they can go to the nucleus and have target engagement.

And just to be clear, Escape, that's actually a good thing. That's what you're trying to do, right? That's the kind of the final chapter in the journey that's very relevant, maybe not the final, but a very important part of the chapter there is the release once you get to target destination, right? And I think sometimes Escape has multiple meanings. But here, to be clear, it's absolutely important. And then we sit here. A year ago you were with us, mid-2023, continued progress strategically talk to us about your strategic priorities and where things are at, at this midpoint of the year.

Yes. Thanks for that. Yes, it's been quite a lot of progress in the past year for us. And so in this market, obviously, cash is something that's very, very important for lots of companies, and we're pleased that our cash runway lasts into the second half of 2025. And a lot of that is fueled not only by disciplined spending, but also a transformative deal with our new partners at Vertex for our DM1 program. So it was a preclinical -- it is a preclinical program. And Vertex invested $224 million upfront for that and $26 million in equity, and there's a whole host of milestones as well, too. But that was a transformational deal, not only for the patients, but also for the validation of the EEV platform. And so continuing to move forward with our partnership on DM1 will be a very important strategic priority this year. Continuing to move forward and progress our early DMD franchise to get our 44 program, our ENTR-601-44 program into the clinic, is a huge priority this year, followed on by our 45 program, followed on by our 51 and 50 programs. So there's a cadence of events that will occur within our DMD franchise. So that's another huge priority. I think the final priority is goes once again back to the versatility and flexibility of the EEVs. And we started to talk a little bit about -- in a recent K, we talked a little bit about our disease focus and modality focus that is different than oligos and outside of neuromuscular. And we're looking forward to hopefully presenting some ocular data as the year progresses, looking at other modalities such as gene editing as well too, which once again will tie really well to the flexibility and power of the EEV. So expanding outside of neuromuscular is probably the third big priority for this year as well.

Right. And again, this platform is often just guarded and readily used, but it genuinely is and you have a strategic focus and opportunities to flex beyond that. So -- but let's focus with front and center and thinking about that, I'll turn it to Stephen now to go through in a disciplined way, what your projects are and the status -- and take it away, Stephen.

Sure. Thanks, Chris, and thank you both for being here today. Let's start with your DMD program, the lead asset, ENTR-601-44, next-generation exon skipping approach for DMD patients amenable to exon 44 skipping. I think 2 days, the preclinical data has been very strong in our view, some of the -- [ that resulted in ] exon skipping as well as dystrophin production in DMD mouse models as well as high levels of exon skipping in nonhuman primates. Maybe another [ action ]. Can you just walk through incrementally since we were speaking last year, what kind of preclinical data have you put out that gives you more confidence in the platform and this program in particular?

Yes. Thanks for the question. If you look at our nonhuman primate data -- with reasonable doses, we get almost saturating levels of exon skipping in the skeletal muscles. Moreover we get very robust exon skipping in the heart. And that's one part of it. The second part, which is even more exciting, is that after a single dose, we are seeing exon skipping going up to 3 to 4 months. And when we think about patient compliance used to the patients, et cetera, that's very, very important to have a therapy that we have convenient dosing frequencies. So those are the data that have been put out for 44. And we have, of course, given data on 45 again, looks very, very exciting from -- in terms of the very first in class data as well.

I want to dig a little deeper on the question on dosing. I know other competitors, some of the approved agents for DMD showed some pretty exciting clinical data at high dose concentrations, but they really had to walk that back when they got into humans due to some tolerability issues. Can you talk about how you're thinking about this? And yes, you mentioned at low doses you're seeing these profound effects. So should we expect that the doses you're setting preclinically will kind of translate to what we're seeing in humans?

So when we go back to the platform itself, the EEV binds to phospholipid, which are conserved across animal kingdom. So that's why I think our data would translate very well into humans. And when we look at our therapeutic index in animal models, it's -- we have a very good therapeutic index, and we are very confident that we can get to doses which are very efficacious in humans.

I think just to add to that a little bit, Stephen, and it's a very, very good question. It really is all about therapeutic index. And the ability to have the flexibility to go higher, to go lower, go somewhere in the middle, but at the end of the day, having that flexibility to be able to customize your dose and your treatment to the specific patient that is suffering from that disease. And I think the data over the past 12 months, once again, this is arguably the most robust data set across multiple mouse models that are phenotypically representative of the disease. But also the NHPs that are nonhuman primates that we show exon skipping and of course, we show safety in as well too. Those data in combination give us a lot of confidence because of the therapeutic window and the ability to see a translation at arguably very, very low doses when we think about the patients who hopefully will be taking our 44 program.

Okay. Obviously, we're anticipating the Phase I to initiate, hopefully, near term. Can you provide us a range of potential doses they'd be looking at both on the low end and the upper end? Or is it still early days and will we have to wait for that data?

It's just a [ specific qualify ], you mean in the clinic?

Yes.

So it's a good question, right? And so at the end of the day, we have a subchronic study that is -- subchronic NHP study that is ongoing, which will influence the data or the dosing within patients. But when we start to think of the first trial, which is a healthy normal volunteer study, we are going to be evaluating that in a range of doses, right? And so the good thing about that range of doses, which I don't think we've specified what they are, but it is exactly that. It is a range of doses that cut across from the low to the middle to the high. Once again, it goes -- it goes -- it's a testament to the therapeutic index that we've been able to develop with these EEVs.

Okay. Got it. Okay. I know there's been strong data supporting the translation of exon skipping to dystrophin production to clinical benefit. So let's focus on safety, which has been another key aspect. I think some competitors have seen hypomagnesemia. Can you just talk about that adverse event in particular, if you've seen that preclinically and if that's something you'd expect in clinical studies, if you're designing protocols to mitigate those effects?

Yes. So when we look at our animal studies, hypomagnesemia, is not something that we have seen. So we are confident of our data. But again, when we think about human studies, these are easily monitorable symptoms and that our mitigation is already in place for others. So should we find such an event, we can intervene, we can monitor it in domain. And that's what is good about these kind of symptoms, which are easily monitorable and treatable.

But the key there, as Natarajan said, is that, we did not -- we have not seen hypomag. And so -- which is different than what some of the landscape of other companies that are focusing on DMD have seen. And once again, I think that goes right back to the profile of these EEVs and how Natarajan and his team conjugate them to the oligonucleotide.

Got it. Okay. And maybe addressing "the elephant in the room", this program has done a clinical hold since, I think, about mid-December. Can you just talk about this whole -- how we should be thinking about next steps. And I think more importantly, bringing this in the context of development programs from competitors, which I think this field has been riddled with clinical hold, most of them have been overcome. So it's...

Yes. No, and it's a very, very good question. And we haven't -- we don't really shy away from the hold. I think at the end of the day, it is unfortunate that a lot of companies in this division of FDA have been placed on hold. But as you said, Stephen, they do get off of the hold as well. I think at the end of the day, we are very, very confident. As every day goes by and we have a little bit more data, our confidence does not stay the same, it increases around how we view this 44 program in terms of how it's going to work in the clinic. And so the hold, which seems to -- somebody quoted a rite of passage in this division is a temporary work block for us. However, remember, we're doing a healthy normal volunteer study. The healthy normal volunteer study will be in only one country. And at the end of the day, like we will look at every single disease that we are pursuing, we look at these in a global setting. And so we are committed and we're convinced and we're optimistic and frankly, very confident that we will run a trial for a 44 program in healthy normal volunteer studies this year in 2023. We wouldn't be saying that if we were not confident in our ability to do that. So -- and then importantly, as we look ahead in terms of other exons or other DMD programs, we plan on going straight to patients with our 45 program, our 51 program and our 50 program. So our exon 44 program will lay the foundation, and some of that is difficult because we are on hold, and we'll work through that. But once we get through that, it will hopefully allow us to have our 45, 51 and 50 programs go straight into patients. I will also say that the 44 program uses the same EEV as our DM1 program that we partnered with Vertex as well. And so once again, we are very confident in the ability to move these programs into the clinic and in short order.

Okay. Yes. And you mentioned that there is potential for OUS recruitment for this healthy normal volunteer bond share Phase I study. How your development plan taking into account, okay -- like is there a certain time that you're looking at if we resolve the hold by this time, we'll do in the U.S. versus after that, we really need to get this initiated outside the U.S. together.

Yes. No, it's once again, it's a good question. And I think speed is something that's important, of course, right, especially for our 44 program in that -- there are no approved treatments for 44 for those patients who are -- have the 44 mutation. So speed is important. Quality is obviously super important to us as well, too. And so I think for the audience that's listening in, I mean, we are very, very patient focused. We've been working with the patient group since the beginning of the company, a lot of us come from patient advocacy backgrounds as well, too. And we will run this trial for 44, whether it's in the U.S. or outside the U.S., we will run this trial. We will run this trial with the quality that it deserves so that we can get a treatment out there for these patients in short order. So we're not -- whether it's in the U.S., whether it's outside the U.S., we continuously navigate the time lines between the two. But at the end of the day, all that matters is what's the right thing to do for patients, and that's the north star for us.

Got it. Well, we definitely look forward to developments on that front and hearing more about the study. Maybe we can move on to the second DMD asset targeting exon 45 where there are approved assets. Can you just remind us from an epidemiology standpoint, how these 2, exon 44 versus exon 45 patient populations differ, and if there are unique considerations when developing a candidate here or running clinical trials in patients.

Yes. I'll address the first part and then Natarajan can address the second. So epidemiology-wise, our ENTR-601-44 program represents roughly around 7.5% to 8% of those patients that are in the category of 44, 50, 51, 45, 53. And so that roughly translates to 2,000 or so patients in the U.S. and EU. 45 is actually similar in a lot of regards. It's a little bit bigger. So it represents roughly around 8% of the population, which then translates to roughly 2,700 patients. The difference, side to side, for a second, Natarajan will answer that. The difference is that there is an improved program for 45. And I think that's important. And -- but there are no approved programs for 44, so it's a little bit more open. But the -- for 45 specifically, maybe you could talk about how that data looks and specifically also about how it's looking when we think of it from a landscape perspective.

Yes. So when I start with the data that we have. In vitro, we have shown very robust exon skipping. And that translates very nicely into dystrophin production and functional data as well in vitro. In human DMD mouse model, we have shown very robust exon skipping, not only in the skeletal muscles but also in the cardiac tissue. So very exciting data. In terms of differences in diseases, each exon is almost like a different disease from that perspective. The internal/external junctions are different and the amenability for exon skipping is slightly different between each exon. And of course, when you make a protein that is deleted in a few exons, the stability of those proteins are also different. But 45% and 44%, as Dipal said, that's somewhat similar in this category.

Okay. And I guess, digging a little deeper there, is the quality of the dystrophin in either of those patient populations better. And do they have a different clinical phenotype on the whole?

So the -- from the quality of the protein point of view, you have EMD patients, which are real evidence that you can skip these exons and get a quality protein that shows enough function for these patients to be different from DMD. So DMD really gives us an idea of how -- whether there will be a functional correction in these patients when you skip these 2 exons. So from that point of view, we are very confident that for both these exons as well as for 50 and 51, we have a good path forward.

I think the foundation even of the 44 data and the amount of work and the amount of analysis that's been done across the canonical MDX mouse model, the D2 MDX mouse model, the human dystrophin mouse model then, of course, NHPs, we'll cut across 45 to 51 to 50 as well too. So foundation in 44, great exon skipping, really encouraging dystrophin production, long duration, which is really important and also low doses, we feel that those 4 characteristics will cut across the other exons as well.

And thinking about clinical development, as we've talked about, there are approved options for exon 44 or 45 amenable patients. How do you envision that impacting patient enrollment when you do start patient-based studies. And I guess the additional consideration now, potentially near term will have an approved gene therapy for these patients. Do you expect competition for these patients and the likelihood -- or they're just talking about that general...

Yes. I think at the end of the day, these are -- the DMD patient groups and the patient advocacy efforts around DMD are remarkably sophisticated. And the patient groups have been working on supporting treatments for years. And I think the parents of the -- whether they're young boys or young men who have this disease are very cognizant of the different data that's out there for these diseases. And I think the data will drive enrollment. And all we could say for 44 because there is no real competition there right now is that, those data are compelling. And those data will carry over to 45 as well, too. But like a lot of companies, we will work with the patient groups to enroll these studies diligently across the globe. I think to your question around gene therapy, I think a lot of us watch that ad -- [ come and ] listen into that [indiscernible] very closely 8 to 6 votes. I still think there's a tremendous amount of questions that have remained unanswered around the gene therapy program. And we're excited that there might be an option here as well too. But if you really take a step back, the same questions are still there. Microdystrophin is still something that's not well understood. Gene therapy for DMD still has the issues of dosing or redosing and a waning effect and the inability of starting to stop. And those limitations really kind of lend well to a much more flexible approach, which is what our EEVs are and our EEV-led therapeutics are in that we are able to customize dosing to a patient. We are able to have these remarkably long duration of effects. Right now, we're targeting at least dosing every 6 weeks, which standard of care is every week. And so the profile or the therapeutic product profile what we're developing here for our DMD programs are -- they mirror a lot of the benefits or perceived benefits that these gene therapies have. And so -- but they just have the flexibility around doing what's around meeting the patient as to where they are at a certain time period.

Got it. Maybe one last question on DMD before we move on to some of your other programs. Related to this point, we're just talking about, how do you think about designing clinical enrollment criteria for your DMD studies? Because if there is an approved gene therapy and for 45, there will be approved therapies, will you allow patients that have had prior therapies? Or are you looking for naive treatment naive patients?

Yes, it's a good question. I think only time will tell, right? We don't know what the label is going to look like for gene therapy. I think that's first and foremost, right? And so we don't know what the exclusion criteria is going to look like in terms of what the label says. So I think we have to kind of push pause on that and see how that evolves. For 45, I still think, once again, we'll work with the patient groups, and we will work to enroll the study and whether or not they need to be treatment naive or have a washout period from a specific for casimersen or whatnot, I think remains to be seen. But what does not remain to be seen is the fact that exon 45 has a profound unmet clinical need. And so at the end of the day, the data is what's going to drive hopefully the patients to enroll into a specific study.

Got it. Okay. That's all very helpful. Let's move on to the DM1 coverage from Vertex. I'm curious what peak Vertex's interest in your program, obviously, you do have a strong preclinical database and interesting results there. There are other programs further along in development, some with clinical data. So what made them choose your program over the others?

Yes, just to be -- just to use one word, it's just data, right? And at the end of the day, the data that they saw and how that data can frankly convert, hopefully, into a clinical drug that helps patients check the boxes for them, right? And so they did a tremendous amount of diligence on the asset. And they know the asset extremely well. They know the disease extremely well. But I think at the end of the day, Nataraj can get into more specifics. But the fact of the matter is that the specificity of this approach is really important when you think of some of the other companies that are going after DM1 from a DMPK knockdown perspective because it could be indiscriminate at times as well, too. But the specificity of this allele-specific focus that Entrada has developed for DM1 is probably what peaked our friends at Vertex, but maybe you can go to the...

Yes. I think that's a very important point, right? So when we think about allele-specific knockdown of DMPK, so you -- that way, you preserve the function of DMPK and just get rid of the pathogenic part of the mRNA. And also the data, right? So when we look at the splice correction and myotonia correction, we have best-in-class data there as well. The duration of effect, again, is very profound. So all of that added up.

Got it. And can you remind us of Entrada's responsibilities in this collaboration? I believe you're still responsible for some development early on, just speak to that.

Yes. I mean it's a pretty stringent delineation of responsibilities. We're responsible for all the preclinical work. And they mean Vertex are responsible for regulatory, clinical and commercial. So essentially, anything past the IND is Vertex's responsibility.

Got it. And obviously, Vertex is one of the premier larger biotech companies. Can you speak to what learnings you've had. Obviously, you're working very tightly together, and I'm sure the way they look at development is slightly different than the Entrada team does via what takeaways have you had the...

Yes. I mean I think the common vision of the management teams of both companies is really, really important. And I think we all collectively see the world in the same place or in the same way. And so our learnings are -- they're remarkable what they've done with CF and what they're continuing to do with other diseases being a trailblazer in terms of commitment to the patients, commitment to the data, creativity, sense of urgency is something that is infectious in a lot of regards. And I think we frankly -- we know we're a lot smaller. We strive to be what they are as the company continues to build and taking a lot of that knowledge, having our teams work together allows us to be able to learn from some of the things that we may not see in that they have seen. And DM1 is a clear example of that because the story for DM1 is still being teased out. And what clinical endpoints are going to look like, what approval endpoints are going to look like, there's ambiguity around that as well, too. And working with the Vertex team that's dealt with this many, many times is something that is really important for us to learn from them as well.

Great. And are you at liberty to discuss kind of the progress of this program, what the next updates would be? We should expect the time lines to be generally similar to how Entrada had laid them out initially?

Yes. I think unfortunately, I know Reshma presented yesterday, but we -- they really control the time lines because most of the updated time lines are going to be regulatory and clinical. The preclinical package looks really, really good, and we're confident in that. But right now, we'd have to defer to them in terms of time lines for clinical trial initiation.

Okay. Now looking for updates on that front. And then as you alluded to earlier in the presentation, and trials not just about DMD, not just about DM1, you have this very compelling platform that could be applied to multiple new modalities as well as disease areas. Can you just talk about the progress here, what you find most compelling? And then you're an early-stage biotech company. How do you balance these priorities given that there's only limited cash to go around?

Yes. So I'll start a little bit at a high level and then Natarajan can hopefully talk a little bit more about like why we're so excited about our non-neuromuscular program. At the end of the day, we all have to make choices. And yes, cash is finite. A good thing we don't have to raise cash in the immediate future in this year. However, for us being able to focus on diseases of high unmet clinical need, being able to focus on diseases where we think that the platform will be able to substantially change the course of the disease is really, really important. And we've shown that with DMD, and we're showing that with DM1. What we don't want to be is a company that's good at a lot of little things, right? Because that doesn't move the needle, right? What we want to do is be able to show our commitment within the neuromuscular disease is to use that as a launch pad for these other diseases. Have the same type of critical features in terms of how we prosecute data, how we -- how our scientists are curious about different experiments. The thoroughness of our concentration within looking at those diseases. And answering the question, like what will move the needle for a patient. That's what's going to drive us -- that's what's driven us in neuromuscular and that's what's going to drive us in nonneuromuscular. And specifically, maybe we can talk a little bit about some of those areas.

Yes. I think when we look at the data for DMD, right, and when we look at dystrophin expression restoration in a muscle, not only us, but most of the experts in the field are excited how uniformly we can cover a tissue. And that speaks to the versatility and modularity of the platform. And then we asked the question, what are the other areas that we could go and that we would be differentiated because of our platform. We had overly guided that we are looking at ocular indications. Again, getting to -- in retina and others is not all that simple for other platforms. You may have edge there. The other thing that we are looking at is gene editing, where you have that you have CAS 9, you have guide RNA and they have to be delivered efficiently. EEV has size constraints when can we look at the whole field without the constraints of a size. So those are things -- some of the things that we think about that are very exciting in the near term.

Got it. And obviously, it's early. Is there any time frame where we should be expecting more updates from those programs?

Yes. I think you guys know as well in that we won't unveil a lot of this until we're absolutely ready to share those data, but the fact that we're starting to speak to it shows our level of confidence. But hopefully, we'll have more to share as the months come.

Okay. And Chris, I'll turn it over to you after this last question. But as we sit here, looking forward, say, 12 to 18 months, maybe this time next year, we're hosting you again, what will Entrada look like?

Yes. I think it's going to look very different. I think it's going to be a step progression. And I think we can look at last year to this year as an example for that. So for next year, 44 in the clinic, 45 on the verge of an IND or a regulatory submission, could be an IND could be something else as well, too. That will go straight into patients. We'll have announced a candidate for our 51 program or 50 program. DM1, of course, will be further along as well, too. And we will have shared the aforementioned really compelling non-neuromuscular data. So I think at the end of the day, it's just going to be a progression in the clinic. And starting to see what else. What excited us 7 years ago when we started this company, hopefully starts to come even into more fruition.

Perfect. Well, thank you both for joining us and for the insightful comments here. I think the space that you guys are part of interrogating, particularly from the clinical development side and the scientific innovation is fascinating to watch. So we will look forward to monitoring your progress and exciting second half of the year. Thank you both.

Thanks, guys.

Thank you. Great job, Stephen.