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

Good afternoon. Thank you all for being here today. My name is Raji Gunasekera, I'm a Vice President on the health care team at JPMorgan. Pleased to introduce a company that's doing very exciting things in the DMD space. Today, we have Entrada Therapeutics. And I'm excited to introduce you to the CEO, Mr. Dipal Doshi. Thank you.

Good morning. Thank you, Raji, and thank you to the JPMorgan team for inviting us to present. So I look forward to talking to you today about Entrada and frankly, what we're up to -- it appears to clinker, sorry. Okay. Before I begin, and I'm going to read this off the slide. I need to remind you that during the presentation, I will be making forward-looking statements. Please refer to our public SEC filings for risks and uncertainties that could impact our business. So now to the good stuff. So Entrada enters 2025 with a significant amount of momentum. We're starting this year on a really good foot. And by the end of the year, if we fast forward 12 months, we expect to have 4 Phase I multiple ascending dose patient studies in DMD and DM1 by the end of this year. So it's a fundamentally different company and a tremendous amount of growth that we anticipate between now and then. Our positive results from our ENTR-601-44 study, which was in healthy normal volunteers, have really enabled us to rapidly expand our DMD clinical franchise. And now we expect to have 2 global Phase I MAD studies in the first half of 2025 and 1 in the second half of 2025. We also have a very strong relationship with Vertex Pharmaceuticals, and they are accelerating the DM1 program that we licensed to them not too long ago. And specifically, they've initiated the MAD portion of the VX-670 global Phase I/II study to evaluate safety and efficacy. That partnership continues to be fantastic, very collaborative and Vertex is doing exactly what Vertex does and really looking at this from the patient perspective and expediting this trial based upon the data that has been presented to date. So really, the tip of the spear at Entrada is neuromuscular with DMD and DM1, but there's more than that. And we look forward to sharing more of what Entrada can do. And we are generating preclinical data outside of neuromuscular programs that include [indiscernible] and other exciting things that we'll talk about a little bit as well, too. The company remains very cash efficient and I'm proud to announce that we've expanded our -- extended our cash runway into the second quarter of 2027. So it allows us to get through a lot of very, very meaningful inflection points along the way. So really, at the end of the day, 2025 really represents a very, very important year for Entrada. So just to take a step back, our mission really is to treat devastating diseases with intracellular therapeutics. But one of the key aspects of my job that I really enjoy is interacting with the patient groups. And what we commonly hear from them is one, I think, from an industry perspective, they're happy with the fact that we're focused on these diseases that don't get a tremendous amount of attention. But they also ask what's next, right? And how can we help their child or their young adults. And that's something that's core to the Entrada message. And so we are really working on developing safe and effective therapies, not only for Duchenne patients, but also for DM1 patients and other diseases for both pediatrics and young adults. So let's talk a little bit about how we do this, right? So Entrada, as I said, is really based upon intracellular therapeutics. As we know, the majority of cells -- I'm sorry, the majority of disease cause and targets are inside the cell. And if we go left to right here, we see that 75% of diseases are caused inside the cell. The problem and the challenge for this industry is that we don't have a very efficient or viable way to address these diseases. And that's where Entrada fits into this problem. And so what we have been able to do is essentially look at the natural biology of a cell, which essentially clears the therapeutic before it reaches its intended target and turn it on its head. And that's like the magic or the magic sauce of Entrada. And what we do is we utilize what we call endosomal escape vehicles or EEVs, which are a family of cyclic cell-penetrating peptides that have some very unique properties. And those properties include increasing the cellular uptake and improving the endosomal escape, which is extremely important and key to Entrada. The ability to get out of the early endosome and get to the target that we want to get to is really core to the thesis of this entire company. And frankly, is what our data is based upon, which we'll come back to. And what we've been able to do with these EEVs and these EEVs conjugated to oligonucleotides is develop what we think are potentially best-in-class therapeutics with an initial focus on DMD and DM1. So let's talk a little bit about these EEVs and what makes them so special. So how does this all work, right? So there's really 4 key components of the EEVs. And we have a little caricature here, but it really starts with the ability to get into the cell. So there's about a 90% uptake into the cell. And the reason why we can do this is because of the unique chemistry of these cyclic cell-penetrating peptides. Now the cyclic structure of these EEVs allow for both an extended half-life and increased stability, which is really, really important when you're going after these intracellular targets. What we've been able to show within our data is the ability to get out of the endosome. But then what the data, which I will present to you will show is a consistent and predictable pharmacokinetic profile, which is fantastic and fascinating at the same time. All of our DMD programs that we're currently -- that I'll speak to you today about and DM1 all use the same EEV. So what we've been able to see is consistent parameters of being able to get into the cell, out of the early endosome and then to the target that we need to get to. And that leads us to what a robust pipeline looks like today. So top to bottom, and as any company, this can extend, this can contract. But when you look at the ability to get into the cell and out of the endosome into a target, this pipeline can expand to 2 to 3 to 4 pages because of these unique characteristics. But today, we'll start with DMD and DM1. But we're also looking beyond neuromuscular. And through this year, we look forward to sharing more data around ocular as well, which once again has another profound unmet clinical need and then also sharing more information about other methods of how we can actually address these diseases from an intracellular perspective, including areas of interest in terms of gene editing, mRNA delivery and a very, very interesting antibody platform that we've developed. So lots of shots on goal, which I think is obviously, a terminology that's used a lot, but this is truly lots of shots on goal for us. So as I've said, these EEV therapies have the potential for best-in-class data within neuromuscular diseases. So let's dive into this a little bit. So as I also mentioned, we delivered this positive Phase I data in 2024 for our ENTR-601-44 program. What we saw here is not only a robust clinical validation within healthy normal volunteers, but more than that. I think it's really important that there were no, I mean, and absolutely no treatment-related adverse effects. And that's a big deal for this class of therapy. We also showed remarkable target engagement and muscle concentration and plasma concentration as well. And importantly, for these patients, the ability to have dosing regimen that is flexible, but also long in duration is really important. So really, what we plan on doing in the clinic is looking at this from a 6-week dosing interval. So the ability for the patient to come in every 6 weeks. These strong translational data within our ENTR-601-44 healthy normal volunteer study have really allowed us to essentially put pedal to the metal, so to speak, and leverage those data to push forward our 50 program, our 45 program and our 51 program. Once again, they all use the same EEV. And we feel as though the ability to go after all 4 of those targets will allow us to pursue an efficient direct-to-patient clinical strategy. It all starts with leveraging the nonclinical data and the clinical healthy normal volunteer data for the 44 program. As I said in the opening, Vertex partnership continues to further validate the platform as well from an EEV perspective. The 670 program continues to move quite well. They completed the SAD portion of the study last year, and they've initiated the MAD portion of the study as well, too. And that MAD portion will not only evaluate safety, but also efficacy for patients with DM1. So we're very excited about what Vertex has to share in the months to come around our DM1 product. So when we think of how this 44 program, the healthy normal volunteer study read out, the design of the program on this slide was a very efficient design, 24 subjects on the study, normal randomization of 6:2. And the outcome measures really were safety and tolerability, followed by the evaluation of PK and PD and then target engagement by exon skipping. And what we were able to show here was exactly that. We went up to 6 mgs per kg and the clinical safety up to 6 mgs per kg, as I said, was very clean. And we really do feel as though there's a potential for best-in-class pharmacokinetics and pharmacodynamics in patients. So safety is paramount, right? If you look at the class of therapies that we are evaluating, especially with the naked PMOs that really started this industry from a DMD perspective, safety is something that, of course, every agency is going to look at, and we're going to look at and parents are going to look at as well, too. And so it's a little bit of a graph here, but what's important here is the fact that out of the 24 patients or 24 subjects on the study, no adverse events related to the study drug. The most common was really a headache and I believe a toothache, but no clinically significant findings with lab values, et cetera. So very, very clean profile, which is one of the key reasons why we're taking this and moving it expeditiously into patient studies. I went backwards, sorry -- Great. So pharmacokinetics, right? So I think this is super important. We go left to right. When we think of the plasma concentration, you can see that as the dose increased, so did the plasma concentration. So a very dose-dependent relationship between the product itself and how -- the concentrations within the plasma. And so that high drug concentration supports a potential efficacy at very, very low doses, and we'll come back to that as well. On the right side of the slide, it's a little bit -- very, very fascinating and very interesting from a PK perspective. But what we've seen here is that for every doubling of the dose, there is more than a doubling of the metabolite excretion, right, implying that there's a potential for increasing the efficacy without increasing the potential risk of toxicity or safety. This is a fascinating finding, right? And the pharmacokinetics profile of the HNV study for this drug really has propelled us to say this could potentially be best-in-class. And we're happy to answer questions around the pharmacokinetics during the Q&A. So once again, at 6 mgs per kg, what we were able to show was a remarkable target exposure and engagement. So left to right, once again, if you look at the skeletal muscle concentration, what we were able to see, you can see where we were at 3 mgs per kg and then where we were at 6 mgs per kg. So a dose-dependent relationship between the 2. On the right side, from an exon skipping perspective, and for those of you that are not familiar with DMD, it starts with exon skipping and then ultimately hopefully leads to dystrophin production, which is what the patients are lacking. But what we were able to show here was a robust target engagement as measured by exon skipping and a statistically significant response here as well. So once again, the recipe for -- another component of a very solid recipe for a potential drug for these patients. And so when I talk about acceleration, right, and not starting with 44, but going into 45 and 50 and 51, this is what Entrada is up to. In the last year, our guidance was that we were going to submit regulatory applications for our 44 program and our 45 program. I'm happy to report here that we did do that late last year. And so right now, for our 44 program in the U.K., the U.S. and the EU, those discussions are underway with the regulatory agency. So we're excited about that. And in the background, we're, of course, preparing for our Phase I/II studies. For our 45 program, we're going to adopt an ex-U.S. strategy here, so we're going to go ex U.S. and then bring those data back to the U.S. And why we're doing this is because of the efficiency around going ex U.S. and then coming back the U.S. And so we're excited about that. But then 50 and 51 are right behind that. So it's a staggered approach. But 50, we expect to submit our regulatory applications in the second half of 2025 and then hopefully start our Phase I study in Q4 of this year. And then for our 51 program, we selected the candidate in December of 2024, and we expect to submit those regulatory filings in early 2026. So you see the staggered approach from a DMD pipeline perspective. So we're really excited. It's a very, very busy year. And as you can see on the right side of the slide, the epidemiology around these patients is quite robust, especially considering the profound unmet clinical need based upon the current therapeutics that are approved today. So we really feel as though we have a very, very unique value proposition here based upon the data and, of course, the opportunity. The clinical strategy is very efficient. And what we are adopting for our 44 program, our 45 program and the 50 program are very, very similar. The 44 program and the healthy normal volunteer data that I discussed is the only healthy normal volunteer study we plan on running. Every other exon that we focus on will go direct to patients. And that's what we have here, right? We have a multiple ascending dose study to really kind of understand what the dose is going to be and then we go in straight into a Phase IIb. And you could see here from the 44, 45 and 50 program, that's what we expect to do. In the U.S. We believe that the accelerated approval pathway will continue to be open, especially for diseases that have such a high unmet clinical need. And so we will continue to pursue that. Ex U.S., of course, is a different regulatory mechanism. However, we will continue to push forward with regulatory approvals there as well, too. So once again, a very, very busy year with a very, very robust clinical regulatory strategy but a very efficient strategy that would allow us to move these programs forward with haste. And so from a DMD perspective, in summary, we feel as though we have a robust preclinical data set, it supports a direct-to-patient strategy for a Phase I/II MAD clinical studies across this franchise. Pushing away from 44 for a second, the 45 program from a preclinical perspective, we showed robust dystrophin restoration in the del44 human dystrophin DMD mouse model after just 3 doses, and those were 6 weeks apart. We also showed, which is really important, a complete functional correction and maintenance of correction, 6 weeks post wash out. I don't know if those data have actually been presented before by anyone who's looking at DMD, but the complete functional correction is a big deal. For our 50 program, we've shown robust dose-dependent response and saturation of exon 50 skipping in the human DMD mouse model. Once again, after 3 doses, 6 weeks apart. And so we feel as though those data will allow us to project a very, very high and persistent dystrophin restoration within patients. And then our 51 program, which is behind a little bit for the 45 and 50 program, once again, a dose-dependent response within this healthy -- within this human dystrophin mouse model, and again, the potential for very high dystrophin production as well. So as I said before, from a clinical strategy and regulatory strategy perspective, all of these studies are projected to go straight into patients into Phase I/II MAD studies, and then the regulatory files will continue post that from a global perspective as well. So very, very busy from a DMD perspective. Vertex is very busy from a DM1 perspective. But once again, the tip of the spear, when you look at these EEVs and the ability to get into the cell, out of the early endosome and get to the target in an efficient manner with a tremendous amount of concentration allows us to look well beyond neuromuscular. And what we have on this slide really is what I characterize as Entrada 2.0. And this is the strategy that we will continue to enact outside of neuromuscular. We will continue to look at different approaches with different goals. At the end of the day, we fundamentally do not have a bias as to how we go after a disease. The important thing is the ability to go after the disease and move it in a meaningful way for the patients. And I think we have a lot of tools that we can utilize within our toolkit, so to speak, to be able to go after these diseases. And so multiple and -- many multiple and long-term value drivers. As I've said repeatedly, 4 clinical programs expected in 2025, our 44 program, 45 program and 50 program will all be in the clinic. Our 51 program will have those IND-enabling studies. VX-670 from the Vertex side will continue. And for more information there, Vertex controls that program, so they will disclose as they need to. And then moving beyond neuromuscular, what Entrada 2.0 will look like. This platform, as I said, is broadly applicable to a variety of intracellular targets, right? As I said, 75% of all those diseases are intracellular. And so we have an efficient development framework in place here where we can advance these therapeutic candidates, preclinical data, very, very regimented and thoughtful screening mechanism that's in place here to look across a bunch of different diseases to look in -- look to see how high of a therapeutic index we can get within multiple modalities. And then importantly, beyond DMD and DM1, we will share more data on ocular, but we're also very interested in metabolic diseases as well, too, and a whole host of other things as well. Cash runway, as I said, runs into Q2 of 2027. That's important because it allows us to get through a lot of really key inflection points between now and then. And so we're excited about that. And that's it. Happy for Q&A.

We'll take questions from the audience now. Okay. I think off the top of my head, one of the questions we had was you have potentially 4 Phase I/II multiple ascending dose studies at the end of this year that you've initiated. When do you think we can start to see some patient level data?

Yes. It's a good question. As I said in one of the slides, we have ongoing regulatory discussions with multiple agencies, right? I think we need to finalize those discussions and get that feedback, and then we'll be able to address that. But what I can say is that we are looking to get these trials up and running ASAP. We have a very strong clinical operations team that has scoured the globe from a patient perspective, also from a site perspective. So I think at the end of the day, let us get through the regulatory discussions, and then we'll certainly share that with the public.

Great. I think you may have also mentioned you have about 2.5 years of cash runway, which is obviously great. But any thoughts on how you plan to extend that going forward?