Great. Good morning, everybody. It's my pleasure to be moderating this chat with James McArthur, CEO and President of PepGen. I'm going to ask James to just give a quick overview and update of the company on the DMD and DM1 programs, and then we will do Q&A. James, thanks again, and please take it away.
Great. Thanks, Paul. Really appreciate it. Yeah, this is a momentous year for PepGen. A lot of big data readouts for us. We've already kicked off the year strong with a strong dataset from our EDO-DM1 FREEDOM single-ascending dose clinical study. Just to remind everyone, in myotonic dystrophy type 1, missplicing is the cause of all the pathology of DM1. There we demonstrated 29% correction of splicing with a single dose at 10 mg / kg. This is higher than other approaches have achieved following even repeat doses out to nine months. We're now dosing at 15 mg / kg. To remind everyone, in the mouse model, we've been able to demonstrate that with repeat doses of EDO-DM1, we see even higher levels of splicing correction.
I will note the drug has been very well tolerated in patients to date, and our early data suggest movement of 10-meter walk/run greater than what other approaches have seen, even through multi-dose studies. With that, turning to DMD, we're reading out the DMD EDO-51 dystrophin readout from our 10 mg / kg dose cohort this summer. Just to remind everyone, we showed higher levels of exon 51 skip transcript at 5 mg / kg after three months of dosing than what other approaches have shown at 10 mg / kg in six months of dosing. We are really excited to see what the dystrophin results look like at 10 mg / kg for our study. To remind everyone, there have been no treatment-related serious adverse events with that program.
All AEs that we've seen as of the last update at the end of January were mild in nature. Further, additional data readouts include the 15 mg/ kg data readout in DM1 later this year, and early next year, the first multiple ascending dose data from our DM1 program. At the last K, we reported that we had over a year of cash on hand, and we continue to manage our cash very efficiently to allow us to get through all of these readouts. I think be able to demonstrate the power of the EDO platform technology to deliver oligos into the nucleus, which is where they need to be for both of these diseases, also speak to where else we can take this technology in terms of new indications, and be able to deliver on the promise that we've put forward to investors and patients.
Sorry, my Zoom was not unmuting. That's great, James. Thank you. Yeah, maybe let's talk about the DM1 data for a bit. You saw this really nice splicing effect. Maybe walk through that data. On the other side of the coin, right, the vHOT data was super noisy, and you know there may be some reasons for that, but you know what should we kind of take away from the totality of the data there?
Yeah. Let's start off with the basics. We saw a nice dose response in terms of splicing correction. We saw a 12% splicing correction at 5 mg / kg, and we saw a 29% splicing correction at 10 mg / kg. This is using the 10-gene panel that others have used. As such, you can go and directly correlate these results with, for instance, the 12%-16% splicing correction seen by Avidity or the 25% splicing correction that was seen in multi-dose studies with Dyne. Great comparability in terms of the methodology, robust dataset, and we're essentially using the same 22-gene panel that everyone should be using to go and assess splicing. We're really pleased with these results. Again, this is a single-dose study. This exceeded our expectations. As you know, we were hoping for perhaps 10% after a single dose.
To get 12% at 5 mg / kg and 29% at 10 mg / kg really, really pleased us. Again, with that understanding that we expect to see higher levels with repeat dose studies. In terms of the outcome measures, we reported out 10-meter walk/run, which, as I mentioned in my intro, we saw a change in terms of 10-meter walk/run that was actually greater than what others have seen in multi-dose studies, a 0.35-second change at the 10 mg / kg dose cohort. As you correctly point out, vHOT or video hand opening time and measurement of myotonia was very noisy. We saw a greater change in our placebo group than what others have reported with their therapies after months of treatment. Clearly something is going on there.
When we go back and look at our patient selection for vHOT, we selected a patient group that we think are particularly prone for a lot of variability. We selected a group that had extraordinarily high baseline measurements. These patients, when you go back and look at the natural history data, have a proclivity to go back and see a reversion to the mean. I think that's what we were essentially seeing. We've made changes so that we can better assess vHOT as an outcome measure. These changes include both selecting a patient group that is more in line with what other companies are doing, looking at about a two-second change in vHOT at baseline, and secondarily, looking at two different vHOT measurements at baseline so that we'll have a better sense of baseline to which all other data is compared.
Regardless of that, we know splicing is the basis of this disease. If we move the needle in such a profound way as what we're doing right now, with repeat doses, we'll change the underlying biology and we'll be able to move these outcome measures. I think 10-meter walk/run may be the beginning of us seeing that effect, and we expect to be able to see it in other outcome measures as well.
Great. Makes sense. As it relates to splicing specifically, the data is really promising. I mean, the only caveat is the sample size. I think at this high dose where you saw 29%, it's four patients. Anything you can say that's more granular? You know, we've seen in other datasets where there can be like an outlier here or there. You know, just how, when you look at this on a patient level, like how well does it actually stand out or stand up to scrutiny, I mean?
Yeah. I will say we saw quite a bit of variability at the 5 mg / kg dose cohort where five of six patients showed splicing correction. At 10 mg / kg, the lowest splicing correction that we observed was 17%. Let me just say that again. The smallest effect size we saw was 17%. By back calculating, you can figure that we saw a fairly profound effect in the three of four evaluable patients. Why do we have only four evaluable patients? First off, one of these individuals, unfortunately, at the time of biopsy, they hit an artery and there was a pseudoaneurysm. The patient is fine, but unfortunately, they drew blood instead of muscle, and so there was no evaluable tissue at day 28.
The other individual who was dropped from this cohort was a rather curious one in that both at baseline and at day 28, there was essentially almost no missplicing. The splicing assay has a lower limit of detection of about, sorry, a lower limit of validation down to about 0.05 in terms of splicing change. This individual, both at baseline and at day 28, had a splicing change that was below 0.05. As such, by the predetermined criteria for the assay, that was a non-evaluable patient. We do not know why that individual essentially was not demonstrating missplicing in both of those samples at day 0 and day 28. We do know the patient was diagnosed as a patient with DM1.
We do know that the patient had at least 100 repeats in a sample drawn from the blood, so CUG repeats, which is the hallmark of this disease. We don't know why essentially there was no detectable missplicing. In the absence of missplicing, we can't measure a change in missplicing.
Makes sense. Okay. Looking ahead, do you want to just talk about where you are with the MAD study? You are moving forward with five. What's the timing of moving forward with 10, and what should we expect for just the cadence of data disclosure there?
Yeah. First off, in the single-ascending dose data, we're going to see the 15 mg / kg dataset later this year. I want to point out why we think that's important. One, we'll be able to look at, is there a plateau as others seem to have encountered at 25% splicing correction? Can we go beyond 29% splicing correction at 15 mg / kg by just increasing the dose level? We anticipate this dose will be safe and well tolerated, but we'll get that data as well. Just to remind you, our DMD drug EDO-51 and our DM1 drug EDO-DM1 are very different drugs. Although they share similar chemistry, their difference is both in terms of sequence as well as the size of the oligo with these two drugs. As such, we've always seen that EDO-DM1 has an even better safety profile than EDO-51, our DMD drug.
We'll begin to get human data that further confirms this. We already know at 10 mg / kg in our single-dose study that we're seeing no movement in kidney biomarkers in the serum, which was not the case with EDO-51, our DMD drug, where we did see in half the patients a small transient movement in serum kidney biomarkers. At 15 mg / kg with EDO-DM1, we expect to see it'll be safe and well tolerated as well. With EDO-51, we saw a more profound movement in kidney biomarkers. The 15 mg / kg data, I think, will speak both to splicing as well as to safety, which is obviously a big question that everyone has. Now, moving on to the multiple ascending dose study.
The 5 mg / kg multiple ascending dose cohort will be very interesting because we'll be able to see with that dataset in early next year whether or not we're able to build upon the 12% splicing correction that we saw with a single dose at 5 mg / kg. It'll give an indication of is the mouse model essentially correct in that with repeat doses, we can build upon the splicing correction. It'll give us a good sense of what we can do with the 10 mg / kg cohort. We've not provided a timing yet on when the 10 mg / kg MAD dataset will come in. We'll provide an update on that later this year, but you can expect it next year.
Great. Why do you think biologically we're seeing this plateauing effect with the transferrin compounds? Is that related to the DMPK degradation mechanism, or is it just something else about this disease where there are alternative pathways or workarounds inside the cell that we don't understand and everyone's going to play?
Yeah. If you look at, for instance, the dataset from Dyne, there was a nice dose response when they increased the dose for monthly dosing from 1.8 to 3.4 to 5.4 mg / kg. At that point, they moved to a once every two-month regimen, and there it plateaued. Now, we do not know if it is just you are not really getting much more drug into the cell when you look at 5.4 vs 6.8 with a once every two-month regimen. We do not know if it is because this mechanism gets it into the cell, but does not have a real clear mechanism to get out of the endosome. It could be because, as you correctly point out, half of the drug at least is being expended on degrading normal DMPK RNA present in the cytoplasm that does nothing in terms of contributing to the pathology.
You're effectively wasting at least half the drug binding to and degrading a normal DMPK molecule as opposed to focusing on nuclear pathogenic CUG repeat DMPK, which forms the foci, binds MBNL1, and essentially drives all of this disease. That's the nice thing about this approach. We're focused on that pathogenic RNA as opposed to wasting drug.
Yeah. Okay. That is one possibility. I guess we will see more data from you guys, and that will help answer that question. As it relates to safety, I mean, you talked about how the programs are different and they have different preclinical profiles, right? The know-how for DM1 is higher than DMD. I mean, we have talked about this before. I guess when I talk to investors about safety of the peptides, these are the concerns that they raise, and I would love to hear, or not they, some investors raise, and I would love to hear kind of your countercase to them. One is just the peptide is the same, right, between DM1 and DMD, and the peptide is likely the cause of the tox. Two is, you know, look, the DM1 data look really clean. It is only a single dose.
How much does that really de-risk? What would you say to these points?
Yeah. I might actually perhaps modify your second statement there from the standpoint of tox is caused by the peptide. It's actually caused by the drug. The reason I point that out is these drugs do behave differently. We have seen across the five or six molecules, or more than that at this point, perhaps 10 molecules that we've put into non-human primates that they do not all share a similar no-observed- adverse- effect level. They actually move around. We pointed out previously that the no-observed- adverse effect level in subchronic toxicology for the DM1 program is 60 mg / kg, whereas for the 51-molecule in subchronic tox is 45 mg / kg. That seems to be carrying through in humans. We don't completely understand why we see different points where you begin to start seeing kidney engagement, but it's very clear that we do.
It could very well be that the difference in size of the oligo has an impact on clearance and accumulation in the kidney. Again, we don't know if that's the case, but it's certainly reasonable as a hypothesis. What is very nice is that non-human primates indicated a better safety profile for DM1 than our 51 drug. So far, the human experience seems to bear that out, where we've seen no movement in kidney biomarkers in the blood, including creatinine, BUN, and cystatin C. Whereas we did see at 10 mg / kg with our 51 molecule the beginnings of movement of these biomarkers. Transient though they may be, we just did not see any individuals with our 50 of the six individuals with our DM1 drug going above the upper limit of normal.
Yeah. Okay. For DMD, can you give us any context on what the safety profile looked like after one dose? Like, is it something where you could juxtapose it and it did actually look different?
Yeah. That is why I was trying to highlight. The best comparator, you know, Paul, I think, is the healthy volunteer single-dose study because those were adults. The single-dose dataset we had with DM1, because those are also adults. As I'd mentioned, at 10 mg / kg with our DMD drug, we had three of six individuals go above the upper limit of normal for creatinine, then come back down to baseline. At 15 mg/ kg with our DMD drug, we had six of six individuals go above the upper limit of normal, and we had two cases of hypomag with our DMD drug. With our DM1 drug, as I'd mentioned, no one has gone above the upper limit of normal at 10 mg / kg. We will read out the 15 mg/ kg data later this year.
Yeah. Okay. Okay. All right. Thanks for the extra clarification there. I appreciate it. All right. Great. I guess one more question on DM1. Like, what is your view on the regulatory path, the right endpoints? It seems like, I mean, it seems like every, you know, whatever strategy you try to use, be it splicing with clinical corroboration or, you know, relying on vHOT, I mean, these all have like pros and cons, right? It feels like even for a drug that works, like the signal-to-noise ratio risk with these endpoints, at least in a small sample, is high. You know, baseline is a determinant of effect size in vHOT or splicing, you can have one wonky biopsy. In the context of all of that, like, what's your perspective on the right way to get a drug to market in this space?
Yeah. Let's start off with basics, right? Splicing underlies this entire disease. Better splicing will produce better outcome measures. That's clear from animal modeling. It's clear when you go and look at the natural history data set that splicing correlates extremely well with 10-meter walk/run, hand grip strength, and ankle dorsiflexion. It correlates less well with vHOT. That's probably because of the variability of vHOT as an outcome measure, as unfortunately our initial data indicated. Selection of different patients with different levels of vHOT produced very different results. That's probably why one clinician had told us that basing everything on vHOT would make her very nervous. I believe that showing differences in splicing is critically important because it underlies the disease.
Right now, FDA has not agreed that that is a biomarker on which you can get approval because they don't know what level of splicing change is sufficient to result in a clinical outcome measure that matters. We plan on moving forward with both splicing and then showing an impact on things that do matter, like 10-meter walk/run, hand grip strength, and of course, vHOT. Ultimately, the one outcome measure that FDA is particularly interested in is the DM1-Activ patient report outcome measure, where you're asking patients, you know, what is the impact on your ability to put on pants, to make the bed, pick up dishes, things that matter in the quality of life, which ultimately that's how drugs get approved.
Yeah. Yeah. Okay. All those things you're looking at in the MAD. Is that right?
That is correct.
Yeah. Okay. Okay. Great. Anything to add on DM1 before we cover DMD?
No, I think, you know, we, like I said, we're very, very pleased with this result. It really points to the ability of the EDO platform technology to drive oligo delivery into the nucleus where all of this business has to happen. It speaks well to what we'll be able to do with the platform with other things, DMD and other indications.
Okay. Great. Yeah. Maybe give us the update on DMD and more about the thought process of the recent update you gave on the study as it relates to, you know, just your thought, your current thoughts on dose escalation and prioritizing DMD versus DM1. Like, you know, I think some people interpreted the DMD update as thinking, okay, is PepGen less excited about DMD now? You know, I do not know. You know, help us not read the tea leaves and give us your context, James.
Yeah. I can completely understand that interpretation. It's not correct. We just decided we need to focus in on the basics. What do I mean by that? We believe the dataset that we're going to get from CONNECT1-EDO51, which reads out this summer, which we're excited about. That's based on our exon 51 skipping data we reported last year, where we saw very high levels of exon 51 skip transcript. This is a disease where in the absence of a functional transcript, you don't make a functional protein. We believe with more transcript, we'll make more protein. With more protein, we'll see benefit in patients. We're excited about that dataset. We just decided, you know, we've got four patients on study right now. They're moving along nicely. There have been no serious adverse events.
We want to see what that data reads out in terms of exon skipping and dystrophin production. That'll inform us both in terms of our ability to engage with the FDA and other regulators in terms of moving this program forward. To go and do that, we decided voluntarily that we are going to pause the CONNECT2 study until we get that dataset and be able to then move forward more informed and better able to demonstrate the benefit of EDO-51 for patients with DMD.
Yeah. Okay. Okay. What do you make of the whole Sarepta thing with their PPMO and no longer a path forward on dystrophin? You know, it looks like Dyne, you know, again, if we believe, you know, others' regulatory feedback or their depiction of what the FDA is saying, right? Dyne saying, hey, you know, we've heard this path is still open. I don't know. If you take both of those at face value, it feels like the FDA had specific concerns with the risk-benefit for safety for Sarepta's PPMO that kind of counterweighed, you know, any sort of enthusiasm about greater dystrophin. In the context of that, like, what, again, what do you think about the regulatory path of DMD?
Yeah. I think what Sarepta was seeing in terms of a safety profile with their PPMO program is very different than what we and others have seen as well. They had severe adverse events, complete dysregulation of a variety of molecules, including magnesium and potassium, that even with stopping dosing did not resolve. That gave clinicians and obviously regulators tremendous concern, particularly where they had to operate at 30 mg / kg to produce even moderate levels of muscle-adjusted dystrophin. We do not know what their total dystrophin numbers were, of course, as you have always pointed out to us. Given that amount of dystrophin and that amount of concern around the safety, I can understand why that program is not continuing. That is not what we are seeing. Again, everything we have seen has been mild in nature. There have been no serious adverse events.
What we've seen has been reversible. The only question we still have to answer, I think, with that program is how much dystrophin can EDO-51 produce in this four-dose study? We'll get that data this summer.
Yep. Okay. Great. In the last minute here, anything else you'd like to highlight, James? Maybe talk a little bit just about cash runway and what catalysts can you comfortably fund the company through?
Yeah. As we mentioned, when we provided the K at the end of February, we had over a year of cash on hand. We've taken some steps to further conserve capital and draw that out further. This will certainly allow us to get through all of the readouts that we've been discussing today, the 15 mg / kg single ascending dose dataset from FREEDOM-DM1, which comes out this fall, the EDO-51 CONNECT1-EDO51 data readout at 10 mg / kg this summer, the 5 mg / kg readout from our FREEDOM-DM1 clinical study, and continue pushing forward with our multiple ascending dose FREEDOM-DM1 clinical study. We also are continuing to look at other applications for this drug and look forward to being able to provide an update on that this summer as well. We continue to look at opportunities to raise capital.
Because we have been so thoughtful in terms of managing our cash with a burn rate far below a lot of other companies, small incremental capital raises will allow us to extend that runway even further still. Regardless, we're focused on reporting out this data, demonstrating the power of the EDO technology across these diseases, and creating value for our shareholders, and demonstrating that we indeed can move the needle for patients living with these devastating diseases.
Yep. Okay. Great. Perfect timing. Thank you, James. Appreciate the update. Always good to talk to you. Best of luck.
Thank you, Paul.
All right. We'll talk soon. Thanks.
Bye-bye.
Thanks everyone for listening.