All right. Good morning, and thank you for joining Guggenheim's 2025 Healthcare Innovations Conference. I am Debjit, one of the therapeutic analysts here. Our next presenting company is PepGen, and my privilege to host James McArthur, President and CEO, and Paul Streck, EVP and Head of R&D. Thank you very much for joining us today.
Thank you.
Before we get into the Q&A, let's do a very quick intro of where PepGen currently stands on the milestones for 2026.
Yeah, so we're focused on neuromuscular diseases using the EDO platform technology to deliver therapeutic oligonucleotides, not just into muscle cells, but into a wide range of cells, and importantly, get into the nuclei. For many of these diseases, like DM1, it's absolutely critical you get the therapeutic oligo into the nuclei because that's where the pathogenic RNA is. We reported out this year results from our 5, 10, and 15 mg/kg single-dose FREEDOM clinical study, and we're very pleased to report very high levels of splicing correction. Splicing, or rather missplicing, drives the pathology of DM1. Being able to correct it is critically important to be able to show a benefit to patients. We reported at our top dose 54% splicing improvement. This has never been seen before. Previously, following 11 months of therapy with a transferrin receptor-mediated approach, they had achieved 22% splicing improvement.
We more than doubled that at our top dose, which was generally very safe and well tolerated, with no treatment emergent serious adverse events, and all adverse events related to treatment, mild or moderate in nature, and reversed without intervention. We are now really excited as we are heading forward, having raised capital to drive us into the second half of 2027, that we will be reporting out next year in the first quarter results from our multiple ascending dose study, where we expect to build upon the 12% splicing improvement we saw with a single dose. In the second half of next year, we will report out data from our second cohort at 10 mg/kg, where we expect to be able to build upon the 29% splicing improvement that we reported out earlier this year.
We're in a great position, I think, to be able to demonstrate that EDO DM1 has the potential to be a best-in-class therapeutic for what is a very substantial market, the DM1 patient population, with more than five times the number of patients of SMA, and where there are no approved therapies currently in DM1.
Got it. You talked about the 15 mg dose, unprecedented splicing data. While that's not the go-forward dose, can you talk to the therapeutic index that you currently think you can access?
Sure. Sure. I would say that we saw a better-than-dose-dependent increase in both muscle concentration as well as splicing. We went from 12% to 29% to 54%. Certainly, from an adverse event perspective, as James mentioned, we saw mild transient changes in renal function, slight elevations in renal biomarkers. I think the thing from a therapeutic index that gives me the most confidence is that all increases, which were mild in biomarker elevation or depression, depending on what the excursion was, lasted only 24-48 hours. That being said, we are not going to dose for 28 days. I do feel like from the robust splicing that we had, compounded with relatively transient changes in biomarker, that our therapeutic window is open and that over the course of time, with redosing, functional outcomes will manifest themselves.
Got it. Can we just talk about the preclinical data, both in terms of muscle tissue concentration and splicing improvements that you saw when you went from single ascending dose to multiple ascending dose?
Yeah, so we've previously reported data using the HSALR mouse model, which is a model of DM1, that following comparing single dose versus four monthly doses, we saw about a three-and-a-half-fold increase in terms of the concentration of oligo in the muscle. We went from about 60% splicing improvement to essentially maxing out the splicing assay that we use for the mouse model. We are very hopeful that in the repeat dose study, as we've said before, that we have the ability to build upon these unprecedented results we reported from the single dose study, build upon the 12% splicing we saw at 5 mg/kg, build upon the 29% splicing improvement that we saw at 10 mg/kg.
Got it. Are you monitoring safety on a real-time basis on the 5 mg/kg multiple ascending dose cohorts?
Of course, as all trials do. We're certainly blinded, but we're keeping a close eye on safety as patients progress through.
I just want to touch upon the DMD while it's no longer a focus for the company. Any read-through from DMD into DM1?
Maybe I could first speak from the standpoint of what we had seen preclinically. We always had seen that with our DMD program, it did not have as good a safety profile as our DM1 program. Fundamentally, we stopped that program, not for safety reasons, but because we were not seeing the efficacy that we wanted to see in terms of dystrophin production. We did not see good translation from the Healthy Volunteer single-dose study to the multi-dose study in patients. One of the great things about our DM1 program is we're going from patients in our single-dose study to patients in our multi-dose study. We anticipate good translatability there.
Got it. There were some changes to the biopsy hardware. Do you think that could impact in any shape or form the output or comparability?
I think the short answer is no. We're taking the biopsy from the same place. The key aspect of the biopsy is getting the appropriate mass of tissue that one needs to do to run the assays. Certainly, safety is a prime concern. We don't feel as though changing the needle biopsy out will in any way impact splicing results.
Got it. So the 5 mg/kg data expected in the first quarter next year, from your perspective, what would be the best-case outcome?
Yeah, I think number one, I would love to see us build on the 12% splicing. So that increases meaningfully. How high that goes, I don't even want to care to speculate, but certainly seeing that increase. Certainly, I think just confirming that we don't see any changes in biomarkers with repeat dosing is very important. I think ultimately what we really want to see is a functional improvement on some front, whether that's VHAT, 10 Meter Walk/Run, something that is trending in a majority of the patients who receive the drug. I think those three items are met, that the road will be very open for the 10 and then subsequently whatever the peak dose is.
How should we think about the VHATs? Because obviously the VHAT data from the single ascending dose study was not interpretable simply because your placebo group was way too high, reversion to the mean. What have you done to sort of address that?
Yeah, you know I think VHAT has its place. It's certainly a single transcript that impacts myotonia, compounded with the fact that it takes nine muscles to open your hand versus over 200 muscles to walk, for example. You are dealing with a smaller number of muscles in a single transcript. We've learned that number one, patients who have higher baseline VHAT tend to have higher levels of variability. We've done things to correct that, i.e., taking multiple VHAT measurements, for example, at screening at baseline to decrease that. The second thing is that we've decreased the severity of myotonia that can enter the trial. We feel with those things that we should be able to control. I mean, I'm glad that we did it in the single ascending dose trial.
While it was confounding, I think we certainly got a very good sense of what good looks like in terms of VHAT and confirmed that our process in terms of how we evaluate the patient is accurate and valid.
Is there a sort of baseline that you're aiming for in VHATs? They call it 8-10 seconds to maximize the clinical data?
Correct. Correct. I mean, those higher VHATs that we had, that 10 seconds is, certainly were far higher than we will be accepting for our med data, our med program.
And just for reference, Dyne and Avidity have chosen patients who typically start off with a baseline of 8-10 seconds. And when you go and look at our 10 and 15 mg/kg single-dose VHAT data, both of those were in that range as well in terms of a starting point. Both of those showed improvement, and the improvement was similar to what Dyne or Avidity have shown, except in their multi-dose studies. We think with greater splicing, we have potentially the ability to show faster outcomes, more profound outcomes across a broader selection of outcome measures.
Got it. Can we spend a couple of minutes talking about the platform? Because these splicing data are clearly best in class, even after a single dose. What's driving that? Is it the peptide, or are you getting more delivery, or is it the underlying differentiated clinical or differentiated mechanism of action?
I think it's really both of those. I think you hit the nail on the head that we've got a technology, the EDO platform, that shows 100-fold higher levels of nuclear delivery in DM1 patient cells compared to naked oligo. Getting into the nucleus is critical because that's where the toxic RNA is, that's where the foci are, that's where we need to liberate MBNL1. The second component is our targeting approach that specifically goes after the CUG repeats as opposed to indiscriminately binding to and degrading both normal and pathogenic DMPK. We focus on that RNA species that is driving the disease, not wasting drug on non-pathogenic RNA. I think those two together have allowed us to see these really quite extraordinary results in terms of correction of missplicing after a single dose.
Are there specific secondary endpoints outside of, other than VHAT, that you want to focus in on at the 5 mg/kg dose to give you a better sense of what the clinical hurdles are going to look like?
Yeah, I think certainly we saw all 10 Meter Walk/Run improve. We certainly see a high correlation with hand grip strength, so we'll be looking at those. I do have optimism about the other secondaries that we're looking at in terms of swallowing, in terms of diaphragmatic movement for breathing, to look to those with exposure for three months to have improvement in the larger muscle groups with higher levels of splicing.
By the time the program matures, you potentially have two companies who are in the process of registration filings. What do you think is going to be the most logical pathway for PepGen?
I think it's important to note that when we talk to patients, when we talk to clinicians, while they're really excited by all the advances that are being made, we hear over and over again, if you have a drug that is approved for VHAT for myotonia alone, it's not that compelling. There's already an approved drug out there for myotonia, mexiletine. Frankly, about 20% of patients have no myotonia at all. We were talking to a patient in a forum who said, "I'd love to get involved in a clinical study, but I do not have myotonia." This is a person who had dysarthria, had movement disorders, but had no myotonia. It's important that we go beyond myotonia, both in terms of differentiation of the drug as well as for the patients as well.
We think with more profound changes in terms of splicing correction, we have the ability to potentially be able to do that for patients. I think in terms of the path forward, we're looking forward to continuing to build on the splicing, demonstrating improvement across multiple outcome measures.
Do you think the accelerated approval pathway with myotonia is something that the company is likely to pursue, or do a single large phase III study with a hard clinical endpoint?
I think it's too early for us to go and speak to what that regulatory path could be. Certainly, we think the accelerated approval path forward would be available because of the differentiation of this drug, different mechanism of getting into the cell, different safety profile, different way of targeting the disease, and potentially more profound impact on both the underlying disease as well as the functional outcomes that stem from that missplicing. I think it's certainly an open path, but too early for us to really say until we have that phase two data in hand what that path forward would look like for us.
Given your confidence on the platform, if the target product profile evolves and you sort of have a really compelling drug, let's say at the 10 mg/kg dose, how do you compete? Or it's a moot question because data dictates adoption.
This is a large indication for a rare disease opportunity. The number of patients is probably five-fold larger than what you have with SMA, where you've got multiple approved drugs moving forward, different modalities. We think, again, differentiation both based on the targeting approach, how we get into the cell, safety, and outcomes is how we differentiate ourselves with these patients.
Any thoughts on sort of moving away from IV delivery to reformulating for a subQ autoinjector stuff because that makes it so much easier?
Yeah, right now we're focused on driving forward the data with the IV formulation. We think it's compatible with current patient care and has the least risk associated with it.
If the DM1 program looks clean back end of next year, are there other neuromuscular indications or anything else that you would like to pursue?
Yeah, so I think it's too early to tell. We've looked at diseases like Charcot-Marie-Tooth. We believe with this approach, we can go and look at both blocking translation as well as modulation of transcription, releasing transcription factors. There's a variety of mechanisms one could pursue even with this technology. Right now, we're exquisitely focused on DM1.
With the 10 mg/kg enrollment, that's supposed to start in the fourth quarter?
Yeah, we'll have a DSMB meeting following all patients receiving a second dose of the 5 mg cohort and subsequently begin enrolling the 10. We're certainly opening territories up. Execution is going to be very key. We deliver, as discussed and have disclosed, Q1 and then second half of the year for the 10 mg. I think we've got a lot of very positive momentum, a lot of enthusiasm that's been generated related to the outcomes. Hopefully, that'll continue as we can hopefully begin to see some improvements in outcome and our safety profile as well.
Are you planning to have patients both in the U.S. and ex-U.S., or?
Yes.
Got it. For the 5 mg/kg dose, 1Q, is it more towards the back end of the quarter?
Yeah, we've not provided further granularity on that. We will be providing updates coming up.
Got it. If all tracks are going to plan, your 10 mg/kg dose should be more of a fourth quarter event?
Again, the granularity we have right now is second half next year, but as we get more line of sight on that, we'll provide an update.
All righty. Thank you for your time and really looking forward to the 5 mg/kg data next week or next year. Sorry, we have weeks away anyway. Thank you for making time for us and good luck.
Thanks, Debjit.
Thanks very much.
Thank you.
Thank you, Paul.