Good afternoon, everyone. Thank you for joining the 24th Annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next presenting company, PepGen. Joining us today from the company is CEO James McArthur. For those of you joining on the webcast, if you would like to ask a question, please do so at any time. You can submit a question using the chat box feature at the bottom of your screen. With that, we'll get started. I'll turn it over to James for the presentation.
Great. Thank you very much, Joey, and thanks for the invitation. I look forward to taking you through where we are today at PepGen. In spite of the environment we find ourselves in, we think we're positioned to deliver on meaningful data over the course of the next year. I'm looking forward to taking you through that. If I could advance the slides, that's interesting.
Are you having issues with the slide transition, James?
Indeed.
Okay. We'll see if we can get our operator. Great.
Thank you very much. Sorry about that pause. Here are my forward-looking statements. What we're focused on here at PepGen is deriving value and advancing drugs that are going to move the needle in a fundamental fashion for patients with devastating diseases using our Enhanced Delivery Oligonucleotide platform, the delivery of therapeutic oligonucleotides to cells that matter for all of these different diseases. Using this platform technology, we have two programs today in clinical trials: our EDO-51 program in the Connect Clinical Studies. This is for the exon 51-skippable patients who have Duchenne Muscular Dystrophy. That program is in phase II, multiple dose clinical studies, and we'll be reading out later this year. Our second program is our EDO-DM-1 program. This is in the FREEDOM Clinical Studies.
We read earlier this year data from our 5 and 10 mg/kg single ascending dose FREEDOM Clinical Study. Later this year, we'll be reading out on the 15 mg/kg dose cohort from this study. Early next year, the 5 mg/kg FREEDOM 2, the first cohort of our multiple ascending dose study. Behind this, we have additional programs, which I won't talk about today in our research portfolio, focused on both neuromuscular as well as neurologic diseases. Now, the fundamental challenge for the delivery of therapeutic oligonucleotides is highlighted here, whereas we know they can go and address the fundamental challenge of many of these diseases but stand from the problem of not being able to get up into sufficient quantities into the nucleus of cells.
This is highlighted showing on the right-hand side the level of a naked or non-conjugated oligonucleotide stained in red and showing the amount that gets into cells, the cell bodies in green, the nuclei in blue. As you can see, very little is getting into the cells. In contrast, we go and conjugate the exact same oligonucleotide to our EDO peptide, and you can see dramatically higher levels of delivery both into the cell bodies as well as into the nuclei. The EDO technology is based on a short linear peptide, which has been engineered specifically for the delivery of oligonucleotides into cells. It comprises three motifs: two polyarginine sequences, which are highlighted schematically in this figure in dark blue, and then between the two of them, a hydrophobic core.
The hydrophobic core is an essential component of this, not just in being able to get into the cell, but importantly, being able to get out of the endosomes, which is where all oligonucleotides end up getting trapped in the absence of a mechanism of being able to escape. It turns out the EDO technology is very good at not only getting oligos into cells, but also getting oligos out of the endosome such they can get access to the nuclei. That is really highlighted on the right-hand side, where you can see dramatically higher levels of oligos stained red, not just in the cell bodies in green, but also in the blue nuclei, which is where they need to be for the diseases we're going to talk about today. This is actually shown here in this particular figure. We're on the left-hand side in this in vitro assay.
We can show seven-fold higher levels of EDO oligo delivery into cells compared to naked oligo. On the right-hand side, we could show 24-fold higher levels of endosomal escape, which, as I mentioned, is critical if you want to be able to get your oligonucleotide into the nucleus where it needs to be to act. This is the basis of our EDO-DM-1 program. Now, DM1, for those of you not familiar with it, is a multisystemic disease that stems from a CUG triplet repeat expansion in one of the two copies of the DMPK gene. This produces a toxic RNA species, which we'll talk more about in a few moments. Symptoms occur across a variety of different tissues and organs and produce myotonia and muscle weakness, cardiac arrhythmias, loss of lung function, fatigue. These can result in a significantly shortening of lives for patients.
Currently, there are no approved therapies with over 110,000 patients living with this disease in the U.S. and the EU. The basis of this disease is highlighted here on the left-hand side. These CUG repeats in the RNA produce what are called stem loop structures, the structures you see in the middle of the nuclei on the left-hand side. These structures act as a matrix, a sponge, to go and bind a protein called MBNL1. MBNL1 is required for the normal splicing of RNAs that produce a wide range of different proteins. With the stem loop structures that are present in DM1 patients, MBNL1 is trapped. As a result of that, you get missplicing of a wide range of different transcripts and mis-expression of a wide range of different proteins. This is what produces the pathology in DM-1.
Now, our approach is rather unique in that we focus on binding specifically to the CUG repeats that form these stem loop structures. That is highlighted on the right-hand side by the red EDO-DM-1 oligonucleotides binding to and opening up of those stem loop structures. When those stem loop structures are no longer forming these double-strand motifs, we release MBNL1 protein, and it is free to do its normal job. We get correction of splicing and normal protein expression. This is expected to go and reduce all the signs and symptoms associated with myotonic dystrophy type 1. We can go and demonstrate this in cells from patients shown here on the left-hand side. You can see the toxic foci that are formed by these stem loop structures and the proteins that bind them in the top left, the pink dots highlighted by white arrows.
These pink dots, these toxic foci, are reduced with EDO-DM-1 shown on the bottom right. We can also show liberation of that protein MBNL1 required for splicing. You can see it highlighted with the white dots in the center green panels at the top. Those white dots are reduced in number with treatment with EDO-DM-1. This produces in patient cells an improvement in splicing. We see in a dose-dependent fashion in these cells, 69% improvement of missplicing of transcripts. We can also show this in a mouse model of the disease. Shown on the left-hand side is tissue levels of EDO-DM-1, our drug, in the muscle of mice following either one dose or following four monthly doses.
You can see an accumulation of EDO-DM-1 as we go from 56 nanograms per gram with a single 30 mg/kg dose up to 120 nanograms per gram following four monthly doses. You can go and see that with one dose, we get correction of significant missplicing in the mouse model of this disease, 68% correction of splicing. With four monthly doses, we get almost 100% correction, 99% correction of missplicing. One of the features of this disease, myotonia, which is the tensing up of muscles and the inability to release them, is also treatable in the mouse model with EDO-DM-1. A single dose reduced the myotonia observed in this mouse model by 76%. Four monthly doses were able to reduce myotonia by 99%. On the basis of this and extensive other data, we advanced this into clinical studies.
We recently reported out the 5 and 10 mg/kg data sets from our FREEDOM single ascending dose Clinical Study. This is a dose approved to go to 20 mg/kg in the U.S., Canada, and U.K. We have reported out the data for 5 and 10, which I'll tell you about in a few moments. We are now dosing patients at 15 mg/kg. When we look at the patient demographics, we go and see that they were quite well balanced based on age, gender, body mass, splicing index, and 10-meter walk run. There was a particular misbalance in terms of vHOT Baseline measurements, where the placebo group had a much higher level of myotonia, a higher vHOT measurement of 14 seconds compared to only 9 seconds in the 10 mg/kg dose group. I'll talk more about this in a few moments. Let's first look at the safety.
The drug was generally very well tolerated. The majority of treatment-related adverse events were mild and moderate in nature. We did have one serious adverse event related to study drug that was confounded, however, by the prohibited off-label use of a drug that has as a side effect abdominal pain. This particular individual took this drug unbeknownst to the PI the morning of being dosed with EDO-DM-1. All of these, however, did resolve over time and had no long-term sequelae. There was, in terms of other serious adverse events, one other serious adverse event I want to point to, and this was not drug-related. Associated with the biopsy on day 28 to obtain muscle for analysis, we observed a right anterior tibial artery pseudoaneurysm. Essentially, during the biopsy procedure, unfortunately, an artery was hit.
Although the patient was fine long-term, this did result in us not obtaining a muscle sample from that particular patient on day 28. There were no adverse events related to electrolytes or renal biomarkers. Highlighting that is shown here on this slide, levels of serum creatinine. What we observed is that none of the participants went above the upper limit of normal for any serum kidney biomarker that we looked at. This is to be differentiated by what we observed in our single dose study with EDO-51, where we did have individuals in a transient fashion go above the upper limit of normal for males. That was not the case with EDO-DM-1, and again, speaks to the really excellent safety profile we have observed to date. Looking at tissue concentrations, we can see a greater-than-dose proportional increase as we go from 5 to 10 mg/kg. We are at 10 mg/kg.
We saw a threefold increase in tissue levels of EDO-DM-1. These tissue levels began to approximate what we observed in the mouse model at 30 mg/kg. We were extremely pleased to go and see what we observed in terms of an improvement in the splicing index in treated patients. In the placebo group, there was an approximately 7.5% worsening of the splicing index that occurred from day 0 to day 28 when we obtained the second biopsy. In contrast, in EDO-DM-1 treated patients at 5 mg/kg, we observed a 12% improvement from day 0 to day 28. At 10 mg/kg, we observed an average 29% improvement in the splicing index as we went from day 0 to day 28 following treatment. All of this data is single-dose data.
To put this in context, this 29% improvement in splicing index that we observed using the 22-gene panel was greater than that which has been observed with other approaches, even in multi-dose longer-term studies. It's worth noting that at 10 mg/kg, all the participants who showed a splicing improvement, three of four assessable individuals here, demonstrated at least 17% correction of splicing. This was a very robust finding. As we look at the functional outcomes, we didn't expect to see much following a single dose. Looking at the 10-meter walk run test, we did observe that at 10 mg/kg, there was a 0.35-second improvement in terms of the 10-meter walk run time. This is similar to what others have observed, albeit in those cases following multi-dose studies. The myotonia assessment vHOT, however, was complicated by the fact that we had significant variability in our placebo group.
In the placebo group, we also saw a 7-second improvement from day 0 to day 28. We believe that we've now taken steps that will allow us to reduce this variability. The first step is that in future studies, we will be looking at patients who do not have as extreme a level of myotonia at baseline as the patients had in this placebo group in this study. Two, we'll be looking at two baseline measurements as opposed to a single baseline measurement to further reduce the variability that we observe. We anticipate that based on the splicing results that we've seen, which drive all the pathology of this disease, that we anticipate being able to see in future studies an improvement in all of these outcome measures, particularly in the multi-dose study data, which we'll be reporting out early next year.
As I've highlighted, we're very pleased with our results to date with EDO-DM-1 demonstrating a favorable emerging safety profile, demonstrating a greater-than-dose dependent increase in drug tissue concentrations across the 5 and 10 mg/kg cohorts, and a greater-than-dose dependent increase in evaluable patients in the mean splicing correction going from 12% splicing correction at 5 mg/kg to 29% splicing correction at 10 mg/kg. As I'd mentioned, we are already dosing our 5 mg/kg multi-dose cohort in our FREEDOM 2 Clinical Study. We anticipate reporting out results from this early next year. Let me now move to EDO-51, our treatment for exon 51- skippable Duchenne Muscular Dystrophy patients.
I won't spend a lot of time talking about this disease other than to highlight that currently, patients demonstrate a significant loss of life expectancy and functionality over the course of this disease, and that there are currently 13% of patients who would be amenable to an exon 51- skipping approach for which novel therapies are most definitely needed. We'd previously shown in terms of exon skipping levels in healthy volunteers that we saw significant levels of exon 51 skipping in healthy volunteers following a single dose, and that we saw a dramatic increase in the levels of exon 51 skipped transcript going from 5 mg/kg to 10 mg/kg. On the basis of this and other results, we proceeded with our CONNECT1 open-label Clinical Study.
This was a study looking at 5 and 10 mg/kg where we reported out earlier this year, the 5 mg earlier last year, the 5 mg/kg data, and the 10 mg/kg data will be reported out mid this year. In terms of the safety profile, generally, the safety profile has been quite acceptable. All treatment-related adverse events have been mild. There have been no treatment-related serious adverse events. We did observe two cases of hypomagnesemia, and these data are as of January 23rd, 2025. We've observed two cases of asymptomatic hypomag, which were resolved with low-dose oral magnesium supplementation. We observed in one of these two individuals a transient decrease in eGFR. That eGFR is returning to normal. However, what's interesting is a nuclear scan, which is a direct measurement of the GFR, glomerular filtration rate, demonstrated it was in the normal range. This patient remains asymptomatic.
There have been no sustained elevation in kidney biomarkers, no hypokalemia, anemia, or thrombocytopenia observed with EDO-DM-1 in patients. We previously showed that we saw very high levels of exon 51 skipping at 5 mg/kg. In fact, after four doses in three months, we saw higher levels of exon 51 skipping than what has been observed with a competing technology following six months of dosing and six doses. This is important because in the case of these patients, it's the absence of a functional dystrophin transcript that can make a functional dystrophin protein that causes this disease. Being able to show higher levels of a skipped dystrophin RNA, as we do here, indicates that we eventually will see higher levels of dystrophin protein and thus may be able to improve the health of patients.
When we looked at the muscle content adjusted dystrophin after three months, we saw higher levels of muscle content adjusted dystrophin than what was seen with a competing approach following six doses and six months of therapy. When we looked at the total unadjusted dystrophin, we saw similar levels, and yet we achieved that after half the amount of time on therapy. As we know that with increased doses and with increased time, we'll see higher levels of dystrophin, we're very hopeful about what we will see this summer in terms of the dystrophin production from our 10 mg/kg dose cohort that we will report out.
Just to conclude, over the course of the next year, we'll be reporting out important milestones for both of these programs and for the company, where we'll report out in the second half of this year from our FREEDOM single ascending dose study the 15 mg/kg clinical results, which will allow us to speak more fulsomely about both the ability to go to higher levels of splicing and the safety of the EDO-DM-1 approach for the treatment of myotonic dystrophy type 1. In early next year, we anticipate reporting out for the FREEDOM 2 Clinical Study, the 5 mg/kg multi-dose study.
This will indicate whether or not we can build upon the 12% splicing improvement we saw at 5 mg/kg in the single dose study and what we may be able to do to build upon in the multi-dose 10 mg/kg upon the 29% splicing improvement we saw following a single dose. As I've mentioned, we'll also be reporting out the exciting results from the 10 mg/kg CONNECT1 Clinical Study in DMD, where we'll see indeed with longer dose duration and higher dose levels, will we see higher levels of dystrophin production. We currently have sufficient cash to take us through all of these milestones. Indeed, at the last K reported, over a year of cash on hand and have taken steps to extend that cash runway further. With that, I'll conclude and take any questions. Thank you. Great.
Thank you, James, for that excellent presentation. We'll go ahead and jump into Q&A. Once again, you can ask a question anonymously using the chat box at the bottom of your screen. James, a few from me to start off with. First on DM1, more of a market question here. Obviously, the field is competitive to other notable late-stage competitors with targeted delivery approaches. Is this a winner-take-all market in DM1, or is there room for more than one therapy as the first part of that question? If there is room for more than one, what would be needed in your view to win majority market share?
Yeah. It's certainly a large patient population, and there are very few indications where it's a winner-take-all where you've got such a heterogeneous disease as this and a large number of patients.
I think it's important to note, Joey, that our approach is quite differentiated by those two other approaches that you spoke of in that those approaches are degraders. They degrade both normal DMPK as well as the pathogenic DMPK and seem to have encountered a plateau in terms of how much they can actually improve the splicing. That may be mechanism-related. Our approach is specifically focused on targeting the pathogenic species. In doing so, we may be able to achieve higher levels of splicing correction as certainly we've been able to show following a single dose level and potentially can build upon that with higher doses and in a multi-dose study. In terms of where we think we need to go, we think that because splicing underpins all of the pathology of this disease, with better splicing, we'll see better impacts on this pathology.
We would look to go and see impacts not simply on vHOT, which is a very variable outcome measure, but also see impacts on 10-meter walk run and handgrip strength and patient-reported outcomes in longer-term studies that I think are going to be critically important to show the drug truly changes patients' lives.
For the DMD readout, what levels of dystrophin would you be looking for in terms of maybe a bar for success there?
Yeah. I think you have to look at not just the levels of dystrophin, but you also have to look at the safety profile. As I tried to highlight today and hopefully brought home, the safety profile we've seen is very benign for our DMD drug. Everything we've seen so far has been reversible with no symptomatology associated with that.
The safety profile for our DMD drug at 10 mg/kg is very good. Now, so far, the benchmark is for total dystrophin about 3.2%. That's what's been achieved with alternative approaches when you're looking at the exon skipping space. I think as we look at that and our safety profile, we'd look to see to bring something competitive with that forward that would be compelling for patients. This is a case where we know that with more dystrophin, we should see more benefits. Being able to push to higher levels of dystrophin, which we hope to be able to do, we hope will push greater benefits for the patient and justify driving this program forward for patients and creating value in the company.
In terms of the gene therapy approaches in this space, I think while they certainly have a place, they also have certain risks which have been highlighted recently and need to be borne in mind by parents and by patients. Regardless of where they end up in terms of market share for DMD, I think there's always going to be a place to be able to bring complementary therapies on top of that that can take patients to an even better place in terms of seeing more complete restoration of a more complete dystrophin protein.
Last question from us, James, more of a big picture open-ended question, but what do you think is the biggest disconnect for investors or perhaps put it differently, the most underappreciated or maybe misunderstood aspect of the PepGen story?
Yeah. We've been very transparent in terms of our communications.
I think one of the things that has perhaps confounded the story for folks is the safety question, particularly along the lines of DMD and its potential bleed over to our DM1 story. That is why I really tried to stress today with data that we had previously presented that indeed the safety profile of our DMD drug is eminently acceptable and comparable to what others have seen. Two, what we have seen with DM1 is even more benign in nature. Couple that for our DM1 program with the very high levels of splicing correction that we saw even after a single dose. I think you have got an incredible untapped potential here at PepGen in terms of the value that we are going to see created through the data readouts I outlined for you over the course of this next year.
Great.
Thank you so much, James, for the excellent presentation and informative discussion.
I appreciate the opportunity, Joey. Thank you.
And thanks everyone else for joining on the webcast. Have a good day and a good rest of the conference.