Welcome everyone to our chat with PepGen. I'm Joe Schwartz from the biotech equity research team at Leerink Partners. It's my pleasure to be joined by James McArthur, CEO, and Paul Streck, Head of R&D at the company. Thanks so much for joining us today.
Thank you. Thank you.
It's a good time for us to get an update. Why don't you start us off with the recent progress you've been able to make in your DM1 development, and then we'll get into all the nitty-gritty.
Sounds good. Last year, we reported the results from our FREEDOM-DM1 with our PGN-EDODM1, our molecule for the treatment of myotonic dystrophy type 1. In patients, we went and reported at five mg/kg, 12% splicing improvement. This is a disease where mis-splicing drives all of the pathology of this disease. At 10 mg/kg, we reported 29% splicing improvement, which was the highest level ever seen after a single dose and higher than what other approaches have seen even after 11 months of therapy. At 15 mg/kg, we reported 54% splicing improvement, the highest level of splicing correction ever seen in this disease with any approach. We were super excited about that.
With that, we followed with opening up the Freedom 2, a multiple ascending dose study, currently open in Canada, the U.K., South Korea, Australia, and New Zealand. For that study, Paul and the team are making excellent progress. We have completed enrollment at the five mg per kg dose level, our first dose level. This is four doses delivered once a month, and we'll be reporting out that data by end of this month, and that'll include tissue levels, splicing, and a variety of functional outcomes, as well as, of course, safety. I'm pleased that the DSMB that has reviewed the safety data from that cohort through at least two doses in all patients recommended our moving to 10 mg per kg. We've made excellent progress there.
We've now recruited half those patients, with four of the eight patients receiving up to eight doses at 10 mg per kg. We think that 10 mg per kg could truly be our go-forward dose, given that a single dose at 10 mg per kg resulted in 29% splicing improvement. We expect we can build upon that in our multi-dose study. Our last cohort, which we recently announced, the top dose will be 12.5 mg per kg, will be expected to commence latter part of this year and read out next year. We're very pleased with the progress.
This is a catalyst-rich year for the company, where we expect to be able to deliver on news that will truly demonstrate whether or not EDO-DM1 has the potential to be a best-in-class therapy for the treatment of myotonic dystrophy, an opportunity that has been suggested to be a $3 billion-plus-a-year opportunity. Very excited about that. Behind this, continue to develop the platform technology. We realize all eyes are on DM1 this year.
Great. Okay. Thanks for that excellent introduction. We saw a recently surprising announcement from you regarding the FDA who put PGN-EDODM1 on a partial clinical hold. What were the preclinical toxicology questions that they question marks that they raised that led to that?
Yeah. Yeah, we were, I must say, surprised to get that notice from FDA for a variety of reasons. The data that they focused in on was a mouse toxicology study that they had been in possession of that data since 2024, where we submitted that data as part of our annual update, given we had an open IND and were dosing U.S. patients at that time. At that time, they raised no questions. They did raise questions around this data, which we pointed out to them was mouse-specific pharmacology, not seen in non-human primates, not seen in patients, and ameliorated with slower infusion in the mice. Nothing to do with the kidney, which has been the primary site where we've seen, you know, some evidence of engagement with the kidney.
It was nothing to do with the kidney. We had thought that we had been able to address their question, given they asked this question in response to our IND amendment back in December, and we heard nothing further from them from the preclinical group. To our surprise, this is what was highlighted. It was interesting they did not reference clinical data. They really were pointing to the subchronic toxicology. They highlighted they accept our chronic mouse study, which extended for many more months and where we did a slower infusion and did not see this pharmacology exacerbated. You know, we will work with FDA as we always do to help them understand why we believe this is not relevant to our continuing this program.
Importantly, as I just mentioned, Paul and the team have sort of planned for all eventualities like this. We have sufficient numbers of patients, we believe, in the geographies we have opened, such that we can commit to reporting out the 5-mg data this month, the 10-mg data second half of the year, and cohort three data, assuming DSMB reviews the 10 mg and allows us to escalate, next year.
We will seek to get the FDA to a different place.
Okay. What is your strategy for doing that? I was under the impression that they viewed the non-human primates as the most relevant model for the potential safety profile of this drug.
Indeed. Yeah, Joe, they did say that, but at the same time, it seems as though there's a bit of a disconnect in terms of the non-human or preclinical and clinical group talking. Obviously, we have human data that, you know, in the past has always trumped anything from an animal perspective, and certainly what we're seeing from an animal perspective is explainable. I think it's really for us making sure that we connect the dots, make sure that they understand the totality of the data, and hopefully, like I say, that'll move us forward and enable us to get off clinical hold.
Okay, what's the timeline for that?
We need to file a complete response and then the FDA is on the time clock. They have 30 days to respond to your complete response. Certainly, they can respond with additional questions or other things, but needless to say, we'll be getting that complete response in on the short clock, wait to hear back from them, and hopefully we can resolve this as soon as possible. Hopefully, you know, again, we think that we've got a very good case for it. Again, with the FDA, and again, I'm not gonna comment on the state of affairs there, but you know, we can expedite and give them the things that they need to make the decision.
It's encouraging that you said that, you know, you have sites in many different countries open, and you anticipate being able to get the 5-milligram multi-dose arm enrolled. Where are you in terms of that process, and when are we looking forward to that data?
Just quick clarification. The five mg is fully enrolled, and essentially, we're getting the data. The 10 mg per kg is well on its way to being enrolled, with half of those patients already dosed with up to two doses. Paul?
Yeah, I think, you know, Joe, following the positive will be better at results for the SAD data. We certainly saw an uptick in enthusiasm from investigators to enroll in the trial. We were in the U.S., U.K., and Canada for the SAD study. Obviously, right now, for the U.S., we're on hold. We also recently announced that we opened Asia PAC, so South Korea, Australia, and New Zealand.
Again, like I say, the reference that James makes to half of the 10-milligram cohort being enrolled was driven entirely by the U.K. and Canada. Again, feel good that there's enthusiasm about it. We're also enrolling the open-label extension trial, and all patients are eligible to roll over into that. We had to get that up and running in countries, but we have eight patients currently enrolled in that. There's enthusiasm, and, you know, I think the main thing is, while it's still early, we're not seeing any dropouts or anything like that, which is always a critical dimension of open-label extension study.
Good. Okay. What do you hope to see in terms of splicing correction and any other biomarkers or clinical changes?
Yeah. I, you know, certainly we believe that we can build off of the splicing that we saw after a single dose. We had approximately 12% splicing improvement at the 5-milligram single-dose study. In animal models, you know, which again, you have to take them for, they are just a model, had greater than 50% improvement in splicing between single and multiple doses. Certainly, you know, while I'm not sure that we can get to 50%, I certainly think something in the mid-teens would be promising. Again, you know, I think I'm more concerned about A, are we seeing good penetration, i.e., are all patients in the cohort scattered around a single number as opposed to outlier driving it or something like that?
Certainly, you know, the pure number of patients responding, so we'd love to continue to see the good numbers that we've seen in terms of response rates. You know, we saw, you know, five out of six patients at the in the SAD study respond. We'd like to at least see that or better, and then certainly we're gonna be looking at, you know, safety to ensure there's no accumulation. The last piece of it, at what point do you begin to see improvement in splicing? It is four doses after three months adequate to begin seeing some of these functional measures improve.
Hopefully, we're gonna see things separating from placebo, but, you know, again, with a study like this with the variability in the disease, you know, but, you know, ultimately we think that splicing being the underpinning this disease will drive the outcomes that we're looking for.
Just to build on what Paul said, as we look across all cohorts of the SAD, we saw about 88% of patients demonstrating a positive splicing response. Again, if we continue that and build upon that in the MAD, that'll, I think, speak well to what we can do for this disease because as Paul mentioned, mis-splicing is what drives all the pathology of this disease.
Okay. How are you thinking about the desire for continued dose escalation relative to what you see on the safety front? You had a transient eGFR signal, but that wasn't classified as an SAE?
Correct.
So.
Correct.
What would you have to see in order to, you know, stop going up in dose?
You know, doing this for a long time, Joe, phase II is already met, always met with skepticism. You didn't dose high enough. You dosed too high, whatever the case may be. You certainly try to balance out with efficacy, safety, time that goes along with it. We have three cohorts planned now at five, 10, and 12.5 milligrams, and we do feel like, you know, again, what we're seeing thus far that those feel right in terms of being able to continue to propagate the splicing that we're seeing, you know, keep an eye on any safety signals in check.
I do feel quite comfortable in terms of how the phase II dose finding is progressing, and seem to be threading that needle through the therapeutic window.
I think importantly, when we go and look at the five and 10 mg per kg dose level from the SAD, none of the treatment emergent adverse events were related to kidney, none were related to electrolyte disturbances. Everything we did see at 15 was transient in nature. As such, it gives us a lot of confidence as we move forward, particularly given in the chronic toxicology studies in non-human primates, we didn't see a worsening of any toxicologic signal over time. Everything that we've seen basically comes up typically within 24 hours and is back down to baseline at 10 mg per kg in about 2 days, long before we would be coming back and redosing on day 28.
Okay. You recently announced that the top dose is contemplated to be 12.5.
Correct.
Milligrams per kilogram. What drove that decision?
Yeah, Joe, I mean, in our SAD study, we dosed up to 15. We certainly saw increasing display of renal biomarkers as we dose escalated. We did have a DLT at 15 milligrams that we brought forth. It was a reduction in GFR, which resolved in two days. Nevertheless, we'd really prefer not to go there, so we felt as though, you know, between 10, where it's, you know, we had quite a clean profile and 15 would, you know, kind of be the upper dose where we would get that lift in splicing without tickling the kidney too much.
You've said that you'd like to see what you saw in the animals be repeated again in the five milligram per kilogram repeat dose arm with a 50% improvement going from single to multiple doses. If you see that, and can you talk to us about, like, what you'd have to see on the safety side in order to go up in dose versus maybe take that dose forward into a registrational study?
Maybe I could just speak to that in part. The DSMB has already reviewed the safety data through two doses and has already recommended going to 10 mg per kg, and we're obviously dosing at 10 mg per kg right now. Obviously, getting the safety data precedes our getting the splicing and functional data sets, which don't happen until about two months after the last patient gets their last dose, because we pull all the data together and analyze it in toto. We have to make decisions on dosing and dose escalation prior to that getting that data in hand.
I think if we went and could build upon the 12% we saw with a single dose at five to putting ourselves in mid-teens, and we could build upon the 29% splicing improvement we saw at 10, putting us in 30% or perhaps even higher % splicing, that'd be better splicing improvement than what others have seen at their top dose long term. It offers a real possibility to move functional markers in a more profound way. I think, you know, for us, we'll already be dosing the 12.5 by the time we get that data at 10, but it's still, I think, very useful for us to have that information from a therapeutic window standpoint, and from a standpoint of understanding where are we in terms of maxing out that splicing response.
Okay. How has your approach to enrollment evolved since you saw those really strong splicing improvements and you saw some good functional changes in the drug arm in the SAD, but there were some placebo effects?
Mm-hmm
Seen as well? What have you done to maybe control for some of that noise?
I think, you know, specifically, Joe, the greatest variability. First of all, it was a SAD study, so we didn't expect to see a whole lot from a functional perspective. Within the measurement of the video hand opening time, we saw a fair amount of variability. While all of the subjects in the trial had an improvement in their vHOT, so did the placebo. We have found that individuals who have myotonia tend to have greater levels of variability with more severe myotonia. The steps that we've taken are, A, we lowered the myotonia requirement from a minimum of four seconds to a minimum of two seconds, and we're also taking multiple measures.
We're doing a measurement of the myotonia, both at screening as well as baseline, in hopes to more normalize to understand this variability. Certainly the trial lasting three months as opposed to one month will also help us as well. I think, you know, it's, you know, looking at vHOT, but hopefully you're seeing something in other measures that may be a little bit more stable.
Okay. Beyond vHOT, how do you think about the array of functional measurements that are, you know, people gravitate towards in DM1? Some of them are upper body, some of them are lower body. Do you gravitate more towards any of them in particular?
You know, we've looked at the natural history study in great detail to evaluate that, and there's certainly a lot of inconsistencies in terms of how this disease progresses depending on the individual. There's variability in that respect. I think really what we would wanna do is look to see, based on the splicing that we're getting, what areas are responding the best and go from there.
Pleasantly surprised that, you know, Dyne most recently discussed their primary endpoint, you know, for their registration trial to be Five Times Sit to Stand. I'm just pleased that the FDA is open to other measures other than vHOT to evaluate what improvement in this disease looks like. I think that certainly opens the door for us as we look across a number of different measures that we're doing to see which ones we're getting the response from. Certainly, the data from the open label extension study, looking at that, to really put something that's gonna give us a higher level of confidence and hopefully, you know, a trial that's not too large to have to enroll to get to that, you know, registration.
Yeah. Can you talk about your approach to the CUG blocking as opposed to DMPK knockdown? Do you think that could enable you to have any potential to differentiate beyond the changes in splicing in terms of knocking down the wild type DMPK?
Yeah. I think there are a couple of key differentiators here. One obviously is the delivery technology. So, EDO technology has been demonstrated in vitro at least to produce much higher levels of nuclear delivery of oligos than other approaches. Certainly compared to naked oligo, we can see a 94-fold improvement in terms of nuclear delivery, and that's key for DM1 because in DM1, the pathogenic RNA is located solely in the nucleus. Two, as you highlight, our oligo is specifically targeting the CUG repeat. In doing so, we're not expending oligo binding to normal DMPK transcript in the cytoplasm or nucleus, but focusing our approach to going after that which really drives the disease.
Perhaps that's why we were able to demonstrate in patients the highest level of splicing improvement that has been achieved by any approach, to date. We think that these are key differentiators. They're differentiators in terms of the safety profile. We do not see the elevations in liver enzymes that others have seen. We don't see the ischemic events that others have seen. We don't see the anemia. And because we don't have a large antibody attached to our oligo, but rather a short linear peptide, we don't have the injection site reactions that in some cases have even turned into anaphylactoid reactions. We think there's a lot of differentiators, both on the safety side in a positive way, on the delivery side, and then how we attack the disease focused on what really drives pathology.
Right. Where do you think regulators stand when it comes to splicing improvement as a surrogate biomarker? We've seen different sponsors emphasize different routes to
Mm-hmm
Market and, you know, there's been turnover in sponsorship of different programs and so what's your understanding of the regulatory state-of-the-art?
Paul can speak to our thoughts about the future, but you know, you and I have talked over the years, and I have always said that in our engagement with regulators, FDA and others have said, "Look, splicing is key to this disease. It drives this disease. It's the basis of this disease." Today, we do not have enough knowledge about what 20% splicing versus 40% splicing means in terms of how patient functions and feels. Splicing today is not a biomarker that can be used to support accelerated approval. It obviously is a key metric. The more splicing improvement you see, the better the outcomes should be produced. That's indicated by the natural history dataset in patients. Splicing is key. We're gonna keep reporting splicing.
Others may have given up on reporting it because their splicing numbers may not quite, you know, meet our benchmarks, but it's absolutely key in terms of getting a good understanding about what you're doing about the fundamental biology of this disease. In terms of regulatory in the future?
Yeah. I mean, I think that splicing is an exceptional pharmacodynamic marker. I think we're gonna need much larger sample sizes to show any meaningful correlation between improvement in splicing and a specific improvement in functional measure for that to happen. Well, we'll certainly continue to look at it and try to learn from it. You know, from a regulatory perspective, I think any approval based on splicing at this time is premature. Okay. To wrap up, as we look forward to data from the next two MAD cohorts, maybe three, what overall efficacy and safety profile picture would you like to see in order to take EDO DM1 directly into a phase III trial versus maybe continue to optimize dose and/or schedule?
Yeah. I think, you know, if we continue to see the safety profile we saw in the SAD, and again from toxicology studies, we do not see a worsening of that signal with repeat doses, in part because it's very transient in nature, and it basically is back to baseline, weeks before you redose.
If we see that kind of safety profile, which we think is exemplary compared to, you know, some of the other things we've seen out there, if we can build upon the splicing benefit that we see, you know, produce splicing in the teens at five mg per kg and above 30 at 10 mg per kg, then we differentiate ourselves in terms of target engagement and addressing the fundamental disease, and then seeing that translate into benefit across multiple functional markers, perhaps, you know, at a very low level at five mg per kg, but more robustly so at 10 mg per kg. I think that would indicate that indeed perhaps 10 mg per kg is our go forward dose.
We'll continue to build the data set from the open label extension at five and then 10 mg per kg, which will add to the safety database, and that'll give us much greater confidence in driving this forward.
Okay, great. Well, we look forward to those updates. Thanks so much for the update today.
Thanks, Joe. It's always a pleasure to see you.
Thank you.