Presenting Mr. Nathan Dowden, COO and President of Entrada Therapeutics.
Thank you very much. So first of all, thank you everybody for coming. Thank you to the folks online. Thank you to the Wainwright team for setting up this wonderful event. Thank you to everybody who's participating as we go through this week. I have 20 minutes, so I'm going to run through this very quickly. So my name is Nate Dowden. I'm President and Chief Operating Officer. I've been with Entrada for about five years, since we had 20 people. We now have over 170 people. And just very quickly, Entrada is in the business of treating devastating diseases with intracellular therapeutics.
We have a proprietary platform that I'll go through in just a second, that allows us to do this incredibly efficiently and to treat devastating diseases like, for instance, Duchenne muscular dystrophy, which I'll talk about in just a second. So from a high-level perspective, where are we at Entrada? So right now, we have multiple programs that are either in clinic or moving into clinic. We're advancing new therapeutic options for people living with Duchenne, first with our ENTR-601-44 program. So we ran a healthy, normal volunteer study this year in the United Kingdom. That study exceeded our expectations. We got remarkable data out there, including dose-dependent responses, significant plasma concentration, muscle concentration, and target engagement as measured by exon skipping.
Most importantly, even at a relatively high, and we think will be clinically relevant dose, we had completely clean safety, no serious events, no adverse events, no treatment emergent events, no clinically significant changes in laboratory assessments. And so we think that's going to translate as we move into the clinic in patients with our new global study that we are filing paperwork on across the globe in Q4 into clinically relevant responses, both at our starting dose and then really remarkable dose responses as we dose up. ENTR-601-44 and ENTR-601-45, our second DMD program, will be filing more or less at the same time. These will both be multi-ascending patient studies that will then transition into phase II-B programs. Those will be followed by ENTR-601-50, which will be coming early next year.
All of those, again, moving directly into patients. We completed one healthy, normal volunteer trial. That was a success, and we don't plan to do another. That's basically the basis of our DMD programs and our DMD franchise. Beyond that, we have a transformative partnership with Vertex for the development of myotonic dystrophy Type 1. A large neuromuscular disease, over 100,000 patients in the United States and in Europe, and that program is in clinical trials. Vertex is running the clinical trials. That's in a phase I/II, SAD/MAD. Vertex has said that they expect to complete the SAD portion of that trial by the end of this year, and if you look on ClinicalTrials.gov, the full study should be done by the end of 2026.
That partnership has allowed us to expand the company quite significantly actually, and we have an expanding pipeline of both neuromuscular and non-neuromuscular assets that are working their way through discovery and research, all based on the exciting platform that I'll describe in just a minute. From a financial perspective, we're in extremely strong financial position. We have cash runway into early 2027. As of June 30th, we had about $470 million on the balance sheet. And so we're in a strong position to execute on our strategic initiatives. This is a quick snapshot of the pipeline. This basically depicts what I just mentioned earlier. So to take this forward, so what makes the Entrada program special?
Why do we see therapeutic index, at least in the animal models that we've run, and now increasingly, as we move into the clinic in humans, that's remarkable and perhaps unexpected? It begins and ends with something that we call an EEV, so an Endosomal Escape Vehicle. So these are small cyclic peptides that we chemically conjugate to a wide variety of different therapeutic moieties, be those oligonucleotides, enzymes, antibodies, et cetera. If there's biological material that you need to get to a target within a cell, this is probably the most efficient way to do it. And why do I say that? Historically, one of the big challenges with delivering, whether it's RNA, protein, peptide, what have you, delivering that into a cell is, it gets trapped in something called an endosome.
This is basically a vesicle that the cell uses to process the material. It will either use the material in that endosome, it will take that to something called a lysosome, where it will be destroyed, or it will kick it right back out of the cell. And so consequently, only about 1% or 2% of whatever you put into that cell will ultimately get to the target, whether that target's in the cytosol or whether that target is actually in an organelle. We see 50% getting out of the endosome, and that's really the big differentiator here.
And so effectively, what happens is the EEV binds to the cell surface. It gets taken up via this process of endocytosis, but once it's inside the endosome, in a pH-dependent manner, so the pH drops within the endosome, the binding affinity of the EEV increases by thousands of fold. And as it increases, it basically starts to fold the endosome in such a way that it creates buds. These buds then snap off of the endosome. The endosome remains intact. Imagine soap bubbles coming off of a larger soap bubble. But then they just fall apart because there's nothing holding them together. They're not complex structures as the endosome is. And as they fall apart, they release all of the material into the cytosol, where it can then go and do its job. And so that's a significant differentiator.
As we move into Duchenne muscular dystrophy, we're starting with ENTR-601-44, as I mentioned, then ENTR-601-45, and then ENTR-601-50, and then we have programs beyond that too. Effectively, we're using the same EEV for each one of our neuromuscular diseases. As we develop our programs, we go through a relatively extensive screening process, where we look at different EEVs, we look at different oligonucleotides, and then we combine them to make sure they're appropriately biased to the tissue of interest and to the target of interest. The EEVs associated with each one of the DMD programs are the same. It's also the same EEV that's in the DM1 program that's partnered with Vertex VX-670, as I mentioned before. Let's talk a little bit about the data and why we're so excited about this.
First of all, I'll start with some of the animal data. What you're looking at here actually is something called the del45 DMD mdx mouse model. Now, that's kind of a mouthful, but basically what's been done here is this mouse has been genetically engineered such that it has some of the same phenotypic issues that you might see in a DMD patient, albeit in a mouse. And you're able to, in this case, test ENTR-601-44 against this 45 skip mutation. We can look at what our product, as opposed to some model, would actually potentially do in a patient.
And in this case, what we see is, at very low doses, these are clinically relevant doses if you translate them into the human equivalent dose, at very low doses, you see a virtual saturation of exon skipping, and you see concomitant increases in dystrophin restoration, and this is after one dose. Then, if you move forward and you think about the accumulation of effect over time, what's really important is not only what you see on your first dose, but also what you see over time. And in this case, what we've done is we've looked at something called the D2. mdx mouse. Now, this mouse is challenged because not only does it lack dystrophin production, but it also suffers from fairly significant fibrosis. It has a mutation in the TGF-beta pathway.
And because of this fibrosis, as well as the lack of dystrophin, it to a certain extent recapitulates the same challenges that a patient might face. And what you see here is an accumulation of exon skipping and dystrophin production after only two doses, and these doses are given six weeks apart. And that's important because as we run our clinical trials, as we move to the multi-ascending dose trials and the chronic dosing, we expect to dose patients no more frequently than every six weeks. And what we've seen throughout all of the models now is that should be sufficient to both increase, grow, and maintain dystrophin levels.
What's also really important is, if you look here, and we've shown this in multiple models now, if you look at the percentage of the muscle fibers that are dystrophin positive, that's basically saturated as well. And that's really, really, really important, because the muscle is really only as strong as its weakest link. So you want to make sure that you've got, you know, complete coverage of the entire muscle, not just high levels of dystrophin in any given biopsy. Then, let me talk about the pharmacokinetics a little bit and how pharmacokinetics actually relate to target engagement, because it's important, as I work up to the clinical data presentation here.
So in this data, what you're looking at are non-human primates, and you're looking on the left at mean drug concentration in the blood, and on the right, you're looking at a concomitant exon skipping in the monkey. And right off the bat, you can see that these are almost completely perfectly correlated, number one, which is important to see. Number two, what you see is this hockey stick effect, and others have seen this as well with oligonucleotides, which at a certain point from a concentration perspective, you will see a nonlinear increase in target engagement. And what's important about this number here is, from the perspective of drug concentration in the blood and in the muscle on an AUC basis, that 20 mg per kg, that corresponds to roughly five to 10 mg per kg in a patient.
And we think that's really important because we think we'll hit that hockey stick somewhere between our first and second dose level as we move into the multi-ascending dose trial. So ultimately, to wrap the non-clinical piece of the presentation up, what we see is not only saturation of exon skipping across multiple species, but we see translation across species. We see durable effects. So here you're looking at 12 weeks, you're still seeing exon skipping, which again, is remarkable because the dystrophin protein itself will last two to three months, hence our comfort with dosing every six weeks. And most importantly, as we now start to transition into the human data, what you see in healthy normal volunteers in terms of exon skipping is a shadow of what you expect to see in patients for a variety of different technical reasons.
When we look in vitro, for instance, and others have shown this in mice, and we've seen this now translation in competitive programs, we see about a 20-40 fold difference in exon skipping in patients as opposed to healthy, normal volunteers. As I show you the healthy normal volunteer data, I think that's important to bear in mind. Let's jump to the clinical program. We're really excited about this. I'll start with the pharmacokinetics, both plasma and muscle concentration. First of all, this exceeded our expectations, given the relatively low doses that we were looking at here. This is part of the reason why we expect that even the low dose of 6 mg per kg should be clinically relevant, especially after giving them multiple doses. Remember, this is a single dose trial, healthy, normal volunteers.
We ran this in the U.K. We have four cohorts associated with this trial, and you can see this nice curve, dose dependency in terms of plasma AUC on the left, and then in terms of muscle concentration on the right. Again, almost perfect correlation there, so that's beautiful. That's exactly what you want to see, and then moving forward, same data from a muscle concentration perspective, just depicted slightly differently. We saw a nice relationship then between muscle concentration and exon skipping, again, dose-dependent manner, and at these levels, we think this is actually remarkable, exon skipping. One thing to bear in mind here is when you look at this data, is this was really a safety study, so we took these biopsies at day three.
We know, based on our non-clinical data, as well as data everybody else has put in on the market, that you're not going to see peak exon skipping until somewhere around day seven to 10. So this is actually not optimized for exon skipping, and still, we saw high levels of exon skipping, and we saw dose dependency. So we're extraordinarily excited about the fact that we've shown this, you know, remarkable concentration data. This concentration data has correlated with exon skipping. The exon skipping and the concentration are both dose dependent, but perhaps most importantly is the safety and tolerability associated with this drug. So as you probably know, this class has been fairly challenging from a safety perspective when you look out across the landscape at some of the different programs that are either in the market or are being developed in the clinic.
We saw, to summarize this relatively dense slide, nothing. We saw no treatment-emergent events, we saw no discontinuations, we saw no clinically significant changes from baseline observed in anything, especially some of the more sensitive renal markers that you would expect to see. We saw no changes in creatine kinase, we saw no changes in clinical lab values, we saw no changes in ECGs, we saw no changes in the physical exams. So 6 mg per kg looks like an extraordinarily safe dose, which we think is remarkable, and we have the GLP subchronic tox studies also to back this up.
And we think not only are we going to be able to start at a clinically relevant dose as we move into the multiple-ascending dose patient studies, but that we will be able to dose up at least two to three times that based on some of the subchronic tox work that we've done. So we're very excited about this, and we think we have something that's actually quite special here. I think one really important point to make here is that we don't know what the top dose of this could yet be in patients, because we haven't hit a NOAEL in our non-clinical models yet. We don't know what MTD is.
But one thing we have talked about doing is pushing that as hard as possible, because we know not only do we want to optimize the levels of dystrophin production in the skeletal muscle, in the biceps, where you would normally take your biopsy, but we want to make sure that we're optimizing for the heart as well, because we know ultimately that that's going to be the critical clinical challenge that these boys will face going forward. So you can't take a cardiac biopsy, but we know more is better, and so that's why we will be pushing very, very hard as we dose up. So this is a depiction of the clinical plan as we've shown it. So everything on the left now is done. So that's the first in human, healthy, normal volunteer trial that I mentioned before.
Everything on the right is to come, and this is what I'm talking about as I discuss moving forward in Q4 with the filings for 601-45 , 601-44 and then early next year for 601-50 . The programs will be somewhat different, slightly different probably as we move them forward, but roughly they will look very similar, at least from the perspective of this page, from a high-level perspective. I'll talk briefly in the couple of minutes I have about our 601-45 program . Again, this is one that we're really excited about, and I think you'll see a running theme here. So here again, so now we are looking at the del44 DMD mdx mouse model.
So same idea as I described before, but a different mutation so that we can test this product in this, in this mouse. And again, saturation of exon skipping at a clinically relevant level, concomitant increases in dystrophin restoration, almost complete saturation of the muscle itself in terms of percentage of dystrophin-positive fibers. But in this model, we actually looked at functional correction as well, and what you see is this great correlation now between the saturation of the muscle fiber and functional correction. And this is effectively measured by the force that's maintained when the muscle contracts over time in the mouse. So we're really excited about the fact that not only do we think we're going to see significant dystrophin restoration, but over time, obviously, what's most important is that that will translate into function.
Our primary endpoint in the phase II-B will be dystrophin restoration, but we'll be running then confirmatory studies to look at function, and obviously, that's, at least as of now, what's required to get approval outside of the United States. So the data summary on 45 is very similar to 44, and we'll be moving that regulatory submission at the exact same time we'll be moving it, the 45 regulatory submission. So very briefly, the DM1 program that we have partnered with Vertex. As I mentioned before, this is a neuromuscular disease, but a very different disease from a mechanistic perspective. So we're using the same EEV in this program that we're using in our DMD programs.
But in this case, what you're looking is splice correction, and you're effectively blocking the CUG repeats that are associated with the genetic mutation in this disease. That enables the release of a protein, which then drives downstream splicing and corrects for basically multiple challenges to multiple organs in the patient population. So just a brief overview of that program. So we have a four-year global research collaboration with Vertex. The upfront was $224 million, with a $26 million equity investment, $485 million in milestones, and then royalties on top of that, and we've earned some of those milestones already. Most recently, a $75 million milestone for the advancement of the clinical program.
And as I mentioned before, they expect to finish the SAD portion of the one/two at the end of this year. Final word on pipeline expansion. So as I mentioned before, we've conjugated these EEVs that we bias to multiple different types of tissues, and we have a large library of these that continues to grow. We conjugate these to a variety of different active moieties. So whether those are oligonucleotides, whether those are enzymes, whether those are antibodies, or we've decorated lipid nanoparticles. And what we've been able to show there, we presented at ASGCT earlier this year, what we've been able to show there actually is a remarkable improvement in transfection efficiency, gene editing, mRNA expression, in different types of cells as associated with the EEV-decorated LNP versus the LNP alone.
So we're pretty excited about what the long-term future could hold from the perspective of gene editing, too. Corporate highlights, very quickly. As I mentioned, cash runway into 2027, cash and cash equivalents of $470 million. Common shares outstanding, 37.2 million. We've got about 170 employees across 100,000 sq ft in the Seaport of Boston. We've got a pretty mature group at this point, 75% advanced degrees, 50% PhDs. I would say a relatively seasoned leadership team. My kids would say old. We've been voted a top place to work in the Boston Globe and with BioSpace and MassEcon for multiple years running at this point, and a deep intellectual property portfolio. So that's the end of my presentation. I almost hit 20 minutes.
Thank you very much for your attention, and I'm happy to take questions. I think the Vertex partnership is a great example of the way we think about partnership, right? That was a very large partnership. I don't expect the next partnership to look exactly the same, but you know, when we first started talking to Vertex, it became very clear early on that we had a shared vision for what we wanted to be able to do for patients. We had a shared vision for how you might even develop a program, right? I think those two things are really critical, regardless of who you're talking to or what area you're talking about, and then, from there, what do we think about?
We have to agree on, you know, what the experimental plan would look like, what the biology looks like. Does the target we both think makes sense? What does the partner bring to the table that we can learn from, and then we can build upon, not necessarily in that program, but across the board, right? So we look for synergy there. And then, obviously, the economics have to make sense. But we're fairly careful about the decisions we make around partnership, because ultimately, a lot of its decision-making will still run through, you know, a lot of the same people in the R&D team.
So you want to be mindful of that, because you can't distract from your core programs, especially when you're in a position we are, which is executing on, you know, our first clinical programs as quickly as we can. But all of that said, if there's an opportunity to move an exciting platform, like an LNP platform, for instance, forward with a gene therapy, faster, to a broader population while reducing risk at the same time, we're happy to entertain the conversation.
Good question. The phase I trial, first-in-human.
Yeah.
I guess I'm curious, why not try higher doses for the phase II, and do you have any dystrophin expression data from that first initial cohort?
Those are great questions. So it's really interesting, right? The 601-44 program in healthy normal volunteers, what we were looking for there, again, was safety and pharmacokinetics more than anything else, and then we wanted to make sure there was some target engagement to kind of prove the platform out. We could have gone higher, but honestly, that would have taken longer, and why make patients wait, right? I mean, healthy normal volunteers are not going to benefit from this therapy. And so we didn't want to drag that out. And based on some of the modeling that we've done, there was really no reason to go higher either.
Like I said before, I think we're going to see a clinical response here that's meaningful, even at that six mg per kg dose, especially after we give it multiple times. Now, to the question about dystrophin, we do get that question. So you won't be able to see dystrophin production in a healthy, normal volunteer. Just biologically, it doesn't work that way. So this will be the first dystrophin that we show in patients next year. Yeah.
Yeah, I wasn't clear that it was-
Yeah. Yeah. Fair question.
Open to more questions. Thank you so much.