It's my pleasure to be moderating a discussion here with the team from PepGen, and we'll keep it conversational, but we'll have James McArthur, President and CEO, just kick it off maybe with some opening remarks and an update on the company, and then we'll do Q&A. Thank you, guys. Appreciate it.
Terrific. Appreciate the invitation. Yeah, so this has been a really exciting year for the company. We announced first 5 and 10 mg/kg single-dose data from our FREEDOM-DM1 clinical study early in the year, and I think surprised many people, showing after a single dose very high levels, even at 5 mg/kg, where we saw a 12% splicing improvement, then 10 mg/kg, 29% splicing improvement. Recently we announced the 15 mg/kg results, and that was truly noteworthy. For the first time ever in DM1, we exceeded 50% splicing improvement. No one has been able to really do much above 30% in terms of splicing improvement, and we did that at a dose level that was safe and generally well tolerated, 15 mg/kg in DM1 patients.
On the back of that, we were able to do a financing, which capitalizes the company into the second half of 2027, through a series of readouts, where next year we're going to be reporting out data from our FREEDOM-DM1 multiple ascending dose study of EDO DM1 in DM1 patients. The 5 mg/kg data, which we'll report out in Q1 next year, will be very exciting because we'll get to see whether or not we build upon the 12% splicing improvement we saw with a single dose at 5 mg/kg. We've also made changes to our functional outcome measures so that we've now got, we think, a much better chance of demonstrating functional improvement in patients as well, something which no one has shown in a single-dose study. The 10 mg/kg data, which we'll be reporting out the second half of next year.
A lot going on, a lot of exciting updates from the company as we expand into new geographies with our FREEDOM-DM1 clinical study. Yeah, we're in a great position right now to be able to see whether or not EDO DM1 truly can be transformative for patients living with myotonic dystrophy type 1.
Great. Thank you, James. Let's just start with the efficacy, a couple of questions, and then we'll talk about safety. On the splicing side, why do you think you're seeing with a single dose such a bigger effect than the DMPK degradation mechanism?
I think there are two components to this. One component is the EDO technology, and we've been able to share with you in the past that it does not only a great job at getting into cells, but importantly, getting out of the endosome. For a lot of approaches, whether you're using transferrin receptor or integrins, essentially you get into the endosome and there those receptors stay, and the oligonucleotide is left to its own devices to get out of the endosome into the cytoplasm and ultimately to the nucleus where it needs to get to. We have specifically engineered the EDO platform technology to be able to do that. We can go and show almost 100-fold higher levels of nuclear delivery with our technology compared to naked oligos.
You couple that with our cargo, which specifically targets the CUG repeats which cause the disease, so we're not wasting drug on normal DMPK transcript, but focusing on the pathogenic RNA. We can go and show reduction in foci, correction of splicing, and in the animal models, correction of the myotonia, and now in patients, correction of mis-splicing.
Makes sense. As it relates to the 5 mg/kg data, MAD data that's coming up, what is your expectation for the degree to which the effect on splicing will build with doses?
Yeah, I don't think we necessarily have a target in mind. We have seen from the animal models that multiple doses clearly has a meaningful increase in splicing compared to single dose. We're starting at a good base. We took all of our measurements at day 28 post-dosing. At 5, we had 12%. At 10, we had 29%, and at 15, we had 54%. How much that's going to build, but I think mechanistically we're clearly getting into the nucleus of the cell, so we expect an escalation. I'd also certainly like to see functional benefit translate after four doses in three months. I think those are the things that are really key for us as we unblind the first cohort of the MAD in Q1.
Yeah. And on the, let's hope you show more splicing and can show clinical benefit, as it relates to clinical benefit for VHOT, how are you selecting patients for the MAD? I know you implemented this kind of tool for baseline screening, but just in general, it feels like effect size on VHOT to some degree is a function of baseline. What are you doing there?
Yeah, so VHOT, especially in the short term, is highly variable, as we saw early in our SAD trial that individuals who come in with higher baseline myotonia have higher levels of variability. We had subsequently in the SAD study lowered the baseline myotonia requirement and have also added multiple VHOT measurements, one at baseline, one at screening, to minimize that variability, recognizing that VHOT may very well be the earliest indicator. It is a single transcript that we're dealing with, nine muscles to open the hand versus over 200 muscles to actually walk. At the same time with the splicing levels that we're seeing, hopefully we're going to be able to impact other functional measures early on, which I think will be a competitive advantage to be able to show that.
How well characterized is the natural history and variability of these other functional measures, and do you have any that you think give you a better chance to actually show something beyond VHOT?
When we look at natural history, we can see certain measures correlate better than others in terms of disease progression. Number one, hand strength, ankle dorsiflexion. We saw some trending in 10-meter walk-run. I think really our knowledge is very limited simply because there hasn't been splicing levels that we've seen. What does 50% splicing versus 25% splicing mean in terms of both speed and depth of response? We will be looking at that, but I will tell you, as we've said, splicing is at the basis of the disease, so improving the amount of splicing, I anticipate will improve our functional benefit.
What do you guys see as the optimal path to eventual registration with this in terms of efficacy endpoints?
Certainly think something that is reliable and predictable, of course. I personally would like to, while VHOT seems to be the favorite kind of endpoint, if we could move away from that, I think an endpoint that is approvable as an endpoint alone, as opposed to having to look to secondaries to validate what's the other primary, that'd be very critical for us. Again, what can we see and how quickly can we see it? I think that'll really dictate what we're looking like, looking at it from a registration perspective. I don't want to hedge on you, but at the same time, I think the door is open for meaningful functional benefit improvements in non-VHOT-related measures.
Do you have a view on MD High or quality of life measures and their meaningfulness?
I think they're meaningful. I think they're also very highly variable depending on the patient, depending on the symptoms that they have associated with it. While the agency says they want to look at PROs, there have been very few examples of there actually including any kind of PRO in the label.
Yeah.
One thing to note about VHOT is relatively small movements in terms of the splicing of CLCN1 is thought to have a meaningful benefit in terms of VHOT. That's because you look at the natural history and you can go all the way down to something like 70% of mis-splicing of CLCN1, the receptor that's involved in VHOT, and patients are fine.
How do we know that that's the right gene given there's like 400 genes that are misspliced? How do they tie that back?
High correlation with VHOT, number one. Two, it's thought that it's predominantly a chloride channel that's driving it. For that reason, many people think that it's probably the most responsive endpoint, but it's not the most impactful thing to patients. 20% of patients have no myotonia. For most patients, if we could go and have an impact on more profound things, digestion, breathing, mobility, balance, which I think we can begin to start tapping into with these sort of corrections of mis-splicing that we're seeing, that would have a much more profound impact on patients and I think make caregivers much more excited.
Yep. Yep. Okay. Great. Let's switch gears to safety. For the DM1 program, maybe let's just review what happened with DMD and then the safety data today for DM1 preclinically, clinically, and how should we think about the relative TIs across those two programs?
Yeah. DMD program, we certainly had movements in renal biomarkers. I will tell you that the changes that we saw were mild to moderate in nature and transient in terms of being able to be reversible. We saw some hypomagnesemia that was correctable with relatively low doses of oral magnesium. I will tell you when we had the final DSMB for the DMD program, they said that if we had higher levels of dystrophin, they would have supported a dose escalation. Again, obviously nothing so severe that they felt like we were harming patients. I think you got to think about this in terms of risk-benefit. I think as we transition over to DM1, we're seeing a much larger therapeutic window, i.e., higher levels of splicing at lower doses.
Certainly both the severity of movement and biomarkers and the duration of movement is much shorter than we've seen when we compare that to single-dose healthy volunteers who had much higher excursions in creatinine, took anywhere from 10-20 days to resolve versus 48 hours of resolution of any excursions that we've seen in DM1. We feel like with repeat dosing at day 28, we're really not backing up into any kind of renal accumulation that could be more concerning.
Yeah.
I mean, it's really noteworthy that we did not have at either 5 or 10 mg/kg in the single-dose data in patients any treatment emergent adverse events related to the kidney, which was not the case with the DMD program. We believe we've got good translatability when we go from the single dose into the multi-dose study. In the DMD program, 5 was well tolerated with no kidney signals, and even after a year of therapy at 5 mg/kg, there were no kidney signals in patients. Similarly, about half the patients in the healthy volunteer study had kidney signals after a single dose with the DMD program, and similarly, patients in the multi-dose study. We feel really good about where we are with 5 and 10 in DM1, given how clean they were in the patients.
Okay. So five with DMD didn't see any hypomag or just?
Correct.
Okay. Correct. Okay. Got it. For DM1, good reason to feel pretty good about 5 then. How do you think about your ability to go up to 10 and 15? Do you think you're going to need to go up to 10 and 15? Do you think you'll want to go up to 10 and 15?
I think 10 will be safe and well tolerated for the reasons I just outlined. We did not see movement of magnesium in patients after a single dose. We did not see any AEs related to the kidney after a single dose. We have good translatability as we go from single to multi-dose. I think 10 mg/kg could very well be the target dose level as we go forward because if we can build upon that 25% splicing improvement we saw after a single dose at 10 with the multi-dose study, I think we have a drug that has the potential to really move the needle for patients. I think it is still going to be worthwhile to go and explore doses above, not because we have to, but because that knowledge will be very helpful in terms of engaging with regulators and understanding this drug.
Right. Okay. So where is, when we think about the renal signal that is inevitably dose-limiting at sublevel with CPPs, there's hypomag and then there's sometimes changes seen in eGFR. Are these the same mechanism or are they distinct things? Said another way, if you see hypomag, do we start to get concerned about eGFR or is it like a separate mechanism?
Maybe I could start and then you could add. It's important to note that the changes in eGFR that we saw in one individual in the DMD study was a calculated eGFR. It's based off of, in that particular case, cystatin C. It was the same in the context of 15 mg/kg with DM1. If cystatin C is moving, which is one of these kidney biomarkers that does tend to move along with the creatinine, then you'll get changes in calculated eGFR as well, which may not be reflective of an actual change in terms of GFR. The timing is a little bit different for movement of creatinine and cystatin C versus magnesium, so it could be two different mechanisms. At this point in time, we really don't know how this is happening or why it reverses so quickly back to normal.
Do you have a sense of how the FDA thinks about this risk in the context of benefit? Let's say you do have a dose that works in DM1, but there is hypomag, you supplement, you monitor. Do we have a good understanding of FDA's blood pressure on this issue versus the companies versus doctors?
I think FDA is always going to look at benefit versus risk. How much of an improvement, what's currently available in the market? That's on that. On the risk side, is it transient? Is it reversible? I think those are really the key things that they're looking for. Hopefully with longer-term exposure, they get a lot more comfortable with that. I think what we saw in terms of concerns with clinical hold in DMD was lack of data that they just could not get comfortable with. I would suggest that, no, I'm not overly concerned when we do have things that are transient and reversible. Just as an aside, all patients with DMD, when we stopped the program, baseline eGFR returned to normal. There's no kind of longer-term overhangs associated with that.
Okay. Maybe let's go back to these readouts coming up. Can you help sort of set expectations for how many patients, maybe review the duration again? Are you powered for these various efficacy endpoints?
No. We are doing three in the MAD study, we are doing three cohorts: 5, 10, and then looking between 10 and 15. Eight patients per cohort with three to one randomizations, so six active, two placebo. They will receive four doses, three months, and have a biopsy at baseline and day seven post-last dose. Like I said, we will have a full battery of functional outcomes associated with from VHOT to 10-meter walk-run to pulmonary function test, etc. Really, again, looking for where we're getting movement, understanding what that looks like in terms of how it correlates with splicing.
I guess if we're not powered, what is the right way to think about a good effect size on VHOT? Like three seconds? Is that sort of the ballpark or?
If you go back and look at what other folks have done, right? You have Avidity that I think after a couple of doses and seeing 9% splicing improvement using the 22-gene panel, saw something in the neighborhood of about a three-second movement.
Yeah. That was their good dose. I think the other one didn't separate, right?
Correct.
Yeah.
You've got Dyne at 6.8 after 11 months of therapy showing about 22% splicing improvement. They saw at three months, again, about two and a half, three seconds in terms of VHOT. If we could begin to see any VHOT movement at our 5 mg/kg dose, I would be very pleased because we'd expect to be building on that with the 10 mg/kg. I think it's a reasonable possibility given that the 5 mg/kg demonstrated 12% splicing improvement after a single dose.
Yep. Yep. Okay. Any questions for James and Paul? Anything else you guys want to discuss here?
I think at least from the company standpoint, I think we're in a terrific position to be able to prove, demonstrate that the EDO platform in this disease is well suited to be able to move the needle of fundamental biology, which is mis-splicing. With what we've learned from the phase one study, I think we're in a great position to be able to now begin to start seeing in the multi-dose study changes in terms of functional outcome measures. I think the safety data that we have both preclinically and now clinically, I think supports that we've got a drug here that should be able to be dosed in a repeat dose study safely and move the needle for patients. I think Paul's built a great team. We're now executing. We recently reported that all patients at the 5 mg/kg cohort had received at least one dose.
We'll be reporting that data out with confidence in Q1 next year.
Is this like an early Q1, do we think, or late?
What we've reported is Q1.
Okay. I just didn't know if we were going to be hanging out in your hotel room again looking at this data at JPMorgan.
You can come hang out in my hotel room and we can do whatever.
Sounds good, man.
I think the other thing that's important is we're going to be expanding the geography. Early next year, I anticipate that we'll be able to report out that we've expanded to multiple geographies so that indeed we can fill all our cohorts in a timely fashion and bring the data everyone's waiting to see.