The end of the pop music party means that we're time to do a fireside chat now with the Dyne management team. With me is John Cox, President, and Eric Lucera, Chief Financial Officer. I'm sure most folks in the audience and listening in know Dyne, but maybe we can just have you, John, briefly set the stage and then we'll do Q and A. Sound good. Thank you.
Thanks for hosting us, Paul. Appreciate it. We'll be making some forward looking statements. Happy to be here. Just to kind of set the stage for Dyne. The company is very much a company on a mission to achieve functional improvement in the neuromuscular space. It's a pretty bold kind of statement and mission because, you know, in neuromuscular, typically you're just talking about diseases where there's nothing for these patients, DM1, DMD and at best, people hope for a slowing of progression. We're actually trying to see improvement and the reason we think it's possible, and the data has supported that, is because Dyne had developed a platform that was targeting the transferrin receptor 1.
Unlike first generation versions of trying to go after that platform, which were all about monoclonal antibodies, we've been using an antibody fragment and we think that antibody fragment will allow us to dose higher and deliver genetic payloads in a way that would allow us to get to the billions of cells that matter, both muscle and CNS. That brings us to where we are today. Today we have two medicines, one for DMD and one for DM1. Both of these are moving towards registration. DMD in particular has been a program that is fully enrolled in this registrational cohort pursuing accelerated approval. That particular program is one that we anticipate top line data very soon. DM1 is a program in which we are currently enrolling in a registrational cohort for accelerated approval.
The big picture is Dyne is one of these companies that's in a position as a kind of standalone neuromuscular company to potentially launch two medicines, one in early 2027 for DMD and another in DM1 in early 2028. It's a really meaningful and exciting time and a busy time for the company. I hope that sets it.
Yeah, great. Thanks, John. Maybe like, I want to dive deeper into the DMD readout coming, what you expect and how to kind of think about, you know, what the FDA might want to see for this drug. Maybe just to start, do you want to go through the phase 1/2 data and talk about your expectations for what you'd hope to see in the pivotal readout.
Yeah. First of all, for the top line data, you know, one of the keys here, and the primary endpoint is a biomarker of dystrophin, and everybody knows about that. Our data on dystrophin and the expectation is statistical significance of improvement on dystrophin. Our expectation is that we'll see meaningful dystrophin, robust dystrophin in these patients. Because as you were talking about the phase 1 2, we had seen, that we had seen at the 20 mg per kg cohort, between 3-4% dystrophin unadjusted for muscle, and 8-9% adjusted for muscle content, that is roughly 10 times what a commercial drug can achieve on the market today. It has been supported by really meaningful functional trends.
Those functional trends that we saw in the, again, the phase 1/2 dose escalation included improvement from baseline on stride velocity 95th centile, and included improvement from baseline on things like time to rise, NSAA, 10 meter walk/run. These are kind of the key functional measures. We'll report on those in December. The other expectation is that for accelerated approval you have a reasonably robust set of safety database, and we'll have that as well. All of that will be coming together in December.
Yep. Yep. Okay. You know, I think your agreement with the FDA centers around dystrophin. And then you've also thought about, or I guess hope to see at least some trends on different clinical endpoints. How would you define, like, what is or isn't a clinically significant trend? That would be, I guess, enough to kind of corroborate dystrophin from a regulatory perspective.
You know, medicines have been approved simply on showing a modest decline in progression. Our data, I mean, if we did that, that would be okay, but our expectation is much higher. I mean, it could be okay from a regulatory standpoint, but our expectation is certainly much higher. I would point to, you know, even in the data we presented at the MDA conference back in March, not only do we see improvement at six months across the measures I talked about, we saw sustained continued improvement out to 12 and 18 months at both 10 mg and 20 mg. That's remarkable. I mean, you compare that to gene therapy which was presented at the time is you see this waning of effect over time. We actually see improvement over time, and it shouldn't. It's remarkable.
It may be not surprising because dystrophin has a fairly long half life. We're taking a single measurement at six months. We're seeing meaningful robust dystrophin data at six months. You would expect that to increase over time?
Yep, yep. Okay, so SV95 is an endpoint you've talked about. What are some of the other key findings, functional endpoints that you're hopeful you'll.
See something on the floor that people measure, SV95C, NSAA as well as the 10 meter walk, we have all of those, very good data across those. I'm particularly interested in this time to rise because in this disease, when you think about clinical meaningfulness, how long it takes a boy to get up off the floor, that's how you first notice that there's a problem and maybe they have DMD. When the boy gets to about five seconds, and this is with this exon 51, which is one of the worst, if not the worst type of mutation for DMD, when those boys get to five or six seconds, it is inevitable that they're declining. At eight seconds, it's just a matter of months before they're in a wheelchair. That sort of trajectory is known and so everybody tracks it.
Tracking that data and what we saw in that data was actual improvement, which is amazing. You'll remember in the 20 mg/kg cohort, the average age, the mean age was 8 years old. At 8 years old with exon 51, they are in this inexorable decline to a wheelchair over the next couple of years. That group, it's just six patients, but that group actually improved from baseline across these measures. Let's hope that we get something, anything close to that would be transformative for the field.
Yep, yep. I guess to that point, like, what do you make of the recent outcome of SAPTIS2 confirmatory trials? And like obviously if you show clinical improvement, this is completely different. But how do you just think about the read through onto the space and again, the FDA regulatory standard here, does it raise the bar for functional data?
For Dyne in terms of read through? Read through? I do not see it. The reason is that I do not think it is a surprise to anybody, the outcome of the Sarepta data, that dystrophin at a half a percent to 1% does not result in clear functional benefit should not be a surprise. I think everybody knew that. In its relevance, for the reasons I just mentioned, we are not at a half a percent, 1%, and we are not using a naked PMO to distribute through, you know, IV. It is targeted. It is meant to get broadly to these tissues and skeletal muscle and diaphragm and cardiac. That is what our preclinical thousands. You put all that together, now you start seeing function muscle perform differently. I think it is.
You might say, well, a bar of a half percent, 1% is not good enough now, maybe, probably should not be, but we have been well above that.
Yep. Okay. Okay. Do you have a good sense of what the regulatory standard is in Europe? It's somewhere others haven't been able to get to. Do you feel like that's an option for Dyne on this data?
Yeah, I don't. I do, because. The regulatory standard for Europe has been quite clear. They've been clear that stride velocity 95th centile is an acceptable endpoint, a validated endpoint. It tends to be an early indicator and predictive of other functional benefits. It tends to be not subjective because it's an accelerometer over a couple of weeks, as worn by the boys. They've also said that the MCID is 0.1 meters per second. We've seen a point greater than a 0.1 meter per second improvement in the data that we had presented before in six months from baseline, not from a declining placebo. We've been above the MCID. I think Europe has been very clear. I think part of your question was, can you get expedited approval there? We don't know. We know the bar is a bit higher.
We'd like to pursue it. We'll have our data.
Depends on the data.
Yeah, it depends on the data. Our base case, just to set expectations for people, is that we are planning a robust phase three.
Yep.
That's where we'd pursue in Europe.
Okay, makes sense. You want to talk a little bit about your confidence in safety. You know, there was the SAE or two SAEs at 40 mg per kg. You chose to move forward with 20 for the DMD pivotal. I mean, at this point, the study, I guess, is almost complete. I don't know how much you want to comment on data from an ongoing trial, but, like, just in general, maybe review for people some of the historical context there and your confidence that 20 is going to remain safe.
Yeah. So you're referring to a couple of SAEs from last summer. We reported in September, so well over a year ago, September 24, not this last summer. So well over a year ago. One of those was considered hemolytic uremic syndrome. We haven't seen that since. It was seen at the 40 mg. We couldn't rule out a relationship to drug. We couldn't assign it to the drug, but we couldn't rule it out. That had been at 40 mg. We had had 20 mg per kg data with some very good functional data that was coming out. We moved forward with that as our registrational cohort. We had data we presented at the MDA back in March. I think that was close to 1,000 doses. Over 70 patient years of data. Very favorable safety profile.
We continue to monitor safety throughout the study in a blinded way and we'll have a safety update in December. If there, I mean people have said if you monitor it. Of course. And if there's some kind of material event like we described a year and a half ago, you would have said so. We would have said so. Otherwise, we'll have data here very soon.
Okay, great. Anything else you want to add on DMD ahead of the data?
The only other question is kind of timing and commercial opportunity.
Yeah, I think we all know it's a big opportunity, but how would you frame it?
I think it's a very meaningful opportunity. Listen, I think this field, it's kind of remarkable over the last year how much the field has kind of moved in our direction. Meaning there is a clear need for next generation exon skipping. Gene therapy has waned, sadly. This recent data you talked about from Sarepta tells us that the next generation PMO is a targeted as needed. I feel for the, this patient community has really gone through a lot the last year and a half. They had high hopes and there's really not much. In the United States we're looking at maybe 1,500 to 1,600 patients just for Exon 51. It's the most prevalent. It's the toughest, but it's the most prevalent. We have the data that we talked about. We think there's about 400 patients on eteplirsen. That is a weekly dose.
We know the functional benefit has yet to be proven. Those seem to be fairly straightforward switches. Based on what we hear from the KOLs. We are a monthly dose and you've seen the dystrophin differences being so much higher. There's probably another 300 or 400 that quit on eteplirsen simply because they weren't seeing the.
I think they're largely eteplirsen experienced. Yeah, yeah.
You have probably another 5, 6, 700 who are just taking some steroids and just have not seen anything that would be available for them. I think the opportunity is the unmet need is so significant, the outcome for these patients is inevitable. I think it is a wide open market for us.
Yep. Yep. Okay, great. Let's talk about DM1 again. Maybe give us a quick update there, John, if you don't mind, and then we'll dive into specifics.
Yeah. We had been conducting the Achieve trial and continue, and it had been initially a multi-ascending dose trial guided by splicing correction to determine what is the best dose. We got up to 6.8 mg per kg, and that's what we settled in. We switched that into a registration expansion cohort and decided to enroll up to 60 patients. Recall that we had kind of switched the primary endpoint in that study from splicing to VHAT. We did that last summer and expanded to 60 patients. Recently, we had announced that our guidance of having that 60-patient enrollment being done by the end of the year, that that was going to be delayed into early Q2 of next year. Disappointed in the delay for sure. We've been explaining to people a couple reasons for that.
We'd had most, really all, of our sites have been. We had nine sites operating for the ACHIEVE trial through the multi-ascended dose portion. We had assumed that those sites, while taking care of the existing 50-plus patients, would continue to enroll and add more patients. Several of those sites were running into capacity problems. We hadn't anticipated that. Those capacity problems are anything from needing somebody in the pharmacy for formulations, etc. We've been working through that. We've added two more sites in Europe, and then we also had said in the United States that we would be adding some sites this year. We thought we'd have those started a bit earlier. We now have them started, probably, I'm estimating, about a month later than we had hoped. We added the two sites.
That takes us from nine sites initially up to 13 sites and we'll have two more sites in the U.S. fairly soon. When we look at that kind of enrollment and reassess it, we said okay, we think we've addressed it, we feel confident about the new timeline and obviously not happy about it. The bigger picture, I think the bigger picture is the overall, kind of timeline, from kind of a competitive standpoint, we're still in good shape and we're looking to launch instead of late 2027, early 2028.
Yep, yep. Okay. I think you had said you've enrolled 30 patients so far.
We were. We're closing in on 30, so we're there.
The assumption is, you know, six patients per month would get you to that early, rough, not crazy, roughly. Okay, okay, got it. Yeah. I mean, I guess, you know, I'll ask you the question that you've gotten a million times around the regulatory piece, but, you know, it still comes up regularly when I talk to investors related to your approach using VHAT as an intermediate endpoint and your competitors' approach seemingly potentially using VHAT for full approval. Do you want to just kind of go through the history there and your confidence that if two companies are in front of the FDA with, you know, two different types of trials at the same time, that, you know, the door is open for Dyne to get approved on good data if you're successful?
Sure, maybe. Maybe. Let me just frame kind of the clinical development path that the company had taken from the very beginning, and that was to pursue accelerated approval while at the same time following it up with a very robust phase three. The thought was that the accelerated approval would give us an opportunity to move rapidly on time. We knew there was another sponsor, obviously a company that had been ahead of us, an older company, but it would give us an opportunity to accelerate on time while still generating a fairly robust package, and then we'd follow it up as fast as possible with phase three. I think that that comp. That approach is going to result in a from achieve a very robust data set for accelerated approval that will include VHAT, but it will include many other measures.
We'll have roughly from that study for accelerated approval, about 100 subjects that will have been on drug as part of that package. In terms of the number of patients, it almost looks like a phase three. It's designed differently. We're going to start the phase three in Q1 of this upcoming year, which is about as fast as we could do. I think when people look at this two, three years from now, we are going to have the definitive, most robust set of data on around that looks at and addresses and answers questions about the heterogeneity of the disease. Now, to your question about VHAT. We've always looked at VHAT as an early indicator of the disease. I think the FDA thinks this way too. I think you could argue not that clinically meaningful, but a good indicator and it moves quickly.
Doesn't represent what happens in the CNS, doesn't represent all the other features of the disease that can be important. Which comes back to your question. I don't think this should be just looked at as kind of a near term horse race. If Avidity is approved earlier than we are, there will still be significant unmet need. I don't think anybody argues that. For accelerated approval, there are plenty of analogs and the FDA can approve medicines as long as there is an unmet need. That can be CNS. Our drug gets to the CNS and theirs does not. CNS is a feature. There are all kinds of other functions, well beyond VHAT, that are important. Safety can be differentiating. Our MOA is different. All of those, you know, because we're going to the nucleus.
All of those give the FDA the opportunity to say unmet need. Accelerator approval still open. I think there's plenty of analogues out there.
What's your thought process, John, on endpoints beyond VHAT at this point, both in the registrational cohort that would give you the opportunity to kind of corroborate clinical meaningfulness and then potentially down the line for confirming full approval?
I think there's a number of endpoints that are so meaningful that we've been showing already in our study. You may have seen, I'm sure you saw, Paul from World Muscle, what we presented on quantitative muscle testing, upper and lower limb strength testing. What we had shown was at six months, patients were seeing a 10% increase in strength. What really got people's attention is that when we went up to 12 months, it was 20-20% increase in strength. I don't think anybody showed data close to that. That's one. You've seen some of the data on MDHI, the Myotonic Dystrophy Health Index, which is a fairly comprehensive patient reported outcome set of measures. We saw significant improvement in the total measure of the burden of the disease by MDHI, including. We saw sub measures, subscales, around six subscales related to CNS small data sets.
We saw that kind of improvement. I think all of those are important. As we get into the phase three, we're not going to have a primary endpoint that is how quickly you can open your hand. I mean, we'll have that, but that's not going to be the primary. We will have something clinically meaningful definitively for the field, which could be a time function test. We like things like five times sit to sleep, measures that really pull together all the different muscle groups that are meaningful for a patient and will probably have some relationship to quality of life and morbidity and so on.
When do you think you'll have that firmed up?
Oh, soon, because we're going to start this trial in Q1, so our CMO, Doug Kerr, will be getting in front of people and talking about, I think, what you'll find to be of the field defining kind of phase three for DM1.
Right, right. Okay. Okay. On the commercial side with DM1, who do you see as the potential early adopters to these drugs?
You know those. The patients, virtually any patient that has been diagnosed with DM1. I say that it's been diagnosed because it takes patients about seven years to get diagnosed.
Is that right?
Yeah. The number of patients that are misdiagnosed with GI issues and other things is very, very high. I also think the market, although we're predicting 30,000-40,000 patients now, that's going to grow.
Yeah.
Virtually any patient that has DM1, you know about the heterogeneity of the disease. Our drug is getting to the core pathobiology of the disease. We know that from the splicing correction. If you are correcting splicing, you can start addressing all kinds of different function. That includes CNS. Thirty, 40, 50% of the patients have CNS issues. I think those patients will be coming in for this drug. Any of the patients that have the various other physical issues, GI issues, smooth muscle issues, strength related matters, virtually every patient you could make an argument would be eligible. Certainly the more severe patients are going to get there. Are going to be going there soon.
Makes sense. Maybe in the last couple of minutes. The muscle space, space you're in, right, with biologic conjugates, right, the opportunities are huge, but it's obviously an expensive space to play in. Can you just talk about how you're scaling Dyne right now, both on the clinical side, the commercial side, and like the CMC side, and the degree to which you're setting the company up to be ready to launch a couple drugs?
You want to roll with that?
Yeah, sure.
With respect to the commercial, I think what is best to say is that we hired a very experienced commercial team, a lot of folks out of Biogen that were part of the Spinraza launch. They are very familiar with where we need to sell this. If you have not looked at it, there are about 100 centers that matter. We know where these centers are. We know the doctors, and they are sort of doing that thought experiment and getting ready for launch. With respect to the CMC and manufacturing, obviously, John, you know, is tremendously experienced, leading tech ops at Biogen. He has brought with him, you know, some of his former people from Biogen who are really leading the charge to build a very robust and diverse supply chain that really minimizes the risk of having any issues or being, you know, stocked out in any way.
They, you know, some of these folks started the same day I did. They've made a tremendous amount of progress in just five months. We feel really good, really good about where we are with respect to our supply chain and where the resulting cogs will be.
Yep, yep. Okay. Couple other quick questions. You know, if this upcoming DMD readout is great, as you expect, how quickly could you start to move on other exons and have a broader franchise? Where are you with those efforts?
We have assets preclinically that are in a good position to move forward. I really like the idea, and I know Eric does too, about expanding to create a franchise. Three or four additional exons takes you to 30-40% of all possible patients. And that is a, you know, Exon 51 we just described, which is meaningful.
Right.
Market is 13%. We'd love to do that. Our hope is that when with the data, if it is as compelling as we hope it is, it will also be very compelling to the FDA. If it is, that the FDA will be open to more of a platform basket type approach. It is really about, it is not about kind of us having the assets, or believing in them. It is really about an efficient regulatory and clinical process to make it cost effective. If we can do that, we would love to do it. I think there will be. If that data looks like what we've seen so far, you know, we already hear from patients with the other exons. When can you have that for my boy?
Do you have any, like, IND timelines for the next one or is it too early to say?
Too early to say.
Okay, okay. And then FSHD, where are you with? You know, we've had some promising data validating the mechanism from Avidity. Where are you with efforts there?
We are very serious about FSHD. That is one that we do intend to be giving some timelines this year for 2026. Not quite ready to give them to you yet. It has been in kind of IND and enabling and sort of optimization of the molecule stage and I think we have an opportunity with our platform. I kind of described with Fab how we can dose and so I think we have an opportunity to really optimize that product that potentially could differentiate in FSHD. It's a great market. It's a big market. In some ways Avidity has validated that you could have an impact on the biology. We are excited to pursue that. We will.
Great. Anything else you guys would like to add?
Look at, I think, 2026. Unbelievable year for us, right. DMD data right around the corner, talking about a BLA being filed next year. We're talking about two phase threes being initiated late in 2026. We're going to be talking about launching DMD into 2027 or early 2027, and then we'll talk about FSHD as well. Stay tuned for this coming year.
All right, thank you guys.
Thanks, Paul.
I appreciate it.
Thanks for having us.